Physical Properties of Bacterial Outer Membrane Models: Neutron Reflectometry & Molecular Simulation

The outer membrane (OM) of Gram-negative bacteria is an asymmetric bilayer having phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. This unique asymmetry and the complex carbohydrates in LPS make it a daunting task to study the asymmetrical OM structure and dynamics, its interactions with outer membrane proteins, as well as its roles in translocation of substrates including antibiotics. In this study, we combine neutron reflectometry and molecular simulation to explore physical properties of OM mimetics.

http://bit.ly/2WLZIQ1

Influenza A M2 Channel Clustering at High Protein to Lipid Ratios: Viral Budding Implications

Protein dynamics in crowded environments is important for understanding protein functions in vivo and is especially relevant for membrane proteins due to the roles of protein-protein interactions in membrane protein functions and their regulation. Here, using solid-state NMR spectroscopy in combination with coarse-grained molecular dynamics simulations, we report that the rotational correlation time for the transmembrane domain of the Influenza A M2 proton channel in lipid bilayers increases dramatically at an elevated protein-to-lipid ratio.

http://bit.ly/2RMLsTf

Natural ceramides and lysophospholipids co-segregate in fluid phosphatidylcholine bilayers

The mode of interactions between palmitoyl lysophosphatidycholine (palmitoyl lyso-PC), or other lysophospholipids (lyso-PLs), and palmitoyl ceramide (PCer), or other ceramide analogs, in dioleoylphosphatidylcholine (DOPC) bilayers has been examined. PCer is known to segregate laterally into a ceramide-rich phase at concentrations that depend on the nature of the ceramides and the co-phospholipids. In DOPC bilayers, PCer forms a ceramide-rich phase at concentrations above 10 mol%. In the presence of 20 mol% palmitoyl lyso-PC in the DOPC bilayer, the lateral segregation of PCer was markedly facilitated (segregation at lower PCer concentrations).

http://bit.ly/2RQegdt

Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer

Abstract

Purpose

Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer.

Methods

We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan–Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors.

Results

We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients' outcome within some specific BRCA tumor stages and histological subtypes.

Conclusions

In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.

http://bit.ly/2SJSGw5

Astaxanthin supplementation modulates cognitive function and synaptic plasticity in young and aged mice

Abstract

The incidence of neurodegenerative disorders and cognitive impairment is increasing. Rising prevalence of age-related medical conditions is associated with a dramatic economic burden; therefore, developing strategies to manage these health concerns is of great public health interest. Nutritionally based interventions have shown promise in treatment of these age-associated conditions. Astaxanthin is a carotenoid with reputed neuroprotective properties in the context of disease and injury, while emerging evidence suggests that astaxanthin may also have additional biological activities relating to neurogenesis and synaptic plasticity. Here, we investigate the potential for astaxanthin to modulate cognitive function and neural plasticity in young and aged mice. We show that feeding astaxanthin to aged mice for 1 month improves performance on several hippocampal-dependent cognitive tasks and increases long-term potentiation. However, we did not observe an alteration in neurogenesis, nor did we observe a change in microglial-associated IBA1 immunostaining. This demonstrates the potential for astaxanthin to modulate neural plasticity and cognitive function in aging.

http://bit.ly/2UKdXCQ

Novel small molecule decreases cell proliferation, migration, clone formation, and gene expression through ERK inhibition in MCF-7 and MDA-MB-231 breast cancer cell lines

The Ras–Raf–MEK1/2–ERK1/2 pathway is an attractive target for the development of anticancer agents because of the high prevalence of ERK activation in human cancers. However, resistance is often developed despite initial clinical response, most likely because of activation of cross-talk pathways. In Research Genetic Cancer Center (RGCC), we are in the process of synthesizing a novel ERK inhibitor, targeting the final stage of the pathway, thus minimizing cross-talk. We have synthesized an intermediate molecule –RGCC416 – and tested its biological activity. MCF-7 and MDA-MB-231 cells were used. Cell viability was measured by crystal violet and cell proliferation by the methyl tetrazolium assay using various compound concentrations. Cell migration and colony formation were determined to assess the ability of invasion and single cancer cell growth, respectively. Expression of genes linked to MAPK/PI3K pathways was determined by PCR. ERK and phospho-ERK levels were determined in both the cytoplasm and the nucleus by western blot. It was found that although the compound did not affect viability, it significantly decreased cell proliferation, migration, and colony formation in both cell lines. In MDA-MB-231, this is possibly through retaining phospho-ERK to the cytoplasm, where it cannot activate cancer-associated genes. There was no difference in ERK levels in MCF-7 cells. This could be because of the different pathways that these cells utilize for survival. We have synthesized a molecule, which could be a promising ERK inhibitor, leading to possible novel treatment options for breast cancer patients. Correspondence to Ioannis Papasotiriou, MD, Department of R&D, Research Genetic Cancer Centre, 53100 Florina, Greece Tel: +30 238 504 1950; fax: +30 238 504 1931; e-mail: office@rgcc-genlab.com Received September 21, 2018 Accepted January 25, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2RS9vAt

The effect of fear of falling on prefrontal cortex activation and efficiency during walking in older adults

Abstract

Neural inefficiency is inferred when higher brain activations are associated with similar or worse performance. Improved neural efficiency is achieved when task-related brain activations are reduced after practice. No information is available on the effect of fear-of-falling (FOF) on brain activation during walking. We hypothesized that the presence of FOF would be associated with neural inefficiency and with a delay in improving neural efficiency during dual-task walking. Task conditions included single-task walk (STW), Alpha (cognitive interference), and dual-task walk (DTW). Functional near-infrared spectroscopy (fNIRS)-derived HbO₂ in the prefrontal cortex (PFC) was used to quantify task-related changes in brain activation. Practice included three repeated counterbalanced trials for each task. Participants with FOF (n = 19; mean age = 79.84 ± 6.01 years; %female = 68.42) and without FOF (n = 56; mean age = 76.73 ± 6.39 years; %female = 44.64) were included. The presence of FOF was associated with slower stride velocity (estimate = − 12.354; p = 0.0154) and with greater increases in PFC HbO₂ from STW to DTW (estimate = 0.303, p = 0.0009) and from Alpha to DTW (estimate = 0.387, p < 0.0001). Compared to controls, participants reporting FOF demonstrated an attenuated decline in PFC HbO₂ from the first to the second DTW trials (estimate = 0.264; p = 0.0173). In contrast, compared to controls, participants with FOF demonstrated greater decline in Alpha PFC HbO₂ from trial 1 to trial 2 (estimate = − 0.419, p < 0.0001) and from trial 1 to 3 (estimate = − 0.281, p = 0.0006). The change in PFC HbO₂ over repeated STW trials was not significant and was not moderated by FOF status. The presence of FOF was associated with higher and inefficient PFC activation during DTW in older adults.

http://bit.ly/2WRShqv

Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis

Future Oncology, Ahead of Print.


http://bit.ly/2RPWqaC

KEYNOTE-590: Phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer

Future Oncology, Ahead of Print.


http://bit.ly/2WR3lnS

Analysis of Genetic Diversity and Population Structure in Three Forest Musk Deer Captive Populations with Different Origins

Musk deer (Moschidae), whose secretion is an expensive and irreplaceable component of traditional medicine, have become endangered in the wild due to habitat fragmentation and over-exploitation. In recent years, China has had success in the artificial breeding of forest musk deer, thus relieving the pressure on wild populations. However, many farmed populations are experiencing degradation, and little genetic information is available for conservation management. In this study, we selected 274 individuals from three typical captive populations (originated from the Ta-pa Mountains (Tp), the midrange of the Qinling Mountains (Ql) and the Western Sichuan Plateau (WS), respectively) to evaluate the genetic variations. A total of more than 3.15 billion high-quality clean reads and 4.37 million high-quality SNPs were generated by RAD sequencing. Based on the analysis, we found that captive forest musk deer populations exhibit a relatively low level of genetic diversity. Ql displayed a higher level of genetic diversity than the Tp and WS populations. Tp and WS had experienced population bottlenecks in the past as inferred from the values of Tajima's D. There were high levels of heterozygote deficiency caused by inbreeding within the three populations. Population structure analysis suggested that the three populations have evolved independently, and a moderate amount of genetic differentiation has developed, although there was a low level of gene flow between the Ql and Tp populations. Furthermore, the average quantities of musk secreted by musk deer in the Tp and WS populations were significantly higher than that in the Ql population. The present genetic information should be considered in management plans for the conservation and utilization of musk deer from captive breeding.

http://bit.ly/2RPWiYE

Bidirectional Selection for Body Weight on Standing Genetic Variation in a Chicken Model

Experimental populations of model organisms provide valuable opportunities to unravel the genomic impact of selection in a controlled system. The Virginia body weight chicken lines represent a unique resource to investigate signatures of selection in a system where long-term, single-trait, bidirectional selection has been carried out for more than 60 generations. At 55 generations of divergent selection, earlier analyses of pooled genome resequencing data from these lines revealed that 14.2% of the genome showed extreme differentiation between the selected lines, contained within 395 genomic regions. Here, we report more detailed analyses of these data exploring the regions displaying within- and between-line genomic signatures of the bidirectional selection applied in these lines. Despite the strict selection regime for opposite extremes in body weight, this did not result in opposite genomic signatures between the lines. The lines often displayed a duality of the sweep signatures, where an extended region of homozygosity in one line, in contrast to mosaic pattern of heterozygosity in the other line. These haplotype mosaics consisted of short, distinct haploblocks of variable between-line divergence, likely the results of a complex demographic history involving bottlenecks, introgressions and moderate inbreeding. We demonstrate this using the example of complex haplotype mosaicism in the growth1 QTL. These mosaics represent the standing genetic variation available at the onset of selection in the founder population. Selection on standing genetic variation can thus result in different signatures depending on the intensity and direction of selection.

http://bit.ly/2WLTAY1

A Flexible Open-Source Decision Model for Value Assessment of Biologic Treatment for Rheumatoid Arthritis

Abstract

Objective

The nature of model-based cost-effectiveness analysis can lead to disputes in the scientific community. We propose an iterative and collaborative approach to model development by presenting a flexible open-source simulation model for rheumatoid arthritis (RA), accessible to both technical and non-technical end-users.

