Genetic variation of human neutrophil Fcγ receptors and SIRPα in antibody-dependent cellular cytotoxicity towards cancer cells

The efficacy of cancer therapeutic antibodies varies considerably among patients. Anti-cancer antibodies act through different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) triggered via Fcγ receptors (FcγR). This phagocyte ADCC can be promoted by interference with CD47-SIRPα interactions, but the magnitude of this enhancement also varies among individuals. Both FcγR and SIRPα display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC. Because of linkage disequilibrium between FcγR variants the interpretation of previous reports suggesting a potential link between FcγR polymorphisms and ADCC has been troublesome. We performed an integrated genetic analysis that enables stratification. ADCC by activated human neutrophils towards Trastuzumab-coated breast cancer cells was predominantly dependent on FcγRIIa. Neutrophils from individuals with the FcγRIIa-131H polymorphic variant displayed significantly higher killing capacity relative to those with FcγRIIa-131R. Furthermore, ADCC was consistently enhanced by targeting CD47-SIRPα interactions, and there were no significant functional differences between the two most prevalent SIRPα polymorphic variants. Thus, neutrophil ADCC capacity is directly related to the FcγRIIa polymorphism, and targeting CD47-SIRPα interactions enhances ADCC independently of FcγR and SIRPα genotype, thereby further suggesting that CD47-SIRPα interference might be a generic strategy for potentiating the efficacy of antibody therapy in cancer.

This article is protected by copyright. All rights reserved

http://ift.tt/2fybdd9

Overcoming barriers to integrating patient-reported outcomes in clinical practice and electronic health records

There is burgeoning interest in integrating electronic patient-reported outcomes (PROs) into the workflow of routine cancer care. In general, this involves offering patients an interface for self-reporting their symptoms, distress, physical functioning, and other clinically oriented information through online or telephone systems, with this information conveyed to clinicians through real-time alerts and longitudinal graphic reports.

http://ift.tt/2fP2aBh

Secondary CNS lymphoma: the poisoned needle in the haystack

The term secondary central nervous system (CNS) lymphoma (SCNSL) defines the involvement of the CNS at presentation or relapse in patients with systemic lymphoma. In the 1990s, most reported studies on SCNSL were focused on pediatric series and/or highly aggressive lymphomas. Subsequently, some retrospective studies of adult patients with 'high-grade' lymphomas aimed to identify factors predicting CNS dissemination and several series of rare extranodal lymphomas with varied risk of CNS involvement were reported. More recently, studies on the effect of rituximab on CNS recurrence rate, some proposals of risk scores and the first prospective trials focused on CNS prophylaxis or treatment of SCNSL were published. Despite all these efforts, the level of evidence remains low, and some criticisms of reported studies keep many questions open. In this issue of Annals of Oncology, Gleeson et al. [1] on behalf of the UK NCRI, add new knowledge to this challenging field. The authors analyzed CNS events in 1080 patients with diffuse large B-cell lymphomas (DLBCL) registered in the NCRI R-CHOP14vs21 trial, and, as the main findings, they report a CNS recurrence rate of 1.9% for the whole series and 2.8% for patients selected to receive CNS prophylaxis [1]. Unfortunately, the authors did not identify risk factors, probably due to the small number of events, but they documented CNS relapse sites and confirmed that prognosis of SCNSL patients is poor. The authors should be commended for the collection of a huge mass of data and for the good-sense analysis performed.

http://ift.tt/2xwMVXG

Of mice and men: patient-derived xenografts in cancer medicine

A large proportion of oncological care is directed towards patients in whom the fraction of responders is low and the duration of response short with minimal clinical benefit. As acerbically observed by Roy Porter, 'What an ignominious destiny if the future of medicine turns into bestowing meagre increments of unenjoyed life?' [1]. Thus, it is a priority in cancer research to radically shift from therapies which are used indiscriminately across specific tumour types, to personalized therapies which can both improve efficacy and reduce unnecessary toxicities and futile treatments [2].

http://ift.tt/2xx7TpA

ESMO-Magnitude of Clinical Benefit Scale version 1.1

Abstract

Background

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review.

Methods

The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board.

Results

Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1).

Conclusions

ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies.

http://ift.tt/2fPwvQ3

Midostaurin: a magic bullet that blocks mast cell expansion and activation

Abstract

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

http://ift.tt/2fPwuLZ

Treatment of squamous cell carcinoma of the anal canal (SCCA): a new era?

There are no therapies available after progression on cisplatin and 5-FU that can improve survival for patients with squamous cell carcinoma of the anal canal (SCCA). Recently, two studies have been published [1, 2] that open the era of checkpoint inhibitors in SCCA.

http://ift.tt/2xwQ3CS

Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors

Abstract

Background

While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.

Patients and methods

Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.

Results

We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.

Conclusions

Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

http://ift.tt/2fP2akL

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study

Abstract

Background

Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.

Patients and methods

Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.

Results

Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43–0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.

Conclusions

First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.

http://ift.tt/2xwQ21M

Right–left or midgut–hindgut?

In their recent article in Annals of Oncology, Arnold et al. suggest that primary tumour side may play a role as a predictive clinical marker for efficacy of systemic antineoplastic treatment in patients with advanced colorectal cancer [1]. We would like to make a few comments and questions to the authors.

http://ift.tt/2fQMXj2

Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Abstract

Background

Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient.

Methods

Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)].

Results

The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0–767), after a median number of 0 (0–3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%–50%), and 17.1% (0%–50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%–100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001).

Conclusions

This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

http://ift.tt/2fQd2il

Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review

Abstract

Background

Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class.

Methods

Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ² tests and multivariable regression models were used to analyse for effect size and associations.

Results

We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.

Discussion

CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.

http://ift.tt/2xwb0Og

Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies

Abstract

Background

Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease.

Patients and methods

From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously.

Results

The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial–myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen.

Conclusions

Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.

http://ift.tt/2fPiKRB

Changes in the use of end points in clinical trials for elderly cancer patients over time

Abstract

Background

Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s.

Patients and methods

All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials.

Results

Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period.Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported.

