Localized Controlled Delivery of Gemcitabine via Microsol Electrospun Fibers to Prevent Pancreatic Cancer Recurrence

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2ABchGX

Safety, efficacy and compliance of extended thromboprophylaxis in hepatobiliary and upper gastrointestinal surgery

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2OxPvlQ

Cost‐effectiveness analysis of post‐polypectomy colonoscopy surveillance using Japanese data

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NTEnyP

Reply to Letter

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LCARMp

Achievements and Challenges in Facial Transplantation

The first facial transplantation in 2005 ushered in a new era in reconstructive surgery, offering new possibilities for the repair of severe disfigurements previously limited by conventional techniques. Advances in allograft design, computerized preoperative planning, surgical technique, and postoperative revisions have helped push the boundaries in this new frontier of vascularized composite allotransplantation. Over the past 12 years, 40 of these procedures have been performed across the world, offering the field the opportunity to reflect on current outcomes. Successes achieved in the brief history of facial transplantation have resulted in a new set of obstacles the field must now overcome. In this review, we aim to highlight the achievements, major challenges, and future directions of this rapidly evolving field.

https://ift.tt/2umGpiJ

The role of carfilzomib in treatment of newly diagnosed multiple myeloma

Future Oncology, Ahead of Print.


https://ift.tt/2OvWKuM

First-line axitinib versus sorafenib in Asian patients with metastatic renal cell carcinoma: exploratory subgroup analyses of Phase III data

Future Oncology, Ahead of Print.


https://ift.tt/2AqTtKl

Diagnosis of Toxocara eggs in faeces and hair coat of a Persian cat—a case study

Abstract

The present communication report about the occurrence of Toxocara spp. eggs on the hair coat of cat and faeces reported. A Persian female cat about 14 months of age was presented to the hospital with a history of reduced food intake, vomiting, diarrhoea and alopecia. Microscopic examination of the faecal sample and skin scrapings revealed the presence of Toxocara spp. eggs. The cat was administered with pyrantel pamoate at 5 mg/kg body weight orally for three consecutive days along with the supportive therapy and showed uneventful recovery after treatment.

https://ift.tt/2LLT5dD

P-Glycoprotein Expression in Indian Breast Cancer Patients with Reference to Molecular Subtypes and Response to Anthracycline-Based Chemotherapy—a Prospective Clinical Study from a Developing Country

Abstract

Chemo-resistance is an important factor determining the response of tumor to neoadjuvant chemotherapy (NACT). Our study was aimed to determine the role of P-glycoprotein (P-glyp) expression as a predictor of response to NACT in locally advanced breast cancer (LABC) patients with special reference to molecular subtypes. Sixty cases of locally advanced breast cancer (LABC) were subjected to trucut biopsy and the tissue samples were evaluated immunohistochemically for P-glyp, ER, PR, and Her 2 neu status. Pre- and post-NACT P-glyp expression was correlated with clinical response (using WHO criteria after three cycles of CEF regimen) and molecular subtypes. The change in the P-glyp expression before (pre-) and after (post-) NACT was statistically significant with higher stage (p = 0.02), hormonal negative molecular subtypes (p = 0.01), and poor clinical response (p = 0.01). Pre-NACT-positive P-glyp expression is associated with higher stage and hormonal negative molecular subtypes and poor clinical response. The increased expression of P-glyp induced by NACT likely explains the concept of acquired chemo-resistance and may prove as an intermediate checkpoint in determining chemo-sensitivity for further treatment so that additional doses of ineffective chemotherapy may be avoided in non-responders translating into better patient safety.

https://ift.tt/2v0lumW

A randomised investigation of journal responses to academic and journalist enquiry about possible scientific misconduct

We investigated whether responses about possible scientific misconduct from journals to journalists would differ in speed, usefulness, and tone from responses to academics. Twelve journals that published 23 cl...

https://ift.tt/2As8CuW

Six Years and Counting: Restoration of Photopic Retinal Function and Visual Behavior Following Gene Augmentation Therapy in a Sheep Model of CNGA3 Achromatopsia

Human Gene Therapy, Ahead of Print.


https://ift.tt/2AmnJWy

Therapies Targeting the Tumor Stroma and the VEGF/VEGFR Axis in Pancreatic Ductal Adenocarcinoma: a Systematic Review and Meta-Analysis

Abstract

Abundant tumor stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and is suggested to play a role in the resistance of this deadly disease to systemic treatment. Despite promising results from preclinical studies, clinical trials with therapies targeting the tumor stroma and the vascular endothelial growth factor (VEGF) and its receptor VEGFR yielded conflicting results. With this systematic review and meta-analysis, we aim to summarize the existing evidence in this important field with a special focus on anti-VEGF/VEGFR therapy. A total of 24 clinical studies were included in the qualitative synthesis, and six randomized controlled trials (RCTs) investigating anti-VEGF/VEGFR agents were further included in the quantitative synthesis. The qualitative synthesis revealed a treatment advantage of combined therapy with nab-paclitaxel, while the meta-analysis on anti-VEGF/VEGFR drugs demonstrated marginal improvement of objective response rates and progression-free survival, but not overall survival. Stroma targeting is a promising and rapidly-developing treatment strategy in PDAC. However, novel drugs balancing stroma depletion and modulation are needed.

https://ift.tt/2Khf9bg

Genetic determinants of penicillin tolerance in Vibrio cholerae [PublishAheadOfPrint]

Many bacteria are resistant to killing ("tolerant") by typically bactericidal antibiotics due to their ability to counteract drug-induced cell damage. Vibrio cholerae, the cholera agent, displays an unusually high tolerance to diverse inhibitors of cell wall synthesis. Exposure to these agents, which in other bacteria leads to lysis and death, results in a breakdown of the cell wall and subsequent sphere formation in V. cholerae. Spheres readily recover to rod-shaped cells upon antibiotic removal, but the mechanisms mediating the recovery process are not well-characterized. Here, we found that the mechanisms of recovery are dependent on environmental conditions. Interestingly, on agarose pads, spheres undergo characteristic stages during the restoration of rod shape. Drug inhibition and microscopy experiments suggest that class A Penicillin Binding Proteins (aPBPs) play a more active role than the Rod system, especially early in sphere recovery. TnSeq analyses revealed that LPS and cell wall biogenesis genes as well as the sigma E cell envelope stress response were particularly critical for recovery. LPS core and O-antigen appear to be more critical for sphere formation/integrity and viability than Lipid A modifications. Overall, our findings demonstrate that the outer membrane is a key contributor to beta lactam tolerance and suggest a role for aPBPs in cell wall biogenesis in the absence of rod-shape cues. Factors required for post-antibiotic recovery could serve as targets for antibiotic adjuvants that enhance the efficacy of antibiotics that inhibit cell wall biogenesis.

https://ift.tt/2OwAGA7

Sulfide protects Staphylococcus aureus from aminoglycoside antibiotics but cannot be regarded as a general defense mechanism against antibiotics [PublishAheadOfPrint]

Sulfide production has been proposed to be a universal defense mechanism against antibiotics in bacteria (Shatalin K, Shatalina E, Mironov A and Nudler E. Science 334:986-90,2011, doi: 10.1126/science.1209855). To gain insight into the mechanism underlying sulfide protection, we systematically and comparatively addressed the interference of sulfide with antibiotic activity against Staphylococcus aureus as model organism. The impact of sulfide and sulfide precursors on the antibiotic susceptibility of S. aureus towards the most important classes of antibiotics was analyzed using modified disk diffusion assays, killing kinetics and drug uptake studies. In addition, sulfide production and the impact of exogenously added sulfide on the physiology of S. aureus was analyzed. Sulfide protection was found to be limited to aminoglycoside antibiotics, known to be taken up by bacterial cells in an energy dependent process. The protective mechanism was found to rely on an inhibitory effect of sulfide on the bacterial respiratory chain leading to reduced drug uptake. S. aureus was found to be incapable of producing substantial amounts of sulfide. We propose that bacterial sulfide production should not be regarded as a general defense mechanism against antibiotics since, (i) it is limited to aminoglycosides and (ii) production levels vary considerably among species and, as for S. aureus, may be too low for protection.

https://ift.tt/2Aqjjhh

Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis [PublishAheadOfPrint]

Practitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient's characteristics from adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using non-linear mixed effects modeling with first-order conditional estimation method. A two-compartment model with first-order elimination best-described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for CL and Vd, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 3.06 L/h, 14.4 L, 17.1 L and 0.925 L/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ compared with individuals without cystic fibrosis. However, further investigations are needed to confirm these results, and thus the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

https://ift.tt/2mWsfS5

Characterization of mutations conferring resistance to rifampicin in Mycobacterium tuberculosis clinical strains [PublishAheadOfPrint]

Resistance of Mycobacterium tuberculosis to rifampicin, mediated by mutations in the rpoB gene, coding for the beta-subunit of RNA polymerase, poses a serious threat to the efficacy of clinical management and thus control programs of TB. The contribution of many individual rpoB mutations to the development and level of RMP resistance remains elusive. In this study, the incidence of mutations throughout the rpoB gene among 115 Mycobacterium tuberculosis clinical isolates, both resistant and susceptible to RMP was determined. Of the newly-discovered rpoB mutations, the role of three substitutions in the causation of RMP resistance was empirically tested. The results from in vitro mutagenesis experiments were combined with the assessment of the prevalence of rpoB mutations, and their reciprocal co-occurrences, across global M. tuberculosis populations.