Methods

The RA model is a discrete-time individual patient simulation with 6-month cycles. Model input parameters were estimated based on currently available evidence and treatment effects were obtained with Bayesian network meta-analysis techniques. The model contains 384 possible model structures informed by previously published models. The model consists of the following components: (i) modifiable R and C++ source code available in a GitHub repository; (ii) an R package to run the model for custom analyses; (iii) detailed model documentation; (iv) a web-based user interface for full control over the model without the need to be well-versed in the programming languages; and (v) a general audience web-application allowing those who are not experts in modeling or health economics to interact with the model and contribute to value assessment discussions.

Results

A primary function of the initial version of RA model is to help understand and quantify the impact of parameter uncertainty (with probabilistic sensitivity analysis), structural uncertainty (with multiple competing model structures), the decision framework (cost-effectiveness analysis or multi-criteria decision analysis), and perspective (healthcare or limited societal) on estimates of value.

Conclusion

In order for a decision model to remain relevant over time it needs to evolve along with its supporting body of clinical evidence and scientific insight. Multiple clinical and methodological experts can modify or contribute to the RA model at any time due to its open-source nature.

http://bit.ly/2UVoFH5

A T-cell-engaging B7-H4/CD3 bispecific Fab-scFv antibody targets human breast cancer

Purpose: The B7 homolog 4 (B7-H4, VTCN1) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 monoclonal antibody that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3 bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model. Experimental Design: Complementary DNAs of the antibody-binding fragment (Fab)-single-chain variable fragment (scFv) and scFv-scFv of the anti-B7-H4/CD3 BsAb were synthesized, and the BsAb antibodies were produced in HEK293 cells. The anti-tumor activity against human breast cancer cells by human peripheral blood mononuclear cells (hPBMC) with BsAb was measured by lactate dehydrogenase (LDH) release in vitro, and in vivo using hPBMC transplanted major histocompatibility (MHC) class I and class II-deficient NOG mice. Results: hPBMCs with anti-B7-H4/CD3 BsAbs successfully lysed the human breast cancer cell line MDA-MB-468 (EC50: 0.2 ng/ml) and other B7-H4-positive cell lines in vitro. When BsAb was injected in a humanized mouse model, there was an immediate and strong antitumor activity against MDA-MB-468, HCC-1954 and HCC-1569 tumors and CD8⁺ and granzyme B⁺ CTL infiltration into the tumor, and there were no adverse effects after long-term observation. CD8⁺ T cell depletion by an anti-CD8 antibody mostly reduced the antitumor effect of BsAb in vivo. Conclusions:An anti-B7-H4/CD3 bispecific antibody may be a good therapeutic tool for patients with B7-H4-positive breast cancers.

http://bit.ly/2GxZ5E3

Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies

Purpose:Thyroid cancer cell lines are valuable models but have been neglected in pan-cancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design:We performed next-generation sequencing and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell cycle checkpoint, histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced vs. differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF^V600Evs. RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future pre-clinical studies exploring tumor-specific dependencies.

http://bit.ly/2DYXF3u

Patient, Doctor Communication Priorities Differ in Ulcerative Colitis

FRIDAY, Feb. 8, 2019 -- There is discordance in communication priorities for patients with ulcerative colitis (UC) and their gastroenterology physicians (GIs), and the emotional impact of UC should not be underestimated, according to two studies...

http://bit.ly/2SJqDNi

Johnson & Johnson to Provide Drug Prices in TV Ads

FRIDAY, Feb. 8, 2019 -- In a drug industry first, Johnson & Johnson will start giving the list prices of its prescription drugs in television ads. The new policy will begin in late March with the popular blood thinner pill Xarelto, said Scott...

http://bit.ly/2MX1c5x

Predictors of Kidney Stone Recurrence Identified

FRIDAY, Feb. 8, 2019 -- A model has been developed for predicting recurrence among kidney stone formers, according to a study published in the February issue of the Mayo Clinic Proceedings. Lisa E. Vaughan, from the Mayo Clinic in Rochester,...

http://bit.ly/2Sz6zwZ

Walgreens Worst Violator in Tobacco Sales to Minors, FDA Says

FRIDAY, Feb. 8, 2019 -- Walgreens' high rate of violations for selling tobacco products to minors has led U.S. Food and Drug Administration Commissioner Scott Gottlieb, M.D., to ask for a meeting with the company to discuss the issue. In a statement...

http://bit.ly/2MX19Xp

Measles Outbreak Triggers Sharp Rise in Demand for Vaccine

FRIDAY, Feb. 8, 2019 -- Health clinics in Clark County, Washington, are scrambling to meet the sharply increased demand for measles vaccination as people seek protection during an outbreak of the highly contagious virus. State health department data...

http://bit.ly/2SCo4fF

Contents

http://bit.ly/2tdlm1O

Elsewhere in The AGA Journals

http://bit.ly/2UVnkA3

Neutrophil-to-Lymphocyte Ratio; an Independent Predictor of Mortality or Just a Surrogate Marker of Underlying Complications?

We read with interest the recently published article by Rice et al1 illustrating the prognostic value of admission neutrophil-to-lymphocyte ratio (NLR) in patients with cirrhosis.

http://bit.ly/2tdiq5m

No Maintenance, No Gain in Long-term Treatment of Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergen-induced/immune-mediated disease that has been rapidly increasing in incidence and prevalence and now accounts for substantial health care costs and utilization.1–3 The chronicity of EoE has been supported by a number of investigations, including a seminal natural history study by Straumann et al4 in which esophageal eosinophilia and dysphagia persisted in EoE patients over a mean follow-up period of more than 7 years without anti-inflammatory treatment.

http://bit.ly/2URv5a5

Editorial Board

http://bit.ly/2tfbKDM

Cover

http://bit.ly/2UNWsSk

Information for Authors and Readers

Clinical Gastroenterology and Hepatology is the go-to resource on a broad spectrum of themes in clinical gastroenterology and hepatology. The official clinical practice journal of the AGA Institute brings you the best original research in the field with a unique combination of reviews, editorials, podcasts, video abstracts, and outcomes research—all supporting clinical practice. Articles on education, policy, and practice management highlight issues pertinent to clinicians.

http://bit.ly/2ta0Lf0

Clostridium difficile

Clostridium difficile is a bacterial infection of the intestine that may cause gut symptoms such as:

http://bit.ly/2UQPoo1

Reply

On behalf of our co-authors, we appreciate the interest of Macaluso et al1 regarding our study, "Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression,"2 and agree with their comment regarding the lack of consensus on which patients should receive primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP). We also agree with their suggestion that PJP prophylaxis be considered in inflammatory bowel disease (IBD) patients treated with a calcineurin inhibitor and we also believe, as noted in our article, that patients on triple immunosuppression should be considered at higher risk.

http://bit.ly/2tbszQd

Issue Highlights

Although anti-thrombotic agents are a known risk factor for upper gastrointestinal (GI) bleeding, their impact on patient outcomes is unclear. In this issue of Clinical Gastroenterology and Hepatology, Dunne and colleagues1 reported results from a multi-center, multi-national prospective cohort study to assess the effect of anti-thrombotic agents on outcomes in patients with high-risk upper GI bleeding. The authors evaluated 568 patients with acute upper GI bleeding who underwent endoscopy between March 2014 and March 2015, of whom 44% used anti-thrombotic agents.

http://bit.ly/2UVnjvZ

Reply

We appreciate the interest by Karakonstantis et al in our article showing that NLR associates with mortality in hospitalized patients with cirrhosis.

http://bit.ly/2UNCp6r

Reply

We thank Drs Van Kruiningen and Sura for their letter and interest in the topic of granuloma detection in patients with Crohn's disease. We agree that our study had an overall lower rate of granuloma detection, but offer the following explanation for this difference with prior literature.

http://bit.ly/2tbsw6Z

Reply

We thank Drs Gracie and Ford for their interest in our recent article.1 We appreciate their comments and discussion of the recent data from the Inflammatory Bowel South-Eastern Norway study,2 highlighting both the clinical significance of functional gastrointestinal symptoms in inflammatory bowel disease (IBD) as well as the critical importance of investigating noninflammatory mechanisms in this patient population. Findings further raise the question of whether histologic remission is a sufficient therapeutic target in IBD patients with persistent symptoms.

http://bit.ly/2tbsuvT

Functional Gastrointestinal Symptoms in Inflammatory Bowel Disease: Rising to the Challenge

We read the recent article by Colombel et al1 with interest. We applaud the authors for drawing attention to the plight of patients with inflammatory bowel disease (IBD) who report ongoing symptoms in the absence of inflammation. Recently, the inflammatory bowel South-Eastern Norway study has highlighted that, even among patients with ulcerative colitis (UC) in deep histological remission, 1 in 3 may report these so-called functional symptoms.2 Whether such symptoms are due to genuine coexisting functional disease3 or not, they have a substantial impact on the quality of life and psychological health of patients.

http://bit.ly/2UTjaZr

Study Tests Targeted Drugs for Multiple Myeloma [News in Brief]

The MyDRUG trial matches patients with therapies based on tumor mutations.

http://bit.ly/2WRyM1d

Monophosphorylation Regulates Activities of RB during G1 [Research Watch]

