APRT deficiency: the need for early diagnosis

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder which leads to accumulation of poorly soluble 2,8-dihydroxyadenine in kidneys resulting in nephrolithiasis as well as chronic kidney disease from crystal nephropathy. This report describes a 55-year-old previously fit man who presented with shortness of breath and the investigative pathway that eventually led to a diagnosis of APRT deficiency. Early diagnosis has aided in timely institution of allopurinol, thereby improving his renal function and possibility of weaning off renal replacement therapy. Genetic testing has enabled early identification of other family members at risk and prevention of renal failure by commencing xanthine oxidoreductase (XOR) inhibitors. The issues surrounding kidney donation by a member of this family are also discussed. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition, complications of which can be easily prevented by early institution of XOR inhibitor therapy.

https://ift.tt/2EIgmep

Congenital hypoplasia of depressor anguli oris muscle (CHDAOM): an uncommon cause of asymmetric crying facies in childhood

Description 

A 2-year-old developmentally normal girl presented to us with a history of deviation of angle of mouth to right only during crying, persisting from neonatal period. She was born at term by normal vaginal delivery to a primigravida mother with a birth weight of 2.2 kg and smooth perinatal transition. Parents noticed asymmetry of face from neonatal period visible only during crying, which disappeared when she was consoled, without any drooling, regurgitation of feeds or poor sucking. There is no history suggestive of any other neurological or systemic abnormality in index case or in family.

Local examination revealed thinning of lower lip near left angle of mouth on palpation. There was no facial asymmetry while the child was calm (figure 1A), however, on crying there was deviation of the angle of mouth downwards and towards right side (figure 1B). There was no evidence of hypoplasia...

https://ift.tt/2OMfHgk

Dynamics of PAR proteins explain the oscillation and ratcheting mechanisms in dorsal closure

We present a vertex-based model for Drosophila dorsal closure that predicts the mechanics of cell oscillation and contraction from the dynamics of the PAR proteins. Based on experimental observations of how aPKC, Par-6 and Bazooka translocate from the circumference of the apical surface to the medial domain, and how they interact with each other and ultimately regulate the apicomedial actomyosin, we formulate a system of differential equations that capture the key features of dorsal closure, including distinctive behaviors in its early, slow and fast phases.

https://ift.tt/2AoO0BE

The Impact of Technology on Surgery: The Future Is Unwritten

No abstract available

https://ift.tt/2yAaRrD

Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar a...

https://ift.tt/2OJ8FsN

Decompressive craniectomy for herpes simplex encephalitis complicated by frank intracerebral hemorrhage: a case report and review of the literature

Herpes simplex encephalitis is the most common type of sporadic encephalitis worldwide. Frank intracerebral hemorrhage complicating the disease course in herpes simplex encephalitis patients is rare, especiall...

https://ift.tt/2O2DinX

Facile Engineering of Long‐Term Culturable Ex Vivo Vascularized Tissues Using Biologically Derived Matrices

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2Se8kg4

Regressing grasping using force myography: an exploratory study

Partial hand amputation forms more than 90% of all upper limb amputations. This amputation has a notable effect on the amputee's life. To improve the quality of life for partial hand amputees different prosthe...

https://ift.tt/2z2QELk

Semivariogram and Semimadogram functions as descriptors for AMD diagnosis on SD-OCT topographic maps using Support Vector Machine

Age-related macular degeneration (AMD) is a degenerative ocular disease that develops by the formation of drusen in the macula region leading to blindness. This condition can be detected automatically by autom...

https://ift.tt/2SbR3E1

Cancers, Vol. 10, Pages 396: Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells

Cancers, Vol. 10, Pages 396: Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells

Cancers doi: 10.3390/cancers10110396

Authors: Lukasz Skalniak Justyna Kocik Justyna Polak Anna Skalniak Monika Rak Agnieszka Wolnicka-Glubisz Tad A. Holak

The protein p53 protects the organism against carcinogenic events by the induction of cell cycle arrest and DNA repair program upon DNA damage. Virtually all cancers inactivate p53 either by mutations/deletions of the TP53 gene or by boosting negative regulation of p53 activity. The overexpression of MDM2 protein is one of the most common mechanisms utilized by p53wt cancers to keep p53 inactive. Inhibition of MDM2 action by its antagonists has proved its anticancer potential in vitro and is now tested in clinical trials. However, the prolonged treatment of p53wt cells with MDM2 antagonists leads to the development of secondary resistance, as shown first for Nutlin-3a, and later for three other small molecules. In the present study, we show that secondary resistance occurs also after treatment of p53wt cells with idasanutlin (RG7388, RO5503781), which is the only MDM2 antagonist that has passed phase II and entered phase III clinical trials, so far. Idasanutlin strongly activates p53, as evidenced by the induction of p21 expression and potent cell cycle arrest in all the three cell lines tested, i.e., MCF-7, U-2 OS, and SJSA-1. Notably, apoptosis was induced only in SJSA-1 cells, while MCF-7 and U-2 OS cells were able to restore the proliferation upon the removal of idasanutlin. Moreover, idasanutlin-treated U-2 OS cells could be cultured for long time periods in the presence of the drug. This prolonged treatment led to the generation of p53-mutated resistant cell populations. This resistance was generated de novo, as evidenced by the utilization of monoclonal U-2 OS subpopulations. Thus, although idasanutlin presents much improved activities compared to its precursor, it displays the similar weaknesses, which are limited elimination of cancer cells and the generation of p53-mutated drug-resistant subpopulations.

https://ift.tt/2SbQNVw

A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families

Abstract

Background

Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.

Methods

Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.

Results

A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.

Conclusion

Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.

https://ift.tt/2PRvtmT

Oxalate content of raw, wok‐fried, and juice made from bitter gourd fruits

Food Science &Nutrition, EarlyView.


https://ift.tt/2JclbLu

Protocol, rationale and design of SELPHI: a randomised controlled trial assessing whether offering free HIV self-testing kits via the internet increases the rate of HIV diagnosis

Among men who have sex with men (MSM) in the UK, an estimated 28% have never tested for HIV and only 27% of those at higher risk test at least every 6 months. HIV self-testing (HIVST), where the person takes t...

https://ift.tt/2SgDdR5

Outcome of untreated lung nodules with histological but no microbiological evidence of tuberculosis

The outcome of lung nodule(s) with histopathological findings suggestive of tuberculosis (TB) but lack of microbiologic confirmation remains unclear. Whether these patients require anti-TB treatment remains un...

https://ift.tt/2z2Gn1I

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in Triple-Negative Breast Cancer Patient

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2EPUA8G

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer, Published online: 24 October 2018; doi:10.1038/s41416-018-0210-y

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

https://ift.tt/2PSUYUM

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy, Published online: 24 October 2018; doi:10.1038/s41416-018-0271-y

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

https://ift.tt/2PYNVd2

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review, Published online: 24 October 2018; doi:10.1038/s41416-018-0305-5

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review

https://ift.tt/2PpL14p

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer, Published online: 24 October 2018; doi:10.1038/s41416-018-0309-1

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer

https://ift.tt/2PQF5y5

Manual lymphatic drainage adds no further volume reduction to Complete Decongestive Therapy on breast cancer-related lymphoedema: a multicentre, randomised, single-blind trial

Manual lymphatic drainage adds no further volume reduction to Complete Decongestive Therapy on breast cancer-related lymphoedema: a multicentre, randomised, single-blind trial

Manual lymphatic drainage adds no further volume reduction to Complete Decongestive Therapy on breast cancer-related lymphoedema: a multicentre, randomised, single-blind trial, Published online: 24 October 2018; doi:10.1038/s41416-018-0306-4

Manual lymphatic drainage adds no further volume reduction to Complete Decongestive Therapy on breast cancer-related lymphoedema: a multicentre, randomised, single-blind trial

https://ift.tt/2PnGTlq

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the <i>BRCA</i> genes, Published online: 24 October 2018; doi:10.1038/s41416-018-0274-8

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

https://ift.tt/2PnGO16

Statin use and risk of contralateral breast cancer: a nationwide cohort study

Statin use and risk of contralateral breast cancer: a nationwide cohort study

Statin use and risk of contralateral breast cancer: a nationwide cohort study, Published online: 24 October 2018; doi:10.1038/s41416-018-0252-1

Statin use and risk of contralateral breast cancer: a nationwide cohort study

https://ift.tt/2PlrS3i

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis, Published online: 24 October 2018; doi:10.1038/s41416-018-0228-1

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

https://ift.tt/2PRpiPE

Elastography can map the local inverse relationship between shear modulus and drug delivery within the pancreatic ductal adenocarcinoma microenvironment

Purpose: High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density, features of the tumor microenvironment known to influence tissue pressure. Experimental Design: Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models (AsPC1 (n=25) and BxPC­3 (n=25)). Results: Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (p < 0.0001). Comparing drug uptake images and shear wave elastographic images with histological images revealed that: (1) drug delivery and shear modulus were inversely related, (2) shear modulus increased linearly with increasing collagen density, and (3) shear modulus was marginally correlated with the local assessment of hyaluronic acid content. Conclusions:These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.

