Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.
https://ift.tt/2quipbN
Δευτέρα 5 Νοεμβρίου 2018
Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway
Association between cirrhosis and aneurysmal subarachnoid hemorrhage
Annals of Clinical and Translational Neurology, EarlyView.
https://ift.tt/2APu9M7
Clinical Anatomy for the Innervated Pattern and Boundary of the Subdeltoid Bursa
The aim of this study was to accurately identify the distribution of sensory nerve branches running to bursa with mesoscopic dissection and boundaries following the injection of gelatin into the bursa. Eighteen shoulders of 11 Korean soft cadavers (average age, 65 years; age range, 43 - 88 years) were dissected. The most prominent point of greater tubercle of the humerus (GT) was used as a reference point. The horizontal line passing through GT was used as the x-axis while the vertical line passing through the GT was used as the y-axis. Average distances of the anterior, posterior, superior, and inferior from the GT were 1.9±0.6, 2.4±1.3, 2.1±0.7, and 3.2±1.5 cm, respectively. In 15 cases of 18 shoulders, the anterior branch of the axillary nerve was distributed to the subdeltoid bursa that was running posteriorly. The muscular branch of the anterior and middle parts of the deltoid was distributed to the branch of nerve that was running into the subdeltoid bursa. A branch of the posterior cord of brachial plexus was distributed to the subdeltoid bursa that was running anteriorly in three cases. Most of the branches of the axillary nerve were distributed into the posterolateral area. The branches of the posterior cord of brachial plexus were distributed in the anterolateral area. These results might be useful for preventing residual pain on the anterior shoulder region following an injection for the relief of shoulder pain.
https://ift.tt/2F35NT6
Modulating Survivin as a Radioresistant Factor, Caspase-3, and Apoptosis by Omega-3 Docosahexaenoic Acid Sensitizes Mutant-p53 Colorectal Cancer Cells to γ-Irradiation
Cancer Biotherapy and Radiopharmaceuticals, Volume 33, Issue 9, Page 387-395, November 2018.
https://ift.tt/2QiUHe8
Hepatoprotective potential of aqueous extract of Allium eriophyllum Boiss in high-fat diet-induced fatty liver diseases
Abstract
In recent years, Iranian traditional medicine has been used to control, prevent, and treat various diseases such as fatty liver. One of these plants is Allium eriophyllum Boiss. In this research, we assessed the potential of aqueous extract of A. eriophyllum in the treatment of fatty liver disease in Wistar male rats. At beginning of the study, a total of 10 rats were selected as the negative control, and 50 rats were treated with a high-fat diet for 4 months. Then, the animals were randomly divided into six subgroups, including negative healthy control, untreated negative control, and four groups receiving the aqueous extract of A. eriophyllum at 25, 50, 100, and 200 mg/kg concentrations. After 2 months, the rats were sacrificed, and blood and liver samples were collected. The data were analyzed by SPSS 21 software. All groups of A. eriophyllum (especially A200) could significantly (p ≤ 0.05) decrease the raised weights of body and liver and the concentrations of ALP, AST, ALT, GGT, cholesterol, LDL, triglyceride, total and conjugated bilirubin, glucose, and GR and increase the concentrations of HDL, total protein, albumin, SOD, CAT, and GPx as compared to the untreated group. Also, A. eriophyllum (especially A200) decreased the degree of hepatic steatosis as compared to the untreated group. In finally, it appears that the aqueous extract of A. eriophyllum can treat the fatty liver disease in rats.
https://ift.tt/2SPngBy
A de Novo EDA-Variant in a Litter of Shorthaired Standard Dachshunds with X-Linked Hypohidrotic Ectodermal Dysplasia
In this study, we present a detailed phenotype description and genetic elucidation of the first case of X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund. This condition is characterized by partial congenital hypotrichosis, missing and malformed teeth and a lack of eccrine sweat glands. Clinical signs including dental radiographs and histopathological findings were consistent with ectodermal dysplasia. Pedigree analysis supported an X-recessive mode of inheritance. Whole-genome sequencing of one affected puppy and his dam identified a 1-basepair deletion within the ectodysplasin-A (EDA) gene (CM000039.3:g.54509504delT, c.458delT). Sanger sequencing of further family members confirmed the EDA:c.458delT-variant. Validation in all available family members, 37 unrelated shorthaired standard Dachshunds, 128 further Dachshunds from all other coat and size varieties and samples from 34 dog breeds revealed the EDA:c.458delT-variant to be private for this family. Two heterozygous females showed very mild congenital hypotrichosis but normal dentition. Since the dam is demonstrably the only heterozygous animal in the ancestry of the affected animals, we assume that the EDA:c.458delT-variant arose in the germline of the granddam or in an early embryonic stage of the dam. In conclusion, we detected a very recent de-novo EDA mutation causing X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund.
https://ift.tt/2zrMRHM
Nuclear Transcriptomes of the Seven Neuronal Cell Types That Constitute the Drosophila Mushroom Bodies
The insect mushroom body (MB) is a conserved brain structure that plays key roles in a diverse array of behaviors. The Drosophila melanogaster MB is the primary invertebrate model of neural circuits related to memory formation and storage, and its development, morphology, wiring, and function has been extensively studied. MBs consist of intrinsic Kenyon Cells that are divided into three major neuron classes (, α'/β' and α/β) and 7 cell subtypes (d, m, α'/β'ap, α'/β'm, α/βp, α/βs and α/βc) based on their birth order, morphology, and connectivity. These subtypes play distinct roles in memory processing, however the underlying transcriptional differences are unknown. Here, we used RNA sequencing (RNA-seq) to profile the nuclear transcriptomes of each MB neuronal cell subtypes. We identified 350 MB class- or subtype-specific genes, including the widely used α/β class marker Fas2 and the α'/β' class marker trio. Immunostaining corroborates the RNA-seq measurements at the protein level for several cases. Importantly, our data provide a full accounting of the neurotransmitter receptors, transporters, neurotransmitter biosynthetic enzymes, neuropeptides, and neuropeptide receptors expressed within each of these cell types. This high-quality, cell type-level transcriptome catalog for the Drosophila MB provides a valuable resource for the fly neuroscience community.
https://ift.tt/2SONpAq
iProteinDB: An Integrative Database of Drosophila Post-translational Modifications
Post-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing their stability, interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, most commonly serine, threonine and tyrosine in metazoans. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that any given phosphorylation site might be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites. To facilitate the identification of conserved phosphosites, we generated a large-scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://ift.tt/2KAr9ov), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila. At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus tropicalis, Danio rerio, and Caenorhabditis elegans.
https://ift.tt/2zuKNyI
Effects of Microplate Type and Broth Additives on Microdilution MIC Susceptibility Assays [Analytical Procedures]
The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires media supplemented with Ca2+ and the lipoglycopeptides dalbavancin and oritavancin require Tween-80 to be added to the growth media to prevent depletion of free drug via adsorption to the plastic microplate. In this report we examine systematically the effects of several different plate types on microdilution broth MIC values for a set of antibiotics against Gram-positive and Gram-negative bacteria, both in media alone and in media supplemented with commonly used additives Tween-80, lysed horse blood, and 50% human serum. We observe very significant differences in measured MICs (up to 100-fold) for some lipophilic antibiotics, such as the Gram-positive lipoglycopeptide dalbavancin and the Gram-negative lipopeptide polymyxins, and find that non-specific binding plates can replace the need for surfactant additives. Microtitre plate types and any additives should be specified when reporting broth dilution MIC values as results can vary dramatically for some classes of antibiotics.