Conclusion

During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.

http://ift.tt/2xvvAhZ

‘Thursday’s child has far to go’—interpreting subgroups and the STAMPEDE trial

STAMPEDE is a multi-arm multi-stage randomised controlled trial protocol, recruiting men with locally advanced or metastatic prostate cancer who are commencing long-term androgen deprivation therapy. Opening to recruitment with five research questions in 2005 and adding in a further five questions over the past 6 years, it has reported survival data on 6 of these 10 RCT questions over the past 2 years [1–3]. Some of these results have been of practice-changing magnitude [4, 5], but, in conversation, we have noticed some misinterpretation, both over-interpretation and under-interpretation, of subgroup analyses by the wider clinical community which could impact negatively on practice. We suspect, therefore, that such problems in interpretation may be common. Our intention here is to provide comment on interpretation of subgroup analysis in general using examples from STAMPEDE. Specifically, we would like to highlight some possible implications from the misinterpretation of subgroups and how these might be avoided, particularly where these contravene the very design of the research question. In this, we would hope to contribute to the conversation on subgroup analyses [6–11].

http://ift.tt/2fPwnA3

Vemurafenib in patients with BRAF V600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study

Abstract

Background

The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAF^V600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.

Patients and methods

Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m² every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.

Results

Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96); P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.

Conclusions

Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.

ClinicalTrials.gov

NCT01006980.

http://ift.tt/2xvxBLb

Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation

Abstract

Background

Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required.

Patients and methods

We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).

Results

NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRD^NGS(−)] (defined as <10⁻⁶) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRD^NGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRD^NGS(−) (n = 24) showed a significantly better PFS than those that were MRD^NGS(+) (n = 15) (P =0.02). Moreover, MRD^NGS(−) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRD^NGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10⁻⁷) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33).

Conclusions

Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.

http://ift.tt/2fQHnxj

Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study

Abstract

Background

Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD.

Patients and methods

Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999–2010 period. The study PC cohort comprised 22 084 patients aged ≥18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling.

Results

The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12–1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41–0.76).

Conclusion

PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy.

http://ift.tt/2xw5ifj

Clonal diversity and detection of carbapenem resistance encoding genes among multidrug-resistant Acinetobacter baumannii isolates recovered from patients and environment in two intensive care units in a Moroccan hospital

Carbapenem-resistant Acinetobacter baumannii has recently been defined by the World Health Organization as a critical pathogen. The aim of this study was to compare clonal diversity and carbapenemase-encoding gen...

http://ift.tt/2xzL8Pi

Orbital apex syndrome secondary to a fungal nasal septal abscess caused by Scedosporium apiospermum in a patient with uncontrolled diabetes: a case report

Orbital apex syndrome is a localized type of orbital cellulitis, where mass lesions occur at the apex of the cranial nerves. Although nasal septal abscess is uncommon, the organism most likely to cause nasal s...

http://ift.tt/2k356yH

Predictive accuracy of particle filtering in dynamic models supporting outbreak projections

While a new generation of computational statistics algorithms and availability of data streams raises the potential for recurrently regrounding dynamic models with incoming observations, the effectiveness of s...

http://ift.tt/2y6AuCB

Ethanol extract of propolis and its constituent caffeic acid phenethyl ester inhibit breast cancer cells proliferation in inflammatory microenvironment by inhibiting TLR4 signal pathway and inducing apoptosis and autophagy

Propolis and its major constituent – caffeic acid phenethyl ester (CAPE) have good abilities on antitumor and anti-inflammation. However, little is known about the actions of propolis and CAPE on tumor in infl...

http://ift.tt/2xJZlLI

The ameliorative effect of bloodletting puncture at hand twelve Jing-well points on cerebral edema induced by permanent middle cerebral ischemia via protecting the tight junctions of the blood-brain barrier

Cerebral edema, erupting simultaneously with severe ischemic stroke, might lead to increased intracranial pressure, cerebral herniation, and ultimately death. Studies conducted previously by our team have demo...

http://ift.tt/2fytSVW

Clinical Snippets

http://ift.tt/2yrOSlk

FRT – FONDATION RENE TOURAINE

http://ift.tt/2xzxBHo

Issue Information

http://ift.tt/2ysthck

Changes in the Proteome of HaCaT Keratinocytes Induced by Cytotoxic Substance Triton X-100

Changes in the proteome of keratinocytes of immortalized HaCaT line exposed to cytotoxic substance Triton X-100 in concentrations of 12.5 and 25 μg/ml were studied by liquid chromatography combined with mass spectrometry. The appearance of proteins involved in the regulation of mitosis, RNA stability, and catabolic processes were detected; the number of apoptosis-associated proteins increased, while the number of proteins involved in differentiation and energy metabolism of keratinocytes decreased.

http://ift.tt/2wVmvuj

Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab

Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early stage non-small cell lung cancer (NSCLC) patients. Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab Phase II study of 24 treatment-naïve patients with Stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28 dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated TILs than those observed in PBMCs. Surprisingly, we found 4 cases of pre-existing tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating Tregs and MDSCs. Conclusions: This study did not meet the primary endpoint of detecting an increase in blood based tumor associated antigen T cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunological data from combined immune checkpoint blockade immunotherapies.

http://ift.tt/2yGTIfs

Head and neck squamous cell carcinomas are characterized by a stable immune signature within the primary tumor over time

Purpose: Genetic and morphological heterogeneity is well-documented in solid cancers. Immune cells are also variably distributed within the tumor; this heterogeneity is difficult to assess in small biopsies, and may confound our understanding of the determinants of successful immunotherapy. We examined the transcriptomic variability of the immunological signature in head and neck squamous cell carcinoma (HNSCC) within individual tumors using transcriptomic and immunohistochemical assessments. Experimental design: Forty-four tumor biopsies from 16 HNSCC patients, taken at diagnosis and later at resection, were analyzed using RNA-sequencing. Variance filtering was used to identify the top 4000 most variable genes. Principal component analysis, hierarchical clustering and correlation analysis were performed. Gene expression of CD8A was correlated to immunohistochemical analysis. Results: Analysis of immunological gene expression was highly consistent in replicates from the same cancer. Across the cohort, samples from the same patient were most similar to each other, both spatially (at diagnosis) and notably, over time (diagnostic biopsy compared to resection); comparison of global gene expression by hierarchical clustering [p=<0.0001] and correlation analysis [median intrapatient r=0.82; median interpatient r=0.63]. CD8A gene transcript counts were highly correlated with CD8 T-cell counts by immunohistochemistry (r=0.82). Conclusion: Our data demonstrate that in HNSCC the global tumor and adaptive immune signatures are stable between discrete parts of the same tumor and also at different timepoints. This suggests that immunological heterogeneity may not be a key reason for failure of immunotherapy and underpins the use of transcriptomics for immunological evaluation of novel agents in HNSCC patients.