https://ift.tt/2O0wqqZ

Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma

Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness. Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared to UCB, TP53, RB1and ERBB2were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q<0.001), whereas FGFR3and HRASwere more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q<0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1and TP53. Comparison of UCB to corresponding UTUC tumors from the same patient supports their clonal relatedness. Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.

https://ift.tt/2OHnlsy

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Purpose: Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays. Results: WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. While APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank hazard ratio 2.4, p=0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50<2.5nM). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, while it had no effect in an SBA wild-type ERBB2 model. Conclusions: The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbors these alterations.

https://ift.tt/2O1w3MU

Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection

Purpose: Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC. Experimental Design: We measured serum NRDC levels in 98 ICC patients who underwent surgical resectionin two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 ICC patients. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing. Results: High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n=79) and validation (n=19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman's =0.413, p=0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growthin xenografts, andincreased sensitivity to gemcitabine. The gene knockdown of NRDC was also accompanied by significant changes in the expression of several epithelial-mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1,in surgical specimens from ICC patients. Conclusions:Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.

https://ift.tt/2OMhPoD

Leveraging bioorthogonal click chemistry to improve 225Ac-radioimmunotherapy of pancreatic ductal adenocarcinoma

Purpose: Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce non-specific toxicities as compared to conventional radioimmunotherapy (RIT). Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugates evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models. Results: A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g. prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but - importantly - further allowed for the ex vivo monitoring of 225Ac's radioactive daughters redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared to control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce haematotoxicity while maintaining therapeutic effectiveness. Conclusions:The ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.

https://ift.tt/2O3irRk

SMAC mimetic Debio 1143 and ablative radiation therapy synergize to enhance anti-tumor immunity against lung cancer

Purpose: Adaptive anti-tumor immunity following ablative radiation therapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T cell (Treg) infiltrates. We hypothesized treatment with ART and a SMAC mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity. Experimental Design: To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNF-α, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30Gy) with or without anti-CD8, anti-TNF-α, or anti-IFN- antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNF-α, IFN-, and IL-1β and the immunosuppressive IL-10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA Results: ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNF-α, and IFN- with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs. Conclusions: Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNF-α, IFN-, and CD8 + T cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART

https://ift.tt/2AoQu36

Targeting cancer cells and tumor microenvironment in preclinical and clinical models of Hodgkin lymphoma using the dual PI3K{delta}/{gamma} inhibitor RP6530

Purpose: Tumor-associated macrophages (TAMs) and the hyperactivation of phosphoinositide 3-kinase(PI3K)/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma (HL) and affect disease outcome. Since the and isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3K/ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Experimental design: HL cell lines (L-540, KM-H2 and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in HL cell line xenografts. Results: In vitro, RP6530 besides killing and inhibiting the proliferation of HL cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3K/-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator Pyruvate Kinase M2 (PKM2) as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into pro-inflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, HL patients experiencing objective responses (CR and PR) in a phase 1 trial using RP6530 showed a significant inhibition of circulating MDSCs and an average mean reduction in serum TARC levels of 40% (range, 4-76%). Conclusions: Our results support PI3K/ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat HL patients.

https://ift.tt/2CzXonn

Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target

Purpose: Our aim was to identify predictive factors of abiraterone acetate (AA) efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial. Experimental Design:We defined AA response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a Nanostring platform and performed immunohistochemistry (IHC) using tissue microarrays. We assessed AA and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo. Results: Classical IHC apocrine markers including AR, FOXA1, GGT1 and GCDFP15, from patients' tumors allowed identifying AA responders and non-responders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in non-responders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. Based on cell line experiments, AA and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy. Conclusions: This study suggests that apocrine features can be helpful in the identification of AA-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

https://ift.tt/2AoQqQU

Activation of KRAS mediates resistance to targeted therapy in MET ex on 14 mutant non-small cell lung cancer

Purpose: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (MET ex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. Experimental Design: We examined clinical and genomic data from 113 lung cancer patients with MET ex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. Results: Five of 113 patients (4.4%) with MET ex14 had concurrent KRAS G12 mutations, a rate of KRAS co-occurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 MET ex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. Conclusions: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in MET ex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.

https://ift.tt/2CA8JDS

Targeting resistance to targeted therapies: combating a resilient foe

While the advent of third generation therapies have dramatically changed the treatment paradigm for EGFR mutated lung cancer, resistance to these agents inevitably emerges. Understanding resistance mechanisms and their genomic underpinnings is crucial for developing innovative strategies that are capable of meaningfully prolonging patient survival.

https://ift.tt/2Ar0qZT

Mouse models of overexpression reveal distinct oncogenic roles for different type I protein arginine methyltransferases

Protein arginine methyltransferases (PRMTs) are generally not mutated in diseased states, but they are overexpressed in a number of cancers, including breast cancer. To address the possible roles of PRMT overexpression in mammary gland tumorigenesis, we generated Cre-activated PRMT1, CARM1 and PRMT6 overexpression mouse models. These three enzymes are the primary Type I PRMTs and are responsible for the majority of the asymmetric arginine methylation deposited in the cells. Using either a keratin 5-Cre recombinase (K5-Cre) cross or an MMTV-NIC mouse, we investigated the impact of PRMT overexpression alone or in the context of a HER2-driven model of breast cancer, respectively. The overexpression of all three PRMTs induces hyper-branching of the mammary glands and increased Ki-67 staining. When combined with the MMTV-NIC model, these in vivo experiments provided the first genetic evidence implicating elevated levels of these three PRMT in mammary gland tumorigenesis, albeit with variable degrees of tumor promotion and latency. In addition, these mouse models provided valuable tools for exploring the biological roles and molecular mechanisms of PRMT overexpression in the mammary gland. For example, transcriptome analysis of purified mammary epithelial cells isolated from bigenic NIC-PRMT1Tg and NIC-PRMT6Tg mice revealed a deregulated PI3K/AKT pathway. In the future, these PRMTTg lines can be leveraged to investigate the roles of arginine methylation in other tissues and tumor model systems using different tissue-specific Cre crosses, and they can also be used for testing the in vivo efficacy of small molecule inhibitors that target these PRMT.

https://ift.tt/2CYTZzu

Polymer thin film-induced tumor spheroids acquire cancer stem cell-like properties

Although cancer stem cells (CSC) are thought to be responsible for tumor recurrence and resistance to chemotherapy, CSC-related research and drug development have been hampered by the limited supply of diverse, patient-derived CSC. Here we present a functional polymer thin film (PTF) platform that promotes conversion of cancer cells to highly tumorigenic three-dimensional (3D) spheroids without the use of biochemical or genetic manipulations. Culturing various human cancer cells on the specific PTF, poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) (pV4D4), gave rise to numerous multicellular tumor spheroids within 24 hours with high efficiency and reproducibility. Cancer cells in the resulting spheroids showed a significant increase in the expression of CSC-associated genes and acquired increased drug resistance compared with 2D monolayer-cultured controls. These spheroids also exhibited enhanced xenograft tumor-forming ability and metastatic capacity in nude mice. By enabling the generation of tumorigenic spheroids from diverse cancer cells, the surface platform described here harbors the potential to contribute to CSC-related basic research and drug development.

https://ift.tt/2PPhbmz

USPSTF Recommends Screening Women for Partner Violence

TUESDAY, Oct. 23, 2018 -- Clinicians should screen women of reproductive age for intimate partner violence (IPV) and refer women to ongoing support services if necessary, according to a U.S. Preventive Services Task Force (USPSTF) final...

https://ift.tt/2SbqPl0

Thermal Ablation Acceptable for Early Lung Cancer

TUESDAY, Oct. 23, 2018 -- Thermal ablation (TA) is a safe, effective treatment for stage 1 non-small cell lung cancer (NSCLC), according to a study recently published in Radiology. Johannes Uhlig, M.D., from the Yale School of Medicine in New Haven,...

https://ift.tt/2yXGU4Z

White House Unveils New Insurance Option for Small Firms

TUESDAY, Oct. 23, 2018 -- A plan to allow small businesses to use tax-free accounts to provide health coverage for employees was announced today by the Trump administration. The plan would expand health reimbursement arrangements so workers could...

https://ift.tt/2SbMwBy

Preeclampsia Tied to Increased Risk for Vascular Dementia

TUESDAY, Oct. 23, 2018 -- Preeclampsia seems to be associated with an increased risk for dementia, especially vascular dementia, with a stronger correlation for late-onset disease, according to a study published online Oct. 17 in The BMJ. Saima...

https://ift.tt/2z1xbur

A-Fib Patients With Cancer Less Likely to See Cardiologist

TUESDAY, Oct. 23, 2018 -- Atrial fibrillation (AF) patients with cancer are less likely to see a cardiologist and fill prescriptions for anticoagulants, according to a study published in the Oct. 16 issue of the Journal of the American College of...