https://ift.tt/2quW91L
Rapid Detection of ERG11-Associated Azole Resistance and FKS-Associated Echinocandin Resistance in Candida auris [Mechanisms of Resistance]
Candida auris is an emerging multidrug-resistant yeast that can cause serious invasive infections. Accurate and rapid assessment of antifungal resistance is important for effective patient management. A novel and highly accurate diagnostic platform was established for rapid identification of ERG11 mutations conferring azole resistance and FKS1 mutations associated with echinocandin resistance in C. auris. Using allele-specific molecular beacons and DNA melting curve analysis following asymmetric PCR, a duplex ERG11 assay and a simplex FKS1 HS1 assay were developed to identify the most prominent resistance-associated mutations (Y132F and K143R in ERG11; S639F in FKS1 HS1) within 2 h. Assays were validated by testing a blinded panel of 94 C. auris clinical isolates. The molecular diagnostic results from the assays were 100% concordant with DNA sequencing results. This platform has the potential to overcome the deficiencies of existing in vitro susceptibility-based assays to identify azole and/or echinocandin resistant C. auris, and thus, it holds promise as a surrogate diagnostic method to direct antifungal therapy more effectively.
https://ift.tt/2qv8iDG
Whole genome sequencing for predicting clarithromycin resistance in Mycobacterium abscessus [Susceptibility]
Mycobacterium abscessus is emerging as an important pathogen in chronic lung diseases with concern regarding patient to patient transmission. The recent introduction of routine whole genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterise the genetic determinants of resistance. We conducted a systematic review to catalogue all known resistance determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the erm(41) and rrl genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there was paired genotype/phenotype data. A search for novel resistance determining mutations was conducted using an heuristic algorithm.
The sensitivity of existing knowledge for predicting resistance in clarithromycin was 95% (95% CI 89 - 98%) and the specificity was 66% (95% CI 54 - 76%). Subspecies alone was a poor predictor of resistance to clarithromycin. Eight potential new resistance conferring SNPs were identified. WGS demonstrates probable resistance determining SNPs in regions the NTM-DR line probe cannot detect. These mutations are potentially clinically important as they all occurred in samples predicted to be inducibly resistant, and for which a macrolide would therefore currently be indicated. We were unable to explain all resistance, raising the possibility of the involvement of other as yet unidentified genes.
https://ift.tt/2Qs0KNC
MSH2 gene point mutations are not antifungal resistance markers in Candida glabrata [Mechanisms of Resistance]
The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n=81), subsequent candidemia episodes (n=9), endocarditis (n=2), and in vitro-generated echinocandin-resistant isolates (n=32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro, and patient prognosis. MSH2 gene was sequenced and isolates were genotyped using six microsatellite markers and MLST based on six housekeeping genes. According to EUCAST, isolates causing candidemia (n = 90) were echinocandin susceptible, and four of them were fluconazole resistant (MIC ≥ 64 mg/L). One isolate from the heart valve was resistant to micafungin and anidulafungin (MIC= 2 mg/L and 1 mg/L, respectively). MSH2 gene mutations were present in 44.4% of incident isolates, the most common being V239L. Presence of MSH2 mutations was not correlated with in vitro or in vivo antifungal resistance. Microsatellite and MLST respectively revealed 27 genotypes and 17 sequence types. Fluconazole-resistant isolates were unrelated. Most MSH2 mutations were found in cluster isolates; conversely, some mutations were found in more than one genotype. No clinical differences – including previous antifungal use – were found between patients infected by wild-type MSH2 gene isolates and isolates with any point mutation. The presence of MSH2 gene mutations in C. glabrata isolates causing candidemia is not correlated with specific genotypes, the promotion of antifungal resistance, or the clinical outcome.
https://ift.tt/2qvROv1
Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment [Pharmacology]
WCK 5222 is a novel β-lactam-β-lactam enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative PBP2 and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogens. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in forty-eight subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR 60 to < 90 mL/min), moderate (n = 6; CLCR 30 to < 60 mL/min), severe (n = 6; CLCR < 30 mL/min; not on dialysis), end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR ≥ 90 mL/min). Healthy control subjects, mild and moderate renal impairment subjects received a single 60-min IV infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min IV infusion of WCK 5222, 1.5 g (1 g FEP/0.5 g ZID). Body and renal clearance decreased and plasma half-life (T1/2) and AUC0- (hr*µg/mL) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function.
https://ift.tt/2QiIVQR
Effect of rifampin/isoniazid-containing antituberculosis therapy on efavirenz pharmacokinetics in HIV-infected children aged 3 to 14 years old [Clinical Therapeutics]
We compared efavirenz pharmacokinetic (PK) parameters in children with TB/HIV coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children aged 3 to 14 years old with HIV infection with and without TB were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization recommended antituberculosis drugs dosages were used in the co-infected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated LC/MS/MS assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon Rank-sum test and within group by Signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age-Z-score and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz Cmax, C12h, Cmin and AUC0-24h were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin and AUC0-24h were lower in TB/HIV co-infected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children.
https://ift.tt/2qwJ1sS
Inducible cell fusion permits use of competitive fitness profiling in the human pathogenic fungus Aspergillus fumigatus. [Mechanisms of Action]
Antifungal agents directed against novel therapeutic targets are required for treating invasive, chronic and allergic Aspergillus infections. Competitive fitness profiling technologies have been used in a number of bacterial and yeast systems to identify druggable targets however, development of similar systems in filamentous fungi are complicated by the fact that they undergo cell fusion and heterokaryosis. Here we demonstrate that cell fusion in A. fumigatus under standard culture conditions is not predominately constitutive, as with most ascomycetes, but can be induced by a range of extracellular stressors. Using this knowledge, we have developed a barcode-free genetic profiling system that permits high throughput parallel determination of strain fitness in a collection of diploid A. fumigatus mutants. We show heterozygous null mutants in cyp51A and arf2 have reduced fitness in the presence of Itraconazole and Brefeldin A respectively and a heterozygous null of atp17 is resistant to Brefeldin A.
https://ift.tt/2QmRrOX
Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via Both Non-Obligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus [Antiviral Agents]
Human adenovirus (AdV) can cause fatal disease in immune suppressed individuals, but treatment options are limited - in part because the antiviral cytidine analog, cidofovir (CDV), is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, non-nephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. We have therefore examined the effect of CDVpp on DNA synthesis by a purified AdV5 DNA polymerase (pol). CDVpp was incorporated into nascent DNA strands, and promoted a non-obligate form of chain termination (i.e., AdV5 pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 pol. At elevated concentrations, CDVpp inhibited AdV5 pol in a manner consistent with both chain termination and direct inhibition of pol activity. Finally, a recombinant AdV5 virus was constructed, containing pol mutations (V303I, T87I) that were selected following extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated EC50 for BCV, and 1.9 fold increased EC50 for CDV - thus confirming that viral resistance to BCV and CDV can be attributed to mutations in the viral pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA pol, and that their antiviral activity may occur via both (non-obligate) chain termination and (at high concentration) direct inhibition of AdV5 pol activity.
https://ift.tt/2qv8jaI
Azole resistance reduces susceptibility to the tetrazole antifungal VT-1161 [Experimental Therapeutics]
Tetrazole antifungals designed to target fungal lanosterol 14α-demethylase (LDM) appear effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artefacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6xHis) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely-used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of C. albicans and C. glabrata. VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug.