http://ift.tt/2wThqru

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

British Journal of Cancer 117, 1048 (26 September 2017). doi:10.1038/bjc.2017.286

Authors: Javier Gayarre, Paloma Martín-Gimeno, Ana Osorio, Beatriz Paumard, Alicia Barroso, Victoria Fernández, Miguel de la Hoya, Alejandro Rojo, Trinidad Caldés, José Palacios, Miguel Urioste, Javier Benítez & María J García

http://ift.tt/2vX11jH

The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

British Journal of Cancer 117, 1007 (26 September 2017). doi:10.1038/bjc.2017.249

Authors: Pirjo Åström, Krista Juurikka, Elin S Hadler-Olsen, Gunbjørg Svineng, Nilva K Cervigne, Ricardo D Coletta, Juha Risteli, Joonas H Kauppila, Sini Skarp, Samuel Kuttner, Ana Oteiza, Meeri Sutinen & Tuula Salo

http://ift.tt/2upzCTg

Comprehensive geriatric assessment in 326 older women with early breast cancer

Comprehensive geriatric assessment in 326 older women with early breast cancer

British Journal of Cancer 117, 925 (26 September 2017). doi:10.1038/bjc.2017.257

Authors: D O Okonji, R Sinha, I Phillips, D Fatz & A Ring

http://ift.tt/2utrJBv

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

British Journal of Cancer 117, 932 (26 September 2017). doi:10.1038/bjc.2017.264

Authors: Wen-Ying Lin, Chih-Peng Lin, Chih-Hung Hsu, Ying-Hui Lee, Yi-Ting Lin, Meng-Chi Hsu & Yu-Yun Shao

http://ift.tt/2vBGkue

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

British Journal of Cancer 117, 1026 (26 September 2017). doi:10.1038/bjc.2017.254

Authors: Nikki R Adler, Rory Wolfe, John W Kelly, Andrew Haydon, Grant A McArthur, Catriona A McLean & Victoria J Mar

http://ift.tt/2vjFkZ0

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

British Journal of Cancer 117, 938 (26 September 2017). doi:10.1038/bjc.2017.271

Authors: Alastair Greystoke, Nicola Steele, Hendrik-Tobias Arkenau, Fiona Blackhall, Noor Md Haris, Colin R Lindsay, Raffaele Califano, Mark Voskoboynik, Yvonne Summers, Karen So, Dana Ghiorghiu, Angela W Dymond, Stuart Hossack, Ruth Plummer & Emma Dean

http://ift.tt/2xhlj6f

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study

British Journal of Cancer 117, 1070 (26 September 2017). doi:10.1038/bjc.2017.268

Authors: Hannah Oh, Hannah Arem, Charles E Matthews, Nicolas Wentzensen, Kerryn W Reding, Louise A Brinton, Garnet L Anderson, Sally B Coburn, Jane A Cauley, Chu Chen, Deborah Goodman, Ruth M Pfeiffer, Roni T Falk, Xia Xu & Britton Trabert

http://ift.tt/2wUvBJj

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

British Journal of Cancer 117, 947 (26 September 2017). doi:10.1038/bjc.2017.276

Authors: Maeva Dufies, Sandy Giuliano, Julien Viotti, Delphine Borchiellini, Linsay S Cooley, Damien Ambrosetti, Mélanie Guyot, Papa Diogop Ndiaye, Julien Parola, Audrey Claren, Renaud Schiappa, Jocelyn Gal, Antoine Frangeul, Arnaud Jacquel, Ophélie Cassuto, Renaud Grépin, Patrick Auberger, Andréas Bikfalvi, Gérard Milano, Bernard Escudier, Nathalie Rioux-Leclercq, Camillo Porta, Sylvie Negrier, Emmanuel Chamorey, Jean-Marc Ferrero & Gilles Pagès

http://ift.tt/2iHkdNM

Non-conventional role of haemoglobin beta in breast malignancy

Non-conventional role of haemoglobin beta in breast malignancy

British Journal of Cancer 117, 994 (26 September 2017). doi:10.1038/bjc.2017.247

Authors: Marco Ponzetti, Mattia Capulli, Adriano Angelucci, Luca Ventura, Simona Delle Monache, Cinzia Mercurio, Alessia Calgani, Patrizia Sanità, Anna Teti & Nadia Rucci

http://ift.tt/2u9pP8H

RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

British Journal of Cancer 117, 954 (26 September 2017). doi:10.1038/bjc.2017.277

Authors: Saoirse O Dolly, Mark D Gurden, Konstantinos Drosopoulos, Paul Clarke, Johann de Bono, Stan Kaye, Paul Workman & Spiros Linardopoulos

http://ift.tt/2xav2ez

Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

British Journal of Cancer 117, 1017 (26 September 2017). doi:10.1038/bjc.2017.250

Authors: David Sefrioui, France Blanchard, Emmanuel Toure, Paul Basile, Ludivine Beaussire, Claire Dolfus, Anne Perdrix, Marianne Paresy, Michel Antonietti, Isabelle Iwanicki-Caron, Raied Alhameedi, Stephane Lecleire, Alice Gangloff, Lilian Schwarz, Florian Clatot, Jean-Jacques Tuech, Thierry Frébourg, Fabrice Jardin, Jean-Christophe Sabourin, Nasrin Sarafan-Vasseur, Pierre Michel & Frédéric Di Fiore

http://ift.tt/2upNihi

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

British Journal of Cancer 117, 965 (26 September 2017). doi:10.1038/bjc.2017.278

Authors: Francis Lévi, Abdoulaye Karaboué, Raphaël Saffroy, Christophe Desterke, Valerie Boige, Denis Smith, Mohamed Hebbar, Pasquale Innominato, Julien Taieb, Carlos Carvalho, Rosine Guimbaud, Christian Focan, Mohamed Bouchahda, René Adam, Michel Ducreux, Gérard Milano & Antoinette Lemoine

http://ift.tt/2vHkHYv

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

British Journal of Cancer 117, 1036 (26 September 2017). doi:10.1038/bjc.2017.255