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Progressive waves of IL-1β release by primary human monocytes via sequential activation of vesicular and gasdermin D-mediated secretory pathways

Progressive waves of IL-1β release by primary human monocytes via sequential activation of vesicular and gasdermin D-mediated secretory pathways

Progressive waves of IL-1β release by primary human monocytes via sequential activation of vesicular and gasdermin D-mediated secretory pathways, Published online: 23 October 2018; doi:10.1038/s41419-018-1121-9

Progressive waves of IL-1β release by primary human monocytes via sequential activation of vesicular and gasdermin D-mediated secretory pathways

https://ift.tt/2OL9UaS

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals, Published online: 23 October 2018; doi:10.1038/s41419-018-1127-3

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals

https://ift.tt/2O1ygYX

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer, Published online: 23 October 2018; doi:10.1038/s41419-018-1126-4

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

https://ift.tt/2OKI92n

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

https://ift.tt/2q5qFPq

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

https://ift.tt/2R8YLO0

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer

https://ift.tt/2q5IGgm

Statin use and risk of contralateral breast cancer: a nationwide cohort study

https://ift.tt/2R8iixX

Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis

https://ift.tt/2q96j86

Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review

https://ift.tt/2PRnl5C

Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma

Although craniospinal irradiation (CSI) is crucial in treating medulloblastoma, clinical medulloblastoma protocols have not been faithfully modeled in a preclinical setting. We used the Small Animal Radiation Research Platform to deliver fully-fractionated, image-guided CSI to mice bearing patient-derived orthotopic xenografts of very-high-risk medulloblastoma. The preclinical application of this protocol was well tolerated, significantly prolonged survival, and yielded differential dose responses across medulloblastoma subgroups.

https://ift.tt/2PRrfeO

Contemporary Guidelines in Whole-Breast Irradiation: an Alternative Perspective

The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on whole-breast radiation therapy for patients with early-stage invasive breast cancer and ductal carcinoma in situ. This commentary points out areas where we believe the data are too limited to make definitive recommendations and where alternative approaches are also supported by evidence.

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Not all NAFLD patients are the same: We need to find a personalized therapeutic approach

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Manual lymphatic drainage adds no further volume reduction to Complete Decongestive Therapy on breast cancer-related lymphoedema: a multicentre, randomised, single-blind trial

https://ift.tt/2PSEAne

The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer

https://ift.tt/2D2a9Z6

Large Cell Neuroendocrine Carcinoma of the Cervix with Sequential Metastasis to Different Sites: A Case Report

Neuroendocrine carcinoma of the cervix is rare, and prognosis is very poor. Because of its rarity, effective treatment of neuroendocrine carcinoma of the cervix has not been established. It has distinct patterns of metastasis, but can be successfully treated with radical surgery and platinum-based chemotherapy. We report a 50-year-old woman who was diagnosed with large cell neuroendocrine carcinoma of the cervix and underwent radical surgery followed by adjuvant chemoradiation therapy. She experienced recurrence several times and to different sites, with sequential metastasis to the lung, breast, and retroperitoneum, but nevertheless survived more than 5 years.
Case Rep Oncol 2018;11:665–670

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Breast Cancer Metastasis in the Skin with Hyperkeratotic Pigmentation Caused by Melanocyte Colonization

Pigmented breast cancer in the skin caused by nonneoplastic melanocytes of epidermal origin is a rare condition of metastasis from breast cancer, but the pathogenesis of this phenomenon is almost unknown. In this report, we describe a case of breast cancer metastasis in the skin with prominent hyperkeratotic pigmentation caused by nonneoplastic melanocyte colonization. Immunohistochemical staining revealed that the metastatic tumor cells produced IL-23, which is reported not only to induce IL-17 but also to inhibit cell apoptosis in breast cancer cells, which affects tumor progression. In addition to IL-23, substantial numbers of IL-17-producing cells were detected at the peritumoral area, suggesting that IL-17 might induce not only melanogenesis but also keratinocyte proliferation and tumorigenesis. Our report suggests possible mechanisms of hyperkeratotic pigmentation of breast cancer metastasis in the skin.
Case Rep Oncol 2018;11:660–664

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Role of interventional inflammatory bowel disease in the era of biological therapy: a position statement from the Global Interventional IBD Group

Interventional (or therapeutic) inflammatory bowel disease (IBD) endoscopy has an expanding role in the treatment of disease and surgical adverse events. Endoscopic therapy has been explored and used in the management of strictures, fistulas/abscesses, colitis-associated neoplasia, post-surgical acute or chronic leaks, and obstructions. The endoscopic therapeutic modalities include balloon dilation, stricturotomy, stent placement, fistulotomy, fistula injection and clipping, sinusotomy, endoscopic mucosal resection, and endoscopic submucosal dissection.

https://ift.tt/2Ao3DZW

Diagnostic Yield and Miss Rate of EndoRings in an Organized Colorectal Cancer Screening Program: the SMART (Study Methodology for ADR-Related Technology) Trial

The add-on EndoRings has been claimed to improve adenoma detection at colonoscopy, but available data are inconsistent. When testing a new technology, parallel and crossover methodologies measure different outcomes, leaving uncertainty on their correspondence. Aims of this study were to compare the diagnostic yield and miss rate of the EndoRings for colorectal neoplasia.

https://ift.tt/2CCeTnj

Panchromoendoscopy Increases Detection of Polyps in Patients With Serrated Polyposis Syndrome

SPS, characterized by multiple and/or large proximal serrated lesions, increases risk of CRC. Chromoendoscopy increases detection of adenomas and serrated lesions in average-risk populations. International guidelines and expert groups recommend the use of chromoendoscopy for SPS patient surveillance, despite little evidence. In a randomized controlled study of patients with SPS, indigo carmine panchromoendoscopy detected 2-fold more serrated lesions than high-definition white-light endoscopy during surveillance colonoscopy of cleared colon. Chromoendoscopy should be considered as the standard of care for SPS surveillance, but studies are needed to determine the effects of this strategy on incidence of advanced neoplasia.

https://ift.tt/2Sbyb8c

Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: A Systematic Review and Meta-Analysis

Gastric reflux could lead to chronic mucosal inflammation and contribute to development of laryngeal malignancies, although there is controversy over this association. We performed a systematic review and meta-analysis to assess this relationship and determine risk of laryngeal malignancy in patients with reflux disease.

https://ift.tt/2yX02jG

Lifestyle Habits, Dietary Factors, and the Metabolically Unhealthy Obese Phenotype in Youth

To determine whether lifestyle habits and dietary factors at age 8-10 years predict the development of metabolically unhealthy obesity 2 years later among children who were previously metabolically healthy obese.

https://ift.tt/2OK2Rzu

Social Risk Factors Impact Hospital Readmission and Outpatient Appointment Adherence for Children with Congenital Heart Disease

To examine the relations of individual and cumulative social risk factors to hospitalization outcomes and adherence to outpatient cardiology appointments within the first 2 years of life for congenital heart disease survivors.

https://ift.tt/2OLQ1kc

Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges

To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases.

https://ift.tt/2O02w6w

Pediatricians and long-acting reversible contraceptive counseling and provision

We agree with the assertion of Trope et al1 that long acting reversible contraception (LARC) counseling and insertion is an important part of the practice of pediatric medicine and should be prioritized in pediatric residency training. As they noted, the American Academy of Pediatrics (AAP) recommends LARC as first-line contraceptive options for adolescents. However, this recommendation, found in the AAP's Policy Statement, was published in September 2014.2 Pediatricians' contraceptive knowledge deficits and lack of contraceptive counseling practices discussed by Trope et al stem from survey data collected prior to the publication of the Policy Statement.

https://ift.tt/2O02wU4

FDA Launches Global Operation to Crack Down on Websites Selling Illegal, Potentially Dangerous Drugs; Including Opioids

October 23, 2018 -- The U.S. Food and Drug Administration, in partnership with international regulatory and law enforcement agencies, acted this week to target 465 websites that illegally sell potentially dangerous, unapproved versions of opioid,...

https://ift.tt/2SdDDY3

Light-harvesting protein Lhcx3 is essential for high light acclimation of Phaeodactylum tricornutum

The light-harvesting protein complexes (Lhc) play key roles in the processes of light absorption and protection in diatoms. However, different Lhc protein carries out distinct function in photosynthesis. For n...

https://ift.tt/2CyH7iG

High-resolution Patterned Biofilm Deposition Using pDawn-Ag43

We demonstrate a method for depositing Escherichia coli bacterial biofilms in arbitrary spatial patterns with a high resolution using optical stimulation of a genetically encoded surface-adhesion construct.

https://ift.tt/2yvtrSJ

In Vitro Method to Control Concentrations of Halogenated Gases in Cultured Alveolar Epithelial Cells

We describe an easy protocol specifically designed to reach precise and controlled concentrations of sevoflurane or isoflurane in vitro in order to improve our understanding of mechanisms involved in the epithelial lung injury and to test novel therapies for acute respiratory distress syndrome.

https://ift.tt/2JaU9UJ

Beyond borders: Emergency response services and MCIs

What the U.S. can learn from other countries about emergency response to terrorist events

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Changing the political climate to recognize first responders

First responders often feel underappreciated in the public sector

https://ift.tt/2OFWey1

Changing the political climate to recognize first responders

First responders often feel underappreciated in the public sector

https://ift.tt/2R78AvK

Study Improves the Quality of Biopsy Specimens for Cancer Research

An NCI-led team of researchers has developed and tested recommendations for improving the quality of biopsy specimens collected from patients participating in cancer clinical trials.

https://ift.tt/2JcXbIi

Development and evaluation of a rapid analysis for HEPES determination in 68 Ga-radiotracers

Abstract

Background

HEPES is a favorable buffer for ⁶⁸Ga-complexations in radiochemical laboratories. The drawback of this buffer is its prescribed limit of 200 μg per recommended application volume in the final formulation. Currently, a TLC test according to the European Pharmacopoeia (Ph. Eur.) has to be performed for quantification, but this analysis suffers from low reliability and reproducibility and is based on a subjective, semi-quantitative visual evaluation. In this study, the TLC method according to the Ph. Eur. and two literature-known HPLC assays for HEPES quantification were evaluated. Additionally, the development of an improved TLC method was performed.