Site-specific monophosphorylation of RB fine-tunes its regulation of multiple cellular activities.

http://bit.ly/2RLLz1u

Pharmacologic Inhibition of STK19 Impairs NRAS-Driven Melanoma [Research Watch]

Phosphorylation of oncogenic NRAS by STK19 promotes melanomagenesis.

http://bit.ly/2WOhT7v

Ibrutinib plus Palbociclib Has Efficacy in Mantle Cell Lymphoma [Research Watch]

The BTK inhibitor ibrutinib plus the CDK4 inhibitor palbociclib achieves responses in 67% of MCL patients.

http://bit.ly/2RQ9D3l

Targeting the interplay between metabolism and epigenetics in cancer

Purpose of review Metabolic perturbation is a hallmark of cancer favoring tumor progression. It is now demonstrated that cell metabolism has an impact on gene expression through epigenetic modifications. In this review, we expose recent evidences of metabolic-driven epigenetic perturbations in cancer and subsequent therapeutic opportunities. Recent findings The intimate link between metabolism and epigenetics and its rewiring in carcinogenesis is a hot topic. Chromatin-modifying enzymes involved in the dynamics of methylation or acetylation require small metabolites as cofactors or substrates, thus orchestrating the integration between epigenetic and transcriptional states. Mutations in metabolic enzymes such as isocitrate dehydrogenase 1 and 2 cause the accumulation of metabolites that upset the balance of histone and DNA methylation, thus generating widespread deregulation of epigenetically controlled gene expression. Additionally, modifications of catalytic activity and subcellular localization of metabolic enzymes in cancer can impact on epigenetic modifications and gene expression programs to favor tumor progression. Summary The interplay between metabolism and epigenetics and its molecular characterization in cancer cells identifies potential targets for the development of new therapies.

http://bit.ly/2Sz7kGl

Editorial introductions

No abstract available

http://bit.ly/2MWGvGN

Editorial: New Frontiers in Skin Cancer

No abstract available

http://bit.ly/2SJy7jn

Mosaicism, aging and cancer

Purpose of review Genetic mosaicism is the presence of a somatic mutation in a subset of cells that differs from the inherited germline genome. Detectable genetic mosaicism is attractive as a potential early biomarker for cancer risk because of its established relationship with aging, introduction of potentially deleterious mutations, and clonal selection and expansion of mutated cells. The aim of this review is to survey shared risk factors associated with genetic mosaicism, aging and cancer risk. Recent findings Studies have associated aging, cigarette smoking and several genetic susceptibility loci with increased risk of acquiring genetic mosaicism. Genetic mosaicism has also been associated with numerous outcomes including cancer risk and cancer mortality; however, the level of evidence supporting these associations varies considerably. Summary Ample evidence exists for shared risk factors for genetic mosaicism and cancer risk as well as abundant support linking genetic mosaicism in leukocytes to hematologic malignancies. The relationship between genetic mosaicism in circulating leukocytes and solid malignancies remains an active area of research.

http://bit.ly/2MXqGPZ

Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?

Purpose of review Checkpoint inhibitors (CPIs) provide impressive response rates among immunocompetent patients with various solid tumors. So far, organ transplant recipients have been excluded from clinical studies due to the putative risk of allograft rejection however 48 cases of liver and renal transplant patients treated with CPI were already described in literature. Recent findings Here we discuss 19 cases of liver and 29 cases of renal transplant patients who received CPI for advanced cancer. Disease control rate [stable disease, complete response (CR) and partial response (PR) together] was 35% (21% for liver and 45% for kidney transplant patients). Graft rejection was seen in 37% of liver and 45% and kidney transplant patients. Significantly, our analysis shows that an 'ideal' response occurs in 21% of all patients (antitumor response accompanied with durable graft tolerance). Summary We believe that transplant patients can be treated with CPI in a controlled setting and for well informed patients. To obtain a durable antitumor immune response while avoiding rejection, to be able to adjust immunosuppression and to have the opportunity to develop biomarkers for tumor response and transplant rejection, these patients should be treated according to a clinical care path or a prospective clinical trial.

http://bit.ly/2SHdX9m

p53, stem cell biology and childhood blastomas

Purpose of review Childhood blastomas, unlike adult cancers, originate from developing organs in which molecular and cellular features exhibit differentiation arrest and embryonic characteristics. Conventional cancer therapies, which rely on the generalized cytotoxic effect on rapidly dividing cells, may damage delicate organs in young children, leading to multiple late effects. Deep understanding of the biology of embryonal cancers is crucial in reshaping the cancer treatment paradigm for children. Recent findings p53 plays a major physiological role in embryonic development, by controlling cell proliferation, differentiation and responses to cellular stress. Tumor suppressor function of p53 is commonly lost in adult cancers through genetic alterations. However, both somatic and germline p53 mutations are rare in childhood blastomas, suggesting that in these cancers, p53 may be inactivated through other mechanisms than mutation. In this review, we summarize current knowledge about p53 pathway inactivation in childhood blastomas (specifically neuroblastoma, retinoblastoma and Wilms' tumor) through various upstream mechanisms. Laboratory evidence and clinical trials of targeted therapies specific to exploiting p53 upstream regulators are discussed. Summary Despite the low rate of inherent TP53 mutations, p53 pathway inactivation is a common denominator in childhood blastomas. Exploiting p53 and its regulators is likely to translate into more effective targeted therapies with minimal late effects for children. (see Video Abstract, Supplemental Digital Content 1, http://bit.ly/2SwjAaD).

http://bit.ly/2MXqErl

Sunbeds and melanoma risk: time to close the debate

Purpose of review In spite of the established scientific evidence on the association of sunbed use with melanoma risk, some have recently expressed scepticism about the carcinogenicity of indoor tanning. This may have raised confusion among both physicians and patients. The purpose of this review is to make the point about the real impact of sunbed use on melanoma risk in light of the most recently published evidence. Recent findings Seven themes were covered: recent studies on age at first sunbed exposure and melanoma risk; sunbed use and melanoma at different body sites; sunbed use and development of additional primary melanomas; new studies on proportion of melanomas attributable to sunbed use; sunbed use and melanoma risk factors; economic burden of sunbed use; and recent debate over whether indoor tanning contributes to melanoma. Summary We were able to apply all epidemiological criteria for causality to the relationship between sunbed use and melanoma. Together with the new evidence on the strength, dose response, and temporality of the association of sunbeds with melanoma, this will hopefully close the debate over whether indoor tanning contributes to melanoma.

http://bit.ly/2N0u8cQ

Post-transcriptional regulations of cancer stem cell homeostasis

Purpose of review Although extensively studied for over a decade, gene expression programs established at the epigenetic and/or transcriptional levels do not fully characterize cancer stem cells (CSC). This review will highlight the latest advances regarding the functional relevance of different key post-transcriptional regulations and how they are coordinated to control CSC homeostasis. Recent findings In the past 2 years, several groups have identified master post-transcriptional regulators of CSC genetic programs, including RNA modifications, RNA-binding proteins, microRNAs and long noncoding RNAs. Of particular interest, these studies reveal that different post-transcriptional mechanisms are coordinated to control key signalling pathways and transcription factors to either support or suppress CSC homeostasis. Summary Deciphering molecular mechanisms coordinating plasticity, survival and tumourigenic capacities of CSCs in adult and paediatric cancers is essential to design new antitumour therapies. An entire field of research focusing on post-transcriptional gene expression regulation is currently emerging and will significantly improve our understanding of the complexity of the molecular circuitries driving CSC behaviours and of druggable CSC weaknesses.

http://bit.ly/2SBwQux

New perspectives in Merkel cell carcinoma

Purpose of review Merkel cell carcinoma (MCC), a rapidly progressing skin cancer, has poor prognosis. We reviewed the epidemiology, pathogenesis, diagnosis and treatment of MCC, with a focus on recent therapeutic advancements. Recent findings Risk factors for MCC, such as old age, immunosuppression, polyomavirus infection and exposure to UV radiation have already been identified, but the underlying mechanisms leading to carcinogenesis still need clarification. On the basis of recent advances, immunotherapy – in particular, inhibition targeting the programmed cell death protein 1/programmed death-ligand 1 (PD1)/PDL1) immune checkpoint blockade – is currently being investigated in the treatment of metastatic MCC. Avelumab, an anti-PDL1 antibody, was the first drug to be approved internationally as second-line monotherapy for patients with advanced MCC, based on results from the JAVELIN Merkel 200 clinical trial. Avelumab has also recently been approved as first-line treatment for advanced MCC in Europe. Pembrolizumab (anti-PD1) in first-line and nivolumab (anti-PD1) in first-line and second-line treatments are two other checkpoint inhibitors that are under investigation, and showing promising results. New innovative therapies are also in development. Summary New insights concerning advances in MCC diagnosis and treatment have been highlighted. Immunotherapy for metastatic MCC constitutes a recent breakthrough in an unmet medical need, but alternative therapies should continue to be investigated.

http://bit.ly/2MYhESK

Chordoma: update on disease, epidemiology, biology and medical therapies

Purpose of review Chordoma is an exceedingly rare subtype of bone sarcoma. This review aims to provide a comprehensive insight into chordoma epidemiology, and an update on the recent advances in disease, biology and medical therapies. Recent findings The incidence of chordoma is approximately 0.08/100 000 and the 5-year overall age-adjusted relative survival is 72% in the United States and 61% in Europe. Over the last years, significant steps forwards have been done in the comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described and potentially druggable molecular targets identified. This is becoming all the more relevant today, as new potentially active agents are under development. Summary Chordoma is a complex disease because of its rarity, biological heterogeneity and peculiar clinical behaviour. Despite the progress done, the outcome in this disease remains unsatisfactory and the identification of active systemic treatments remains an urgent, unmet medical need.

http://bit.ly/2SJy5Ih

A feasibility study of mediastinoscopic radical esophagectomy for thoracic esophageal cancer from the viewpoint of the dissected mediastinal lymph nodes validated with thoracoscopic procedure: a prospective clinical trial

Abstract

Purpose

A prospective trial evaluated the feasibility and safety of "mediastinoscopic esophagectomy with lymph node dissection" (MELD).