Twenty-two different types of mutations in the rpoB gene were identified and distributed among 59 (90.8%) RMP-resistant strains. The minimum inhibitory concentrations (MICs) of RMP were within the range of 40-800 mg/L, with MIC50 and MIC90 values of 400 and 800 mg/L, respectively. None of the mutations (Gln429His, Met434Ile, Arg827Cys) inspected for their role in the development of RMP resistance produced a RMP-resistant phenotype in isogenic M. tuberculosis H37Rb strain-derived mutants. These mutations are supposed to compensate for fitness impairment incurred by other mutations directly associated with drug resistance.

https://ift.tt/2AAEIEX

Impact of inducible blaDHA-1 on susceptibility of Klebsiella pneumoniae clinical isolates to LYS228 and identification of chromosomal mpl and ampD mutations mediating upregulation of plasmid borne blaDHA-1 expression [PublishAheadOfPrint]

Twenty three K. pneumoniae (bla_DHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/mL for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of bla_DHA-1 were selected from representative isolates. These had mutations in the chromosomal peptidoglycan recycling genes mpl or ampD. Pre-existing mpl mutations were also found in some of the clinical isolates examined and these had strongly upregulated expression of bla_DHA-1.

https://ift.tt/2OyVzLc

The monobactam LYS228: mode of action and mechanisms decreasing in vitro susceptibility of Escherichia coli and Klebsiella pneumoniae [PublishAheadOfPrint]

The monobactam scaffold is attractive for the development of new agents to treat infections caused by drug-resistant Gram-negative bacteria since it is stable to metallo-β-lactamases (MBLs). However, the clinically used monobactam aztreonam lacks stability to serine β-lactamases (SBLs) that are often co-expressed with MBLs. LYS228 is stable to MBLs and most SBLs. LYS228 bound purified Escherichia coli penicillin binding protein 3 (PBP3) similarly to aztreonam (k₂/K_d = 367504 s^-1M^-1 and 409229 s^-1M^-1, respectively) according to stopped-flow fluorimetry. A gel-based assay showed that LYS228 bound mainly to E. coli PBP3, with weaker binding to PBP1a and PBP1b. Exposing E. coli cells to LYS228 caused filamentation, consistent with impaired cell division. No single-step mutants were selected from twelve Enterobacteriaceae strains expressing different classes of β-lactamases at 8X the minimum inhibitory concentration (MIC) of LYS228 (frequency <2.5x10^-9). At 4X the MIC, mutants were selected from two of twelve strains at frequencies of 1.8x10^-7 and 4.2x10^-9. LYS228 MICs were ≤ 2 μg/mL against all mutants. These frequencies compared favorably to those for meropenem and tigecycline. Mutations decreasing LYS228 susceptibility occurred in ramR and cpxA (Klebsiella pneumoniae) and baeS (E. coli and K. pneumoniae). Susceptibility of E. coli ATCC 25922 to LYS228 decreased 256-fold (MIC 0.125 to 32 μg/mL) after 20 serial passages. Mutants accumulated mutations in ftsI (encoding the target, PBP3), baeR, acrD, envZ, sucB and rfaI. These results support the continued development of LYS228, which is currently undergoing Phase II clinical trials for complicated intraabdominal infection and complicated urinary tract infection (https://clinicaltrials.gov/ct2/show/NCT03377426; https://clinicaltrials.gov/ct2/show/NCT03354754).

https://ift.tt/2AnQFNQ

Absence of K13 Polymorphism in Plasmodium falciparum Parasites from Brazilian Endemic Areas. [PublishAheadOfPrint]

P. falciparum ART-resistant parasites can be evaluated examining polymorphisms in the Kelch (PfK13) domain. 69 samples from falciparum malaria patients were analyzed. All samples were from Brazilian endemic areas of the following states: Acre (n=14), Amapá (n=15), Amazonas (n=30) and Pará (n=10). After DNA alignment with the 3D7 reference sequence all samples were found to be wild-type. These data provide a baseline on PfK13 and reinforce the pertinence of ACTs treatment in Brazilian areas.

https://ift.tt/2mZ7vcA

Ceftazidime-Avibactam Susceptibility Breakpoints Against Enterobacteriaceae and Pseudomonas aeruginosa [PublishAheadOfPrint]

Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2000-500 mg every 8 hours (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI and EUCAST as susceptible, MIC ≤8 mg/L, and resistant, MIC >8 mg/L. The key supportive data from PK/PD analyses, in vitro surveillance including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials, are collated and analyzed here.

https://ift.tt/2AnQFxk

Past and Present Perspectives on {beta}-Lactamases [PublishAheadOfPrint]

β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years. These well-studied enzymes, currently numbering almost 2800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally-occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active site serine. Metallo-β-lactamases also exist, with one, or two, catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently-approved cephalosporins, monobactams and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole genome sequencing studies. Often these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.

https://ift.tt/2OwAf8X

Antibiotic-induced dysbiosis predicts mortality in an animal model of Clostridium difficile infection [PublishAheadOfPrint]

Background

Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality.

Methods

We administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D₁) to D₅, and challenged them with a C. difficile toxigenic strain at D₃. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D₀ and D₃ using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D₁₆. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals.

Results

Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p<10^-5 for the change of Shannon index in moxifloxacin-treated animals and p<10^-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively.

Conclusions

Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.

https://ift.tt/2AqiYev

Extensive Genetic Commonality among Wildlife, Wastewater, Community, and Nosocomial Isolates of Escherichia coli Sequence Type 131 (H30R1 and H30Rx Subclones) That Carry blaCTX-M-27 or blaCTX-M-15 [PublishAheadOfPrint]

Escherichia coli sequence type 131 (ST131) is currently one of the leading causes of multi-drug-resistant extraintestinal infections globally. Here we analyzed the phenotypic and genotypic characteristics of 169 ST131 isolates from various sources (wildlife, wastewater, companion animals, community, and hospitals) to determine whether wildlife and the environment share similar strains with humans, supporting transmission of ST131 between different ecological niches. Susceptibility to 32 antimicrobials was tested by disc diffusion and broth microdilution. Antibiotic resistance genes, integrons, plasmid replicons, 52 virulence genes, and, fimH-based subtypes were detected by PCR and DNA sequencing. Genomic relatedness was determined by pulsed-field gel electrophoresis (PFGE). The genetic context and plasmid vs. chromosomal location of extended-spectrum beta-lactamase (ESBL) genes was determined by PCR and probe hybridization, respectively. The 169 ST131 study isolates segregated predominantly into bla_CTX-M-15H30Rx (60%) and bla_CTX-M-27H30R1 (25%) subclones. Within each subclone, isolates from different source groups were categorized into distinct PFGE clusters; genotypic characteristics were fairly well conserved within each major PFGE cluster. Irrespective of source, the bla_CTX-M-15H30Rx isolates typically exhibited virotype A (89%), an F2:A1:B- replicon (84%), and a 1.7 kb class 1 integron (92%), and had diverse structures upstream of the bla_CTX-M region. In contrast, the bla_CTX-M-27H30R1 isolates typically exhibited virotype C (86%), an F1:A2:B20 replicon (76%), and a conserved IS26-ISEcp1-bla_CTX-M-like structure. Despite considerable overall genetic diversity, our data demonstrate significant commonality between E. coli ST131 isolates from diverse environments, supporting transmission between different sources, including humans, environment, and wildlife.

https://ift.tt/2OtV7hd

In Vitro Activity of Isavuconazole versus Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories [PublishAheadOfPrint]

Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of isavuconazole against 4,856 invasive yeasts and moulds collected worldwide.

The 4,856 clinical fungal isolates, including 2351 Candida spp. isolates, 97 non-Candida yeasts, 1,972 Aspergillus spp. isolates, and 361 non-Aspergillus moulds, including 292 Mucorales isolates collected in 2015-2016, were tested using CLSI methods.

The MIC values for isavuconazole versus Aspergillus ranged from 0.06 μg/ml to ≥16 μg/ml. The modal MIC for isavuconazole was 0.5 μg/ml (range 0.25 μg/ml [A. nidulans and A. terreus species complex] to 4 μg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated isavuconazole MIC values at ≥8 μg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales. The lowest modal isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 μg/ml). Candida spp. isolates were inhibited by ≤0.25 μg/ml of isavuconazole (range 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 μg/ml for 95.5% of C. glabrata and for 100.0% of C. krusei. Isavuconazole was active against the non-Candida yeasts, including C. neoformans (100.0% at ≤0.5 μg/ml).

Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus. Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and moulds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of isavuconazole against species of Rhizopus as determined by CLSI methods.

https://ift.tt/2ArzDOU

Development and validation of a phenotypic high-content imaging assay for assessing the antiviral activity of small-molecule inhibitors targeting the Zika virus [PublishAheadOfPrint]

Zika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat infection, and accordingly there is an unmet medical need for discovery of new therapies. High-throughput drug screening efforts focusing on indirect readouts of cell viability are prone to a higher frequency of false positives in cases where the virus is viable in the cell but the cytopathic effect is reduced or delayed. Here, we describe a fast and label-free phenotypic high-content imaging assay used to detect cells affected by the viral-induced cytopathic effect (CPE) using automated imaging and analysis. Protection from CPE correlates with a decrease in viral antigen production as observed by immunofluorescence. We trained our assay using a collection of nucleoside analogues against ZIKV; the previously reported antiviral activities of 2'-C-methylribonucleosides and ribavirin against the Zika virus in Vero cells were confirmed using our developed method. To validate the ability of our assay to reveal new anti-ZIKV compounds, we profiled a novel library of 24 natural product derivatives and found compound 1 as an inhibitor of ZIKV-induced cytopathic effect; activity of the compound was confirmed in human fetal neural stem cells (NSCs). The described technique can be easily leveraged as a primary screening assay for profiling large compound libraries against ZIKV, and can be expanded to other ZIKV strains and other cell lines displaying morphological changes upon ZIKV infection.

https://ift.tt/2OtH8b6

Sensitivity of the C-terminal nuclease domain of Kaposi's sarcoma-associated herpesvirus ORF29 to two classes of active site ligands [PublishAheadOfPrint]

Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, belongs to the Herpesviridae family, whose members employ a multicomponent terminase to resolve nonparametric viral DNA into genome-length units prior to their packaging. Homology modeling of ORF29 C-terminal nuclease domain (pORF29C) and bacteriophage Sf6 gp2 have suggested an active site clustered with four acidic residues, D⁴⁷⁶, E⁵⁵⁰, D⁶⁶¹ and D⁶⁶² that collectively sequester the catalytic divalent metal (Mn⁺⁺), and also provided important insight into a potential inhibitor binding mode. Using this model, we have expressed, purified and characterized the wild type pORF29C and variants substituted at the proposed active site residues. Differential scanning calorimetry demonstrated divalent metal-induced stabilization of WT and D⁶⁶¹A pORF29C, consistent with which these two enzymes exhibited Mn⁺⁺-dependent nuclease activity, although the latter mutant was significantly impaired. Thermal stability of WT and D⁶⁶¹A pORF29C was also enhanced by binding of an α-hydroxytropolone (α-HT) inhibitor shown to replace divalent metal at the active site. For the remaining mutants, thermal stability was unaffected by divalent metal or α-HT binding, supporting their role in catalysis. pORF29C nuclease activity was also inhibited by two classes of small molecules reported to inhibit HIV ribonuclease H and integrase, both of which belong to the superfamily of nucleotidyltransferases. Finally, α-HT inhibition of KSHV replication suggests ORF29 nuclease function as a potential antiviral target that could be combined with latency-activating compounds as a "shock-and-kill" antiviral strategy.

https://ift.tt/2AmbyJk

Pooled Resistance Analysis in HCV Genotype 1-6 Infected Patients Treated With Glecaprevir/Pibrentasvir in Phase 2 and 3 Clinical Trials [PublishAheadOfPrint]

Over 2200 HCV genotype (GT)1-6 infected patients with or without cirrhosis who were treatment-naïve or experienced to interferon, ribavirin and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12 or 16 weeks in 8 registrational phase 2/3 clinical studies. High SVR12 rates were achieved with <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BP) in NS3 at amino acid positions 155 or 168 was low (<3%) in GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid positions 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients with GT1-6 infection, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when using the recommended durations, allows for a pangenotypic treatment option without the need for baseline resistance testing.

https://ift.tt/2mV3UvQ

Population Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body Sizes [PublishAheadOfPrint]

Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients relative to healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously-described study in normal weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1 g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total-body weight as a covariate on clearance (CL=1.79·[Weight/95.90]^0.278) and BSA as a covariate on central volume (Vc=4.76·[BSA/2.06]^1.86). After accounting for fixed effects, the estimated interindividual variability was very low (<10% for all clearance and volume terms). Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. Using the developed population pharmacokinetic model and simulation, reliable estimates of ertapenem serum exposures, which can be utilized to evaluate various dosing regimens in subjects with a wide range of body sizes, are expected.

https://ift.tt/2ApCND3

Population pharmacokinetics of artemether, dihydroartemisinin and lumefantrine in Rwandese pregnant women treated for uncomplicated Plasmodium falciparum malaria [PublishAheadOfPrint]

The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women of second (n=11) and third trimester (n=11) with uncomplicated Plasmodium falciparum malaria.

These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled to tandem mass spectroscopy and data analyzed using nonlinear mixed-effects modelling.

Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 hours, followed by a bi-phasic disposition model. The median AUC_0- for lumefantrine was 641 h.mg/L. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/mL), a threshold associated with increased risk of recrudescence. Pharmacokinetics of artemether was time-dependent and the auto-induction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 hours. The typical oral clearance, which started at 475.7 L/hr, increased 1.43 fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.

https://ift.tt/2OwJ56v

Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae [PublishAheadOfPrint]

Resistance to colistin, a polypeptide drug used as an agent of last resort for treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria including carbapenem-resistant Enterobacteriaceae (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant Enterobacteriaceae isolates, 15 of which are also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the four most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

https://ift.tt/2AsgyMI

Novel approaches to kill Toxoplasma by exploiting the uncontrolled uptake of unsaturated fatty acids and vulnerability to lipid storage inhibition of the parasite [PublishAheadOfPrint]

Toxoplasma gondii, an obligate intracellular parasite replicating in mammalian cells within a parasitophorous vacuole (PV), is an avid scavenger of lipids retrieved from the host cell. Following lipid uptake, this parasite stores excess lipids into lipid droplets (LD). Here, we examined the lipid storage capacities of Toxoplasma upon supplementation of the culture medium with various fatty acids at physiological concentrations. Supplemental unsaturated fatty acids (oleate (OA), palmitoleate, linoleate) accumulate in large LD and impair parasite replication whereas saturated fatty acids (palmitate, stearate) neither stimulate LD formation nor impact growth. Examination of parasite growth defects with 0.4 mM OA reveals massive lipid deposits outside LD, indicating enzymatic inadequacies for storing neutral lipids in LD in response to the copious salvage of OA. Toxoplasma exposure to 0.5 mM OA leads to irreversible growth arrest and lipid-induced damage, confirming a major disconnect between fatty acid uptake and the parasite's cellular lipid requirements. The importance of neutral lipid synthesis and storage to avoid lipotoxicity is further highlighted by the selective vulnerability of Toxoplasma, both the proliferative and the encysted forms, to subtoxic concentrations of the acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) pharmacological inhibitor T863. T863-treated parasites do not form LD, but instead build up large membranous structures within the cytoplasm, which suggests improper channeling and management of lipid excess. Dual addition of OA and T863 to infected cells intensifies the deterioration of the parasite. Overall, our data pinpoint Toxoplasma DGAT as a promising drug target against toxoplasmosis, without incurring risk of toxicity for mammalian cells.

https://ift.tt/2Ow29Cb

Low Meropenem Concentration in Brain-Dead Organ Donors: A Single-Center Pharmacokinetic Study and Simulation [PublishAheadOfPrint]

Meropenem is an ultrabroad-spectrum antibiotic of carbapenem family. In brain-dead organ donors, administration of standard meropenem dosages does not reach therapeutic levels. Our objectives were to determine the plasma concentration of meropenem after administration of standard meropenem dose and to estimate an improved dosage regimen for these patients. One gram of meropenem was administered as 1-h infusion every 8 h for 1–3 days, and blood samples were collected. The plasma concentration of meropenem was measured and subjected to pharmacokinetic analysis. Simcyp simulation was performed to predict the optimum plasma levels and dosage based on the patients' individual pharmacokinetic parameters. The maximum plasma concentration of meropenem was 3.29 μg/ml, which was lower than four times the minimum inhibitory concentration of 8 μg/ml. Although mean creatinine clearance of patients was moderately low (67.5 ml/min), apparent volume of distribution at steady state (V_ss) and time-averaged total body clearance (CL) of meropenem were markedly elevated (4.97 l/kg and 2.06 l/h/kg, respectively) owing to massive fluid loading to decrease the high sodium levels and to treat shock or dehydration. The simulation revealed that dose and infusion time of meropenem should be increased based on patients' V_ss and CL and loading dose is recommended to reach rapidly the target concentration. In conclusion, standard meropenem regimen is insufficient to achieve optimal drug levels in brain-dead patients and increase in dose and extended or continuous infusion with intravenous bolus administration of loading dose are recommended for these patients.

https://ift.tt/2Aql3qR

Sunitinib prior to planned nephrectomy in metastatic renal cell carcinoma: angiogenesis biomarkers predict clinical outcome in the prospective Phase 2 PREINSUT trial

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in metastatic renal-cell carcinoma (mRCC) patients. Experimental Design: This French multicentre, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS). Results: Thirty-two patients were enrolled. Median PFS was 4.5 months and median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P=0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ³10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response); sVEGFR2 (PFS); and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome. Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in anti-angiogenic therapy guidance.

https://ift.tt/2KbtuWA

Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma

Purpose: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free micro(mi)RNA may serve this purpose. Experimental Design: Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of two preclinical MCC models, sera of 109 MCC patients and 30 healthy controls by nCounter^®human-v2-miRNA expression or miR-375 specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. Results: miR-375 expression was high in MCC cell lines and tissues compared to non-MCCs. It was readily detected in MCC conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing MCC patients than in tumor-free patients or healthy controls (p<0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (p=0.037) but not in tumor-free (p=0.372) MCC patients. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free MCC patients as demonstrated by receiver operating characteristic curve analysis in the retrospective cohorts (AUC=0.954 and 0.800) as well as in the prospective cohorts (AUC=0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of MCC patients during therapeutic interventions. Conclusions: Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity, it thus appears to be useful for therapy monitoring and the follow-up of MCC patients.

https://ift.tt/2LBUWm6

MELK inhibition in Diffuse Intrinsic Pontine Glioma

Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG. Experimental design: We evaluated the antitumor efficacy of the small molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells. In addition, we determined the blood-brain barrier (BBB) penetration of OTSSP167 and evaluated its translational potential by treating mice bearing patient-derived DIPG xenografts. Results: This study shows that MELK is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures. Inhibition of MELK in DIPG cells functions through reducing inhibitory phosphorylation of PPAR, resulting in an increase in nuclear translocation and consequent transcriptional activity. Brain pharmacokinetic analyses show that OTSSP167 is a strong substrate for both MDR1 and BCRP, limiting its BBB penetration. Nonetheless, treatment of MDR1/BCRP knockout mice carrying patient-derived DIPG xenografts with OTSSP167 decreased tumor growth, induced remissions and resulted in improved survival. Conclusion: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK-PPAR signaling axis as a putative therapeutic target in this disease.

https://ift.tt/2K9nnSJ

Molecular targeted therapies elicit concurrent apoptotic and GSDME-dependent pyroptotic tumor cell death

Purpose: The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacological intervention have not been systematically characterized. Experimental Design: Pyroptotic cell death was assessed by immunoblot, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of lung cancer patients were analyzed using immunohistochemistry. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models. Results: We showed that diverse small molecule inhibitors specifically targeting KRAS-, EGFR- or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered and ALK-rearranged adenocarcinomas. As a result, co-occurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models. Conclusions: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anti-cancer therapeutics.

https://ift.tt/2LG9AbU

Pathological response and survival in triple-negative breast cancer following neoadjuvant carboplatin plus docetaxel