Results

The assay according to Antunes et al. provided a reasonable quantification of HEPES using HPLC. Additionally, a reliable and conclusive TLC method was developed, which facilitates quantitative analysis by means of a pixel-based evaluation. A comparison of those two methods with the Ph. Eur. TLC assay pinpoints the superiority of the HPLC as well as the new TLC assay. Furthermore, evaluation of HEPES contents using both TLC assays by 28 subjects supported the conclusion that the newly developed TLC method is clearly favorable.

Conclusion

The TLC method according to the Ph. Eur. provides unsatisfactory results in terms of conclusiveness and reproducibility. In contrast, a reported HPLC assay showed valid results, with the drawback of high technical effort. An optimized alternative is provided by the improved TLC method described in this work that results in reliable outcomes and additionally offers quantitative analysis.

https://ift.tt/2D03Nta

End tidal carbon dioxide monitoring in acute asthma: a prospective pilot study in emergency department patients

Background The peak expiratory flow rate (PEFR) is the gold standard for monitoring asthmatic patients. However, its measurement requires understanding and active participation. End tidal carbon dioxide (EtCO2) may be considered an accurate surrogate for PaCO2, a severity marker in acute asthma. We studied the use of EtCO2 as a monitoring tool in acute asthma. Patients and methods This was a prospective study that included consecutive patients admitted to our emergency department for acute asthma exacerbation. Data were collected at first medical contact (T0) and after 1 h of treatment (T60). The primary endpoint was the change in EtCO2; the secondary endpoints included changes in the EtCO2Q angle value, plateau T time, and change in EtCO2 values for the patients with a PEFR ratio less than 50% after treatment. Results Fifty-five patients were included and 36 waveforms were analysed. The mean age was 37 years and 26 (47%) were women. The median initial PEFR was 200 [interquartile range (IQR): 150–240]; the median EtCO2 at T0 and T60 was 35 (IQR: 30–38) and 34 (IQR: 29–37). There was no significant change in EtCO2 after treatment. There was no significant change in the Q angle and the T time after treatment. At T60, 20 (36%) patients had a PEFR ratio less than 50%. Change in EtCO2 from T60 to T0 was associated with a PEFR ratio less than 50%. Conclusion After 1 h of treatment, there was no significant change in EtCO2. A decrease in EtCO2 seems to be associated with a higher risk of PEFR ratio less than 50% after treatment. Correspondence to Jennifer Truchot, MD, Hopital Lariboisiere, 75010 Paris, France Tel: +33 149 956 391; fax: +33 149 959 049; e-mail: jennifer.truchot@aphp.fr Received February 26, 2018 Accepted June 24, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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ASCO update 2018: upper gastrointestinal cancer

Summary

Results from studies in upper gastrointestinal cancer presented at the 2018 American Society of Clinical Oncology (ASCO) meeting are promising. Prophylactic treatment of Barrett's esophagus with high proton pump inhibitor therapy plus aspirin showed positive results on death, esophageal adenocarcinoma and dysplasia. Current studies on the treatment of gastric cancer included the following: S‑1 plus docetaxel as postoperative adjuvant chemotherapy in Asian patients, triplet therapy (cisplatin, S1, and docetaxel) in Asian patients, paclitaxel vs. pembrolizumab, and a biomarker study for trastuzumab continuation. Advances in the treatment of pancreatic cancer are likely to be practice changing: combined chemotherapy mFOLFIRINOX clearly improved disease-free survival in patients with resected pancreatic ductal adenocarcinomas. In the palliative setting, the introduction of FOLFIRINOX and gemcitabine/nab-paclitaxel may allow treatment with lower toxicity and allow broader patient selection. In the treatment of cholagiocellular cancer, gemcitabine plus S‑1 was non-inferior to gemcitabine plus cisplatin. Preliminary data in the treatment of neoendocrine tumors with temozolomide plus capecitabine are promising. Finally, the second-line treatment of hepatocellular carcinoma with ramucirumab showed a significant survival benefit.

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High-throughput Measurement of Gut Transit Time Using Larval Zebrafish

The goal of this protocol is to measure the transit time of fluorescently labeled food through the gut of larval zebrafish in a high throughput fashion.

https://ift.tt/2O0MSaS

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Here, we present a protocol for the isolation of healthy and functional primary mouse hepatocytes. Instructions for detecting hepatic nascent protein synthesis by non-radioactive labeling substrate were provided to help understand the mechanisms underlying protein synthesis in the context of energy-metabolism homeostasis in the liver.

https://ift.tt/2OKDIV2

Advance Care Planning Lowers Symptoms in Teens With HIV

TUESDAY, Oct. 23, 2018 -- Family-centered pediatric advance care planning (FACE pACP) is associated with a lower likelihood of symptoms and suffering for adolescents with HIV, according to a study published online Oct. 19 in Pediatrics. Maureen E....

https://ift.tt/2Jb1js2

Unrestricted Diet OK More Than One Day Before Colonoscopy

TUESDAY, Oct. 23, 2018 -- Unrestricted diets are acceptable more than one day before colonoscopy among patients using a split-dose bowel regimen, according to a study published in the October issue of Gastrointestinal Endoscopy. Anna M. Leszczynski,...

https://ift.tt/2JccYqK

Intensive SBP Tx Cuts Kidney Damage Biomarkers in Incident CKD

TUESDAY, Oct. 23, 2018 -- Patients with incident chronic kidney disease (CKD) in the setting of intensive systolic blood pressure (SBP) treatment have decreases rather than increases in kidney damage biomarkers, according to a study published online...

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ACS: Accepting Liver From Older Donor Better Than Waiting

TUESDAY, Oct. 23, 2018 -- Accepting a liver from an older liver donor (OLD) is associated with long-term survival benefit, according to a study presented at the annual meeting of the American College of Surgeons, held from Oct. 21 to 25 in...

https://ift.tt/2JfdVOM

Periodontitis Linked to Higher BP in Adults With Treated HTN

TUESDAY, Oct. 23, 2018 -- For adults with treated hypertension, periodontitis is associated with higher mean systolic blood pressure (BP) and with increased odds of unsuccessful hypertensive treatment, according to a study published online Oct. 22...

https://ift.tt/2yuk0CW

Kids' Sport Participation Tied to Higher Bone Mass in Young Adults

TUESDAY, Oct. 23, 2018 -- Children who are consistent sport participators have greater bone mineral content (BMC) at age 20 years, according to a study published online Oct. 17 in the Journal of Bone and Mineral Research. Joanne A. McVeigh, Ph.D.,...

https://ift.tt/2yukLfg

Neglect Higher in For-Profit Nursing Homes

TUESDAY, Oct. 23, 2018 -- Residents of for-profit nursing homes are more likely to suffer neglect compared with elderly residents living in the community or in not-for-profit facilities, according to a study published online Oct. 9 in...

https://ift.tt/2JdBis2

Policy Denying Coverage for Nonemergent ED Visits Imprecise

TUESDAY, Oct. 23, 2018 -- A policy retrospectively denying insurance coverage if an emergency department discharge diagnosis is determined to be nonemergent is not associated with accurate identification of unnecessary emergency department visits,...

https://ift.tt/2yxtuNK

ACS: Opiate-Free Surgery Feasible for Elective Colectomy

TUESDAY, Oct. 23, 2018 -- Opiate-free surgery is feasible for patients undergoing elective colon resections with anastomosis, with shorter length of stay for patients not receiving narcotics, according to a study presented at the annual meeting of...

https://ift.tt/2Jc2kjL

Inadequate Reimbursement May Mar Diabetes Prevention Program

TUESDAY, Oct. 23, 2018 -- The costs of delivering a new Medicare Diabetes Prevention Program (MDPP) may be higher than the expected reimbursement, according to a study published in the November issue of Medical Care. Natalie D. Ritchie, Ph.D., and...

https://ift.tt/2yupFcl

Salvage radiotherapy with simultaneous integrated boost in non small-cell lung cancer patients with mediastinal relapse after surgery: a pilot study

Abstract

Background

The aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed.

Methods

Fourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m²) was administered to 8 (57.1%) patients.

Results

Five (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036).

Conclusions

Salvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.

https://ift.tt/2AnS5pM

FDG and FMISO PET-guided dose escalation with intensity-modulated radiotherapy in lung cancer

Abstract

Background

Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on ¹⁸FDG and ¹⁸F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy.