Methods

Eligible patients had thoracic esophageal squamous cell carcinoma, excluding T4, a bulky primary lesion or distant metastasis. Ten patients were enrolled and treated between September 2015 and March 2018. Additionally, to verify the integrity of the mediastinal lymph node dissection, thoracoscopic observation and lymph node dissection were followed. The primary end point was the integrity of mediastinal lymph node dissection. The secondary end points were the short-term outcomes, including mortality and morbidity.

Results

The median number of dissected lymph nodes in the upper mediastinal to cervical region and middle to lower mediastinal region by mediastinoscopy/thoracoscopy was 27/0.5 and 11.5/0, respectively. The median total operation time was 615 min, the median bleeding amount was 476 ml, and the median postoperative hospital stay was 15.5 days. Regarding complications of more than grade III according to the Clavien–Dindo classification, four had sputum excretion difficulty, one had pneumothorax and one had bilateral recurrent nerve palsy, but none required conversion to thoracotomy, and no operative deaths occurred.

Conclusion

Although the rate of recurrent nerve palsy still should be reduced, our mediastinoscopic lymphadenectomy technique is closely similar to radical esophagectomy.

http://bit.ly/2E1q358

Don’t Smoke ‘em if you got ‘em—Tobacco Exposure Increases Risk of Serrated Polyps

http://bit.ly/2Bvrd7j

Pancreatic cysts: Let’s start looking at the patient before poking at the cyst

http://bit.ly/2TFb7Pv

Healthcare Utilization and Costs for Patients With End-stage Liver Disease are Significantly Higher at the End of Life Compared to Those of Other Decedents

Patients with end-stage liver disease (ESLD) have progressively complex medical needs. However, little is known about their end of life health care utilization or associated costs. We performed a population-based study to evaluate the end of life direct utilization and costs for patients with ESLD among health care sectors in the province of Ontario.

http://bit.ly/2Boh2RW

Colorectal Cancer in Individuals With Familial Adenomatous Polyposis, Based on Analysis of the Danish Polyposis Registry

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that increases risk for colorectal cancer (CRC). We assessed changes in the incidence and prevalence of CRC, and survival times, of patients with FAP participating in the Danish follow-up study.

http://bit.ly/2TFb1r7

American ancestry is a risk factor for suspected non-alcoholic fatty liver disease in Hispanic/Latino adults

Non-alcoholic fatty liver disease (NAFLD) disproportionally affects Hispanic/Latino populations. However, the magnitude varies among Hispanic/Latino ethnic groups. We investigated the mechanisms of these disparities.

http://bit.ly/2Bs7ipU

Gastric Tumoral Melanosis: a Rare Manifestation of Successfully Treated Malignant Melanoma

http://bit.ly/2TDswbh

Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection

The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous groups of patients in North America.

http://bit.ly/2Bt6HnJ

Refractory perforated gastric ulcer after particle beam radiation therapy followed by bevacizumab treatment

http://bit.ly/2TEIZfz

Importance of tissue acquisition in gastric submucosal tumor with unusual EUS features

http://bit.ly/2Skd3Ay

Anaplastic Lymphoma Kinase (ALK)-positive Tumors: Clinical, Radiographic and Molecular Profiles, and Uncommon Sites of Metastases in Patients With Lung Adenocarcinoma

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non–small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC. Methods: All patients with metastatic ALK+ NSCLC at the City of Hope Cancer Center in Duarte, California from 2010 to 2017 were selected for retrospective chart review. The demographic variables were collected. The molecular statuses of patients were evaluated through commercially available platforms for next-generation sequencing. Three-dimensional volumetric images were generated for the primary lesion and different sites of metastasis. Results: Sixty two patients with ALK+ NSCLC were identified from 2010 to 2017. The median age was 59 with 36 (58%) female individuals and only 20 (32%) smokers. Twenty four patients had uncommon sites of metastasis which were thyroid, soft tissue, chest and abdominal wall, spleen, peritoneum, omentum, kidney, and ovary. Common characteristics of the primary lesions were right upper lobe location (N=23 [37%]), oval shape (N=22 [35%]), irregular margins (N=26 [42%]), solid lesions (N=27 [44%]), presence of pleural contact or effusion (N=22 [35%]). Twenty four patients had next-generation sequencing testing which showed coexisting mutations such as TP53 (N=8), EGFR (N=5), KRAS (N=3). Patients with uncommon sites of metastasis had a decreased median survival compared with common sites (39 vs. 82 m, P=0.046). Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes. 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. http://bit.ly/1hexVwJ This study was supported by NIH/NCI P30CA033572 and NIH/NCI 1U54CA209978-01A1. The authors declare no conflicts of interest. Reprints: Ravi Salgia, MD, PhD, Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010. E-mail: rsalgia@coh.org. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2SBixGi

Delays in palliative care referral among surgical patients: perspectives of surgical residents across the state of Michigan

Palliative care services (PCS) are underutilized and frequently delayed among surgical patients. Surgical residents often serve at the forefront for patient issues, including conducting conversations regarding prognosis and goals of care.

http://bit.ly/2SlND5e

Female Representation and Implicit Gender Bias at the 2017 American Society of Colon and Rectal Surgeons’ Annual Scientific and Tripartite Meeting

BACKGROUND: Women surgeons are underrepresented in academic surgery and may be subject to implicit gender bias. In colorectal surgery, women comprise 42% of new graduates, but only 19% of Diplomates in the United States. OBJECTIVE: We evaluated the representation of women at the 2017 American Society of Colon and Rectal Surgeons Scientific and Tripartite Meeting and assessed for implicit gender bias. DESIGN: This was a prospective observational study. SETTING: The study occurred at the 2017 Tripartite Meeting. MAIN OUTCOME MEASURES: The primary outcome measured was the percentage of women in the formal program relative to conference attendees and forms of address. METHODS: Female program representation was quantified by role (moderator or speaker), session type, and topic. Introductions of speakers by moderators were classified as formal (using a professional title) or informal (using name only), and further stratified by gender. RESULTS: Overall, 31% of meeting attendees who are ASCRS members were women, with higher percentages of women as Candidates (44%) and Members (35%) compared with Fellows (24%). Women comprised 28% of moderators (n = 26) and 28% of speakers (n = 80). The highest percentage of women moderators and speakers was in education (48%) and the lowest was in techniques and technology (17%). In the 41 of 47 sessions evaluated, female moderators were more likely than male moderators to use formal introductions (68.7% vs 54.0%, p = 0.02). There was no difference when female moderators formally introduced female versus male speakers (73.9% vs 66.7%, p = 0.52); however, male moderators were significantly less likely to formally introduce a female versus male speaker (36.4% vs 59.2%, p = 0.003). LIMITATIONS: Yearly program gender composition may fluctuate. Low numbers in certain areas limit interpretability. Other factors potentially influenced speaker introductions. CONCLUSIONS: Overall, program representation of women was similar to meeting demographics, although with low numbers in some topics. An imbalance in the formality of speaker introductions between genders was observed. Awareness of implicit gender bias may improve gender equity and inclusiveness in our specialty. See Video Abstract at http://bit.ly/2SEaKrb.

http://bit.ly/2N3amxr

Announcements

No abstract available

http://bit.ly/2MV6f6k

The Evidence Speaks for Itself

No abstract available

http://bit.ly/2SGuuug

Laparoscopic Mesorectal Excision in Obesity: Novel Insights and Technical Strategies

INTRODUCTION: Obesity is a burgeoning problem worldwide. Although beneficial in obese patients, conventional laparoscopic mesorectal excision for rectal cancer is technically challenging, with a higher conversion rate to open compared with nonobese patients. We describe novel strategies to circumvent these difficulties. TECHNIQUE: The key steps are 1) lateral-to-medial colonic mobilization and left-sided mesorectal excision with the surgeon on the patient's right; 2) switching to the patient's left for right-sided mesorectal excision; 3) further rectal retraction with cotton tape and preperitoneal fat sling; and 4) caudal-to-cephalad mobilization of colon after distal transection, which facilitates extrapelvic mesenteric dissection and vessel ligation. RESULTS: These techniques optimize gravity to negate the lack of exposure due to visceral obesity. Triangulation is improved by changing the surgeon's position during mesorectal dissection. This allows accurate identification of anatomical planes and avoids excessive pneumoperitoneum pressures and Trendelenburg tilt. CONCLUSIONS: Adopting these strategies can facilitate laparoscopic mesorectal excision in the obese patient and may reduce conversion to open.

http://bit.ly/2MV66ji

Adjuvant Chemotherapy for Colon Cancer

No abstract available

http://bit.ly/2SBhkih

Consequences of Increasing Complexity in Anorectal Surgery Performed at an Academic Center