Purpose: Prognostic value of pCR and extent of pathological response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in TNBC is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathological response in patients treated with carboplatin (Cb) plus docetaxel (D) NAC. Experimental Design: 190 patients with stage I-III TNBC were treated with neoadjuvant Cb(AUC6) plus D(75mg/m²) every 21 days x 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual Cancer Burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathological response was associated with RFS and OS using the Kaplan-Meier method. Results: Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. 5% of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR (HR=0.30; 95% CI: 0.14-0.62, P=0.0001). 3-year OS was 94% in patients with pCR and 79% in those without pCR (HR=0.25; 95% CI: 0.10-0.63, P=0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS. Conclusions: Neoadjuvant CbD yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.

https://ift.tt/2LCSYlu

Therapeutic targeting of TFE3/IRS-1/PI3K/mTOR axis in translocation renal cell carcinoma

Purpose: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that is not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. Experimental Design: We have established and characterized a tRCC patient-derived xenograft (PDX), RP-R07, as a novel preclinical model for drug development by using next generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. Results: The presence of a SFPQ-TFE3 fusion (t(X;1) (p11.2; p34)) with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, microRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3-tRCC models were confirmed by significantly higher expression of phospho-S6 (P<0.0001) and phospho-4EBP1 (P<0.0001) in established tRCC cell lines compared to clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater anti-proliferative effect both in vitro (P<0.0001) and in vivo (P<0.01) compared to single node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. Conclusions: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3-tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for TFE3-tRCC patients.

https://ift.tt/2K9nde5

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma

Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (Indotecan), LMP776 (Indimitecan) and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics and target engagement were determined. Results: The maximally tolerated doses (MTDs) were 17.5 mg/m²for LMP 776 and 100 mg/m²for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m²LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744;gH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions:These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ift.tt/2xzI4Bk) for evaluating novel therapies in immune-competent pets with cancers.

https://ift.tt/2LDdeDn

Acute Effects of Drugs on Caenorhabditis elegans Movement Reveal Complex Responses and Plasticity

Many drugs act very rapidly; they can turn on or off their targets within minutes in a whole animal. What are the acute effects of drug treatment and how does an animal respond to these? We developed a simple assay to measure the acute effects of drugs on C. elegans movement and examined the effects of a range of compounds including neuroactive drugs, toxins, environmental stresses and novel compounds on worm movement over a time period of 3 hours. We find that many treatments show complex acute responses, where a phase of rapid paralysis is followed by one or more recovery phases. The recoveries are not the result of some generic stress response but are specific to the drug e.g. recovery from paralysis due to a neuroactive drug requires neurotransmitter pathways whereas recovery from a metabolic inhibitor requires metabolic changes. Finally, we also find that acute responses can vary greatly across development and that there is extensive and complex natural variation in acute responses. In summary, acute responses are sensitive probes of the ability of biological networks to respond to drug treatment and these responses can reveal the action of unexplored pathways.

https://ift.tt/2mXHMBj

Complex Haplotypes of GSTM1 Gene Deletions Harbor Signatures of a Selective Sweep in East Asian Populations

The deletion of the metabolizing Glutathione S-transferase Mu 1 (GSTM1) gene has been associated with multiple cancers, metabolic and autoimmune disorders, as well as drug response. It is unusually common, with allele frequency reaching up to 75% in some human populations. Such high allele frequency of a derived allele with apparent impact on an otherwise conserved gene is a rare phenomenon. To investigate the evolutionary history of this locus, we analyzed 310 genomes using population genetics tools. Our analysis revealed a surprising lack of linkage disequilibrium between the deletion and the flanking single nucleotide variants in this locus. Tests that measure extended homozygosity and rapid change in allele frequency revealed signatures of an incomplete sweep in the locus. Using empirical approaches, we identified the Tanuki haplogroup, which carries the GSTM1 deletion and is found in approximately 70% of East Asian chromosomes. This haplogroup has rapidly increased in frequency in East Asian populations, contributing to a high population differentiation among continental human groups. We showed that extended homozygosity and population differentiation for this haplogroup is incompatible with simulated neutral expectations in East Asian populations. In parallel, we found that the Tanuki haplogroup is significantly associated with the expression levels of other GSTM genes. Collectively, our results suggest that standing variation in this locus has likely undergone an incomplete sweep in East Asia with regulatory impact on multiple GSTM genes. Our study provides the necessary framework for further studies to elucidate the evolutionary reasons that maintain disease-susceptibility variants in the GSTM1 locus.

https://ift.tt/2Ar2WkP

Gendered Morality and Backlash Effects in Online Discussions: An Experimental Study on How Users Respond to Hate Speech Comments Against Women and Sexual Minorities

Abstract

Hate speech in online users' comments is often targeted toward underprivileged social groups such as immigrants, sexual minorities, and women. Besides the general severity of such offenses, social media users' personal characteristics influence the evaluation of hate comments. We focus on the flagging of hate comments aimed toward women and sexual minorities (i.e., the intention to report such comments as inappropriate to a moderator or platform provider of an online discussion forum). We investigate the influence of user's morality on the intention to flag of such comments. Relying on social role and backlash theory, we scrutinize in how far gender plays a role in flagging intention and in how far people perceive hate comments by women as an act of double deviance. Therefore, we conducted a 2 × 2 online experiment with 457 participants (51% female) recruited through political interest groups and a German news magazine site on Facebook. Results indicate that moral judgments are to some extent gendered as women are more concerned about fairness and avoiding harm to others than men are. Deviant and agentic online behavior by women is judged more strictly than such behavior by men. Results implicate that moderators of online discussions and platform providers should be sensitive to how gender stereotypes influence online discussions.

https://ift.tt/2mXU9wU

Curcumin Attenuates Testicular Injury in Rats with Streptozotocin-Induced Diabetes

Oxidative damage, inflammation, and apoptosis are the primary features of diabetic testicular damage. Curcumin protects against diabetic testicular injury, but the underlying mechanisms remain obscure. This study examined the effect of curcumin on type 2 diabetes mellitus- (T2DM-) induced testicular injury, oxidative stress, and apoptotic changes. T2DM rats were intraperitoneally injected with 40 mg/kg STZ after being fed a high-fat diet for 8 weeks. One week after STZ injection, 100 or 200 mg/kg curcumin was administered orally to the diabetic rats for 16 weeks. Histological changes in the testes were determined by HE staining. Serum testosterone was measured. Markers of superoxide levels, such as SOD activity and MDA content, and markers of cell death, including the expression of Bax, Bcl-2, and MAPK family members, were measured by molecular biology or immunohistochemical techniques. Degeneration and disruption of seminiferous tubule structure were observed in diabetic rats. Serum testosterone levels were markedly lower in diabetic rats than in control rats. Moreover, testicular apoptosis and Bax expression were much higher in diabetic rats than in control rats. Superoxide generation, the NADP+/NADPH ratio, and NADPH oxidase subunit expression, including expression of the ,, and subunits, increased, while antioxidant enzyme levels decreased in diabetic rats. Furthermore, the MAPK signaling pathway was activated in diabetic rats. Curcumin partially prevented diabetes-induced microstructural abnormalities and significantly increased serum testosterone levels compared to untreated T2DM rats. Additionally, curcumin reduced testicular apoptosis by regulating apoptotic proteins and markedly inhibited oxidative stress levels by downregulating MDA expression, decreasing NADPH activity, and restoring antioxidant enzymes. Remarkably, curcumin treatment also suppressed MAPK activation. Thus, curcumin may have therapeutic value in the treatment of diabetes-induced testicular injury due to its prevention of testicular apoptosis and attenuation of oxidative stress.

https://ift.tt/2NXQLOb

Alveolar ridge regeneration of damaged extraction sockets using deproteinized porcine versus bovine bone minerals: A randomized clinical trial

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2LDj3B0

Do short implants have similar survival rates compared to standard implants in posterior single crown?: A systematic review and meta‐analysis

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2M3ioVC

Modeling the effect of osseointegration on dental implant pullout and torque removal tests

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2LCFJkM

Retrospective radiographic observational study of 1692 Straumann tissue‐level dental implants over 10 years. II. Marginal bone stability

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2M3iigI

Implant rehabilitation of the edentulous jaws: Does tilting of posterior implants at an angle greater than 45° affect bone resorption and implant success?: A retrospective study

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2LDiqYa

A randomized controlled clinical trial assessing initial crestal bone remodeling of implants with a different surface roughness

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2K7MQMx

The prosthetic abutment height can affect marginal bone loss around dental implants

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2mYzyZG

Esthetic evaluation of natural teeth in anterior maxilla using the pink and white esthetic scores

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2M3kZPr

In vitro evaluation of barrier function against oral bacteria of dense and expanded polytetrafluoroethylene (PTFE) membranes for guided bone regeneration

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2LDigjw

“Simpli5y” a noval concept for fixed rehabilitation of completely edentulous maxillary and mandibular edentulous arches: A 3‐year randomized clinical trial, supported by a numerical analysis

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2KcY02m

The micromechanical behavior of implant‐abutment connections under a dynamic load protocol

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2mXohsB

Role of vitamin C in wound healing after dental implant surgery in patients treated with bone grafts and patients with chronic periodontitis

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2M4nO2F

Five‐year cohort prospective study on single implants in the esthetic area restored using one‐abutment/one‐time prosthetic approach

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2mVHvPd

Comparison of clinical and radiographic peri‐implant parameters among obese and non‐obese patients: A 5‐year study

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2M4SrFd

Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1‐tumor predisposition syndrome is underreported in cancer patients

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2OyMfHc

Medical Boards May Contribute to Mental Health Stigma for Doctors

MONDAY, July 30, 2018 -- Existing policy has been amended to encourage licensing boards to require disclosure of physical or mental health conditions only when these would negatively impact a physicians' ability to practice medicine, according to an...

https://ift.tt/2mXiraF

Better Care Quality Needed for Universal Health Coverage

MONDAY, July 30, 2018 -- In order to achieve universal health coverage, stakeholders must focus on the quality of health services, including provision of effective, safe, timely, equitable, integrated, and efficient health services, according to a...

https://ift.tt/2Ao1aRj

AMA Opposes Proposed Cuts, Gag Orders for Reproductive Health

MONDAY, July 30, 2018 -- The American Medical Association (AMA) strongly objects to the Trump administration's plan to withhold federal family planning funding from Planned Parenthood and other entities, according to a statement released by the...

https://ift.tt/2OrEXES

Teen Boy Suffers Serious Burns After 'Hot Water Challenge'

MONDAY, July 30, 2018 -- An Indianapolis teen suffered serious burns after his friends poured boiling hot water on him as part of fad called the "Hot Water Challenge." The boiling water was poured on Kyland Clark, 15, as he slept. He suffered...

https://ift.tt/2Am1qAc

American Association of Colleges of Pharmacy, July 21-25

The American Association of Colleges of Pharmacy The annual meeting of the American Association of Colleges of Pharmacy was held from July 21 to 25 in Boston and attracted approximately 2,700 participants, including clinicians, academicians, allied...

https://ift.tt/2OsufxX

Copy number variant analysis using genome‐wide mate‐pair sequencing

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2NUpcFA

Two novel fusion genes, AIF1L‐ETV6 and ABL1‐AIF1L, result together with ETV6‐ABL1 from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2LDcSgi

The prognostic value of [ 123 I]-vascular endothelial growth factor ([ 123 I]-VEGF) in glioma

Abstract

Purpose

Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [¹²³I]-VEGF scintigraphy in patients with histologically verified brain tumors.