Authors: Cuijuan Shi, Linlin Ren, Cuiyun Sun, Lin Yu, Xiuwu Bian, Xuexia Zhou, Yanjun Wen, Dan Hua, Shujun Zhao, Wenjun Luo, Run Wang, Chun Rao, Qian Wang & Shizhu Yu

http://ift.tt/2vjmMs8

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

British Journal of Cancer 117, 974 (26 September 2017). doi:10.1038/bjc.2017.292

Authors: Meng Li, Jingyu Yang, Wenlong Zhou, Yong Ren, Xiaoxuan Wang, Huiping Chen, Jingyuan Zhang, Junli Chen, Yuhong Sun, Lijuan Cui, Xing Liu, Lihui Wang & Chunfu Wu

http://ift.tt/2gpfBv7

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

British Journal of Cancer 117, 1063 (26 September 2017). doi:10.1038/bjc.2017.267

Authors: Albina N Minlikeeva, Jo L Freudenheim, Rikki A Cannioto, Kevin H Eng, J Brian Szender, Paul Mayor, John L Etter, Daniel W Cramer, Brenda Diergaarde, Jennifer A Doherty, Thilo Dörk, Robert Edwards, Anna deFazio, Grace Friel, Marc T Goodman, Peter Hillemanns, Estrid Høgdall, Allan Jensen, Susan J Jordan, Beth Y Karlan, Susanne K Kjær, Rüdiger Klapdor, Keitaro Matsuo, Mika Mizuno, Christina M Nagle, Kunle Odunsi, Lisa Paddock, Mary Anne Rossing, Joellen M Schildkraut, Barbara Schmalfeldt, Brahm H Segal, Kristen Starbuck, Kathryn L Terry, Penelope M Webb, Emese Zsiros, Roberta B Ness, Francesmary Modugno, Elisa V Bandera, Jenny Chang-Claude & Kirsten B Moysich

http://ift.tt/2vHUMQI

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

British Journal of Cancer 117, 984 (26 September 2017). doi:10.1038/bjc.2017.243

Authors: Nicola Cirillo, David J Morgan, Maria Carmela Pedicillo, Antonio Celentano, Lorenzo Lo Muzio, Michael J McCullough & Stephen S Prime

http://ift.tt/2uL9suE

Influence of dietary insulin scores on survival in colorectal cancer patients

Influence of dietary insulin scores on survival in colorectal cancer patients

British Journal of Cancer 117, 1079 (26 September 2017). doi:10.1038/bjc.2017.272

Authors: Chen Yuan, Ying Bao, Kaori Sato, Katharina Nimptsch, Mingyang Song, Jennie C Brand-Miller, Vicente Morales-Oyarvide, Emilie S Zoltick, NaNa Keum, Brian M Wolpin, Jeffrey A Meyerhardt, Andrew T Chan, Walter C Willett, Meir J Stampfer, Kana Wu, Edward L Giovannucci, Charles S Fuchs & Kimmie Ng

http://ift.tt/2wUKA60

Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced anti-neoplastic activities both in vitro and vivo. An integrative analysis using both whole-transcriptome sequencing (RNA-Seq) and chromatin-immunoprecipitation sequencing (ChIP-Seq) pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2 and the long non-coding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease.

http://ift.tt/2fq0aPz

Design, Development, and Optimization of Dexibuprofen Microemulsion Based Transdermal Reservoir Patches for Controlled Drug Delivery

The aim of the study was to develop a reservoir-type transdermal patch for a controlled delivery of dexibuprofen and to evaluate its in vivo anti-inflammatory activity in Albino Wistar rats. In order to develop these patches, six formulations of dexibuprofen microemulsion comprising ethyl oleate, Tween 80: PG (2 : 1), and water were prepared by simplex lattice design and characterized. The reservoir compartment was filled with these microemulsions and in vitro release and skin permeation were assessed. The optimized patch was obtained on the basis of the responses: and flux. The impact of drug loading, surface area, membrane thickness, adhesive, and agitation speed on drug release and permeation was also studied. The skin sensitivity reaction and in vivo anti-inflammatory activity of optimized patch were evaluated. Stability study at three different temperatures for three months was carried out. The result suggests that a membrane based patch with zero-order release rate, of 79.13 ± 3.08%, and maximum flux of 331.17 µg/cm2h can be obtained exhibiting suitable anti-inflammatory activity with no visible skin sensitivity reaction. The outcomes of stability study recommend storage of patches at 4°C having shelf-life of 6.14 months. The study demonstrates that the reservoir-type transdermal patch of dexibuprofen microemulsion has a potential of delivering drug across skin in controlled manner with required anti-inflammatory activity.

http://ift.tt/2y5X7Hl

IFN-α Boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine Promoted Th1 Type Cellular Response and Protection against M. tuberculosis Infection

The role of type I IFNs in the pathogenesis and control of mycobacterial infection is still controversial. It has been reported that type I IFNs exacerbated M. tuberculosis infection through hampering Th1 type cellular immune response. However, under certain conditions they can act as natural immune adjuvants for commercial vaccines. At this point, we have reported recently that successive IFN-alpha boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccinated mice protected adult mice from intradermal M. lepraemurium infection and a difference in iNOS was observed. In the present work, we have found that intramuscular IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine, either in vitro (human cell line or macrophages derived from PBMC) or in vivo (aerosol mouse model of MTb infection), promoted mostly the development of specific anti-antimycobacterial Th1 type cytokines (IFN-γ; IL-12, TNF-alpha, and IL-17; IL1β) while bacterial load reduction (0.9 logs versus PBS or BCG vaccine) was observed. These findings indicate that, under the experimental settings reported here, interferon alpha can drive or affect the TH cellular immune response in favour of BCG-inducing immunity against M. tuberculosis infection.

http://ift.tt/2k17aXX

Effects of Acupuncture on Alzheimer’s Disease in Animal-Based Research

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and severe functional deficits in the brain. The pathogenesis and treatment of AD remain topics of investigation and significant global socioeconomic issues. The effect of complementary medicine has been investigated in managing AD. Acupuncture, a form of therapy practiced for more than 3000 years, has shown positive effects on several neurological disorders including AD. Animal studies have evaluated the specific utility and neuropathological mechanisms addressed by acupoint manipulation; however, no study has summarized the relationships among different acupoints and their therapeutic effects in the context of AD. Therefore, we reviewed the effects of acupuncture at different acupoints in animal models of AD. In general, acupuncture produced therapeutic benefits in rodent models of AD. Studies demonstrate the utility of GV20 as a valuable acupoint for electroacupuncture and manual acupuncture. GV20 stimulation suppresses Aβ generation, improves glucose metabolism, and attenuates neuropathological features in various disease models. However, a lack of sufficient evidence in preclinical and clinical studies makes these results controversial. Additional studies are required to confirm the exact utility of specific acupoints in clinically managing AD.

http://ift.tt/2k2NzXk

What Urinary Colony Count Indicates a Urinary Tract Infection in Children?