Method

Twenty-one NSCLC patients, selected from a prospective phase II trial, had ¹⁸FDG- and ¹⁸F-miso PET/CT before the start of radiotherapy and ¹⁸FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment ¹⁸FDG hotspot (70% of SUV_max) (plan 2), pre-treatment ¹⁸F-miso target (SUV_max > 1.4) (plan 3) and per-treatment ¹⁸FDG residual (40% of SUV_max). (plan 4).

Results

The mean target volumes were 4.8 cc (± 1.1) for ¹⁸FDG hotspot, 38.9 cc (± 14.5) for ¹⁸F-miso and 36.0 cc (± 10.1) for per-treatment ¹⁸FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for ¹⁸FDG hotspot, ¹⁸F-miso and per-treatment ¹⁸FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in ¹⁸FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in ¹⁸F-miso and per-treatment ¹⁸FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to ¹⁸F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for ¹⁸FDG hotspot and per-treatment ¹⁸FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to ¹⁸FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for ¹⁸FDG hotspot and ¹⁸F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios.

Conclusion

Escalated doses can be selectively planned in NSCLC target volumes delineated on ¹⁸FDG and ¹⁸F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials.

Trial registration

(RTEP5, NCT01576796, registered 15 june 2012)

https://ift.tt/2CzTHOw

Expression of calcium pumps is differentially regulated by histone deacetylase inhibitors and estrogen receptor alpha in breast cancer cells

Abstract

Background

Remodeling of Ca²⁺ signaling is an important step in cancer progression, and altered expression of members of the Ca²⁺ signaling toolkit including the plasma membrane Ca²⁺ ATPases (PMCA proteins encoded by ATP2B genes) is common in tumors.

Methods

In this study PMCAs were examined in breast cancer datasets and in a variety of breast cancer cell lines representing different subtypes. We investigated how estrogen receptor alpha (ER-α) and histone deacetylase (HDAC) inhibitors regulate the expression of these pumps.

Results

Three distinct datasets displayed significantly lower ATP2B4 mRNA expression in invasive breast cancer tissue samples compared to normal breast tissue, whereas the expression of ATP2B1 and ATP2B2 was not altered. Studying the protein expression profiles of Ca²⁺ pumps in a variety of breast cancer cell lines revealed low PMCA4b expression in the ER-α positive cells, and its marked upregulation upon HDAC inhibitor treatments. PMCA4b expression was also positively regulated by the ER-α pathway in MCF-7 cells that led to enhanced Ca²⁺ extrusion capacity in response to 17β-estradiol (E2) treatment. E2-induced PMCA4b expression was further augmented by HDAC inhibitors. Surprisingly, E2 did not affect the expression of PMCA4b in other ER-α positive cells ZR-75-1, T-47D and BT-474. These findings were in good accordance with ChIP-seq data analysis that revealed an ER-α binding site in the ATP2B4 gene in MCF-7 cells but not in other ER-α positive tumor cells. In the triple negative cells PMCA4b expression was relatively high, and the effect of HDAC inhibitor treatment was less pronounced as compared to that of the ER-α positive cells. Although, the expression of PMCA4b was relatively high in the triple negative cells, a fraction of the protein was found in intracellular compartments that could interfere with the cellular function of the protein.

Conclusions

Our results suggest that the expression of Ca²⁺ pumps is highly regulated in breast cancer cells in a subtype specific manner. Our results suggest that hormonal imbalances, epigenetic modifications and impaired protein trafficking could interfere with the expression and cellular function of PMCA4b in the course of breast cancer progression.

https://ift.tt/2q7JUrN

A novel feedback loop between high MALAT-1 and low miR-200c-3p promotes cell migration and invasion in pancreatic ductal adenocarcinoma and is predictive of poor prognosis

Abstract

Background

It was demonstrated that long non-coding RNAs occupied an important position in tumor pathogenesis and progression. We have previously found that the metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) promotes cell proliferation and metastases in pancreatic ductal adenocarcinoma (PDAC). The present study was aimed to discuss the underlying mechanisms.

Methods

Bioinformatics method was used to identify the miRNA target of MALAT-1. Expressions of relative genes were assessed by quantitative real-time PCR and western blotting, respectively. Sulforhodamine B assay and Transwell assay were employed to detect cell proliferation, migration and invasion, respectively. Moreover, RNA immunoprecipitation was performed to determine whether RNA-induced silencing complex contained MALAT-1 and its potential binding miRNA. Luciferase assays was used to confirm potential binding site.

Results

Bioinformatics search predicted that miR-200c-3p was a direct target of MALAT-1. Further, we found a reciprocal suppression between MALAT-1 and miR-200c-3p expression. In terms of mechanisms, high MALAT-1 and low miR-200c-3p may form a novel feedback loop. On the one hand, MALAT-1 functioned as a competing endogenous RNA to suppress miR-200c-3p expression, leading to upregulation of ZEB1 expression. On the other hand, miR-200c-3p inhibited the level of MALAT-1 expression was in a way similar to miRNA-mediated downregulation of target genes. Clinical data further indicated that MALAT-1 and ZEB1 expression was negatively correlated with miR-200c-3p transcript level of PDAC tissues. There was a positive correlation between MALAT-1 and ZEB1 level. MALAT-1 (high)/miR-200c-3p (low) correlated with shorter overall survival of PDAC patients. Multivariate analysis revealed that both MALAT-1 and miR-200c-3p levels were independent prognostic factors.

Conclusion

Our findings firstly revealed a novel feedback loop between high MALAT-1 and low miR-200c-3p. Targeting the feedback loop between high MALAT-1 and low miR-200c-3p will be a therapeutic strategy for PDAC.

https://ift.tt/2R4dSIy

Protocol for a phase III RCT and economic analysis of two exercise delivery methods in men with PC on ADT

Abstract

Background

Androgen deprivation therapy (ADT) is commonly used to treat prostate cancer. However, side effects of ADT often lead to reduced quality of life and physical function. Existing evidence demonstrates that exercise can ameliorate multiple treatment-related side effects for men on ADT, yet adherence rates are often low. The method of exercise delivery (e.g., supervised group in-centre vs. individual home-based) may be important from clinical and economic perspectives; however, few studies have compared different delivery models. Additionally, long-term exercise adherence and an understanding of predictors of adherence are critical to achieving sustained benefits, but such data are lacking. The primary aim of this multi-centre phase III non-inferiority randomized controlled trial is to determine whether a home-based delivery model is non-inferior to a group-based delivery model in terms of benefits in fatigue and fitness in this population. Two other key aims include examining cost-effectiveness and long-term adherence.

Methods

Men diagnosed with prostate cancer of any stage, starting or continuing on ADT for at least 6 months, fluent in English, and living close to a study centre are eligible. Participants complete five assessments over 12 months (baseline and every 3 months during the 6-month intervention and 6-month follow-up phases), including a fitness assessment and self-report questionnaires. Biological outcomes are collected at baseline, 6, and 12 months. A total of 200 participants will be randomized in a 1:1 fashion to supervised group training or home-based training supported by smartphones, health coaches, and Fitbit technology. Participants are asked to complete 4 to 5 exercise sessions per week, incorporating aerobic, resistance and flexibility training. Outcomes include fatigue, quality of life, fitness measures, body composition, biological outcomes, and program adherence. Cost information will be obtained using patient diary-based self-report and utilities via the EQ-5D.

Discussion

To disseminate publicly funded exercise programs widely, clinical efficacy and cost-effectiveness have to be demonstrated. The goals of this trial are to provide these data along with an increased understanding of adherence to exercise among men with prostate cancer receiving ADT.

Trial registration

The trial has been registered at clinicaltrials.gov (Registration # NCT02834416). Registration date was June 2, 2016.

https://ift.tt/2q77ip6

Thick-wall cavity predicts worse progression-free survival in lung adenocarcinoma treated with first-line EGFR-TKIs

Abstract

Background

Cavity occurs in 5.7 to 14.9% of patients with lung adenocarcinoma (ADC). However, the impact of cavity on the therapeutic response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in ADC patients with EGFR mutations remains unclear. The aim of the present retrospective study was to elucidate the incidence and detailed characteristics of EGFR-mutant cavitary ADC and investigate the efficacy of EGFR-TKI treatment in this subgroup.

Methods

Two hundred seventy-six consecutive patients with advanced EGFR-mutant lung ADC treated with first-line EGFR-TKIs were enrolled. Cavitation and the thickness of cavity wall were assessed based on high-resolution computed tomography scans. Progression-free survival (PFS) was analyzed by the Kaplan-Meier plots and the log-rank test was used to calculate the significance between groups.