Methods

23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [¹²³I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [¹¹C]-methionine PET ([¹¹C]-MET PET) was performed in eight of the 23 patients. Both [¹²³I]-VEGF and [¹¹C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.

Results

World Health Organization (WHO) grade IV glioma lesions showed [¹²³I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [¹²³I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [¹¹C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).

Conclusion

Our results suggest that [¹²³I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [¹²³I]-VEGF may provide relevant prognostic information in patients with glioma.

https://ift.tt/2K5gmCF

Correction: Severe Vitamin D3 Deficiency in the Majority of Patients with Diabetic Foot Ulcers

Horm Metab Res
DOI: 10.1055/a-0661-2290

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2OyJ3eG

Safe pseudo‐elastic limit range under torsional loading with Reciproc Blue

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2v49y3n

Impact of root canal preparation performed by ProTaper Next or Reciproc on the quality of life of patients: a randomized clinical trial

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vsk8AP

Biocompatibility of Mineral Trioxide Aggregate Flow and Biodentine

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2v49uAF

Dentine decalcification and smear layer removal by different EDTA and HEDP species

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NY2Pz0

A unique case of mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1 sarcoma with epitheliotropism mimicking intestinal T cell lymphoma

Abstract

Myeloid sarcomas and extramedullary manifestations of mixed phenotype acute leukemia (MPAL) without leukemic involvement are rare. We present an unusual case of myeloid sarcoma of T/myelomonocytic biphenotypic nature and BCR-ABL1 translocation demonstrating an epitheliotropism in the gastrointestinal tract and mass-forming lesions in the lungs without bone marrow involvement. A 69-year-old gentleman presented with non-bloody diarrhea and abdominal pain complicated by weight loss. CT scan showed diffuse mural thickening in the jejunum, distal ileum, transverse colon, and splenic flexure and bilateral pulmonary nodules. Biopsies of the ileum and colon were performed. An initial diagnosis of T cell lymphoma was made based on intestinal infiltration with CD4 and CD7 positive monomorphic atypical cells. Despite treatment, the patient's lung masses grew. A comprehensive immunohistochemistry panel was performed on the lung biopsy based on the classic morphologic appearance of sheets of atypical cells and that CD4 and CD7 are also expressed in a subset of myeloid cells. The panel demonstrated CD34 (subset), CD68, muramidase/lysozyme, and CD117 expressions. Flow cytometry showed an aberrant myelomonocytic population. The presence of T lineage blasts was confirmed by a subset of blasts with cytoplasmic CD3. The diagnosis of mixed phenotype T/myeloid sarcoma with myelomonocytic differentiation and t(9;22)(q34.1;q11.2);BCR-ABL1 was made. Epitheliotropism has not been previously described as a histologic feature of intestinal myeloid sarcomas. The epitheliotropism, enteropathy-like features and gastrointestinal symptoms mimicked T cell lymphomas. This case highlighted the pivotal role of flow cytometry and clinicopathological correlation in making a diagnosis of myeloid sarcoma with MPAL phenotype.

https://ift.tt/2v3ejKC

Water drinking enhances the gain of arterial baroreflex control of muscle sympathetic nerve activity in healthy young humans

Experimental Physiology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Ox67tY

Thirty minutes of handgrip exercise potentiates flow‐mediated dilation in response to sustained and transient shear stress stimuli to a similar extent

Experimental Physiology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AqPsFJ

Right ventricular dyssynchrony during hypoxic breathing but not during exercise in healthy subjects a speckle tracking echocardiography study

Experimental Physiology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2mWVUe5

Myths and Methodologies: Reducing scientific design ambiguity in studies comparing sexes and/or menstrual cycle phases

Experimental Physiology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AnUS49

Combining Data from Multiple Sources to Study Mechanisms of Aneurysm Disease: Tools and Techniques

International Journal for Numerical Methods in Biomedical Engineering, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LPoo7r

Numerical Accuracy Comparison of Two Boundary Conditions Commonly used to Approximate Shear Stress Distributions in Tissue Engineering Scaffolds Cultured under Flow Perfusion

International Journal for Numerical Methods in Biomedical Engineering, Volume 0, Issue ja, -Not available-.


https://ift.tt/2KaM6pV

Hyposmia in a simple smell test is associated with accelerated cognitive decline in early Parkinson's disease

Acta Neurologica Scandinavica, EarlyView.


https://ift.tt/2AqcMmT

Effects of multidisciplinary therapy on physical function in Huntington's disease

Acta Neurologica Scandinavica, EarlyView.


https://ift.tt/2mTU90W

Underdiagnosis of Unilateral Spatial Neglect in stroke unit

Acta Neurologica Scandinavica, EarlyView.


https://ift.tt/2Apic1H

Disposable income trajectories of working‐aged individuals with diagnosed multiple sclerosis

Acta Neurologica Scandinavica, EarlyView.


https://ift.tt/2Ow3TeK

Assessing the role of innovative therapeutic paradigm on multiple sclerosis treatment response

Acta Neurologica Scandinavica, EarlyView.


https://ift.tt/2AsAsXS

Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vhSw19

CXCR3high CD8+ T cells with naïve phenotype and high capacity for interferon‐ γ production are generated during homeostatic T‐cell proliferation

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LDPmj9

Human MAIT cells are rapidly activated by Aspergillus ssp. in an antigen presenting cell‐dependent manner

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vf3T9Y

Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LAYmpc

IL‐1β activation in response to Staphylococcus aureus lung infection requires inflammasome‐dependent and independent mechanisms

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vrRYG7

Blimp‐1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2OqJWFU

Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LDPkrx

Kallikrein‐related peptidases are activators of the CC chemokine CCL14

European Journal of Immunology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vhsg6Y

Assessment of Dermal Absorption of Aluminum from a Representative Antiperspirant Formulation Using a 26Al Microtracer Approach

Clinical and Translational Science, EarlyView.


https://ift.tt/2LBYTYa

Design and Conduct Considerations for First‐in‐Human Trials

Clinical and Translational Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2viOR3a

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy

Clinical and Translational Science, EarlyView.


https://ift.tt/2LAJNBW

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Methadone in Participants Receiving Maintenance Opioid Agonist Therapy

Clinical and Translational Science, EarlyView.


https://ift.tt/2NZrkfl

Risk factor model of mechanical complications in implant‐supported fixed complete dentures: A prospective cohort study

Clinical Oral Implants Research, EarlyView.


https://ift.tt/2LUASLj

Implant survival rates and biologic complications with implant‐supported fixed complete dental prostheses: A retrospective study with up to 12‐year follow‐up

Clinical Oral Implants Research, EarlyView.


https://ift.tt/2viZ9QB

Patterns of care and outcomes for men diagnosed with prostate cancer in Victoria: an update

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2M4xIRZ

‘Watch and wait’ after chemoradiotherapy for rectal cancer

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2LRfmXu

Isolated port‐site prostate metastasis after robot‐assisted laparoscopic radical prostatectomy: case report

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2NYEg57

Retroperitoneal necrotizing soft tissue infection post perforated diverticulitis: a rare case reiterating the need for caution in patients with delayed presentation

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2LMdeQP

Liver resection in octogenarians: are the outcomes worth the risk?