Post-hoc analysis of the Randomized Intervention for Children with Vesicoureteral Reflux study suggests that, in concordance with European guidelines, using bacteriologic criterion of ≥10 000 colony forming units/mL of a single organism does not decrease diagnostic specificity of an urinary tract infection in children aged 2 months to 6 years in a properly collected urine if symptoms/fever and pyuria are present.

http://ift.tt/2hvxCYW

Mitochondrial DNA “common deletion” in post-FNA infarcted oncocytic thyroid tumors

Thyroid fine needle aspiration (FNA) can rarely induce morphological changes potentially hindering the histopathological diagnosis, especially in Hurthle cell tumors (HCT), which may easily undergo post-FNA infarction or necrosis. HCTs contain mitochondrion (mt)-rich cells that may bear mtDNA mutations, the most frequent being the so-called "common deletion" (CD). The aim of this study was to determine the presence and extent of the mtDNA CD in a series of thyroid HCT that underwent extensive infarction following FNA procedure, in comparison with a control series of HCT lacking post-FNA ischemic/hemorrhagic alterations.

http://ift.tt/2wiJgJe

Ki-67 labeling index may be a promising indicator to identify “very high risk” gastrointestinal stromal tumor (GIST): a multicenter retrospective study of 1022 patients

We sought to determine whether Ki-67 labeling index (LI) was an independent prognostic factor for gastrointestinal stromal tumor (GIST). A multicenter cohort of 1022 patients undergoing surgical resection of primary GIST between August 2004 and October 2015 were retrospectively analyzed. Immunohistochemical analysis was performed to evaluate expression of Ki-67 in their parafin-embedded tissue samples. The optimal cutoff value of Ki-67 LI was determined as 6% by receiver operating characteristics (ROC) curve analysis.

http://ift.tt/2foZwBx

The Effectiveness of Psychosocial Interventions for Psychological Outcomes in Paediatric Oncology: A Systematic Review

This review summarises the current randomised controlled trials literature on psychological and physical outcomes of psychosocial interventions in paediatric oncology.

http://ift.tt/2y6nxch

Body mass index change during adulthood and risk of oesophageal squamous-cell carcinoma in a Japanese population: the Japan Public Health (JPHC)-based prospective study

Body mass index change during adulthood and risk of oesophageal squamous-cell carcinoma in a Japanese population: the Japan Public Health (JPHC)-based prospective study

British Journal of Cancer advance online publication, September 26 2017. doi:10.1038/bjc.2017.332

Authors: Huan Song, Eiko Saito, Norie Sawada, Sarah K Abe, Akihisa Hidaka, Taichi Shimazu, Taiki Yamaji, Atsushi Goto, Motoki Iwasaki, Shizuka Sasazuki, Weimin Ye, Manami Inoue & Shoichiro Tsugane

http://ift.tt/2wVkSwQ

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours

British Journal of Cancer advance online publication, September 26 2017. doi:10.1038/bjc.2017.327

Authors: Jeffrey R Infante, Ronald L Korn, Lee S Rosen, Patricia LoRusso, Samuel S Dychter, Joy Zhu, Daniel C Maneval, Ping Jiang, H Michael Shepard, Gregory Frost, Daniel D Von Hoff, Mitesh J Borad & Ramesh K Ramanathan

http://ift.tt/2wUL76K

A positive-feedback loop between tumour infiltrating activated Treg cells and type 2-skewed macrophages is essential for progression of laryngeal squamous cell carcinoma

A positive-feedback loop between tumour infiltrating activated Treg cells and type 2-skewed macrophages is essential for progression of laryngeal squamous cell carcinoma

British Journal of Cancer advance online publication, September 26 2017. doi:10.1038/bjc.2017.329

Authors: Wei Sun, Fan-Qin Wei, Wei-Jin Li, Jia-Wei Wei, Hua Zhong, Yi-Hui Wen, Wen-Bin Lei, Lin Chen, Hang Li, Han-Qing Lin, Muhammad Iqbal & Wei-Ping Wen

http://ift.tt/2wV7b0M

Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations

Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations

British Journal of Cancer advance online publication, September 26 2017. doi:10.1038/bjc.2017.345

Authors: Carlo Visco, Jinfen Wang, Maria Chiara Tisi, Lijuan Deng, Emanuele S G D'Amore, Alexandar Tzankov, Santiago Montes-Moreno, Karen Dybkær, Govind Bhagat, Eric D Hsi, J Han van Krieken, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Miguel A Piris, L Jeffrey Medeiros, Zijun Y Xu-Monette & Ken H Young

http://ift.tt/2wV1XlC

Nomogram individually predicts the overall survival of patients with gastroenteropancreatic neuroendocrine neoplasms

Nomogram individually predicts the overall survival of patients with gastroenteropancreatic neuroendocrine neoplasms

British Journal of Cancer advance online publication, September 26 2017. doi:10.1038/bjc.2017.315

Authors: Cheng Fang, Wei Wang, Xingyu Feng, Jian Sun, Yu Zhang, Yujie Zeng, Junjiang Wang, Huishan Chen, Muyan Cai, Junzhong Lin, Minhu Chen, Ye Chen, Yong Li, Shengping Li, Jie Chen & Zhiwei Zhou

http://ift.tt/2wV5lgF

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

http://ift.tt/2fqV4T9

Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

http://ift.tt/2wiz0AN

The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

http://ift.tt/2fpRokA

Comprehensive geriatric assessment in 326 older women with early breast cancer

http://ift.tt/2wiyWRz

Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

http://ift.tt/2fouIB8

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

http://ift.tt/2y7f9Jo

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

http://ift.tt/2k2jkzN

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

http://ift.tt/2y6ix7l

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

http://ift.tt/2k1JnaD

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

http://ift.tt/2y7Qgxk

Non-conventional role of haemoglobin beta in breast malignancy

http://ift.tt/2k1blmE

RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

http://ift.tt/2y6HrE2

Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

http://ift.tt/2k10itD

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

http://ift.tt/2y7eqb8

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

http://ift.tt/2jYVmp8

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

http://ift.tt/2y8jvQk

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

http://ift.tt/2jYV8OO

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

http://ift.tt/2y6HjEy

Influence of dietary insulin scores on survival in colorectal cancer patients

http://ift.tt/2k0ZFAh

Facility Volume and Survival in Nasopharyngeal Carcinoma

Definitive treatment of nasopharyngeal carcinoma (NPC) is challenging due to its rarity, complicated regional anatomy and the intensity of therapy. In contrast to other head and neck cancers, the effect of facility volume has not been well described in NPC.