https://ift.tt/2Qr7b3v
In Vitro Activity of Sulopenem, an Oral Penem, Against Urinary Isolates of Escherichia coli [Susceptibility]
The in vitro activity of sulopenem was assessed against a 2014-2016 collection of 539 urinary isolates of Escherichia coli from Canadian patients using CLSI-defined broth microdilution methodology. A concentration of sulopenem of 0.03 µg/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by non-susceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant (MDR) phenotypes, extended-spectrum β-lactamases (ESBLs), or AmpC β-lactamases.
https://ift.tt/2qwSznO
Characterization of the first OXA-10 natural variant with increased carbapenemase activity [Mechanisms of Resistance]
While carbapenem resistance in Gram-negatives is mainly due to production of efficient carbapenemases, β-lactamases with narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10 type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study two novel OXA-10 variants were identified as the sole carbapenem hydrolyzing enzymes in meropenem resistant Enterobacteria isolated from hospital waste water and found by NGS to express additional β-lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host plasmids. Compared to OXA-10 they both harbor a Thr26Met substitution with OXA-655 also baring leucine instead of valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural blaOXA plasmids and of recombinant clones expressing OXA-10 and the novel variants in isogenic background indicated that OXA-655 is a more efficient carbapenemase. The carbapenemase activity of OXA-655 is due to the Val117Leu substitution as shown by steady state kinetic experiments where the kcat of meropenem hydrolysis was increased 4-fold. In contrast, OXA-655 has no activity towards oxyimino β-lactams while its catalytic efficiency against oxacillin is significantly reduced. Moreover, the Val117Leu variant is more efficient against temocillin and cefoxitin. Molecular dynamics indicated that Val117Leu affects the 117-Leu155 interaction leading to structural shifts in the active site that may alter carbapenem alignment. The evolutionary potential of OXA-10 enzymes towards carbapenem hydrolysis combined with their spread by promiscuous plasmids indicates that they may pose a future clinical threat.
https://ift.tt/2QnsaUK
Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-lactamase Inhibitor, in Combination with Meropenem [Experimental Therapeutics]
Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 – 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model.
https://ift.tt/2qv3D4A
Daptomycin resistance and tolerance due to loss-of-function in Staphylococcus aureus dsp1 and asp23 [Mechanisms of Resistance]
Lipopeptide daptomycin is a last line cell membrane-targeting antibiotic to treat multidrug-resistant Staphylococcus aureus. Alarmingly, daptomycin-resistant S. aureus isolates have emerged. The mechanisms underlying daptomycin resistance are diverse, share similarities with resistance to cationic antimicrobial peptides and other lipopeptides, but remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in ST8 S. aureus HG003. Insertions in conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23). Markerless loss of function mutants were then generated for comparison. All transposon mutants and knockout strains exhibited increased daptomycin resistance compared to wild type and complemented strains. Null and transposon insertion mutants also exhibited increased resistance to cationic antimicrobial peptides. Interestingly, dsp1 also showed increased resistance to vancomycin, a cell wall targeting drug with a different mode of action. Null mutations in both dsp1 and asp23 displayed increased tolerance as reflected by reduced killing to both daptomycin and vancomycin, as well as an increased tolerance to surfactant (Triton X-100). Neither mutant exhibited increased resistance to lysostaphin, a cell wall targeting endopeptidase. These findings identified two genes core to the S. aureus species, that make previously uncharacterized contributions to antimicrobial resistance and tolerance in S. aureus.
https://ift.tt/2QlGwVv
Rutin attenuates vancomycin-induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats [Pharmacology]
Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment of serious infections caused by multi-resistant Gram-positive bacteria. This study investigated the renal protective activity of rutin in a rat model of VCM-induced kidney injury in male Wistar rats. VCM intraperitoneally at 200 mg/kg twice daily for 7 successive days resulted in significant elevation of blood urea nitrogen and creatinine as well as urinary N-acetyl-β-D-glucosaminidase. Co-administration of VCM with oral rutin at 150 mg/kg significantly reduced these markers of kidney damage. Rutin also significantly attenuated VCM-induced oxidative stress, inflammatory cell infiltration, apoptosis and decreased IL-1β and TNF-α levels (all P<0.05 or 0.01) in kidneys. Renal recovery from VCM injury was achieved by rutin through increases in Nrf2 and HO-1 and a decrease in NF-B expression. Our results demonstrated a protective effect of rutin on VCM-induced kidney injury through suppression of oxidative stress, apoptosis and down regulation of the inflammatory response. This study highlights a role for oral rutin as an effective intervention to ameliorate nephrotoxicity in patients undergoing VCM therapy.
https://ift.tt/2qxNc7P
Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log-phase, Acid-phase and Non-Replicating-Persister (NRP)-phase in an in vitro Assay [Experimental Therapeutics]
Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis (M. tuberculosis). However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF towards killing of M. tuberculosis in Logarithmic growth phase (Log-phase), Acid-phase and Non-Replicating Persister phase (NRP-phase). Respective in vitro data generated for H37Rv and 18b strains, was evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco was used to characterize the nature of interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis in Acid-phase (α = 5.56e–8 with 95% CI = -0.278 to 0.278 and α = 0.408; 95% CI = 0.105 to 0.711), NRP-phase (α = 0.625 with 95% CI =-0.556 to 1.81 and α = 2.92 with 95% CI = 0.215 to 5.63), and Log-phase organisms (α = 1.57e–6 with 95% CI = -0.930 to 0.930 and α = 1.83e–6 with 95% CI= -0.929 and 0.929), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.
https://ift.tt/2QiE56g
Genetic correlation of antibiotic susceptibility and resistance genotyping for Mycobacterium abscessus group [Mechanisms of Resistance]
Treatment efficacy of Mycobacterium abscessus infections depends on bacterial genotype. Here the relationship between genotype, as determined using sequence analysis, and antibiotic resistance phenotype was analyzed. The results demonstrate that Mycobacterium abscessus genotype characteristics, including erm(41) sequevar, and mutations of rrl and rrs, are predictive of clarithromycin and amikacin resistance.
https://ift.tt/2qwVEUW
Majority of Internists Still Have Financial Ties to Industry
MONDAY, Nov. 5, 2018 -- A majority of internists still report financial ties to industry, according to a study published online Oct. 5 in the Journal of General Internal Medicine. Aaron S. Kesselheim, M.D., J.D., from Brigham and Women's Hospital in...
https://ift.tt/2qvKOyf
Characteristics of Black AMI Patients Impact Mortality Rate
MONDAY, Nov. 5, 2018 -- For patients with acute myocardial infarction (AMI), mortality rates differ based on characteristics associated with race, according to a study published online Nov. 2 in JAMA Network Open. Garth N. Graham, M.D., M.P.H., from...
https://ift.tt/2quNJrb
The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response
The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response
The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response, Published online: 06 November 2018; doi:10.1038/s41416-018-0238-z
The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib responsehttps://ift.tt/2SMwcYh
FDA Issues Draft Guidance on MRD Testing [News in Brief]
Agency aims to help drug sponsors incorporate low-level tumor burden assessments into blood cancer trials.