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2M40Sk5

Distal mesonephric duct anomalies in association with penile ectopia and complex hypospadias

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2v1ygS4

Somatosensory and auditory deviance detection for outcome prediction during postanoxic coma

Annals of Clinical and Translational Neurology, EarlyView.


https://ift.tt/2LBUuo6

Pre‐amyloid stage of Alzheimer's disease in cognitively normal individuals

Annals of Clinical and Translational Neurology, EarlyView.


https://ift.tt/2M30ulX

Population‐based cohort study of diabetes mellitus and mortality in gastric adenocarcinoma

BJS, EarlyView.


https://ift.tt/2NTeXkP

Lymph node regression and survival following neoadjuvant chemotherapy in oesophageal adenocarcinoma

BJS, EarlyView.


https://ift.tt/2LPeZNb

Open or endovascular revascularization in the treatment of acute lower limb ischaemia

BJS, EarlyView.


https://ift.tt/2NZcwgO

Ruptured popliteal artery aneurysm

BJS, EarlyView.


https://ift.tt/2LOrOHy

Strong SOX10 expression in HPV-related multiphenotypic sinonasal carcinoma: report of six new cases validated by high-risk HPV mRNA in situ hybridization test

HPV-related multiphenotypic sinonasal carcinoma (HMSC) is associated with high-risk human papillomavirus (HR-HPV) infection. Using HR-HPV mRNA in situ hybridization (ISH), we reported six new HMSC cases and compared their histopathology with that of sinonasal adenoid cystic carcinoma (ACC). Using p16 immunohistochemistry (IHC) and HR-HPV ISH, we retrospectively identified six HMSC cases. All HMSC cases were positive for HR-HPV mRNA ISH and p16 IHC. Two HMSC cases had overlying atypical squamous epithelium and one also had invasive squamous cell carcinoma (SCC).

https://ift.tt/2NZcrK2

Effects of 10 MV and Flattening-Filter-Free Beams on Peripheral Dose in a Cohort of Pediatric Patients

Reducing peripheral dose is important for pediatric radiotherapy patients. This study assesses peripheral photon and neutron doses from volumetric modulated arc therapy (VMAT) deliveries for 10 MV FFF (flattening-filter-free) and 6 MV FFF x-ray beams compared to 6 MV-flattened beams. A significant reduction in peripheral dose was found in FFF beams compared to 6 MV-flattened beams

https://ift.tt/2LMoqNr

Phase I/II Study of Stereotactic Ablative Radiotherapy Including Regional Lymph Node Irradiation in Patients with High-Risk Prostate Cancer (SATURN): Early Toxicity and Quality of Life

Two-year toxicity and quality of life (QOL) results are reported from a dose-escalated prostate SABR study for high-risk prostate cancer. Prostate, seminal vesicles, and pelvic lymph nodes were treated using a dose-painting schema up to 40Gy and 25Gy in 5 fractions, respectively, delivered weekly, in combination with androgen deprivation therapy. No grade 3 or higher CTCAE v 3.0 toxicity was noted. EPIC quality of life in all 4 domains was comparable to baseline at 24 months.

https://ift.tt/2vloU2C

Utilization of a web-based conferencing platform to improve global radiation oncology education and quality—proof of principle through implementation in India

Chartrounds (www.chartrounds.com) is a free web-based platform for radiation oncologists to review cases with leading disease-site experts. Chartrounds has been well-utilized in the US since 2010 and is now expanding internationally. A dedicated site for India (ind.chartrounds.com) was launched in June 2017. Herein, we report our initial experience with this initiative and demonstrate that an online platform for radiation oncology case review and education can be successfully implemented globally with utilization of local disease-site experts.

https://ift.tt/2vlD7Nh

Non-measurable speckled contrast-enhancing lesions appearing during course of disease are associated with IDH mutation in high-grade astrocytoma patients

Clinically asymptomatic, speckled contrast-enhancing lesions (≤ 0.5 cm) (SCEs) appeared frequently during course of disease in patients with gliomas and challenge the definition of progression and clinical management. Appearance of SCEs was significantly associated with IDH mutation in astrocytoma WHO °III and glioblastoma and with a favorable prognosis in glioblastoma. Most SCEs remained stable or disappeared without treatment necessitating a careful definition of progression and its confirmation in follow-up MRIs prior to initiation of treatment.

https://ift.tt/2LL4Tgd

Daily versus weekly prostate cancer image-guided radiotherapy: Phase 3 multicenter randomized trial

The optimal frequency of prostate cancer image-guided radiation therapy (IGRT) has not yet been clearly identified. This phase 3 trial compared the efficacy of daily versus weekly IGRT. Compared to weekly control, daily control, by improving prostate targeting, decreases the risks of recurrences as well as rectal toxicity.

https://ift.tt/2v2Bvsu

Optimization of tea‐leaf saponins water extraction and relationships between their contents and tea (Camellia sinensis) tree varieties

Food Science &Nutrition, EarlyView.


https://ift.tt/2v2CIA5

Determination of citric acid pretreatment effect on nutrient content, bioactive components, and total antioxidant capacity of dried sweet potato flour

Food Science &Nutrition, EarlyView.


https://ift.tt/2NY6FIy

Characterization of protein isolate from Sesamum indicum seed: In vitro protein digestibility, amino acid profile, and some functional properties

Food Science &Nutrition, EarlyView.


https://ift.tt/2uXmNTx

Comparison of sensory and instrumental methods for the analysis of texture of cooked individually quick frozen and fresh‐frozen catfish fillets

Food Science &Nutrition, EarlyView.


https://ift.tt/2vjUxtI

Effects of different thermal processing methods on the structure and allergenicity of peanut allergen Ara h 1

Food Science &Nutrition, EarlyView.


https://ift.tt/2LPebb7

Effect of cooking treatments on the phytochemical composition and antidiabetic potential of Vernonia amygdalina

Food Science &Nutrition, EarlyView.


https://ift.tt/2vhirG8

Issue Information

Food Science &Nutrition, Volume 6, Issue 5, Page 1171-1172, July 2018.


https://ift.tt/2uZJLJQ

Cover Image, Volume 6, Issue 5

Food Science &Nutrition, Volume 6, Issue 5, Page i-i, July 2018.


https://ift.tt/2NXRy1K

Scavenging effect of pasipay (passiflora incarnate L.) on singlet oxygen generation and fatty acid photooxygenation

Food Science &Nutrition, EarlyView.


https://ift.tt/2LNo7lC

Antioxidant and alpha‐amylase inhibitory potentials of Cocos nucifera husk

Food Science &Nutrition, EarlyView.


https://ift.tt/2vilbTH

Pregnancy and birth outcomes in a Danish nationwide cohort of women with autoimmune hepatitis and matched population controls

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2vihptv

Impact of previously cured hepatocellular carcinoma (HCC) on new development of HCC after eradication of hepatitis C infection with non‐interferon‐based treatments

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2LPbTsx

Editorial: Tong‐Xie‐Yao‐Fang (TXYF) for irritable bowel syndrome with diarrhoea (IBS‐D)—ancient medicine meets modern study

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 485-486, August 2018.


https://ift.tt/2vkEFa5

Editorial: aminosalicylates in Crohn's disease—prevalence, risks, costs and time to reassess? Authors’ reply

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 489-489, August 2018.


https://ift.tt/2LJFoMv

Editorial: covert hepatic encephalopathy—silent but serious. Authors’ reply

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 480-481, August 2018.


https://ift.tt/2vl3MK9

Editorial: diabetes in HIV‐infected patients—do not blame the usual suspect!

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 481-482, August 2018.


https://ift.tt/2v4b1qh

Editorial: diabetes in HIV‐infected patients—do not blame the usual suspect! Authors’ reply

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 482-483, August 2018.


https://ift.tt/2vih1v3

Issue Information

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 391-393, August 2018.


https://ift.tt/2v1UtPJ

Editorial: knowledge—a prescription for coeliac disease

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 478-479, August 2018.


https://ift.tt/2voAt9E

Letter: eluxadoline‐associated acute pancreatitis—myth or reality?

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 490-491, August 2018.


https://ift.tt/2LTYlvM

Editorial: covert hepatic encephalopathy—silent but serious

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 479-480, August 2018.


https://ift.tt/2vigQjn

Letter: eluxadoline‐associated acute pancreatitis—myth or reality? Authors’ reply

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 491-492, August 2018.


https://ift.tt/2LUwQCF

Editorial: aminosalicylates in Crohn's disease—prevalence, risks, costs and time to re‐assess?

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 487-488, August 2018.


https://ift.tt/2NXWK5w

Editorial: deciding when to intervene in primary sclerosing cholangitis

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 484-485, August 2018.


https://ift.tt/2v1UuTN

Editorial: Tong‐Xie‐Yao‐Fang (TXYF) for irritable bowel syndrome with diarrhoea (IBS‐D)—ancient medicine meets modern study. Authors’ reply

Alimentary Pharmacology &Therapeutics, Volume 48, Issue 4, Page 486-487, August 2018.


https://ift.tt/2NZplaT

Significant association between the use of different proton pump inhibitors and microscopic colitis: a nationwide Danish case‐control study

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2LLitjH

Inhibition of tumor formation and metastasis by a monoclonal antibody against lymphatic vessel endothelial hyaluronan receptor 1

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LQpf82

Chronic hypoxia‐induced Slug promotes invasive behavior of prostate cancer cells by activating expression of Ephrin‐B1

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Kat96E

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2v4arc5

Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2M1nbXr

Combined effect of cabozantinib and gefitinib in crizotinib‐resistant lung tumors harboring ROS1 fusions

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LQ7JRd

HOTAIR, a long non‐coding RNA, is a marker of abnormal cell cycle regulation in lung cancer

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2M3UDg9

A dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LPMX40

Clinical Profile of Gilteritinib in Japanese Patients with Relapsed/Refractory AML: an Open‐Label Phase 1 Study

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2M4a1Jj

Simvastatin Functions as an Hsp90 Inhibitor to against Triple‐Negative Breast Cancer

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2v1yqsy

LncNEN885 Inhibits EMT Partially via Wnt/β‐catenin signaling in Gastroenteropancreatic Neuroendocrine Neoplasms

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2K9Hr7J

The cytoplasmic LKB1 promotes the growth of human lung adenocarcinoma by enhancing autophagy

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LPa0fr

Genetic and clinical characterization of B7‐H3(CD276) expression and epigenetic regulation in diffuse brain glioma

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2KaQ7L8

Ambra1 Modulates the Sensitivity of Breast Cancer Cells to Epirubicin by Regulating Autophagy via ATG12

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LPaNwP

Perampanel in routine clinical use across Europe: Pooled, multicenter, observational data

Epilepsia, EarlyView.


https://ift.tt/2K7SiPj

Perampanel in patients with refractory and super‐refractory status epilepticus in a neurological intensive care unit: A single‐center audit of 30 patients

Epilepsia, EarlyView.


https://ift.tt/2LUwagB

Intravenous brivaracetam in status epilepticus: A retrospective single‐center study

Epilepsia, EarlyView.


https://ift.tt/2M6vpgX

Enhanced thalamo‐hippocampal synchronization during focal limbic seizures

Epilepsia, EarlyView.


https://ift.tt/2LQ7IN9

Epilepsy surgery near or in eloquent cortex in children—Practice patterns and recommendations for minimizing and reporting deficits

Epilepsia, EarlyView.


https://ift.tt/2K9hx41

The expression of inflammatory markers and their potential influence on efflux transporters in drug‐resistant mesial temporal lobe epilepsy tissue

Epilepsia, EarlyView.


https://ift.tt/2LNBr9z

Conducting and reporting animal experimentation: Quo vadis?