BACKGROUND: Anorectal surgery encompasses a wide range of procedures with varying complexity. The Accreditation Council for Graduate Medical Education Review Committee for Colon and Rectal Surgery recommends minimum case numbers (60) for 1-year specialty trainees in 6 categories of anorectal surgery, with definitions for procedural complexity. OBJECTIVE: The purpose of this study was to assess the scope of anorectal procedures and propose a stratification of procedures based on a consensus of levels of difficulty, as well as to identify a predictive charge cutoff suggestive of procedural complexity. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Patients undergoing anorectal procedures between January 2011 and December 2014 identified by Current Procedural Terminology coding were entered into 6 categories. Codes were stratified as routine or complex based on an assessment of perioperative care and technical expertise required. Patients with an abdominal portion to any procedure were excluded. MAIN OUTCOMES MEASURES: The study measured distribution of complexity in anorectal surgical procedures and procedural charge associated with differentiating routine from complex procedures. RESULTS: Seven colorectal surgeons performed 2483 anorectal procedures (mean = 620 per year). Mean age was 48 ± 16 years. Forty six (64%) of 71 procedures were classified as routine and 25 (36%) of 71 as complex. Most disease processes had subsets with routine or complex procedures, whereas all of the procedures performed for fecal incontinence or advanced anorectal techniques were considered complex. Fistula procedures and transanal excisions were most heterogeneous, with a high procedural complexity rate (37% and 50%). After a procedural complexity rating, intraclass correlation by 6 surgeons was 0.70, demonstrating good correlation. Receiver operating curve assessments of consensus categorization according to billing codes revealed $553 as the optimal cutoff between routine and complex procedures. LIMITATIONS: This was a single-institution retrospective review. CONCLUSIONS: Colorectal residents may benefit from anorectal case stratification, because it serves as a dialogue for those interested in complex anorectal surgery during training. Surgeon categorization of procedures correlates well with a charge-based model of complexity. See Video Abstract at http://bit.ly/2SBhg21.

http://bit.ly/2MV5XMM

Expert Commentary on Adjuvant Chemotherapy for Colon Cancer

No abstract available

http://bit.ly/2N3aJIl

Meta-analyses of Current Strategies to Treat Uncomplicated Diverticulitis

BACKGROUND: Uncomplicated colonic diverticulitis is common. There is no consensus regarding the most appropriate management. Some authors have reported the efficacy and safety of observational management, and others have argued for a more aggressive approach with oral or intravenous antibiotic treatment. OBJECTIVE: The purpose of this study was to perform an updated meta-analysis of the different management strategies for uncomplicated diverticulitis with 2 separate meta-analyses. DATA SOURCES: MEDLINE, Embase, and Cochrane databases were used. STUDY SELECTION: All randomized clinical trials, prospective, and retrospective comparative studies were included. INTERVENTIONS: Observational and antibiotics treatment or oral and intravenous antibiotics treatment were included. MAIN OUTCOME MEASURES: Successful management (emergency management, recurrence, elective management) was measured. RESULTS: After review of 293 identified records, 11 studies fit inclusion criteria: 7 studies compared observational management and antibiotics treatment (2321 patients), and 4 studies compared oral and intravenous antibiotics treatment (355 patients). There was no significant difference between observational management and antibiotics treatment in terms of emergency surgery (0.7% vs 1.4%; p = 0.1) and recurrence (11% vs 12%; p = 0.3). In this part, considering only randomized trials, elective surgery during the follow-up occurred more frequently in the observational group than the antibiotic group (2.5% vs 0.9%; p = 0.04). The second meta-analysis showed that failure and recurrence rates were similar between oral and intravenous antibiotics treatment (6% vs 7% (p = 0.6) and 8% vs 9% (p = 0.8)). LIMITATIONS: Inclusion of nonrandomized studies, identification of high risks of bias (selection, performance, and detection bias), and presence of heterogeneity between the studies limited this work. CONCLUSIONS: Observational management was not statistically different from antibiotic treatment for the primary outcome of needing to undergo surgery. However, in patients being treated by antibiotics, our studies demonstrated that oral administration was similar to intravenous administration and provided lower costs. Although it may be difficult for physicians to do, there is mounting evidence that not treating uncomplicated colonic diverticulitis with antibiotics is a viable treatment alternative.

http://bit.ly/2SBh7vv

Robotic Transanal Minimally Invasive Surgery for the Excision of Rectal Neoplasia: Clinical Experience With 58 Consecutive Patients

BACKGROUND: Given the significant perioperative risks and costs of total mesorectal excision, minimally invasive transanal surgical approaches have grown in popularity for early rectal cancer and rectal polyps. This article discusses a transanal robotic surgery technique to perform full-thickness resections of benign and malignant rectal neoplasms. OBJECTIVE: The purpose of this study was to describe an initial experience with robotic transanal minimally invasive surgery. DESIGN: This was a retrospective cohort study of consecutive patients who underwent robotic transanal minimally invasive surgery. SETTINGS: The study was conducted at a high-volume colorectal surgery practice with a large health maintenance organization. PATIENTS: Patients at Southern California Kaiser Permanente with early rectal cancer and rectal polyps amenable to transanal excision were included. INTERVENTIONS: Transanal resection of rectal tumors were removed using robotic transanal minimally invasive surgery. MAIN OUTCOME MEASURES: Local recurrence of rectal pathology was measured. RESULTS: A total of 58 patients underwent robotic transanal minimally invasive surgery with full-thickness rectal resection by 4 surgeons for the following indications: rectal cancer (n = 28), rectal polyp (n = 18), rectal carcinoid (n = 11), and rectal GI stromal tumor (n = 1). Mean operative time was 66.2 minutes (range, 17–180 min). The mean tumor height from the anal verge was 8.8 cm (range, 4–14 cm), and the mean specimen size was 3.3 cm (range, 1.3–8.2 cm). A total of 57 (98.3%) of 58 specimens were intact, and 55 (94.8%) of 58 specimens had negative surgical margins. At a mean follow-up of 11.5 months (range, 0.3–33.3 mo), 3 patients (5.5%) developed local recurrences, and all underwent successful salvage surgery. LIMITATIONS: The study was limited by being a retrospective, nonrandomized trial with short follow-up. CONCLUSIONS: Robotic transanal minimally invasive surgery is a safe, oncologically effective surgical approach for rectal polyps and early rectal cancers. It offers the oncologic benefits and perioperative complication profile of other transanal minimally invasive surgical approaches but also enhances surgeon ergonomics and provides an efficient transanal rectal platform. See Video Abstract at http://bit.ly/2SBh1UF.

http://bit.ly/2MVUD34

A Team-Based Approach to Anal Cancer Screening and Prevention

No abstract available

http://bit.ly/2N39HvX

Influence of Anastomotic Leak After Elective Colorectal Cancer Resection on Survival and Local Recurrence: A Propensity Score Analysis

BACKGROUND: The occurrence of anastomotic leakage is still a life-threatening complication for patients after colorectal surgery. In literature not only an impact on the short-term outcome but also on long-term survival and local recurrence of colorectal cancer patients is discussed. OBJECTIVE: This study aimed to investigate the impact of anastomotic leakage on long-term survival and local recurrence. DESIGN: A total of 1122 patients with resections for colorectal cancer were analyzed. In 94 patients (8.4%) there was clinical proof of anastomotic leakage. A reference group was defined as the 1028 patients without anastomotic leakage using 1:1 propensity score-matching according to the following criteria: age, sex, International Union Against Cancer stage, Karnofsky index, tumor site, and grading, as well as adjuvant chemotherapy. A calculation of overall survival, disease-free survival, and local recurrence rate was performed for both groups. SETTINGS: The study was conducted using a retrospective matched-pairs analysis, based on a prospectively maintained institutional colorectal cancer database. PATIENTS: Ninety-four patients with anastomotic leakage and 94 matched control subjects from a total of 1122 patients with resections for colorectal cancer were studied. MAIN OUTCOME MEASURES: Overall survival, disease-free survival, and local recurrence rate for patients with colorectal cancer with and without anastomotic leakage were measured. RESULTS: The propensity score matching successfully created 2 groups with no significant differences in the matching criteria. Survival analysis disclosed no significant differences between the groups in terms of overall survival, disease-free survival, and local recurrence rate. Univariate analysis identified age, Karnofsky index, International Union Against Cancer stage, and lymph node metastasis as significant prognostic factors. Multivariable analysis of these variates revealed age and positive lymph nodes as independent predictors of overall survival and disease-free survival. LIMITATIONS: The study was limited by nature of being a retrospective analysis and monocentric study. CONCLUSIONS: This matched-pairs analysis, comparing patients with colorectal cancer with and without anastomotic leakage, revealed no significant differences in overall survival, disease-free survival, and local recurrence rate. Contrary results in the literature might be caused by nonbalanced settings in nonmatched collectives. See Video Abstract at http://bit.ly/2MXRiR8.

http://bit.ly/2SF0PSm

Moving Beyond Representation as a Marker of Gender Equity

No abstract available

http://bit.ly/2SDzxvw

Is the Pathologic Response of T3 Rectal Cancer to High-Dose-Rate Endorectal Brachytherapy Comparable to External Beam Radiotherapy?