https://ift.tt/2zvqBNj
Surgery Restores Boy's Ability to Walk Post-Acute Flaccid Myelitis
MONDAY, Nov. 5, 2018 -- A first-of-its-kind surgery has restored the ability to walk in a boy paralyzed by acute flaccid myelitis (AFM). Brandon Noblitt was struck by the disease in 2016 and could no longer walk. He was eventually seen by Amy Moore,...
https://ift.tt/2QrS6i8
Pediatric Anesthesia Does Not Affect Development Outcomes
MONDAY, Nov. 5, 2018 -- Young children who have surgical procedures that require general anesthesia do not have an increased risk for adverse child development outcomes, according to a study published online Nov. 5 in JAMA Pediatrics. James D....
https://ift.tt/2QiwcOc
Poll: Patients, Caregivers Worry About Cost of Cancer Care
MONDAY, Nov. 5, 2018 -- In addition to fear of pain and suffering, Americans worry about cancer-related expenses, according to the results of the American Society of Clinical Oncology (ASCO) 2018 National Cancer Opinion Survey. The Harris Poll...
https://ift.tt/2qwOjVo
Divergent Long-Term Detection Rates of Proximal and Distal Advanced Neoplasia in Fecal Immunochemical Test Screening Programs A Retrospective Cohort Study
https://ift.tt/2PdGNgD
Kidney Damage Biomarkers and Incident Chronic Kidney Disease During Blood Pressure Reduction A Case–Control Study
https://ift.tt/2EEUJLY
Clinical Outcomes Associated With Sickle Cell Trait A Systematic Review
https://ift.tt/2Da9Awb
Receipt of Overlapping Opioid and Benzodiazepine Prescriptions Among Veterans Dually Enrolled in Medicare Part D and the Department of Veterans Affairs A Cross-sectional Study
https://ift.tt/2C6O2j0
Ten Principles for More Conservative, Care-Full Diagnosis
https://ift.tt/2P9ZQIV
Reconciling the Discrepancies in Medicine's Relationship to Medical Marijuana
https://ift.tt/2Pd9CKp
Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. Most cases are diagnosed incidentally in the primary care or hospital setting on the basis of elevated liver enzyme levels or hepatic steatosis on imaging. NAFLD encompasses a wide spectrum: The vast majority of patients have nonprogressive nonalcoholic fatty liver, and a few of those develop progressive liver injury, inflammation, and fibrosis, a condition termed nonalcoholic steatohepatitis. Cardiovascular disease is the leading cause of death in patients with nonalcoholic fatty liver disease. Persons with nonalcoholic steatohepatitis have increased liver-related mortality. In the absence of regulatory agency–approved drugs, lifestyle modification and weight loss remain the cornerstones of NAFLD therapy.
https://ift.tt/2D8LMbx
Disappearance of the National Guideline Clearinghouse: A Huge Loss for Evidence-Based Health Care
https://ift.tt/2NltrKj
The Next Stage of Buprenorphine Care for Opioid Use Disorder
Buprenorphine has been used internationally for the treatment of opioid use disorder (OUD) since the 1990s and has been available in the United States for more than a decade. Initial practice recommendations were intentionally conservative, were based on expert opinion, and were influenced by methadone regulations. Since 2003, the American crisis of OUD has dramatically worsened, and much related empirical research has been undertaken. The findings in several important areas conflict with initial clinical practice that is still prevalent. This article reviews research findings in the following 7 areas: location of buprenorphine induction, combining buprenorphine with a benzodiazepine, relapse during buprenorphine treatment, requirements for counseling, uses of drug testing, use of other substances during buprenorphine treatment, and duration of buprenorphine treatment. For each area, evidence for needed updates and modifications in practice is provided. These modifications will facilitate more successful, evidence-based treatment and care for patients with OUD.
https://ift.tt/2EEUHUm
Swan, Ganz, and Their Catheter: Its Evolution Over the Past Half Century
Jeremy Swan and William Ganz developed their eponymous pulmonary artery (PA) catheter in the 1970s and, in the process, revolutionized measurement of cardiac output, pressures within the left side of the heart, and resistance in systemic and pulmonary circulations. Their invention enabled diagnostic measurements at the bedside and contributed to the birth of critical care medicine; technologic advances preceding the PA catheter generally could not be used at the bedside and required patients to be stable enough to be taken to the catheterization laboratory. Swan and Ganz worked in the same department but had quite dissimilar backgrounds and personalities. This article describes their lives and careers, the state of intensive care before and after their catheter was introduced, and the natural life cycle the PA catheter faced as new, less invasive technology arrived to replace it.
https://ift.tt/2PanswQ
In Screening for Colorectal Cancer, Is the FIT Right for the Right Side of the Colon?
https://ift.tt/2P9BfE1
Time to Change the Way We Approach Opioid Use Disorder: A Challenge to the Status Quo
https://ift.tt/2ECbuaD
Development and prospective external validation of a tool to predict poor recovery at 9 months after acute ankle sprain in UK emergency departments: the SPRAINED prognostic model
Objectives
To develop and externally validate a prognostic model for poor recovery after ankle sprain.
Setting and participantsModel development used secondary data analysis of 584 participants from a UK multicentre randomised clinical trial. External validation used data from 682 participants recruited in 10 UK emergency departments for a prospective observational cohort.
Outcome and analysisPoor recovery was defined as presence of pain, functional difficulty or lack of confidence in the ankle at 9 months after injury. Twenty-three baseline candidate predictors were included together in a multivariable logistic regression model to identify the best predictors of poor recovery. Relationships between continuous variables and the outcome were modelled using fractional polynomials. Regression parameters were combined over 50 imputed data sets using Rubin's rule. To minimise overfitting, regression coefficients were multiplied by a heuristic shrinkage factor and the intercept re-estimated. Incremental value of candidate predictors assessed at 4 weeks after injury was explored using decision curve analysis and the baseline model updated. The final models included predictors selected based on the Akaike information criterion (p<0.157). Model performance was assessed by calibration and discrimination.
ResultsOutcome rate was lower in the development (6.7%) than in the external validation data set (19.9%). Mean age (29.9 and 33.6 years), body mass index (BMI; 26.3 and 27.1 kg/m2), pain when resting (37.8 and 38.5 points) or bearing weight on the ankle (75.4 and 71.3 points) were similar in both data sets. Age, BMI, pain when resting, pain bearing weight, ability to bear weight, days from injury until assessment and injury recurrence were the selected predictors. The baseline model had fair discriminatory ability (C-statistic 0.72; 95% CI 0.66 to 0.79) but poor calibration. The updated model presented better discrimination (C-statistic 0.78; 95% CI 0.72 to 0.84), but equivalent calibration.
ConclusionsThe models include predictors easy to assess clinically and show benefit when compared with not using any model.