European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.


https://ift.tt/2M4wMNp

Awe as a Scientific Emotion

Cognitive Science, EarlyView.


https://ift.tt/2LP8jhZ

The Path to Routine Genomic Screening in Health Care

Geisinger Health System received considerable attention in May 2018 when it announced that DNA sequencing would become a routine part of its clinical care. This commentary discusses why identifying persons with genetic risk and effectively mitigating that risk is a worthy goal and emphasizes that the timing of the introduction of genetic data into routine clinical care is contingent on further demonstrations of clinical utility and proven implementation models.

https://ift.tt/2Otj6go

Treatment of Dilated Cardiomyopathy With Interleukin-1 Inhibition

https://ift.tt/2ApNc1p

When Tissue Is No Longer the Issue: Tissue-Agnostic Cancer Therapy Comes of Age

Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances have found that the success of biomarker-driven cancer therapy may be relevant across sites of origin. For example, cancer types that show DNA mismatch repair deficiency, such as colon, biliary, and endometrial cancer, are more sensitive to immune checkpoint inhibition. Several large, ongoing clinical trials with a "basket" design are combining tumor tissue genomics with potential off-the-shelf therapies in drug development, and more tissue-agnostic biomarker therapies are reaching the bedside.

https://ift.tt/2mWSCri

Universal Principles of Human Communication: Preliminary Evidence From a Cross‐cultural Communication Game

Cognitive Science, EarlyView.


https://ift.tt/2NZ7DnY

Labeling of Collagen Type I Templates with a Naturally Derived Contrast Agent for Noninvasive MR Imaging in Soft Tissue Engineering

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2OrYaq6

Prevention of Type 1 Diabetes with Acetalated Dextran Microparticles Containing Rapamycin and Pancreatic Peptide P31

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2AnJchP

Printable Graphene Oxide Micropatterns for a Bio‐Subretinal Chip

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2AnJc1j

Bioinspired Structural Hierarchy within Macroscopic Volumes of Synthetic Composites

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2n1JH81

Masthead: (Adv. Healthcare Mater. 14/2018)

Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.


https://ift.tt/2Aq4RWH

A 69‐year‐old woman with Coffin–Siris syndrome

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2mTsqgS

A case of severe TBCE‐negative hypoparathyroidism‐retardation‐dysmorphism syndrome: Case report and literature review

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2AqDV9p

A recognizable phenotype related to 19p13.12 microdeletion

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2OvYbJR

Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2An7aKj

De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2OvY94H

Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2An71GL

Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2mY5e1c

M. Michael Cohen, Jr.: Author, diagnostician, geneticist, teacher, mentor, syndrome scholar extraordinaire (1937–2018)

American Journal of Medical Genetics Part A, EarlyView.


https://ift.tt/2ApOQ2V

Controllable, Wide‐Ranging n‐Doping and p‐Doping of Monolayer Group 6 Transition‐Metal Disulfides and Diselenides

Advanced Materials, EarlyView.


https://ift.tt/2M3Yv0A

Spontaneous Formation of Noble‐ and Heavy‐Metal‐Free Alloyed Semiconductor Quantum Rods for Efficient Photocatalysis

Advanced Materials, EarlyView.


https://ift.tt/2visHOw

Organic Semiconducting Agents for Deep‐Tissue Molecular Imaging: Second Near‐Infrared Fluorescence, Self‐Luminescence, and Photoacoustics

Advanced Materials, EarlyView.


https://ift.tt/2LTLTfw

Printable Graphene Oxide Micropatterns for a Bio‐Subretinal Chip

Advanced Materials, July 2018.


https://ift.tt/2LMrqte

Functionalization of Graphene Oxide Films with Au and MoOx Nanoparticles as Efficient p‐Contact Electrodes for Inverted Planar Perovskite Solar Cells

Advanced Materials, July 2018.


https://ift.tt/2OvSA5Z

Ultra‐Lightweight 3D Carbon Current Collectors: Constructing All‐Carbon Electrodes for Stable and High Energy Density Dual‐Ion Batteries

Advanced Materials, July 2018.


https://ift.tt/2LAAmCG

Template‐ and Metal‐Free Synthesis of Nitrogen‐Rich Nanoporous “Noble” Carbon Materials by Direct Pyrolysis of a Preorganized Hexaazatriphenylene Precursor

Advanced Materials, July 2018.


https://ift.tt/2M5Zb5w

Graphite Microislands Prepared for Reliability Improvement of Amorphous Carbon Based Resistive Switching Memory

Advanced Materials, July 2018.


https://ift.tt/2LF8uNG

Harnessing the Wisdom in Colloidal Chemistry to Make Stable Single‐Atom Catalysts

Advanced Materials, EarlyView.


https://ift.tt/2uX4ptZ

Making a Splash in Homogeneous CO2 Hydrogenation: Elucidating the Impact of Solvent on Catalytic Mechanisms

Advanced Materials, July 2018.


https://ift.tt/2Kb2Qx5

Carbon‐Rich Nanomaterials: Fascinating Hydrogen and Oxygen Electrocatalysts

Advanced Materials, July 2018.


https://ift.tt/2v1yf0i

Exploring Active Sites in Multi‐Heteroatom‐Doped Co‐Based Catalysts for Hydrogen Evolution Reactions

Advanced Materials, July 2018.


https://ift.tt/2OyumIy

Ab Initio Calculations on the Electronic Structure and Photocatalytic Properties of Two‐Dimensional WS2 (0001) Nanolayers of Varying Thickness

Advanced Materials, July 2018.


https://ift.tt/2vjFzUy

Citrate‐Based Fluorescent Biomaterials

Advanced Materials, July 2018.


https://ift.tt/2Kb9y6e

Advanced Porous Materials in Mixed Matrix Membranes

Advanced Materials, EarlyView.


https://ift.tt/2LKmyES

Dissociated Skin Cells Regenerate Hair Follicles in a MicroWound, “The Punch Assay”

Experimental Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AqA7F9

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

Experimental Dermatology, EarlyView.


https://ift.tt/2AqAtvt

Corneocyte Proteomics: Applications to Skin Biology and Dermatology

Experimental Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AqAjUT

Ex‐vivo fluorescence confocal microscopy for intraoperative, real time diagnoses of cutaneous inflammatory diseases: a preliminary study

Experimental Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2OvTY90

A dipeptidyl peptidase‐4 inhibitor promotes wound healing in normoglycemic mice by modulating keratinocyte activity

Experimental Dermatology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2mXnnfG

Issue Information

CA: A Cancer Journal for Clinicians, Volume 68, Issue 4, Page 233-234, July/August 2018.


https://ift.tt/2M6oi8f

Issue Information ‐ Cover

CA: A Cancer Journal for Clinicians, Volume 68, Issue 4, July/August 2018.


https://ift.tt/2LUlrTm

Addressing publication bias in the anatomical literature by reporting zero prevalence of bicuspid aortic valve

Clinical Anatomy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2uXbk6r

Developmental Roles and Evolutionary Significance of AMPA‐Type Glutamate Receptors

BioEssays, EarlyView.


https://ift.tt/2NU6r58

BioEssays 8∕2018

BioEssays, Volume 40, Issue 8, August 2018.


https://ift.tt/2uZw6T4

Cover Image

Chemical Biology &Drug Design, Volume 92, Issue 2, Page i-i, August 2018.


https://ift.tt/2vlwJFN

Issue Information

Chemical Biology &Drug Design, Volume 92, Issue 2, Page 1399-1402, August 2018.


https://ift.tt/2LIG2dd

Identification of 2‐benzoxazolinone derivatives as lead against molecular targets of diabetic complications

Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NXzWmJ

Structural Optimization of Diphenylpyrimidine Scaffold as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation in Non‐small Cell Lung Cancer

Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.


https://ift.tt/2v2yuZc

Maspin mRNA expression in sentinel lymph nodes (SLNs) predicts non‐SLN metastasis in breast cancer patients with SLN metastasis

Histopathology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vfDJDS

Phenotypic and molecular changes in nodule‐in‐nodule hepatocellular carcinoma with pathogenetic implications

Histopathology, EarlyView.


https://ift.tt/2v2ylF8

Issue Information

Academic Emergency Medicine, Volume 25, Issue 7, Page 711-715, July 2018.


https://ift.tt/2NU6nlU

A Case‐Control Study of Sonographic Maximum Ovarian Diameter as a Predictor of Ovarian Torsion in Emergency Department Females with Pelvic Pain

Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.


https://ift.tt/2uX9oeb

Preoperative radiation may improve the outcomes of resectable IIIA/N2 non‐small‐cell lung cancer patients: A propensity score matching‐based analysis from surveillance, epidemiology, and end results database

Cancer Medicine, EarlyView.


https://ift.tt/2vkSwNX

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Cancer Medicine, EarlyView.


https://ift.tt/2v4itBM

A prospective Phase II study to examine the relationship between quality of life and adverse events of first‐line chemotherapy plus cetuximab in patients with KRAS wild‐type unresectable metastatic colorectal cancer: QUACK trial

Cancer Medicine, EarlyView.


https://ift.tt/2NYsMyx

Esophageal squamous cell carcinoma and prognosis in Taiwan

Cancer Medicine, EarlyView.


https://ift.tt/2v1nfjA

Interferon gamma in cancer immunotherapy

Cancer Medicine, EarlyView.


https://ift.tt/2vkxQFA

Interaction between glutathione S‐transferase M1‐null/present polymorphism and adjuvant chemotherapy influences the survival of breast cancer

Cancer Medicine, EarlyView.


https://ift.tt/2LTORRc

Lipase‐catalyzed butanolysis of Echium oil for the selective enrichment in gamma‐linolenic and stearidonic acids

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2KaCV8T

Comparative evaluation of the fatty acids and aroma compounds in selected Iranian nut oils