BACKGROUND: Endorectal brachytherapy is an attractive option in the neoadjuvant setting for locally advanced rectal cancer, but it is not considered standard of care. OBJECTIVE: This study aimed to compare pathologic outcomes of patients with clinical T3 rectal cancer who underwent high-dose-rate endorectal brachytherapy with those who underwent conventional external beam radiotherapy. DESIGN: This study is a retrospective chart review. SETTINGS: This study was conducted in a single large tertiary academic colorectal surgery practice in Canada. PATIENTS: Adult patients with MRI-staged T3 rectal adenocarcinoma treated with neoadjuvant radiotherapy followed by total mesorectal excision from 2007 to 2016 were included. INTERVENTIONS: Neoadjuvant radiotherapy was delivered by high-dose-rate endorectal brachytherapy or conventional external beam radiotherapy. MAIN OUTCOME MEASURES: Primary outcome was pathologic complete response, defined as ypT0N0. Secondary outcomes included tumor (T stage) and lymph node (N stage) downstaging and tumor regression grade. RESULTS: Ninety-nine patients were identified as having clinical T3 rectal cancer based on blinded pretreatment MRI review. Mean age was 66.2 years (± 6.2) and 59 patients (59.6%) were male. Thirty-three patients were clinically node negative (33.3%), 45 had c-N1 disease (45.5%), and 21 had c-N2 disease (21.2%). Sixty-four patients (64.6%) underwent high-dose-rate endorectal brachytherapy and 35 (35.4%) underwent external beam radiotherapy. The high-dose-rate endorectal brachytherapy group had a lower median mesorectal depth of invasion (4 mm vs 5 mm, p = 0.010); all other preoperative tumor characteristics were similar in both groups. Eighteen patients (18.2%) achieved pathologic complete response: 12 in the high-dose-rate endorectal brachytherapy group and 6 in the conventional external beam radiotherapy group (18.8% vs 17.1%, p = 0.84). High-dose-rate endorectal brachytherapy was superior to conventional radiotherapy for tumor (T stage) downstaging (59.4% vs 28.6%, p = 0.0030) but not for lymph node (N stage) downstaging (35.9% vs 51.4%, p = 0.14). LIMITATIONS: This study was limited by its retrospective nature and modest sample size. CONCLUSIONS: Neoadjuvant treatment of T3 rectal cancer with high-dose-rate endorectal brachytherapy appears to achieve equivalent rates of pathologic complete response and superior T-stage downstaging compared with conventional external beam radiotherapy. See Video Abstract at http://bit.ly/2SJjEE5.

http://bit.ly/2N39skx

Medium- to Long-term Follow-up of Obstetric Anal Sphincter Injury

BACKGROUND: Obstetric anal sphincter injury is the primary modifiable risk factor for anal incontinence in women. Currently, endoanal ultrasound is most commonly used to detect residual anal sphincter defects after childbirth. Translabial ultrasound has recently been introduced as a noninvasive alternative. OBJECTIVES: This study aimed to determine medium- to long-term outcomes in women after obstetric anal sphincter injuries diagnosed and repaired at delivery. DESIGN: This is a cross-sectional study. SETTINGS: This study was performed in a tertiary obstetric unit. PATIENTS: Between 2005 and 2015, 707 women were diagnosed with obstetric anal sphincter injuries; 146 followed an invitation for follow-up. INTERVENTIONS: Clinical examination, anal manometry, and translabial ultrasound were performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the St Mark incontinence score and the evidence of sphincter disruption on translabial ultrasound. RESULTS: Of 372 contactable patients, 146 attended at a mean follow-up of 6.6 years (1.7–11.9), of which 75 (51%) reported symptoms of anal incontinence with a median "bother score" of 6 (interquartile range, 3–8). Median St Mark score was 3 (interquartile range, 2–5). Twenty-four (16%) had a score of ≥5. Women who had been diagnosed with a 3c/4th degree tear had more symptoms (58% vs 44%), significantly lower mean maximal resting pressure (p

http://bit.ly/2MXR0K2

Comparison of Anal Versus Rectal Staging in the Prognostication of Rectal Squamous Cell Carcinoma: A Population-Based Analysis

BACKGROUND: Rectal squamous cell carcinoma is a rare malignancy with limited data regarding management and prognosis. It is also unknown whether a rectal squamous cell cancer staging system should be based on size, as for anal squamous cell carcinoma, or depth of invasion, as for rectal adenocarcinoma. OBJECTIVE: The aims of the current study were to determine the optimal management strategy, prognostic factors, and staging system for rectal squamous cell carcinoma. DESIGN: This was a population-based study. SETTINGS: The Surveillance, Epidemiology, and End Results database was used to identify patents diagnosed between 1988 and 2013. PATIENTS: Patients ≥18 years of age undergoing radiation or local excision alone, radiation with local excision, or radiation with radical resection were included. Patients were then staged according to both the American Joint Committee on Cancer classification for rectal adenocarcinoma (American Joint Committee on Cancer-rectum) and anal cancer (American Joint Committee on Cancer-anus). MAIN OUTCOME MEASURES: The main outcome was 5-year, disease-specific survival. RESULTS: In both univariate and multivariate survival analyses, the addition of local excision or radical resection to radiation resulted in similar-to-worse outcomes across all of the stages. Among patients staged according to American Joint Committee on Cancer-rectum (n = 1646), although a significant difference in 5-year survival was observed for stage I as compared with higher stages, no difference was noted between stages II and III (80% vs 61% and 62%). However, in the American Joint Committee on Cancer-anus classification (n = 1327), a significant difference was observed across all of the stages (87% vs 72% vs 59%; p

http://bit.ly/2SAnIGC

System-Wide Improvement for Transitions After Ileostomy Surgery: Can Intensive Monitoring of Protocol Compliance Decrease Readmissions? A Randomized Trial

BACKGROUND: Hospital readmission is common after ileostomy formation and frequently associated with dehydration. OBJECTIVE: This study was conducted to evaluate a previously published intervention to prevent dehydration and readmission. DESIGN: This is a randomized controlled trial. SETTING: This study was conducted in 3 hospitals within a single health care system. PATIENTS: Patients undergoing elective or nonelective ileostomy as part of their operative procedure were selected. INTERVENTION: Surgeons, advanced practice providers, inpatient and outpatient nurses, and wound ostomy continence nurses participated in a robust ileostomy education and monitoring program (Education Program for Prevention of Ileostomy Complications) based on the published intervention. After informed consent, patients were randomly assigned to a postoperative compliance surveillance and prompting strategy that was directed toward the care team, versus usual care. OUTCOME MEASURES: Unplanned hospital readmission within 30 days of discharge, readmission for dehydration, acute renal failure, estimated direct costs, and patient satisfaction were the primary outcomes measured. RESULTS: One hundred patients with an ileostomy were randomly assigned. The most common indications were rectal cancer (n = 26) and ulcerative colitis (n = 21), and 12 were emergency procedures. Although intervention patients had better postdischarge phone follow-up (90% vs 72%; p = 0.025) and were more likely to receive outpatient intravenous fluids (25% vs 6%; p = 0.008), they had similar overall hospital readmissions (20.4% vs 19.6%; p = 1.0), readmissions for dehydration (8.2% vs 5.9%; p = 0.71), and acute renal failure events (10.2% vs 3.9%; p = 0.26). Multivariable analysis found that weekend discharges to home were significantly associated with readmission (OR, 4.5 (95% CI, 1.2–16.9); p = 0.03). Direct costs and patient satisfaction were similar. LIMITATIONS: This study was limited by the heterogeneous patient population and by the potential effect of the intervention on providers taking care of patients randomly assigned to usual care. CONCLUSIONS: A surveillance strategy to ensure compliance with an ileostomy education program tracked patients more closely and was cost neutral, but did not result in decreased hospital readmissions compared with usual care. See Video Abstract at http://bit.ly/2SB8dy2.

http://bit.ly/2N39TeF

Construct Validity and Responsiveness of the Abdominal Surgery Impact Scale in the Context of Recovery After Colorectal Surgery

BACKGROUND: The Abdominal Surgery Impact Scale is a patient-reported outcome measure that evaluates quality of life after abdominal surgery. Evidence supporting its measurement properties is limited. OBJECTIVE: This study aimed to contribute evidence for the construct validity and responsiveness of the Abdominal Surgery Impact Scale as a measure of recovery after colorectal surgery in the context of an enhanced recovery pathway. DESIGN: This is an observational validation study designed according to the Consensus-based Standards for the Selection of Health Measurement Instruments checklist. SETTING: This study was conducted at a university-affiliated tertiary hospital. PATIENTS: Included were 100 consecutive patients undergoing colorectal surgery (mean age, 65; 57% male). INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Construct validity was assessed at 2 days and 2 and 4 weeks after surgery by testing the hypotheses that Abdominal Surgery Impact Scale scores were higher 1) in patients without vs with postoperative complications, 2) with higher preoperative physical status vs lower, 3) without vs with postoperative stoma, 4) in men vs women, 5) with shorter time to readiness for discharge (≤4 days) vs longer, and 6) with shorter length of stay (≤4 days) vs longer. To test responsiveness, we hypothesized that scores would be higher 1) preoperatively vs 2 days postoperatively, 2) at 2 weeks vs 2 days postoperatively, and 3) at 4 weeks vs 2 weeks postoperatively. RESULTS: The data supported 3 of the 6 hypotheses (hypotheses 1, 5, and 6) tested for construct validity at all time points. Two of the 3 hypotheses tested for responsiveness (hypotheses 1 and 2) were supported. LIMITATIONS: This study was limited by the risk of selection bias due to the use of secondary data from a randomized controlled trial. CONCLUSIONS: The Abdominal Surgery Impact Scale was responsive to the expected trajectory of recovery up to 2 weeks after surgery, but did not discriminate between all groups expected to have different recovery trajectories. There remains a need for the development of recovery-specific, patient-reported outcome measures with adequate measurement properties. See Video Abstract at http://bit.ly/2SFxhUz.

http://bit.ly/2N39OHT

Endoscopic Submucosal Dissection With Closure of Colonic Perforation Using Over-the-Scope Clip System

No abstract available

http://bit.ly/2MTHCH4

Profile of Consecutive Fecal Calprotectin Levels in the Perioperative Period and Its Predictive Capacity for Early Endoscopic Recurrence in Crohn’s Disease