Trial registration numberISRCTN12726986; Results.
https://ift.tt/2PHhNhr
BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer
Horm Metab Res
DOI: 10.1055/a-0765-9078
Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Giant Prolactinoma in Men: Clinical Features and Therapeutic Outcomes
Horm Metab Res 2018; 50: 791-796
DOI: 10.1055/a-0752-0741
The aim of the study was to evaluate the clinical features and long-term therapeutic outcome of giant prolactinoma (gPRLoma) in men and to compare them with those of a group of male patients with non-gPRL macroprolactinomas (non-gPRLomas). A retrospective and multicenter study of gPRLomas in men diagnosed in a 20-year period was performed. Clinical data and treatment outcome were registered. The diagnosis of gPRLoma was established when the maximal tumor diameter was ≥40 mm or the tumor had ≥20 mm of suprasellar extension associated to hyperprolactinemia (PRL>1000 ng/ml). Non-gPRLoma was considered when tumor diameter was ≥ 10 mm and<40 mm associated to hyperprolactinemia (PRL≥200 ng/ml). Twenty-three patients with gPRLoma (age 38.3±13.5 years) followed for at least 3 months (follow-up 87.1±60.5 months, range 3–211 months) were evaluated. A group of 42 patients with non-gPRLoma (age 42±16.6 years; NS; follow-up 89±65.9 months, range 3–222 months; NS) served as a control group. More than half (56.5%) of the gPRLoma patients were younger than 40 years at diagnosis. Visual disturbances were significantly more common in gPRLoma than in non-gPRLoma patients (65.2 vs. 25.6%; p=0.004). Prevalence of hypopituitarism was similar in both groups of patients (73.9% vs. 80.9%; gPRLoma vs non-gPRLoma; NS). Serum PRL concentrations were significantly higher in gPRLoma than in non-gPRLoma patients [median (IR), 3978 ng/ml (1179–9012) vs. 907 ng/ml (428–3119); p<0.001]. Maximum tumor diameter in gPRLomas was 4.8±0.8 cm and 2.4±0.7 cm in non-gPRLoma (p<0.001). All patients were treated with dopamine agonists (DA). Twelve (52.2%) gPRLoma patients and 32 (73.8%) non-gPRLoma patients were treated with DA as monotherapy (p=0.045). Surgery was used in 12 (52.2%) gPRLoma patients and in 12 (28.6%) non-gPRLoma patients (p=0.054). Lastly, radiotherapy was used in 5 (21.7%) gPRLoma patients and in 6 (14.2%) non-gPRLoma patients (NS). At last visit, PRL was similar in both groups of patients [16 ng/ml (4–30) vs. 11 ng/ml (4–25); gPRLomas vs. non-gPRLomas; ns] and tumor size decreased significantly (p<0.001) in both groups of patients. Clinical cure (maintained normoprolactinemia without therapy for>1 year and no radiological evidence of pituitary tumor) was achieved in 2 (8.7%) gPRLoma patients and in 2 (4.8%) non-gPRLoma patients (NS). gPRLomas in men are usually diagnosed at a mean age of 40 years, an age similar to that of non-gPRLomas. The only clinical difference with non-gPRLomas is their greater prevalence of visual disturbances. The therapeutic approaches and tumor outcomes were similar to those obtained in patients with non-gPRLomas. Complete cure in gPRLoma is rare, but similar to that achieved in non-gPRLomas, reached in less than 10% of patients.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Horm Metab Res 2018; 50: 783-790
DOI: 10.1055/a-0752-8462
This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify the effect of melatonin supplementation on glycemic control. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until July 30th, 2018. Two reviewers independently assessed study eligibility, extracted data, and evaluated the risk of bias for included trials. Heterogeneity among included studies was assessed using Cochran's Q test and I-square (I2) statistic. Data were pooled using random-effect models and standardized mean difference (SMD) was considered as the overall effect size. Twelve trials out of 292 selected reports were identified eligible to be included in current meta-analysis. The pooled findings indicated that melatonin supplementation significantly reduced fasting glucose (SMD=–6.34; 95% CI, –12.28, –0.40; p=0.04; I2: 65.0) and increased the quantitative insulin sensitivity check index (QUICKI) (SMD=0.01; 95% CI, 0.00, 0.02; p=0.01; I2: 0.0). However, melatonin administration did not significantly influence insulin levels (SMD=–1.03; 95% CI, –3.82, 1.77; p=0.47; I2: 0.53), homeostasis model assessment of insulin resistance (HOMA-IR) (SMD=–0.34; 95% CI, –1.25, 0.58; p=0.37; I2: 0.37) or HbA1c levels (SMD=–0.22; 95% CI, –0.47, 0.03; p=0.08; I2: 0.0). In summary, the current meta-analysis showed a promising effect of melatonin supplementation on glycemic control through reducing fasting glucose and increasing QUICKI, yet additional prospective studies are recommended, using higher supplementation doses and longer intervention period, to confirm the impact of melatonin on insulin levels, HOMA-IR and HbA1c.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Normocalcemic Primary Hyperparathyroidism: A Comparison with the Hypercalcemic Form in a Tertiary Referral Population
Horm Metab Res 2018; 50: 797-802
DOI: 10.1055/a-0752-4533
Normocalcemic primary hyperparathyroidism (NPHPT) is a formally recognized variant of primary hyperparathyroidism (PHPT), characterized by normal total and ionized serum calcium concentrations and elevated parathyroid hormone (PTH) levels, in the absence of secondary causes for hyperparathyroidism. NPHPT has been studied previously, but data are limited and confounded. We aimed to compare the clinical and biochemical data of normocalcemic and hypercalcemic subjects in a hospital-based population.We retrospectively analysed the medical records of 131 subjects diagnosed with PHPT at the university hospital Brussels (UZ Brussel) between January 1st 2007 and December 31st 2016, including 25 normocalcemic and 106 hypercalcemic subjects.The mean values of age, BMI, sex, serum 25-OH vitamin D levels and urinary phosphate excretion were comparable between both groups. Subjects diagnosed with NPHPT had significantly lower plasma PTH levels, lower urinary calcium excretion and lower serum creatinine levels compared to the hypercalcemic subjects with PHPT. Corresponding eGFR values were higher in the normocalcemic group. Normocalcemic subjects (NPHPT) presented with a high prevalence of nephrolithiasis (36%), fragility fractures (12%) and osteoporosis (25%). Clinical manifestations and BMD measurements revealed no statistically significant differences between both groups.Our data show a relative prevalence of 19% NPHPT in PHPT. NPHPT may present the earliest form of PHPT with an extension in time, but is not an indolent disease state. Normocalcemic subjects should be managed as hypercalcemic subjects with PHPT. Further research regarding the pathophysiology and natural course of NPHPT is required.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Levothyroxine Therapy Achieves Physiological FT3/FT4 Ratios at Higher than Normal TSH Levels: A Novel Justification for T3 Supplementation?