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LMiTGF

Preparation and physicochemical properties of a cysteine derivative‐loaded deformable liposomes in hydrogel for enhancing whitening effects

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LZSFgG

Encapsulation of fish oil into low‐cost alginate beads and EPA‐DHA release in a rumino‐intestinal in‐vitro digestion model

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LPT9sX

Comparing the Oil Extraction and Refining Methods for Muscadine Grape Seeds of Noble and Carlos Cultivar

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2KfPKPu

Comparative effects of cholesterol and β‐sitosterol on the liposome membrane characteristics

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LQVO5y

Storage stability of β‐carotene in model beverage emulsions: implication of interfacial thickness

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LZSkdU

The Association between Household Food Insecurity and Body Mass Index: A Prospective Growth Curve Analysis

To examine the association between food insecurity and body mass index (BMI) from early adolescence to adulthood.

https://ift.tt/2mUc8ED

Grip Strength Is Associated with Longitudinal Health Maintenance and Improvement in Adolescents

To assess the effects of muscle strength, as determined by grip strength, on changes in health status in adolescents.

https://ift.tt/2AvoAUO

Disparities in Care for Children with Chronic Kidney Disease

Pediatricians and health policy experts are increasingly concerned about disparities in child health care, not only on a global basis but also nationally and regionally as well. Much attention has been paid to the role of poverty in generating these disparities; children living in poverty may have less access to care, poorer care coordination, suboptimal care, and worse outcomes.

https://ift.tt/2OuTOPa

Performance of 111 In-labelled PSMA ligand in patients with nodal metastatic prostate cancer: correlation between tracer uptake and histopathology from lymphadenectomy

Abstract

Purpose

Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake of ¹¹¹In-labelled PSMA ligand DKFZ-617 (referred to as ¹¹¹In-PSMA-617) in unaffected LN and LNM at the level of single LN.

Methods

Six patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwent ¹¹¹In-PSMA-617-guided lymphadenectomy (LA; four salvage LA and two primary LA). ¹¹¹In-PSMA-617 (109 ± 5 MBq). was injected Intravenously 48 h prior to surgery Template LAs were performed in small subregions: common, external, obturator and internal iliac vessels, and presacral and retroperitoneal subregions (n = 4). Samples from each subregion were isolated aiming at the level of single LN. Uptake was measured ex situ using a germanium detector. Receiver operating characteristic (ROC) analysis was performed based on ¹¹¹In-PSMA-617 uptake expressed as standardized uptake values normalized to lean body mass (SUL).

Results

Overall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p < 0.0001). Based on 38 tumour-containing and 182 tumour-free specimens, ROC analysis revealed an area under the curve of 0.976 (95% CI 0.95–1.00, p < 0.0001). Using a SUL cut-off value of 1.136, sensitivity, specificity, positive predictive value, negative predictive value and accuracy in discriminating affected from nonaffected LN were 92.1% (35/38), 98.9% (180/182), 94.6% (35/37), 98.4% (180/183) and 97.7% (215/220), respectively.

Conclusion

Ex situ analysis at the level of single LN showed that ¹¹¹In-PSMA-617 had excellent ability to discriminate between affected and nonaffected LN in our patients with PCa. This tracer characteristic is a prerequisite for in vivo real-time measurements during surgery.

https://ift.tt/2AsgOv6

Catheter Fracture of Subclavian Venous Chemoport Device at Costoclavicular Junction: Pinch-off Syndrome

Abstract

Chemoport is most commonly used venous access devices for instillation of chemotherapeutic drugs in cancer care. Mechanical complications like catheter fracture can lead to serious morbidity, albeit occurring rarely. We present a case of a 35-year-old lady, a case of carcinoma breast, who had spontaneous fracture of chemoport access device in subclavian vein at the level of clavicle after four successful cycles of chemotherapy. The fracture was suspected on chest x-ray and was subsequently confirmed on contrast linogram. The patient was successfully managed with endovascular interventional technique without suffering any ill effects. It is a rare presentation of pinch-off syndrome.

https://ift.tt/2Kao7Hz

Assessment of the Synaptic Interface of Primary Human T Cells from Peripheral Blood and Lymphoid Tissue

The protocol describes a technique to study the ability of primary polyclonal human T cells to form synaptic interfaces using planar lipid bilayers. We use this technique to show the differential synapse formation capability of human primary T cells derived from lymph nodes and peripheral blood.

https://ift.tt/2Apv0VC

Live Cell Imaging of the TGF- β/Smad3 Signaling Pathway In Vitro and In Vivo Using an Adenovirus Reporter System

Here, we present a protocol for live cell imaging of TGF-β/Smad3 signaling activity using an adenovirus reporter system. This system tracks transcriptional activity in real-time and can be applied to both single cells in vitro and in live animalmodels.

https://ift.tt/2M3TRjd

Acupuncture May Cut Arthralgia From Aromatase Inhibitors

MONDAY, July 30, 2018 -- Acupuncture may cut joint pain among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related pain, according to a study published in the July 10 issue of the Journal of the American Medical...

https://ift.tt/2mVNJyB

Infective Endocarditis More Common with Valve Issues

MONDAY, July 30, 2018 -- Individuals with bicuspid aortic valve (BAV) and mitral valve prolapse (MVP) have a higher risk of developing infective endocarditis (IE) than the general population, according to a study published in the June 19 issue of...

https://ift.tt/2AqB8wM

Health Coverage Interruptions Common in Adults With T1DM

MONDAY, July 30, 2018 -- Interruptions in private health insurance coverage are common among U.S. adults with type 1 diabetes and are associated with an increase in glycated hemoglobin and in use of acute care services, according to a report...

https://ift.tt/2OrmecR

Four Strategies Help Doctors Make Personal, Professional Gains

MONDAY, July 30, 2018 -- In an article published in Physicians Practice, four strategies are presented to help physicians make personal and professional gains. The article provides four strategies for recommendations that can be relied upon for...

https://ift.tt/2Ap7h80

Increased Levels of Human Herpesvirus ID'd in Alzheimer's

MONDAY, July 30, 2018 -- Subjects with Alzheimer's disease have increased levels of two strains of human herpesvirus, according to a study published online July 11 in Neuron. Ben Readhead, M.B.B.S., from the Icahn School of Medicine at Mount Sinai...

https://ift.tt/2OrmatD

Ties Between Self-Regulation, Obesity in Children Differ by Sex

MONDAY, July 30, 2018 -- The association between self-regulation and the risk of obesity differs between boys and girls, according to a study published online July 16 in JAMA Pediatrics. Sarah E. Anderson, Ph.D., from The Ohio State University in...

https://ift.tt/2Al0ADU

No Higher Risk of Autoimmune Disorders After HPV4 Vaccination

MONDAY, July 30, 2018 -- Following quadrivalent human papillomavirus (HPV4) vaccination, girls age 12 to 17 years do not have increased risk of autoimmune disorders, according to a study published recently in CMAJ, the journal of the Canadian...

https://ift.tt/2mThbFj

Tool Improves Identification of Undiagnosed Hypertension

MONDAY, July 30, 2018 -- Use of billing and clinical data can help to identify undiagnosed hypertension, according to research published in the July 27 issue of the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly...

https://ift.tt/2Av1qxQ

Few Health Differences for Trans, Cisgender Veterans

MONDAY, July 30, 2018 -- Transgender U.S. veterans have few health differences compared with cisgender veterans, although the odds of having at least one disability are higher for transgender veterans, according to a study published in the July...

https://ift.tt/2Orm6Kp

Young Cancer Survivors Have High Risk of Endocrine Diseases

MONDAY, July 30, 2018 -- Adolescent and young adult cancer survivors have a 73 percent higher risk of endocrine diseases, according to a study published online June 29 in JAMA Network Open. Mette Vestergaard Jensen, M.D., from the Danish Cancer...

https://ift.tt/2AowcbU

Effect of Lycosome-Formulated Phosphatidylcholine on Parameters of Biological Oxidation after Single Intake of Moderate Amount of Alcohol

Ingestion of a single dose of alcohol, ranging from the intake of a moderate amount alcohol to binge drinking, is the most frequent form of alcohol consumption with poorly understood medical consequences and obscure prophylactics. The study was aimed to determine whether lycosome formulated phosphatidylcholine (PC-Lyc) containing two highly bioavailable antioxidants (PC and lycopene) ingested shortly before the alcohol-containing beverage may alleviate the biochemical markers of liver damage and parameters of biological oxidation associated with the intake of a moderate amount of alcohol. Healthy middle-aged volunteers were requested to consume a moderate amount of alcohol – 0.5 ml/kg or 1.0 ml/kg shortly after ingestion of a capsule containing 450 mg of regular phosphatidylcholine (PC, n=10), PC-Lyc (n=10), or placebo pill (PP, n=10). Serum levels of ethanol (EtOH), acetaldehyde (AA), liver-specific enzymes, total antioxidant capacity of serum (TAC), oxidized LDL (LDL-Px), and malonic dialdehyde (MDA) were measured at 1, 2.5, and 5 hours after dosing with alcohol. Ingestion of PC regardless of the formulation used had no effect on serum EtOH concentration dynamics. However, volunteers supplemented with PC-Lyc showed a better clearance of AA in serum as compared to other groups. There was a reduction in serum TAC values by 18.5% and 16.1% in both placebo groups ingesting 0.5 and 1.0 ml/kg of alcohol, respectively, at the end of observational period. This decline was preventable by supplementation of volunteers with PC and especially with PC-Lyc. Moreover, PC-Lyc promoted a reduction of serum MDA and reversed an increase in serum LDL-Px. In addition, ingestion of alcohol at 1.0 ml/kg dose caused a transient increase in serum alanine-aminotransferase activity which was abolished by both formulations of PC. Therefore, combinatory lycosomal formulation of PC and lycopene may prevent some metabolic abnormalities associated with single intake of moderate amount of alcohol. This trial is registered with ACTRN12617001335381.

https://ift.tt/2M3EWpa