http://ift.tt/2hvAK7e

Body mass index change during adulthood and risk of oesophageal squamous-cell carcinoma in a Japanese population: the Japan Public Health (JPHC)-based prospective study

http://ift.tt/2xDl47s

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours

http://ift.tt/2wUP8I4

Nomogram individually predicts the overall survival of patients with gastroenteropancreatic neuroendocrine neoplasms

http://ift.tt/2xEa3Tt

A positive-feedback loop between tumour infiltrating activated Treg cells and type 2-skewed macrophages is essential for progression of laryngeal squamous cell carcinoma

http://ift.tt/2wV60P4

Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations

http://ift.tt/2xDSBP6

Fabrication and Validation of an Organ-on-chip System with Integrated Electrodes to Directly Quantify Transendothelial Electrical Resistance

This publication describes the fabrication of an organ-on-chip device with integrated electrodes for direct quantification of transendothelial electrical resistance (TEER). For validation, the blood-brain barrier was mimicked inside this microfluidic device and its barrier function was monitored. The presented methods for electrode integration and direct TEER quantification are generally applicable.

http://ift.tt/2wUFp4R

How to fight physician burnout - KevinMD shares his personal experience

Posted at Clinical Cases and Images. Stay updated and subscribe, follow us on Twitter and connect on Facebook.

http://ift.tt/2xKd9WB

Methods for Imaging Intracellular pH of the Follicle Stem Cell Lineage in Live Drosophila Ovarian Tissue

We provide a protocol for imaging intracellular pH of an epithelial stem cell lineage in live Drosophila ovarian tissue. We describe methods to generate transgenic flies expressing a pH biosensor, mCherry::pHluorin, image the biosensor using quantitative fluorescence imaging, generate standard curves, and convert fluorescence intensity values to pH values.

http://ift.tt/2fy8KiG

A genomic screen for angiosuppressor genes in the tumor endothelium identifies a multifaceted angiostatic role for bromodomain containing 7 (BRD7)

Abstract

Tumor angiogenesis is characterized by deregulated gene expression in endothelial cells (EC). While studies until now have mainly focused on overexpressed genes in tumor endothelium, we here describe the identification of transcripts that are repressed in tumor endothelium and thus have potential suppressive effects on angiogenesis. We identified nineteen putative angiosuppressor genes, one of them being bromodomain containing 7 (BRD7), a gene that has been assigned tumor suppressor properties. BRD7 was studied in more detail, and we demonstrate that BRD7 expression is inversely related to EC activation. Ectopic expression of BRD7 resulted in a dramatic reduction of EC proliferation and viability. Furthermore, overexpression of BRD7 resulted in a bromodomain-dependent induction of NFκB-activity and NFκB-dependent gene expression, including ICAM1, enabling leukocyte–endothelial interactions. In silico functional annotation analysis of genome-wide expression data on BRD7 knockdown and overexpression revealed that the transcriptional signature of low BRD7 expressing cells is associated with increased angiogenesis (a.o. upregulation of angiopoietin-2, VEGF receptor-1 and neuropilin-1), cytokine activity (a.o. upregulation of CXCL1 and CXCL6), and a reduction of immune surveillance (TNF-α, NFκB, ICAM1). Thus, combining in silico and in vitro data reveals multiple pathways of angiosuppressor and anti-tumor activities of BRD7.

http://ift.tt/2htDS3A

Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers

Objective

Among individuals with chronic hepatitis B, those with hepatitis B e-antigen (HBeAg)-negative chronic hepatitis (CHB) can be difficult to distinguish from those with HBeAg-negative chronic HBV infection, also referred to as inactive HBV carriers (ICs), but both require different medical management. The level of HBV surface antigen (HBsAg) has been proposed as a marker to discriminate between chronic infection and hepatitis stages. HBsAg consists of large, middle and small HBs. The aim of this study was to determine whether the composition of HBsAg improved the identification of ICs among HBsAg-positive subjects with different phases of HBV infections.

Design

HBV large surface proteins (LHBs) and HBV middle surface proteins (MHBs) were quantified in serum samples from 183 clinically well-characterised untreated patients with acute (n=14) HBV infection, ICs (n=44), CHBs (n=46), chronic HBeAg-positive phase (n=68) and hepatitis delta coinfection (n=11) using an ELISA, with well-defined monoclonal antibodies against the preS1 domain (LHBs) and the preS2-domain (MHBs). A Western blot analysis was used to verify the quantitation of the components of HBsAg. Total HBsAg was quantified using a modified commercially available assay (HBsAg V.6.0, Enzygnost, Siemens, Erlangen).

Results

The composition of HBsAg showed specific patterns across different phases of hepatitis B. Individuals in the IC phase had significantly lower proportions of LHBs and MHBs than patients in acute or chronic phases irrespective of their HBV e-antigen status (p<0.0001) or HBsAg level. Both LHBs and MHBs ratios better predicted the IC phase than total HBsAg levels.

Conclusion

Quantification of MHBs, particularly LHBs represents a novel tool for the identification of the IC stage.

http://ift.tt/2wSmXi0

A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota

Objective

Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).

Design

A randomised, open-label, cross-over trial of 8 weeks' treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week 'washout' period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.

Results

Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.

Conclusion

Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.