Horm Metab Res 2018; 50: 827-831
DOI: 10.1055/a-0751-0498
In euthyroidism, as thyroid Stimulating hormone (TSH) levels increase, the free triiodothyronine (FT3) to free thyroxine (FT4) ratio increases. The aim of this study was to assess if beyond the euthyroid range of TSH levels FT3/FT4 ratio continues to increase and if levothyroxine treatment reduces this ratio, possibly through TSH suppression. This cross sectional retrospective study included a total of 77 832 patients [age 22.76±15.17 years (4 days to 112 years)] evaluated and treated in community clinics between January 2009 and September 2013. Blood samples drawn in community clinics for which TSH, FT4, FT3, age, and gender were available were included. Tests with TSH below 0.5 IU/l were excluded as were samples taken during pregnancy. The FT3/FT4 ratio continued to increase significantly even with TSH above 50 mIU/l (p for trend<0.001) with an increase of more than 50% over the entire TSH range. With increasing age and female gender, the phenomenon was less prominent (p<0.001). Levothyroxine treated patients had significantly lower FT3/FT4 ratios in comparison to untreated patients up to TSH levels of 5.0 mIU/l. In conclusion, increasing TSH increases FT3/FT4 ratio even with severe hypothyroidism, less so with aging. With levothyroxine therapy, a ratio similar to untreated patients is achieved at TSH of above 5.0 mIU/l. Since T3 suppresses TSH better than T4, administration of T3 would likely normalize the FT3/FT4 ratio at a lower, ostensibly more physiological, TSH level. This could be seen as a rationale for add-on T3 therapy.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Association Between Plasma Concentration of Klotho Protein, Osteocalcin, Leptin, Adiponectin, and Bone Mineral Density in Patients with Chronic Kidney Disease
Horm Metab Res 2018; 50: 816-821
DOI: 10.1055/a-0752-4615
Patients with early-stage chronic kidney disease (CKD) are susceptible to changes in metabolic processes. Partial loss of kidney function leads to homoeostatic disturbances in bone and fatty tissue. The aim of this study was to investigate the association between plasma concentrations of Klotho protein, FGF23, leptin, adiponectin, osteocalcin, and bone mineral density (BMD) in patients with CKD in the pre-dialysis period. The study involved 52 patients with CKD and 23 patients with no kidney disease. In both groups, BMD, body mass index and serum or plasma concentrations of lipids, glucose, creatinine, calcium, phosphorus, parathormone, leptin, adiponectin, osteocalcin, Klotho, and FGF23 were measured. The group with CKD had statistically significant higher concentrations of leptin (p<0.001), parathormone (p<0.001), and osteocalcin (p<0.001) in comparison with the control group. Patients with CKD also had statistically significant lower BMD in the femoral neck in comparison with the control group. Osteocalcin correlated negatively with BMD. The results of our study suggest that elevated osteocalcin is the most sensitive marker of decreased bone mass in patients with CKD. Osteocalcin correlated negatively with BMD and GFR. The loss of bone mass in CKD patients was greatest in the femoral neck.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Central Tolerance Mechanisms to TSHR in Graves’ Disease: Contributions to Understand the Genetic Association
Horm Metab Res
DOI: 10.1055/a-0755-7927
In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Development and Pilot Testing of a Simulation to Study How Physicians Facilitate Surrogate Decision-Making Based on Critically Ill Patients’ Values and Preferences
There are no evidence-based programs to train physicians to facilitate shared decision-making based on incapacitated intensive care unit (ICU) patients' values and preferences.
https://ift.tt/2PbpNYG
The Potential for Troponin to Inform Prognosis in Patients With Stable Coronary Artery Disease
https://ift.tt/2QhqHyZ
Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia A Cohort Study
https://ift.tt/2qt6zih
Elements of a Comprehensive Public Health Response to the Opioid Crisis
https://ift.tt/2qubpf9
The Impact of Time Interval between Extubation and Reintubation on Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants
To explore the relation between time to reintubation and death or bronchopulmonary dysplasia (BPD) in extremely preterm infants.
https://ift.tt/2PJlaUQ
Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm
To evaluate if obesity is associated with increased angiotensin II (Ang II) and decreased angiotensin-(1-7) or Ang-(1-7) in the circulation and urine among adolescents born prematurely.
https://ift.tt/2RxkfEm
Living with Severe Bronchopulmonary Dysplasia—Parental Views of Their Child's Quality of Life
To assess parents' views of their children's health-related quality of life (HRQoL) and the association between neonatal morbidities and HRQoL in children with severe bronchopulmonary dysplasia (BPD) who survived to 18-36 months of corrected age.
https://ift.tt/2RHUIbV
Sampling strategies for approximating patient variability in population‐based finite element studies of total hip replacement
International Journal for Numerical Methods in Biomedical Engineering, Volume 0, Issue ja, -Not available-.
https://ift.tt/2RAGzwK
Retired paramedic writes novel inspired by experiences on the job
Albert Kreitz wrote "Partners for Life," which is based on his experience working as an EMT in Los Angeles
https://ift.tt/2FekvXs
Emergency Reporting to Provide Microsoft Azure Gov-Hosted Fire and EMS Records Management and Prevention Software to All United States Army Bases
Bellingham, WA – Emergency Reporting (ER), the leading cloud-based reporting and records management software (RMS) for Fire and EMS agencies, today announced that in collaboration with E-9 Corporation (E-9), the company has been awarded an enterprise contract with the United States Army. Under the contract, ER will expand its current support of the U.S. Army fire departments to include all...
https://ift.tt/2OslD9g
Non‐invasive ventilation and hypercapnia‐associated symptoms in amyotrophic lateral sclerosis
Acta Neurologica Scandinavica, Volume 0, Issue ja, -Not available-.
https://ift.tt/2OlLKyR
Issue Information
Acta Neurologica Scandinavica, Volume 138, Issue 6, Page 463-465, December 2018.
https://ift.tt/2yOfLT1
Most Meds Affecting Neurotransmitters Not Linked to Autism Risk
MONDAY, Nov. 5, 2018 -- Prenatal exposure to most medications affecting neurotransmitter systems is not associated with estimates of autism spectrum disorder (ASD) risk, according to a study published online Oct. 31 in JAMA Psychiatry. Magdalena...
https://ift.tt/2JEW4B5
AHA: Public Automated External Defibrillators Are Cost-Effective
MONDAY, Nov. 5, 2018 -- Public automated external defibrillators (AEDs) are cost-effective for out-of-hospital cardiac arrest (OHCA) and are associated with better outcomes, according to two studies scheduled to be presented at the annual meeting of...
https://ift.tt/2DlfBpW
Removing Appendix May Lower Risk for Parkinson's Disease
MONDAY, Nov. 5, 2018 -- The normal human appendix seems to contain pathogenic forms of α-synuclein, which may impact the risk for developing Parkinson's disease (PD), according to a study published online Oct. 31 in Science Translational...
https://ift.tt/2JFh7DC
Notes Reflecting Financial Considerations ID'd in ICU
MONDAY, Nov. 5, 2018 -- Among patients in the intensive care unit (ICU), 4.2 percent of admissions have at least one note reflecting financial considerations, according to a study published online Nov. 2 in JAMA Network Open. Deborah D. Gordon,...
https://ift.tt/2Do3858
Abnormalities in Genes Linked to IRSP in Alzheimer's Disease
MONDAY, Nov. 5, 2018 -- Individuals with Alzheimer's disease (AD) have abnormalities and reductions in gene expression in the parahippocampal gyri that map to genes associated with the insulin receptor signaling pathway (IRSP), according to a study...
https://ift.tt/2JFF2mD
Cancer Mortality Up for 2nd-, 3rd-Generation Latino Immigrants
MONDAY, Nov. 5, 2018 -- Second- and third-generation Latino immigrants have an increased risk for cancer mortality compared with first-generation Mexico-born immigrants, according to a study presented at the 11th AACR Conference on The Science of...
https://ift.tt/2DnBoxb
Models Project 79 Percent Drop in Lung CA Mortality by 2065
MONDAY, Nov. 5, 2018 -- Existing tobacco control efforts will continue to reduce lung cancer mortality through 2065, according to a study published online Oct. 9 in the Annals of Internal Medicine. Jihyoun Jeon, Ph.D., from the University of...
https://ift.tt/2JEDQzL
AAP Warns of Harms of Corporal Punishment for Children
MONDAY, Nov. 5, 2018 -- Pediatricians should educate parents about positive and effective discipline strategies for children and emphasize the importance of avoiding corporal punishment, according to a policy statement published online Nov. 5 in...