Results

Cavity occurred in 5.4% (15/276) of patients with EGFR-mutant lung ADC and was more prevalent among male patients (66.7% vs. 33.3%, P = 0.008). Of the 15 EGFR-mutant cavitary ADC, 9 patients had exon 19 deletion (19DEL) and 6 harbored L858R mutation, 9 patients had thick-wall cavity while 6 had thin-wall cavity. Cavity had an adverse impact on the PFS of EGFR-mutant ADC treated with first-line EGFR-TKIs (noncavity versus cavity, 11.0 versus 6.5 months, hazard ratio [HR]: 0.33, 95% confidence interval [CI], 0.15–0.73, P = 0.003). The impaired effect was only observed in patients with L858R mutation (11.0 vs. 4.2 months, HR: 0.05, 95%CI, 0.01–0.27, P = 0.0003) but not in those with 19DEL (10.4 versus 9.7 months, HR: 0.73, 95%CI, 0.30–1.75, P = 0.483). All six L858R-mutant cavitary ADC patients had thick-wall cavity while thick-wall cavity was only identified in one thirds (3/9) of patients with 19DEL. Further analyses showed that patients with thick-wall cavity had worse PFS (6.0 versus 11.0 months, P = 0.013). Multivariate analysis identified cavity as an independent predictive factor for PFS (HR: 0.49, 95% CI, 0.26–0.90, P = 0.022).

Conclusion

Cavitary ADC was associated with a worse PFS of first-line EGFR-TKI therapy, mainly in those with L858R mutation. Thick-wall cavity formation may be the main cause that contribute to the worse PFS.

https://ift.tt/2R4dw4G

Feasibility of concomitant cisplatin with hypofractionated radiotherapy for locally advanced head and neck squamous cell carcinoma

Abstract

Background

The evolution of radiotherapy over recent decades has reintroduced the hypofractionation for many tumor sites with similar outcomes to those of conventional fractionated radiotherapy. The use of hypofractionation in locally advanced head and neck cancer (LAHNC) has been already used, however, its use has been restricted to only a few countries. The aim of this trial was to evaluate the safety and feasibility of moderate hypofractionated radiotherapy (HYP-RT) with concomitant cisplatin (CDDP).

Methods

This single-arm trial was designed to evaluate the safety and feasibility of HYP-RT with concomitant CDDP in LAHNC. Stage III and IV patients withnonmetastatic disease were enrolled. Patients were submitted to intensity modulatedradiation therapy, which comprised 55 Gy/20 fractions to the gross tumor and44–48 Gy/20 fractions to the areas of subclinical disease. Concomitant CDDPconsisted of 4 weekly cycles of 35 mg/m2. The primary endpoints were the treatment completion rate and acute toxicity.

Results

Twenty patients were enrolled from January 2015 to September 2016, and 12 (60%) were classified as unresectable. All patients completed the total dose of radiotherapy, and 19 patients (95%) received at least 3 of 4 cycles of chemotherapy. The median overall treatment time was 29 days (27–34). Grade 4 toxicity was reported twice (1 fatigue and 1 lymphopenia). The rates of grade 3 dermatitis and mucositis were 30% and 40%, respectively, with spontaneous resolution. Nasogastric tubes were offered to 15 patients (75%) during treatment; 4 patients (20%) needed feeding tubes after 2 months, and only 1 patient needed a feeding tube after 12 months.

Conclusion

HYP-RT with concomitant CDDP was considered feasible for LAHNC, and the rate of acute toxicity was comparable to that of standard concomitant chemoradiation. A feeding tube was necessary for most patients during treatment. Further investigation of this strategy is warranted.

Trial registration

ClinicalTrials, NCT03194061. Registered 21 Jun 2017 – Retrospectively registered.

https://ift.tt/2q6fm9N

Meta-analysis on resected pancreatic cancer: a comparison between adjuvant treatments and gemcitabine alone

Abstract

Background

Pancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer.

Methods

PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3–4 toxicity.

Results

Pooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70–1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71–1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46–0.74; P < 0.0001) and DFS (HR, 0.63; 95% CI, 0.52–0.75; P < 0.00001) compared with Gem alone. Toxicity analysis showed there was an increased incidence of grade 3/4 diarrhea (risk ratio (RR), 5.11; 95%CI, 3.24–8.05; P < 0.00001) and decreased incidence of grade 3/4 leucopenia (RR, 0.55; 95%CI, 0.31–0.98; P = 0.04), thrombocytopenia (RR, 0.61; 95%CI, 0.39–0.97; P = 0.04) in adjuvant treatments group. Neutropenia (RR, 0.69; 95%CI, 0.36–1.29; P = 0.24) and fatigue (RR, 1.29; 95%CI, 0.95–1.77; P = 0.11) for patients between the two groups were not significantly different.

Conclusions

In our meta-analysis, a significant survival benefit is only observed in the S-1 regimen, but the results are yet to be determined. Optimal cytotoxicity or targeted drug regimens need further validation in clinical trials in the future.

https://ift.tt/2R4dqKm

TROG 15.03 phase II clinical trial of Focal Ablative STereotactic Radiosurgery for Cancers of the Kidney - FASTRACK II

Abstract

Background

Stereotactic ablative body radiotherapy (SABR) is a non-invasive alternative to surgery to control primary renal cell cancer (RCC) in patients that are medically inoperable or at high-risk of post-surgical dialysis. The objective of the FASTRACK II clinical trial is to investigate the efficacy of SABR for primary RCC.

Methods

FASTRACK II is a single arm, multi-institutional phase II study. Seventy patients will be recruited over 3 years and followed for a total of 5 years. Eligible patients must have a biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, have ECOG performance ≤2 and be medically inoperable, high risk or decline surgery. Radiotherapy treatment planning is undertaken using four dimensional CT scanning to incorporate the impact of respiratory motion. Treatment must be delivered using a conformal or intensity modulated technique including IMRT, VMAT, Cyberknife or Tomotherapy. The trial includes two alternate fractionation schedules based on tumour size: for tumours ≤4 cm in maximum diameter a single fraction of 26Gy is delivered; and for tumours > 4 cm in maximum diameter 42Gy in three fractions is delivered. The primary outcome of the study is to estimate the efficacy of SABR for primary RCC. Secondary objectives include estimating tolerability, characterising overall survival and cancer specific survival, estimating the distant failure rate, describing toxicity and renal function changes after SABR, and assessment of cost-effectiveness of SABR compared with current therapies.

Discussion

The present study design allows for multicentre prospective validation of the efficacy of SABR for primary RCC that has been observed from prior single institutional and retrospective series. The study also allows assessment of treatment related toxicity, overall survival, cancer specific survival, freedom from distant failure and renal function post therapy.

Trial registration

Clinicaltrials.gov NCT02613819, registered Nov 25th 2015.

https://ift.tt/2q9af8M

Co-expression of nuclear P38 and hormone receptors is prognostic of good long-term clinical outcome in primary breast cancer and is linked to upregulation of DNA repair

Abstract

Background

P38 mitogen activated protein kinase is an intermediary signal transduction factor with context-specific roles in breast cancer. Recent mechanistic studies add to the growing consensus that P38 is a tumour suppressor, and it may represent a novel target for breast cancer treatment. The aim of this study is to add definitive data on the prognostic value of P38 and its link with biomarkers in primary breast cancer.

Methods

A large, well-characterised series of 1332 primary breast cancer patients with long-term clinical follow-up was assessed for P38 expression by immunohistochemistry. Association of clinicopathological factors and a panel of breast cancer biomarkers was determined by chi-squared test, and multivariate survival analysis was performed using Cox Proportional Hazards regression modelling.

Results

This study shows that nuclear P38 is co-expressed with nuclear hormone receptors (p < 0.001) and is an independent prognostic marker of good long-term clinical outcome in primary breast cancer (hazard ratio 0.796, 95% confidence interval 0.662–0.957, p = 0.015). Significant association was found between expression of P38 and markers of DNA repair including nuclear BRCA1 and RAD51, and cleaved PARP1 (all p < 0.001).

Conclusions

The findings support the proposed role for P38 as a tumour suppressor in breast cancer via upregulation of DNA repair proteins and provide novel hypothesis-generating information on the potential role of P38 in adjuvant therapy decision making.

https://ift.tt/2RcK0Kb

Generation and characterization of MEK and ERK inhibitors- resistant non-small-cells-lung-cancer (NSCLC) cells

Abstract

Background

The RAS/RAF/MEK/ERK pathway is one of the most downregulated pathway in cancer. Inhibitors of RAF and MEK have established clinical use while ERK inhibitors recently faced the clinic. We aimed to generate resistant cell lines which could be helpful for defining new combinations able to overcome resistance.

Methods

the human NSCLC cell line NCI-H727, sensitive to both MEK and ERK inhibitors, was treated with increasing concentrations of MEK162 (as MEK inhibitor) or SCH772984 as ERK inhibitor.

Results

we successfully obtained a MEK resistant subline (H727/MEK, after 40 passages) as well as an ERK resistant subline (H727/SCH, after 18 passages). The two resistant sublines H727/MEK and H727/SCH were cross-resistant to ERK and MEK inhibitors, respectively, but not to RAF inhibitors. The sublines maintained the responsiveness to inhibitors of the parallel PI3K/akt/mTOR pathway as well as to agents with different mechanism of action. Mechanistically, treatment of sensitive and resistant cells with MEK or ERK inhibitors was able to induce a similar inhibition of ERK phosphorylation, while only in parental cells the drugs were able to induce a downregulation of S6 and RSK phosphorylation.