Trial registration number

ISRCTN18662143.

http://ift.tt/2yFhGaA

The CTRB1-CTRB2 risk allele for chronic pancreatitis discovered in European populations does not contribute to disease risk variation in the Chinese population due to near allele fixation

We read with great interest the article by Rosendahl et al1 reporting the identification of CTRB1-CTRB2 (chymotrypsin B1 and chymotrypsin B2) as a new chronic pancreatitis (CP) risk locus by means of genome-wide association study, with the lead single nucleotide polymorphism (SNP) rs8055167 having an OR of 1.35. Moreover, they found that a previously reported 16.6 kb inversion in the CTRB1-CTRB2 locus2 was in linkage disequilibrium with the CP-associated SNPs and optimally tagged by rs8048956. Furthermore, they provided in silico and in vivo evidence showing that the inversion variant changes the expression ratio of the CTRB1 and CTRB2 isoforms, the major risk allele being associated with increased CTRB1 and decreased CTRB2 mRNA expression as compared with the minor allele. Finally, they provided in vitro evidence that CTRB1 was less efficient in degrading anionic trypsinogen (PRSS2) than CTRB2 (note that rapid degradation of PRSS2 conferred by a PRSS2 missense variant...

http://ift.tt/2wSA8zl

Response to 'Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence by Siau et al

We are thankful for the letter of Siau et al1 in response to our article describing the learning curve to satisfactory completion rates in upper GI endoscopy.2

We agree that D2 intubation and successful J manoeuvre are insufficient to define competence. Our article's title stated that we focused on completion rates. We specifically mentioned in our discussion that it is necessary to comply with a host of other measures to be competent. For example, procedural completion and successful J manoeuvre do not ensure complete inspection of the mucosa, nor do they result in correct identification of pathology. We welcome the introduction by Joint Advisory Group of assessment of endoscopic non-technical skills and support direct observation of procedural skills for trainees. Competency assessment should be broad and assess all necessary skills required of high-quality independent endoscopists.

Nevertheless, it is likely that a minimum number of procedures will remain part of...

http://ift.tt/2yFhEiY

Continuous Instream Monitoring of Nutrients and Sediment in Agricultural Watersheds

With the advancement of technology and the rise in end-user expectations, the need and use of higher temporal resolution data for pollutant load estimation has increased. This protocol describes a method for continuous in situ water quality monitoring to obtain higher temporal resolution data for informed water resource management decisions.

http://ift.tt/2xz0CmQ

Study of Siphon Breaker Experiment and Simulation for a Research Reactor

The siphon breaking phenomenon was investigated experimentally and a theoretical model was proposed. A simulation program based on the theoretical model was developed and the results of the simulation program were compared with experimental results. It was concluded that the results of the simulation program matched the experimental results well.

http://ift.tt/2yqIACl

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2k0a3Za

Human papillomavirus 16 E6 antibodies are sensitive for human papillomavirus–driven oropharyngeal cancer and are associated with recurrence

BACKGROUND

Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus–driven oropharyngeal cancer (HPV-OPC).

METHODS

This study identified 161 incident oropharyngeal cancer (OPC) cases diagnosed at the University of Pittsburgh (2003-2013) with pretreatment serum. One hundred twelve had preexisting clinical HPV testing with p16 immunohistochemistry and HPV in situ hybridization (87 were dual-positive [HPV-OPC], and 25 were dual-negative [HPV-negative]); 62 had at least 1 posttreatment serum sample. Eighty-six of the 161 tumors were available for additional HPV16 DNA/RNA testing (45 were dual-positive [HPV16–OPC], and 19 were dual-negative [HPV16–negative). HPV16 E6 antibody testing was conducted with multiplex serology. The following were evaluated: 1) the sensitivity and specificity of HPV16 E6 serology for distinguishing HPV-OPC and HPV16–OPC from HPV-negative OPC, 2) HPV16 E6 antibody decay after treatment with linear models accommodating correlations in variance estimates, and 3) pre- and posttreatment HPV16 E6 levels and the risk of recurrence with Cox proportional hazards models.

RESULTS

Seventy-eight of 87 HPV-OPCs were HPV16 E6–seropositive (sensitivity, 89.7%; 95% confidence interval [CI], 81.3%-95.2%), and 24 of 25 HPV-negative OPCs were HPV16 E6–seronegative (specificity, 96.0%; 95% CI, 79.6%-99.9%). Forty-two of 45 HPV16–OPCs were HPV16 E6–seropositive (sensitivity, 93.3%; 95% CI, 81.7%-98.6%), and 18 of 19 HPV16–negative OPCs were HPV16 E6–seronegative (specificity, 94.7%; 95% CI, 74.0%-99.9%). Posttreatment HPV16 E6 antibody levels did not decrease significantly from the baseline (P = .575; median follow-up, 307 days) and were not associated with the risk of recurrence. However, pretreatment HPV16 E6 seropositivity was associated with an 86% reduced risk of local/regional recurrence (hazard ratio, 0.14; 95% CI, 0.03-0.68; P = .015).

CONCLUSIONS

HPV16 E6 antibodies may have potential clinical utility for the diagnosis and/or prognosis of HPV-OPC. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2y6jjBm

Serum antibodies open the door to prediction and prognostication in human papillomavirus–related head and neck cancer

In human papillomavirus–related head and neck cancer, who can be de-escalated, and who requires more intensive therapy to achieve similar oncologic efficacy? The answers may very well be circulating in saliva and serum. See also pages 000-000.

http://ift.tt/2k0sRaR

Proton Density Fat Suppressed MRI in 3T Increases the Sensitivity of Multiple Sclerosis Lesion Detection in the Cervical Spinal Cord

Abstract

Purpose

Considering the number of multiple sclerosis (MS) patients referred for clinical spinal cord imaging, the optimization of imaging protocols plays a crucial role. We aimed to evaluate the use of proton density (PD) turbo spin-echo (TSE) with spectral attenuated inversion recovery (SPAIR) fat suppression and compare it with the currently recommended T2-TSE-SPAIR in sagittal plane in cervical spinal cord imaging.

Methods

In this study 35 MS patients with clinically suspected or known spinal cord lesions were scanned on a 3.0T magnetic resonance imaging (MRI) system. In addition to the routine protocol, PD-TSE-SPAIR sequences were obtained to quantitatively and qualitatively evaluate lesion detectability and image quality compared to T2-TSE-SPAIR sequences. Quantitative analysis was based on measurements of lesion-to-cord contrast ratio (LCCR), lesion contrast-to-noise ratio (LCNR) and lesion dimensions and the qualitative analysis on ranking with a predetermined score scale. The presence of lesions in these sequences was verified in axial T2 multi-echo gradient echo images.

Results

In quantitative analysis, the lesions on PD-TSE-SPAIR had statistically significantly higher contrast (p < 0.05), according to the statistical test of LCCR, LCNR calculated contrast and measured lesion dimensions. Qualitative analyses were congruent with quantitative results; the median rank of PD-TSE-SPAIR was significantly higher than T2-TSE-SPAIR (p < 0.05). Of the 34 detected lesions 9 (26%) were not visualized in T2-TSE-SPAIR sequence.