BACKGROUND: The perioperative behavior of fecal calprotectin and whether it predicts early postoperative endoscopic recurrence of Crohn's disease are unknown. OBJECTIVE: We aimed to compare the perioperative profiles of fecal calprotectin between patients with Crohn's disease and patients without Crohn's disease undergoing intestinal resection and to identify the association between consecutive fecal calprotectin levels and endoscopic recurrence 3 months after surgery in patients with Crohn's disease. DESIGN: This was a prospective observational study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: One hundred fourteen consecutive patients (90 Crohn's disease, 24 non-Crohn's disease) who underwent resection were recruited. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify variations and risk factors. The predictive accuracy of the possible predictors was assessed by using receiver operating characteristic curves. RESULTS: The fecal calprotectin levels on preoperative day 14 and postoperative days 14, 21, 28, 60, and 90 were higher in the Crohn's disease group than they were in non-Crohn's disease group (p

http://bit.ly/2SEnm1s

Abridged Abstracts From the Medical Literature

No abstract available

http://bit.ly/2Dj4hIy

Factors Related to Health Informatics Competencies for Nurses—Results of a National Electronic Health Record Survey

In 2015, the Finnish Ministry of Social Affairs and Health published an eHealth and eSocial strategy with key objectives that by 2020 health information systems will be smart and providers will be able to maximize their use. Measures include improving system usability and decision support, involving professionals in system and service development, and increasing professionals' training in information management, electronic documentation, data protection, and data security. The aim of this study was to explore the level of nurses' informatics competencies and sufficiency of in-house training regarding technology-induced changes in work practices. An electronic questionnaire produced by the National Institute of Health and Welfare was sent in February to April 2017 to 29 283 Finnish working-age nurses, community nurses, and midwives; 3607 replies were received. Respondents rated their overall informatics competency relatively high, with the lowest competency scores on terminology-based documentation (Finnish Care Classification) and patient-related digital work. Education, electronic health record system used, experience using electronic health record systems, sufficiency of training, higher levels of technical functionality, ease of use, and usefulness were all associated with competency and remained significant after all adjustments. One-third of the respondents felt that they had not received sufficient training. Age and participation in system development were associated with experiences of sufficiency of training. This study was supported by the Strategic Research Council at the Academy of Finland (projects 303607 and 303608) and Ministry of Social Affairs and Health (project 514916001). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Corresponding author: Ulla-Mari Kinnunen, PhD, RN, Virranniementie 3, 78310 Varkaus, Finland (ulla-mari.kinnunen(at)uef.fi). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2tfjfuB

Neutropenic Enterocolitis in Critically Ill Patients: Spectrum of the Disease and Risk of Invasive Fungal Disease

Objectives: Neutropenic enterocolitis occurs in about 5.3% of patients hospitalized for hematologic malignancies receiving chemotherapy. Data from critically ill patients with neutropenic enterocolitis are scarce. Our objectives were to describe the population of patients with neutropenic enterocolitis admitted to an ICU and to investigate the risk factors of invasive fungal disease. Design: A multicentric retrospective cohort study between January 2010 and August 2017. Setting: Six French ICUs members of the Groupe de Recherche Respiratoire en Onco-Hématologie research network. Patients: Adult neutropenic patients hospitalized in the ICU with a diagnosis of enteritis and/or colitis. Patients with differential diagnosis (Clostridium difficile colitis, viral colitis, inflammatory enterocolitis, mesenteric ischemia, radiation-induced gastrointestinal toxicity, and Graft vs Host Disease) were excluded. Interventions: None. Measurement and Main Results: We included 134 patients (median Sequential Organ Failure Assessment 10 [8–12]), with 38.8% hospital mortality and 32.1% ICU mortality rates. The main underlying malignancies were acute leukemia (n = 65, 48.5%), lymphoma (n = 49, 36.6%), solid tumor (n = 14, 10.4%), and myeloma (n = 4, 3.0%). Patients were neutropenic during a median of 14 days (9–22 d). Infection was documented in 81 patients (60.4%), including an isolated bacterial infection in 64 patients (47.8%), an isolated fungal infection in nine patients (6.7%), and a coinfection with both pathogens in eight patients (5.0%). Radiologically assessed enteritis (odds ratio, 2.60; 95% CI, 1.32–7.56; p = 0.015) and HIV infection (odds ratio, 2.03; 95% CI, 1.21–3.31; p = 0.016) were independently associated with invasive fungal disease. Conclusions: The rate of invasive fungal disease reaches 20% in patients with neutropenic enterocolitis when enteritis is considered. To avoid treatment delay, antifungal therapy might be systematically discussed in ICU patients admitted for neutropenic enterocolitis with radiologically assessed enteritis. Drs. Duceau, Azoulay, and Zafrani conceptualized and designed the study. Drs. Picard, Wanquet, Pène, Merceron, Mokart, Moreau, Lengline, Canet, Lemiale, Mariotte, Azoulay, and Zafrani provided the study materials or patients. Drs. Duceau, Picard, Wanquet, Merceron, Moreau, and Zafrani collected and assembled the data. Drs. Duceau, Pirracchio, Azoulay, and Zafrani analyzed and interpreted the data, and wrote the article. All authors approved the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Supported, in part, by the Groupe de Recherche Respiratoire en Réanimation Onco-Hematologique. Dr. Azoulay's institution received funding from Fisher and Paykel, Alexion, Gilead, Baxter, Jazz Pharma, and Ablynx, and he received funding from lecture fees from Alexion, Baxter, Gilead, Merck Sharpe & Dohme, and Astellas. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lara.zafrani@aphp.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://bit.ly/2DqMM9s

Defining the Role Of Language in Infants' Object Categorization with Eye-tracking Paradigms

Here we present a protocol for familiarization-test paradigms which provide a direct test of infant categorization and help to define the role of language in early category learning.

http://bit.ly/2E2i341

Functional Magnetic Resonance Spectroscopy at 7 T in the Rat Barrel Cortex During Whisker Activation

After checking by blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) that the corresponding somatosensory barrel field cortex area (called S1BF) is correctly activated, the main goal of this study is to quantify lactate content fluctuations in the activated rat brains by localized proton magnetic resonance spectroscopy (1H-MRS) at 7 T.

http://bit.ly/2SEc6Ce

Quantitative Examination of Antibiotic Susceptibility of Neisseria gonorrhoeae Aggregates Using ATP-utilization Commercial Assays and Live/Dead Staining

A simple ATP-measuring assay and live/dead staining method were used to quantify and visualize Neisseria gonorrhoeae survival after treatment with ceftriaxone. This protocol can be extended to examine the antimicrobial effects of any antibiotic and can be used to define the minimal inhibitory concentration of antibiotics in bacterial biofilms.

http://bit.ly/2MTNUGE

After Lung Cancer Screening, Follow-Up Procedures May Be Riskier than Thought

In everyday medical care, there may be more complications from invasive diagnostic procedures performed after lung cancer screening than has been reported in large studies.

http://bit.ly/2GxszSd

Using a Real-Time Locating System to Measure Walking Activity Associated with Wandering Behaviors Among Institutionalized Older Adults

This paper discusses the use of a continuous and objective real-time locating system to measure walking activity associated with wandering behaviors, focusing on older adults with cognitive impairment. Walking activity is measured by walking distance, sustained walking distance, and sustained gait speed. Also assessed are gait quality and balance ability.

http://bit.ly/2DmbMi1

Using Ustilago maydis as a Trojan Horse for In Situ Delivery of Maize Proteins

This work describes the cloning of an Ustilago maydis Trojan horse strain for the in situ delivery of secreted maize proteins into three different types of maize tissues.

http://bit.ly/2SlU6NQ

EZH2 inhibitor GSK126 suppresses anti-tumor immunity by driving production of myeloid-derived suppressor cells

Enhancer of Zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on anti-tumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFN-γ+CD8+ T cells, which are involved in anti-tumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil (5Fu) depleted MDSCs, alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors.

http://bit.ly/2UMPzR6

Tumor suppressor microRNA-204-5p regulates growth, metastasis, and immune microenvironment remodeling in breast cancer

Various microRNAs (miRNAs) play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared to normal breast tissues, and its expression levels were associated with increased survival outcome in breast cancer patients. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. Additionally, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of breast cancer patients showed a non-linear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anti-cancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. Additionally, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis.

http://bit.ly/2UNmKUM

Upregulation of PD-L1 via HMGB1-activated IRF3 and NF-kB contributes to UV radiation-induced immune suppression

Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of skin lesions and establishment of tumors by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here we report that UVR exposure significantly increased expression of immune checkpoint molecule PD-L1 in melanoma cells. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the receptor for advanced glycation endproducts (RAGE) receptor to promote NF-kB- and IRF3-dependent transcription of PD-L1 in melanocytes. UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T cell-dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-kB cascade or by blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced upregulation of PD-L1 contributes to immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells and drive melanoma initiation and progression.

http://bit.ly/2tdaRfd

Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status

Mutations in the ALK gene are detectable in ~40% of ALK-rearranged lung cancers resistant to ALK inhibitors. While epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK-inhibitor resistance is largely unknown. In this study, we report that both ALK mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in an ALK-rearranged lung cancer patient. Digital PCR analyses combined with microdissection after immunohistochemical staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pre-treatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pre-treatment followed by a new ALK inhibitors may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.

http://bit.ly/2t9pBf0

Delayed EMS Response Time Tied to Mortality After Car Accident

FRIDAY, Feb. 8, 2019 -- Longer emergency medical service (EMS) response times are associated with higher rates of motor vehicle crash (MVC) mortality, according to a study published online Feb. 6 in JAMA Surgery. James P. Byrne, M.D., Ph.D., from...

http://bit.ly/2GuB0Oa

Slower Gait Speed, Shorter Step Length Tied to Later Depression

FRIDAY, Feb. 8, 2019 -- Older people who develop depression have significantly slower gait speed and shorter step length several years before diagnosis, according to a study published online Feb. 5 in the Journal of the American Geriatrics...

http://bit.ly/2E0LmnC

Diagnostic Delays Common in Inflammatory Bowel Disease

FRIDAY, Feb. 8, 2019 -- Diagnostic delays are common in inflammatory bowel disease, with 68 percent of patients reporting a delay in diagnosis, according to a study presented at the 2019 Crohn's & Colitis Congress, held from Feb. 7 to 9 in Las...