Conclusions

these resistant cells represent an important tool for further studies on the mechanisms of resistance and ways to overcome it.

https://ift.tt/2q8BOyT

Fabrication of Schottky Diodes on Zn-polar BeMgZnO/ZnO Heterostructure Grown by Plasma-assisted Molecular Beam Epitaxy

Attainment of high-quality Schottky contacts is imperative for achieving efficient gate modulation in heterostructure field effect transistors (HFETs). We present the fabrication methodology and characteristics of Schottky diodes on Zn-polar BeMgZnO/ZnO heterostructures with high-density two dimensional electron gas (2DEG), grown by plasma-assisted molecular beam epitaxy on GaN templates.

https://ift.tt/2Ao22Do

An Experimental Protocol for Femtosecond NIR/UV - XUV Pump-Probe Experiments with Free-Electron Lasers

This protocol describes the key steps for performing and analyzing pump-probe experiments combining a femtosecond optical laser with a free-electron laser in order to study ultrafast photochemical reactions in gas-phase molecules.

https://ift.tt/2CzDSHI

Baicalin induces apoptosis in SW480 cells through downregulation of the SP1 transcription factor

Colorectal cancer occurs throughout the world but is most common in developed countries. Cancer progression is believed to be driven by genetic mutations in this complex condition. Risk factors for developing colorectal cancer include a genetic family history, long-term ulcerative colitis, and colonic polyps. The use of baicalin has been reported to be clinically efficacious against colon tumors in Asian countries despite an unclear mechanism of action. Several cancers have been found to be biologically dependent on the specificity protein 1 (sp1) transcription factor family. We hypothesized that baicalin may exert its chemotherapeutic effects by sp1 downregulation. Using the SW480 human colorectal cancer cell line, we investigated the physiological properties of baicalin. Our experiments were designed toward clarifying three goals: (a) to determine the mRNA expression profile of transcription factors in colorectal cancer patients using a microarray-based analysis; (b) to determine the effects of baicalin on the sp1 transcription factor with western blotting and reporter cell assays; and (c) to contrast the effects of mithramycin-A (an sp1 transcription factor inhibitor) and baicalin using western blotting and reporter cell assays. Both baicalin and mithramycin-A downregulated sp1 expression, attenuated SW480 cell proliferation, and increased cell apoptosis. Baicalin inhibited sp1 expression and led to SW480 apoptosis, thus clarifying the effect of this traditional Chinese medicine compound in the treatment of colon cancer. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. https://ift.tt/1hexVwJ Correspondence to Wei Du, MSc, Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 511436, People's Republic of China Tel: +86 020 3710 3235; fax: +86 020 3710 3099; e-mail: neptunemichael@163.com Received August 2, 2018 Accepted October 7, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2q577KS

Ultrasound-guided Corticosteroid Injection in a Patient with Tietze`s syndrome Combined with Costochondral Joint Swelling: A Case Report

Tietze`s syndrome is an uncommon disease of unknown etiology that manifests as pain and tenderness of the parasternal joints. To date, however, there has been no report on ultrasonographic findings concerning swelling of the costochondral joint in Tietze`s syndrome. Moreover, there has been no research investigating images of ultrasound-guided corticosteroid injection, although corticosteroid injection is one of the most important treatments for Tietze`s syndrome. Therefore, we report a case of Tietze`s syndrome where ultrasound images were used in the diagnostic and therapeutic process. A 70-year-old man was seen for left chest pain that had lasted for several weeks. Physical examination at our clinic revealed a focal tenderness of the left third costochondral joint, and an ultrasound showed a swelling of the left third costochondral joint. Considering both the radiological and the clinical examination, the patient received a diagnosis of Tietze`s syndrome with costochondral joint swelling. Then, the patient agreed to an ultrasound-guided left third costochondral corticosteroid injection after receiving a detailed explanation of the disease and treatment. After receiving three ultrasound-guided corticosteroid injections, his chest pain subsided, and the swelling and tenderness also disappeared completely. Collectively, our case suggests that ultrasound is important in the diagnosis and treatment of Tietze`s syndrome. Disclosure: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF- 2017R1D1A1B03033127) No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Conflict of interest : None Acknowledgement: None Address corresponding author: Donghwi Park, M.D. Department of Rehabilitation Medicine, Department of Rehabilitation Medicine, Daegu Fatima Hospital, Ayangro 99, Dong gu, Daegu 41199, Republic of Korea (e-mail: bdome@hanmail.net), Tel : 82-53-940-7821, Fax : 82-53-954-7417 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2PkoBBg

The ‘minimum clinically important difference’ in frequently reported objective physical function tests following a 12-week renal rehabilitation exercise intervention in non-dialysis chronic kidney disease

Objective Chronic kidney disease (CKD) patients are characterized by impaired physical function. The goal of exercise-based interventions is an improvement in functional performance. However, improvements are often determined by 'statistically significant' changes. We investigated the 'minimum clinically important difference' (MCID), 'the smallest change that is important to the patient', for commonly reported physical function tests. Design Non-dialysis CKD patients completed 12-weeks of a combined aerobic (plus resistance training). The incremental shuttle walking test (ISWT), sit-to-stand-5 (STS-5) and 60 (STS-60), estimated 1 repetition maximum (e1RM) for the knee extensors, and VO2peak were assessed. After the intervention, patients rated their perceived change in health. Both anchor- and distribution-based MCID approaches were calculated. Results The MCID was calculated as follows: ISWT, +45m; STS-5, -4.2 seconds; VO2peak, +1.5 ml/kg/min. Due to comparable increases in 'anchor' groups, no MCID was estimated for the STS-60 or e1RM. Conclusion We have established the MCID in CKD for common tests of physical function. These values represent the minimum change required for patients to perceive noticeable and beneficial change to their health. These scores will help interpret changes following exercise interventions where these tests are employed. These MCIDs can be used to power future studies to detect clinically important changes. Corresponding author: Dr. Thomas J Wilkinson, Leicester Kidney Exercise Team, Department of Infection, Immunity and Inflammation, University of Leicester, United Kingdom, LE5 4PW. Email: t.j.wilkinson@leicester.ac.uk Author disclosures The authors report no conflicts of interest. Preliminary results from this analysis have been presented at the American Society of Nephrology Kidney Week 2016 (Chicago). Funding statement This work was gratefully part-funded by the Stoneygate Trust. The research was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2PP78ht

Autologous blood-derived products compared to corticosteroids for treatment of plantar fasciopathy: a systematic review and meta-analysis

Objective This review article evaluated the efficacy of autologous blood-derived products (ABPs), including whole blood (WB) and platelet-rich plasma (PRP), in reducing pain and improving function compared with corticosteroids (CS) for plantar fasciopathy (PF) patients. Design Literature comparing ABP and CS for the treatment of PF was systematically reviewed. Twelve randomized controlled trials (RCTs) and four quasi-experimental studies were included. The visual analogue scale pain score and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score were evaluated at 1.5, 3, and 6 months' follow-up. Subgroup analyses were performed concerning PRP preparation techniques, injection regiments, and study designs. Results CS was found to reduce pain more effectively than WB at 1.5 months and 3 months, but the effect disappeared at 6 months. PRP reduced pain more effectively at 6 months post-injection than CS. However, there was no significant difference in the AOFAS score between PRP and CS injections at any time point. In the subgroup analyses, pain was significantly reduced at 6 months by self-prepared PRP, one-step separation PRP, PRP of more than 3 mL, and PRP without local analgesics. Conclusion The results of this meta-analysis suggest that PRP may provide a long-term effect in relieving pain in PF patients. #These two authors contribute equally to the work Corresponding author: Tung-Yang Yu, Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Linkou, 5, Fushing Street, Kuei-Shan District, Taoyuan City 33305, Taiwan, Tel: +886-3-3281200 ext 3846; Fax: +886-3-3281320; E-mail: mr3964@cgmh.org.tw Author disclosures The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. No party has direct interest neither a financial relationship nor will they be conferred any benefits from writing this submission or the results of this research. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Ultrasound‐guided proximal suprascapular nerve block: A cadaveric study

Clinical Anatomy, EarlyView.


https://ift.tt/2PQiIZN

Fulshear Simonton (TX) Fire Department takes delivery of High Water/Flood Rescue Trucks from Acela Truck Company

FULSHEAR, Texas — The Fulshear-Simonton Fire Department has taken delivery of the first of its two newly purchased purpose-built High Water/Flood Rescue Trucks from Acela Truck Company. With 47-inch tires, 23 inches of ground clearance, all-wheel-drive drivetrains, waterproof alternators and starters and deep-water fording kits, the Acela Monterra-based specialized flood rescue trucks are...

https://ift.tt/2PRsPxd

NK Cells Respond to Checkpoint Blockade [News in Brief]

The cells may be involved in immune response to cancer after treatment with PD-1, PD-L1 inhibitors.

https://ift.tt/2q8yeoG

Duvelisib Approved for Leukemia, Lymphoma [News in Brief]

The PI3K/PI3K inhibitor extends PFS in patients with relapsed/refractory disease.

https://ift.tt/2R8LVPJ

Cancers, Vol. 10, Pages 395: FRoG—A New Calculation Engine for Clinical Investigations with Proton and Carbon Ion Beams at CNAO

Cancers, Vol. 10, Pages 395: FRoG—A New Calculation Engine for Clinical Investigations with Proton and Carbon Ion Beams at CNAO