https://ift.tt/2DnBnJD
AHA: Opioid Use Appears to Up Risk for Atrial Fibrillation
MONDAY, Nov. 5, 2018 -- Opioid use is associated with the risk for developing atrial fibrillation (AF), according to a study scheduled to be presented at the annual meeting of the American Heart Association, held from Nov. 10 to 12 in...
https://ift.tt/2JGR6nw
Older Paternal Age Linked to Adverse Perinatal Outcomes
MONDAY, Nov. 5, 2018 -- Advanced paternal age is associated with adverse infant and maternal outcomes, according to a study published online Oct. 31 in The BMJ. Yash S. Khandwala, M.D., from Stanford University in California, and colleagues...
https://ift.tt/2DprJ9D
Convenient Formulation of 68Ga-BPAMD Patient Dose Using Lyophilized BPAMD Kit and 68Ga Sourced from Different Commercial Generators for Imaging of Skeletal Metastases
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
https://ift.tt/2PdgSWz
Locus and allelic heterogeneity and phenotypic variability in Waardenburg syndrome
Clinical Genetics, Volume 0, Issue ja, -Not available-.
https://ift.tt/2PKfREM
Effect of preoperative biliary drainage on cholestasis‐associated inflammatory and fibrotic gene signatures in perihilar cholangiocarcinoma
BJS, EarlyView.
https://ift.tt/2D4KTQX
Sex differences in national rates of repair of emergency abdominal aortic aneurysm
BJS, EarlyView.
https://ift.tt/2Pc69M8
False positive diagnosis of lymph node metastases in a 34 year old woman with a history of extraskeletal myxoid chondroscarcoma: A root cause analysis
Cancer Cytopathology, EarlyView.
https://ift.tt/2FeBbOy
Alveolar ridge preservation using an open membrane approach for sockets with bone deficiency: A randomized controlled clinical trial
Clinical Implant Dentistry and Related Research, EarlyView.
https://ift.tt/2zsWXYP
Study protocol: Care of Late-Stage Parkinsonism (CLaSP): a longitudinal cohort study
Parkinson's disease (PD) is a chronic progressive disorder leading to increasing disability. While the symptoms and needs of patients in the early stages of their disease are well characterized, little informa...
https://ift.tt/2QlyLPz
Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies
To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease.
https://ift.tt/2qucAeD
Intracranial pressure responsiveness to positive end-expiratory pressure in different respiratory mechanics: a preliminary experimental study in pigs
Respiratory mechanics affects the effect of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP). Respiratory mechanics of the lung and the chest wall was not differentiated in previous studi...
https://ift.tt/2QlXOlB
A panorama of radial nerve pathologies- an imaging diagnosis: a step ahead
Abstract
The radial nerve has a long and tortuous course in the upper limb. Injury to the nerve can occur due to a multitude of causes at many potential sites along its course. The most common site of involvement is in the proximal forearm affecting the posterior interosseous branch while the main branch of the radial nerve is injured in fractures of the humeral shaft. Signs and symptoms of radial neuropathy depend upon the site of injury. Injury to the nerve distal to innervation of triceps brachii results in loss of extensor function with sparing of function of the triceps resulting in the characteristic 'wrist drop'. Injury in the mid-arm is associated with loss of sensation in the dorsolateral aspect of the hand, the dorsal aspect of the radial three-and-a-half digits and in the first web space. Involvement of only the posterior interosseous nerve (PIN) results in weakness of the wrist and digit extensors. Diagnosis relies on clinical examination, electrodiagnostic studies and imaging findings. Plain radiographs are used to identify fracture sites, callus or tumours as cause of compression. Technological advances in ultrasonography have allowed direct visualisation of the involved nerve with assessment of the exact site, extent and type of injury. It yields unmatched information about anatomical details of the nerve. MR imaging adds to soft-tissue details and helps in characterising the lesion. This pictorial review aims to illustrate a wide spectrum of causes of radial neuropathy and emphasises the importance of imaging modalities in diagnosis of neuropathies.
Teaching Points
• Radial nerve injuries are assessed by clinical examination and diagnosed using electrodiagnostic and imaging studies.
• Knowledge of anatomical relations and course of the nerve is necessary to identify the nerve at pre-determined anatomical locations.
• Altered echogenicity and signal intensity, discontinuity of the nerve, focal thickening and cause of compression can be assessed by imaging modalities.
• MR imaging helps in confirmation of the ultrasound findings, differentiating similar appearing lesions and provides additional soft-tissue details.
https://ift.tt/2D5CtJm
Contents: Eur. J. Lipid Sci. Technol. 11∕2018
European Journal of Lipid Science and Technology, Volume 120, Issue 11, November 2018.
https://ift.tt/2Pe2jSE
Cover Picture: Eur. J. Lipid Sci. Technol. 11∕2018
European Journal of Lipid Science and Technology, Volume 120, Issue 11, November 2018.
https://ift.tt/2D4TW4l
Editorial Board: Eur. J. Lipid Sci. Technol. 11∕2018
European Journal of Lipid Science and Technology, Volume 120, Issue 11, November 2018.
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Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.
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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma
Cancer, EarlyView.
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Study finds that cash is effective, but e‐cigarettes are not in helping smokers quit
Cancer, Volume 124, Issue 18, Page 3632-3633, September 15, 2018.
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Issue Information
Cancer, Volume 124, Issue 18, Page 3623-3630, September 15, 2018.
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Survivors of endometrial cancer are more likely to experience cardiovascular problems
Cancer, Volume 124, Issue 18, Page 3633-3633, September 15, 2018.
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American Cancer Society updates its colorectal cancer screening guideline
Cancer, Volume 124, Issue 18, Page 3631-3632, September 15, 2018.
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What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2058-2069, October 2018.
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Molecular genetics of 22q11.2 deletion syndrome
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2070-2081, October 2018.
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Tribute to Our Reviewers
Digestive Endoscopy, Volume 30, Issue 6, Page 814-816, November 2018.
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Cover Image
Digestive Endoscopy, Volume 30, Issue 6, Page i-i, November 2018.
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The 97th Congress of the Japan Gastroenterological Endoscopy Society
Digestive Endoscopy, Volume 30, Issue 6, Page 831-834, November 2018.
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WEO Newsletter
Digestive Endoscopy, Volume 30, Issue 6, Page 835-839, November 2018.
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Issue Information
Digestive Endoscopy, Volume 30, Issue 6, Page 715-717, November 2018.
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Abstract
Digestive Endoscopy, Volume 30, Issue 6, Page 817-830, November 2018.
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Club foot in association with the 22q11.2 deletion syndrome: An observational study
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2135-2139, October 2018.
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The impact of hypocalcemia on full scale IQ in patients with 22q11.2 deletion syndrome
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2167-2171, October 2018.
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Providers Unprepared for Interpreting Unsolicited Genomic Results: Direct‐to‐consumer testing has increased the number of individuals getting genetic testing in the absence of medical concerns yet turning to their providers for interpretation of results
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2051-2052, October 2018.
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Novel Gene‐Editing Technique Cures β‐Thalassemia in Utero: A novel peptide nucleic acid‐based gene–editing technique using a nanoparticle delivery system seemingly cured beta thalassemia in fetal mice
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2052-2053, October 2018.
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Publication schedule for 2018
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2049-2049, October 2018.
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Table of Contents, Volume 176A, Number 10, October 2018
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2045-2048, October 2018.
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Cover Image, Volume 176A, Number 10, October 2018
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page i-i, October 2018.