http://bit.ly/2Gvn32B

Education Not Tied to Rate of Cognitive Change in Seniors

FRIDAY, Feb. 8, 2019 -- Education is associated with global cognition but not with the rate of cognitive change in older adults, according to a study published online Feb. 6 in Neurology. Robert S. Wilson, Ph.D., from the Rush University Medical...

http://bit.ly/2E1m6gT

Misuse of Rx Opioids Linked to Other High-Risk Behaviors

FRIDAY, Feb. 8, 2019 -- Misuse of prescribed opioids is associated with other high-risk drug behaviors, according to a study published online Feb. 5 in Pharmacoepidemiology & Drug Safety. Ramin Mojtabai, M.D., Ph.D., M.P.H., from Johns Hopkins...

http://bit.ly/2E25qG9

Vaccine-Preventable Infections Common After Peds Transplant

FRIDAY, Feb. 8, 2019 -- Hospitalization for vaccine-preventable infections occurs in more than 15 percent of pediatric solid organ transplant recipients in the first five years after surgery, according to a study recently published in JAMA...

http://bit.ly/2GD9uyn

Country-Specific Norms Created for Cancer-Related Quality of Life

FRIDAY, Feb. 8, 2019 -- Country-specific norms have been established for the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire to measure the self-reported quality of life of cancer patients, according to a study...

http://bit.ly/2E0lBUo

Certain Opioids Less Effective With SSRI Antidepressants

FRIDAY, Feb. 8, 2019 -- Certain opioids are less effective for postoperative pain in patients taking selective serotonin reuptake inhibitor (SSRI) antidepressants, according to a study published online Feb. 6 in PLOS ONE. Arjun Parthipan, from...

http://bit.ly/2GyhPDq

High-Risk HPV Infection Linked to Increased Risk for CVD in Women

FRIDAY, Feb. 8, 2019 -- High-risk human papillomavirus (HPV) infection is associated with an increased risk for developing cardiovascular disease (CVD), according to a study published online Feb. 7 in Circulation Research. Eun-Jeong Joo, M.D.,...

http://bit.ly/2E1DJxc

Cancers, Vol. 11, Pages 199: Identification of Cross Talk between FoxM1 and RASSF1A as a Therapeutic Target of Colon Cancer

Cancers, Vol. 11, Pages 199: Identification of Cross Talk between FoxM1 and RASSF1A as a Therapeutic Target of Colon Cancer

Cancers doi: 10.3390/cancers11020199

Authors: Blanchard Czinn Banerjee Sharda Bafford Mubariz Morozov Passaniti Ahmed Banerjee

Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC. This inverse correlation was also observed in mCRC cells lines (T84, Colo 205) treated with Akt inhibitor. Inhibition of FoxM1 expression in mCRC cells as well as in our ex vivo model resulted in increased RASSF1A expression. Reduced levels of RASSF1A expression were found in normal cells (RWPE-1, HBEpc, MCF10A, EC) stimulated with exogenous VEGF165. Downregulation of FoxM1 also coincided with increased YAP phosphorylation, indicative of tumor suppression. Conversely, downregulation of RASSF1A coincided with FoxM1 overexpression. These studies have identified for the first time an integrated signaling pathway between FoxM1 and RASSF1A in mCRC progression, which may facilitate the development of novel therapeutic options for advanced colon cancer therapy.

http://bit.ly/2DkqXIj

An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular Immune Microenvironment in Giant Cell Arteritis

The protocol illustrates the use of histopathologic examination and immunohistochemistry to profile the folate receptor beta macrophage and its relationship with the total immune cell infiltrate in temporal artery biopsies in giant cell arteritis.

http://bit.ly/2E1B2vA

Eukaryotic elongation factor 2 (eEF2) kinase/eEF2 plays protective roles against glucose deprivation-induced cell death in H9c2 cardiomyoblasts

Abstract

During the development of cardiac hypertrophy, glucose deprivation (GD) associated with coronary microvascular rarefaction is caused, leading to cardiomyocyte death. Phosphorylation (inactivation) of eukaryotic elongation factor 2 (eEF2) by eEF2 kinase (eEF2K) inhibits protein translation, a highly energy consuming process, which plays protective roles against nutrient deprivation-induced cell death. We previously showed that eEF2 phosphorylation was increased in isolated heart from several cardiac hypertrophy models. In this study, we investigated whether eEF2K/eEF2 mediates the inhibition of cardiomyocyte death under GD condition. In H9c2 rat cardiomyoblasts cultured with serum-free medium, GD significantly augmented eEF2 phosphorylation and signals related to autophagy [increase of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I ratio] and apoptosis (cleavage of caspase-3) as determined by Western blotting. GD induced cell death, which was augmented by eEF2K gene knockdown using a small interfering RNA. eEF2K gene knockdown significantly augmented GD-induced cleavage of caspase-3 and apoptotic nuclear condensation as determined by 4′, 6-diamidino-2-phenylindole staining. In contrast, eEF2K gene knockdown significantly inhibited GD-induced increase of LC3-II to LC3-I ratio and autophagosome formation as determined by an immunofluorescence staining. An inhibitor of autophagy, 3-methyladenine or bafilomycin A1 significantly augmented GD-induced cleavage of caspase-3. Further, eEF2K gene knockdown significantly inhibited GD-induced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK)α and its downstream substrate, unc-51 like autophagy activating kinase (ULK)1. An inhibitor of AMPK, dorsomorphin significantly inhibited GD-induced increase of LC3-II to LC3-I ratio. In conclusion, we for the first time revealed that eEF2K/eEF2 axis under GD condition mediates the inhibition of apoptotic H9c2 cell death at least in part via promotion of autophagy through AMPKα/ULK1 signaling pathway.

http://bit.ly/2tg27og

Stromal fibronectin expression in patients with resected pancreatic ductal adenocarcinoma

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense stroma, which has a fundamental role in tumor progression. Fibronectin (FN1) is the main constituent of the tumor stroma in pancreatic cancer. This study aimed to explore the association between FN1 and clinicopathological characteristics and disease survival.

Methods

Formalin-fixed paraffin-embedded tissue samples from 138 patients with PDAC were constructed into a tissue microarray, followed by immunohistochemical analysis with a recombinant monoclonal FN1 antibody. Chi-square test or Fisher's exact test were used for comparison of FN1 expression and relevant clinicopathological parameters. Kaplan-Meier survival curves and Cox regression analyses were used to assess the association between FN1 and survival.

Results

FN1 was detected in the stromal compartment in most cases (117/138, 84.8%). Compared to the low FN1 expression group, the high FN1 expression group had significantly larger tumor size (P = 0.002), more advanced T stage (P = 0.039) and N stage (P = 0.009), and also worse AJCC stage (P = 0.003). However, stromal FN1 expression was not associated with disease-free survival or overall survival.

Conclusions

This study suggests that high stromal FN1 expression is associated with aggressive tumor characteristics in patients with resected PDAC. However, no association between FN1 expression and survival was found.

http://bit.ly/2MU2E8x

Primary renal well-differentiated neuroendocrine tumors: report of six cases with an emphasis on the Ki-67 index and mitosis

Primary renal well-differentiated neuroendocrine tumors (WDNETs) also called carcinoid and atypical carcinoid are extremely rare, and little is known about parameters that may predict prognosis at diagnosis.

http://bit.ly/2Shbhjm

Dosimetric predictors of temporal lobe injury after intensity-modulated radiotherapy for T4 nasopharyngeal carcinoma: a competing risk study

Abstract

Background

In patients with T4 nasopharyngeal carcinoma (NPC), death may occur prior to the occurrence of temporal lobe injury (TLI). Because such competing risk death precludes the occurrence of TLI and thus the competing risk analysis should be applied to TLI research. The aim was to investigate the incidence and predictive factors of TLI after intensity-modulated radiotherapy (IMRT) among T4 NPC patients.

Methods

From March 2008 to December 2014, T4 NPC patients treated with full-course radical IMRT at our center were reviewed retrospectively. A nested case-control study was designed for this cohort of patients. The cases were patients with TLI diagnosed by MRI during the follow-up period, and the controls were patients without TLI after IMRT matched 1:1 to each case by gender, age at diagnosis, intercranial involvement, and follow-up time. The end point was time to TLI or death without prior TLI. We analyzed the cumulative incidence function (CIF) and performed a competing risk regression model to identify the predictors of TLI.

Results

With a median follow-up of 40.1 months, 63 patients (63/506, 12.5%) developed TLI as diagnosed by MRI, and 136 deaths occurred during the period. The cumulative incidence of TLI at 5 years was 13.2%, while 26.7% died without prior TLI. The univariate analysis showed that all selected dosimetric parameters were associated with the occurrence of TLI. On multivariate analysis, D1cc and V20 remained statistically significant. Based on the area-under-the-curve (AUC) values, D1cc was considered the most predictive. The patients with D1cc > 71.14 Gy had a 7.920-fold increased risk of TLI compared with those with D1cc ≤71.14 Gy (P < 0.05). Similarly, V20 > 42.22 cc was found to result in a statistically significant higher risk of TLI (subdistribution hazard ratio [sHR] =3.123, P < 0.05).

Conclusions

TL D1cc and V20 were predictive of TLI after IMRT for T4 NPC. They should be considered as first and second priorities of dose constraints of the TL. D1cc ≤71.14 Gy and V20 ≤ 42.22 cc could be useful dose-volume constraints for reducing the occurrence of TLI during IMRT treatment planning without obviously compromising the tumor coverage.

http://bit.ly/2DZOe40

FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma

Abstract

Background

Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.

Methods

The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .

Results

We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.

Conclusion

Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

http://bit.ly/2I036n4