Cancers doi: 10.3390/cancers10110395

Authors: KyungDon Choi Stewart B Mein Benedikt Kopp Giuseppe Magro Silvia Molinelli Mario Ciocca Andrea Mairani

A fast and accurate dose calculation engine for hadrontherapy is critical for both routine clinical and advanced research applications. FRoG is a graphics processing unit (GPU)-based forward calculation tool developed at CNAO (Centro Nazionale di Adroterapia Oncologica) and at HIT (Heidelberg Ion Beam Therapy Center) for fast and accurate calculation of both physical and biological dose. FRoG calculation engine adopts a triple Gaussian parameterization for the description of the lateral dose distribution. FRoG provides dose, dose-averaged linear energy transfer, and biological dose-maps, -profiles, and -volume-histograms. For the benchmark of the FRoG calculation engine, using the clinical settings available at CNAO, spread-out Bragg peaks (SOBPs) and patient cases for both proton and carbon ion beams have been calculated and compared against FLUKA Monte Carlo (MC) predictions. In addition, FRoG patient-specific quality assurance (QA) has been performed for twenty-five proton and carbon ion fields. As a result, for protons, biological dose values, using a relative biological effectiveness (RBE) of 1.1, agree on average with MC within ~1% for both SOBPs and patient plans. For carbon ions, RBE-weighted dose (DRBE) agreement against FLUKA is within ~2.5% for the studied SOBPs and patient plans. Both MKM (Microdosimetric Kinetic Model) and LEM (Local Effect Model) DRBE are implemented and tested in FRoG to support the NIRS (National Institute of Radiological Sciences)-based to LEM-based biological dose conversion. FRoG matched the measured QA dosimetric data within ~2.0% for both particle species. The typical calculation times for patients ranged from roughly 1 to 4 min for proton beams and 3 to 6 min for carbon ions on a NVIDIA&reg; GeForce&reg; GTX 1080 Ti. This works demonstrates FRoG&rsquo;s potential to bolster clinical activity with proton and carbon ion beams at CNAO.

https://ift.tt/2PdwY1F

Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages

The metabolic-inflammatory crosstalk plays a key role in host defense against pathogens and inflammation. Guo and colleagues demonstrate that SCAP-SREBP2 complex integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling during inflammation.

https://ift.tt/2z6stvR

T Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation

RIP2 is the key adaptor molecule for NOD1- and NOD2-mediated intracellular signaling to sense pathogens and cell activation in myeloid cells. Shimada, Porritt, and colleagues demonstrate a previously unappreciated role for RIP2 in Th17 cell regulation and differentiation in a T cell-intrinsic manner.

https://ift.tt/2ScyIH6

A Prospective Randomized Study to Analyze the Efficacy of Balanced Preemptive Analgesia in Spine Surgery

Publication date: Available online 22 October 2018

Source: The Spine Journal

Author(s): Dilip Chand Raja S, Ajoy Prasad Shetty, Balavenkat Subramanian, Rishi Mugesh Kanna, S Rajasekaran

ABSTRACT

Background Context

Surgical procedures involving the spine are known to cause moderate to severe postoperative pain. Inadequate management of acute pain in the postoperative period results in higher morbidity, and consequently may lead to chronic pain due to central sensitization. The role of preemptive and intraoperative analgesia in management of postoperative pain has gained precedence over recent years. Pathophysiology of postoperative pain in spine surgery is unique, as it is a combination of nociceptive, inflammatory and neuronal stimuli. Blockage of all three stimuli in the perioperative period by preemptively administrating a combination of paracetamol (P), ketorolac (K) and pregabalin (PR) might help in adequate management and alleviation of acute postoperative pain.

Purpose

To evaluate the analgesic effect of a combination of paracetamol (P), ketorolac (K), and pregabalin (PR) as preemptive multimodal analgesia, aimed to block or reduce acute postoperative pain after spine surgery.

Study Design

A prospective, randomized, controlled, and double blinded clinical trial.

Patient sample

After Institutional Review Board (IRB) approval, 100 consecutive patients requiring single or double level spinal fusion procedures were randomized into two groups- Preemptive analgesia (PA) and control (C).

Methods

The PA group received P, K, and PR four hours before surgery, as preemptive analgesia. Both groups underwent identical anesthetic and postoperative pain management protocol.

Outcome measures

Demographic and surgical data, four hourly postoperative pain levels- Numeric Pain Rating scale (NRS), Ambulatory NRS scores, level of consciousness - Ramsay sedation scale (RSS), total amount of opioids consumed (TOC) through patient controlled analgesia (PCA), functional levels-Oswestry Disability Index (ODI), surgical satisfaction index-North American Spine Society (NASS) satisfaction scale, duration of hospital stay (DOH), and all complications were recorded and analyzed. A research grant of 6,032 USD was obtained from AO Spine towards this work. There is no conflict to disclose.

Results

Both the groups had identical demographic backgrounds and surgical profiles. The average NRS score within the first 48 hour period in the PA group (2.7±0.79) was significantly less than the C group (3.4±0.98) and the differences were more in the first 12 hours following surgery. Similarly, Ambulatory NRS scores were significantly low in the PA group during the first and second postoperative days. The PA group individuals were found to be more physically motivated, as 95.7% were able to ambulate 50 meters on the first postoperative day compared to 30% in the C group. The PA group had significantly low TOC (3.02±2.29 mg) in comparison to the C group (4.94±3.08 mg). The duration of hospital stay was 4.17±1.02 and 4.84± 1.62 days in the PA and C groups (p=0.017), respectively. No major complications occurred in either groups and were found to be similar in percentage among both the groups, except for nausea and vomiting which were more in C group. Dry mouth was the most common side effect noted irrespective of the groups. All patients had significant improvement in ODI with better results in PA group at first month follow up. The PA group (97.90 %) was extremely satisfied compared to C group (72%, p=0.002) according to NASS scale.

Conclusion

Postoperative pain management in spine surgery is maximized if perioperative painful stimuli can be inhibited, which requires adequate blood levels of analgesic, anti-inflammatory, and neuropathic drugs intraoperatively in the immediate postoperative period. The employed strategy of preoperative administration of balanced analgesia with a combination of paracetamol (P), ketorolac (K), and pregabalin (PR), each having different mechanisms of action, resulted in lesser pain intensity, allowed better ambulation tolerance, improved functional outcomes and has also reduced the requirement of opioids and duration of hospital stay with no additional complications. Thus, this balanced analgesia administered preoperatively would address the complicated postsurgical pain.

https://ift.tt/2yXfWKX

Sinking Skin Flap Syndrome: Phenomenon of Neurological Deterioration after Decompressive Craniectomy

Sinking skin flap syndrome is rare phenomenon that occurs in patients with large craniectomies. Alteration in normal anatomy and pathophysiology can result in wide variety of symptoms including altered mental status, hemodynamic instability, and dysautonomias. Management is largely conservative. We here present a case of a patient with large craniectomy who was admitted to our hospital with pneumonia. Later on, he developed worsening mental status and CT head revealed sinking skin flap with significant midline shift. This is a very rare case of neurological deterioration after craniectomies, commonly known as sinking skin flap syndrome. To our knowledge, only few cases have been reported so far.

https://ift.tt/2CBjzK9

Identifying barriers and finding solutions to implement best practices for cancer surgery at Maputo Central Hospital, Mozambique

Atílio Morais, Matchecane Cossa, Adriano Tivane, Jotamo Come, Volodimir Venetsky, Fernando Torrres, Victor Pacheco, Miguel Reyes, Germano Pires, Mariana Peyroteo, Satish Tulsidas, Ellen Baker, Moshin Sidat, Maria do Rosário O Martins and Lúcio Lara Santos

https://ift.tt/2AmShW3

Why modern-day emergency scenarios necessitate added protection for first responders

A national push from the government to outfit first responders with the right protective gear and the proper training for effective use would show support and respect for first responders

https://ift.tt/2R9pJVz

Emergency management of immune‐related hypophysitis: Collaboration between specialists is essential to achieve optimal outcomes

Cancer, EarlyView.


https://ift.tt/2CYFICV

Do soil bacterial communities respond differently to abrupt or gradual additions of copper?

Abstract

Many experiments that measure the response of microbial communities to heavy metals increase metal concentrations abruptly in the soil. However, it is unclear whether abrupt additions mimic the gradual and often long-term accumulation of these metals in the environment where microbial populations may adapt. In a greenhouse experiment that lasted 26 months, we tested whether bacterial communities and soil respiration differed between soils that received an abrupt or a gradual addition of copper or no copper at all. Bacterial richness and other diversity indices were consistently lower in the abrupt treatment compared to the ambient treatment that received no copper. The abrupt addition of copper yielded different initial bacterial communities than the gradual addition, however these communities appeared to converge once copper concentrations were approximately equal. Soil respiration in the abrupt treatment was initially suppressed but recovered after four months. Afterwards, respiration in both the gradual and abrupt treatments wavered between being below or equal to the ambient treatment. Overall, our study indicates that gradual and abrupt additions of copper can yield similar bacterial communities and respiration, but these responses may drastically vary until copper concentrations are equal.

https://ift.tt/2yWLkcy