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22q11.2 deletion syndrome: A tiny piece leading to a big picture
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2055-2057, October 2018.
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In This Issue
American Journal of Medical Genetics Part A, Volume 176, Issue 10, Page 2054-2054, October 2018.
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B Cell‐Mediated Maintenance of Cluster of Differentiation 169–Positive Cells Is Critical for Liver Regeneration
Hepatology, EarlyView.
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Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis
Hepatology, EarlyView.
https://ift.tt/2RB6YKX
Preemptive Activation of the Integrated Stress Response Protects Mice From Diet‐Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction
Hepatology, EarlyView.
https://ift.tt/2PJmZkW
Hydrogen Evolution Reaction: Mechanochemically Assisted Synthesis of a Ru Catalyst for Hydrogen Evolution with Performance Superior to Pt in Both Acidic and Alkaline Media (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
https://ift.tt/2PIM3IF
Surgical and developmental outcomes of corpus callosotomy for West syndrome in patients without MRI lesions
Epilepsia, EarlyView.
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Anomolous Photovoltaics: Anomalous Photovoltaic Effect in Centrosymmetric Ferroelastic BiVO4 (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Stevens‐Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: An analysis of the US Food and Drug Administration Adverse Event Reporting System
Epilepsia, EarlyView.
https://ift.tt/2AOSVMr
Cognitive outcomes following epilepsy in infancy: A longitudinal community‐based study
Epilepsia, EarlyView.
https://ift.tt/2F54J1i
Issue Information–ISSN page
Epilepsia, Volume 59, Issue 11, Page i-vii, November 2018.
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Epilepsia – November 2018 – Announcements
Epilepsia, Volume 59, Issue 11, Page 2164-2165, November 2018.
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Hot water epilepsy and SYN1 variants
Epilepsia, Volume 59, Issue 11, Page 2162-2163, November 2018.
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Contents: (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Perovskite Solar Cells: A Cryogenic Process for Antisolvent‐Free High‐Performance Perovskite Solar Cells (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Aggregation‐Induced Emission: Dynamic Visualization of Stress/Strain Distribution and Fatigue Crack Propagation by an Organic Mechanoresponsive AIE Luminogen (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Purely Organic Phosphorescence: Resonance‐Activated Spin‐Flipping for Efficient Organic Ultralong Room‐Temperature Phosphorescence (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Organic Electronics: Impact of 2‐Ethylhexyl Stereoisomers on the Electrical Performance of Single‐Crystal Field‐Effect Transistors (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Masthead: (Adv. Mater. 44/2018)
Advanced Materials, Volume 30, Issue 44, November 2, 2018.
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Blood Test Shows Promise for Detecting Genetic Changes in Brain Tumors
A liquid biopsy blood test can detect DNA from brain tumors called diffuse midline gliomas, researchers have found. This minimally invasive test could be used to identify and follow molecular changes in children with these highly lethal brain tumors.
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Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma
Purpose: Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. Experimental Design: We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. Results: Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. Conclusions: DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
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Targeting an Autocrine Regulatory Loop in Cancer Stem-Like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer
Purpose: Cancer stem-like cells (CSCs) contribute to bladder cancer (BCa) chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on BCa. Experimental Design: The expression of the epithelial marker OV6 and other markers in human BCa specimens was examined by immunohistochemistry. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- BCa cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and other assays. An orthotopic BCa mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in BCa. Results: Up-regulated OV6 expression positively associated with disease progression and poor prognosis for BCa patients. Compared with OV6- cells, OV6+ BCa cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ BCa CSCs in an orthotopic BCa model. Conclusions: OV6 could be a helpful indicator of disease progression and prognosis for BCa patients, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced BCa.
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Long noncoding RNA LBCS inhibits self-renewal and chemoresistance of bladder cancer stem cells through epigenetic silencing of SOX2
Purpose: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported contribute to these pathological properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA-LBCS has been identified and explored in BCSCs. Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro and in vivo. Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to hnRNPK and EZH2, and serves as a scaffold to induce the formation of this complex to repress SOX2 transcription via mediating histone H3 lysine 27 tri-methylation (H3K27me3). SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. Conclusions: As a novel regulator, lnc-LBCS plays an important tumor suppressor role in BCSCs self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.
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A Combined Nomogram Model to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors
Purpose:To develop and validate a nomogram model combing radiomics features and clinical characteristics to preoperatively differentiate Grade1 and Grade2/3 tumors in patients with pancreatic neuroendocrine tumors (pNETs). Experimental Design:A total of 137 patients who underwent contrast-enhanced CT from two hospitals were included in this study. The patients from the second hospital (n=51) were selected as an independent validation set. The arterial phase in contrast-enhanced CT was selected for radiomics feature extraction. The Mann-Whitney U test and LASSO regression were applied for feature selection and radiomics signature construction. A combined nomogram model was developed by incorporating the radiomics signature with clinical factors. The association between the nomogram model and the Ki-67 index and rate of nuclear mitosis were also investigated respectively. The utility of the proposed model was evaluated using the ROC, area under ROC curve(AUC), calibration curve and decision curve analysis(DCA). The Kaplan-Meier(KM) analysis was employed for survival analysis. Results: An eight-feature-combined radiomics signature was constructed as a tumor grade predictor. The nomogram model combining the radiomics signature with clinical stage showed the best performance (training set: AUC=0.907; validation set: AUC=0.891). The calibration curve and DCA demonstrated the clinical usefulness of the proposed nomogram. A significant correlation was observed between the developed nomogram and Ki-67 index and rate of nuclear mitosis, respectively. The KM analysis showed a significant difference between the survival of predicted Grade1 and Grade2/3 groups (p=0.002). Conclusions:The combined nomogram model developed could be useful in differentiating Grade1 and Grade2/3 tumor in patients with pNETs.
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A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma
Introduction: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma, an aggressive pediatric malignancy. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors (CDK4/6i) and biologically relevant combinations for use with CDK4/6i in Ewing. Experimental Design: We performed a genome-scale open-reading frame (ORF) screen in two Ewing cell lines sensitive to CDK4/6i to identify genes conferring resistance. Concurrently, we established resistance to CDK4/6i in a Ewing cell line. Results: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6i treatment. The combination of CDK4/6i and IGF1Ri were synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. Conclusions: Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6i in Ewing sarcoma and that dual targeting of CDK4/6 and IGF1R provides a candidate synergistic combination for clinical application in this disease.
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Immunotherapy and hyperprogression: Unwanted outcomes, unclear mechanism.
Hyperprogression (HP) is a recently defined clinical phenomenon in which patients treated with immunotherapy paradoxically exhibit rapid tumor growth. The mechanisms of HP remain ill-defined though recent studies in this issue point to a possible role for Fc receptors in this process.
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Nutritional and anti‐nutritional properties of underutilized Dioscorea spp. tubers grown in Western Ethiopia
Food Science &Nutrition, EarlyView.
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Nutritional value assessment of umufumba: A Rwandan wild edible plant Mondia whytei (Hook. F)
Food Science &Nutrition, EarlyView.
https://ift.tt/2D1Aaa5
Germinated brown rice combined with Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis inhibits colorectal carcinogenesis in rats
Food Science &Nutrition, EarlyView.
https://ift.tt/2PfssQT
Thrombotic microangiopathy associated with Gemcitabine use: presentation and outcome in a national French retrospective cohort
British Journal of Clinical Pharmacology, Volume 0, Issue ja, -Not available-.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