Conclusion

Considering its superiority in contrast ratios and lesion dimensions when compared to T2-TSE-SPAIR in both qualitative and quantitative analyses, we therefore recommend PD-TSE-SPAIR as a pivotal sequence to evaluate demyelinating spinal cord lesions at 3T.

http://ift.tt/2htBwBz

Low-Tech Outreach Methods Improve Colorectal Cancer Screening

Proactive, low-tech outreach approaches can help increase the number of people who get screened for colorectal cancer with a colonoscopy or home stool test and complete the appropriate follow-up.

http://ift.tt/2fpckbh

Genomic disorders 20 years on - mechanisms for clinical manifestations

Genomic disorders result from copy number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and, more recently, whole genome sequencing and whole exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent versus nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of non-coding CNVs to human disease.

http://ift.tt/2wiABqt

Management of precancerous anal intraepithelial lesions in human immunodeficiency virus–positive men who have sex with men: Clinical effectiveness and cost-effectiveness

BACKGROUND

Human immunodeficiency virus (HIV)–positive men who have sex with men (MSM) are at disproportionately high risk for anal cancer. There is no definitive approach to the management of high-grade squamous intraepithelial lesions (HSIL), which are precursors of anal cancer, and evidence suggests that posttreatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves HSIL treatment effectiveness. The objectives of this study were to evaluate the optimal HSIL management strategy with respect to clinical effectiveness and cost-effectiveness and to identify the optimal age for initiating HSIL management.

METHODS

A decision analytic model of the natural history of anal carcinoma and HSIL management strategies was constructed for HIV-positive MSM who were 27 years old or older. The model was informed by the Surveillance, Epidemiology, and End Results–Medicare database and published studies. Outcomes included the lifetime cost, life expectancy, quality-adjusted life expectancy, cumulative risk of cancer and cancer-related deaths, and cost-effectiveness from a societal perspective.

RESULTS

Active monitoring was the most effective approach in patients 29 years or younger; thereafter, HSIL treatment plus adjuvant qHPV vaccination became most effective. When cost-effectiveness was considered (ie, an incremental cost-effectiveness ratio [ICER] < $100,000/quality-adjusted life-year), do nothing was cost-effective until the age of 38 years, and HSIL treatment plus adjuvant qHPV vaccination was cost-effective beyond the age of 38 years (95% confidence interval, 34-43 years). The ICER decreased as the age at HSIL management increased. Outcomes were sensitive to the rate of HSIL regression or progression and the cost of high-resolution anoscopy and biopsy.

CONCLUSIONS

The management of HSIL in HIV-positive MSM who are 38 years old or older with treatment plus adjuvant qHPV vaccination is likely to be cost-effective. The conservative approach of no treatment is likely to be cost-effective in younger patients. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2huzH7y

Design, synthesis and biological evaluation of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives as xanthine oxidase inhibitors

Abstract

A series of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives (1a-p) was designed, synthesized and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC₅₀ values of 8.1 μM and 6.7 μM, respectively. The Lineweaver-Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor. SARs analysis revealed that a carbon atom occupying the X³ position is not as effective as a nitrogen atom; and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.

This article is protected by copyright. All rights reserved.

The little compounds were designed, synthesized and identified as XO inhibitors. SARs analysis revealed that a carbon atom occupying the X³ position is not as effective as a nitrogen atom, and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver-Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by 1k.

http://ift.tt/2xuq5QI

Elastic Inflatable Actuators for Soft Robotic Applications

Abstract

The 20th century's robotic systems have been made from stiff materials, and much of the developments have pursued ever more accurate and dynamic robots, which thrive in industrial automation, and will probably continue to do so for decades to come. However, the 21st century's robotic legacy may very well become that of soft robots. This emerging domain is characterized by continuous soft structures that simultaneously fulfill the role of robotic link and actuator, where prime focus is on design and fabrication of robotic hardware instead of software control. These robots are anticipated to take a prominent role in delicate tasks where classic robots fail, such as in minimally invasive surgery, active prosthetics, and automation tasks involving delicate irregular objects. Central to the development of these robots is the fabrication of soft actuators. This article reviews a particularly attractive type of soft actuators that are driven by pressurized fluids. These actuators have recently gained traction on the one hand due to the technology push from better simulation tools and new manufacturing technologies, and on the other hand by a market pull from applications. This paper provides an overview of the different advanced soft actuator configurations, their design, fabrication, and applications.

The 21^st century's robotic legacy may very well become that of soft robots, which show remarkable features superior to those of conventional robots in tasks requiring delicate manipulation and a high degree of maneuverability. This review discusses a particular type of soft actuators—elastic inflatable actuators—which are driven by pressurized fluids and allow for straightforward integration in soft robotics.

http://ift.tt/2wRx3Q4

A High-On/Off-Ratio Floating-Gate Memristor Array on a Flexible Substrate via CVD-Grown Large-Area 2D Layer Stacking

Abstract

Memristors such as phase-change memory and resistive memory have been proposed to emulate the synaptic activities in neuromorphic systems. However, the low reliability of these types of memories is their biggest challenge for commercialization. Here, a highly reliable memristor array using floating-gate memory operated by two terminals (source and drain) using van der Waals layered materials is demonstrated. Centimeter-scale samples (1.5 cm × 1.5 cm) of MoS₂ as a channel and graphene as a trap layer grown by chemical vapor deposition (CVD) are used for array fabrication with Al₂O₃ as the tunneling barrier. With regard to the memory characteristics, 93% of the devices exhibit an on/off ratio of over 10³ with an average ratio of 10⁴. The high on/off ratio and reliable endurance in the devices allow stable 6-level memory applications. The devices also exhibit excellent memory durability over 8000 cycles with a negligible shift in the threshold voltage and on-current, which is a significant improvement over other types of memristors. In addition, the devices can be strained up to 1% by fabricating on a flexible substrate. This demonstration opens a practical route for next-generation electronics with CVD-grown van der Waals layered materials.

A highly reliable memristor array using floating-gate memory operated by two terminals (source and drain) using van der Waals layered materials is demonstrated. Centimeter-scale samples (1.5 cm × 1.5 cm) of MoS₂ as a channel and graphene as a trap layer grown by chemical vapor deposition are used for the array fabrication with Al₂O₃ as the tunneling barrier. In the bending test of the tunneling random-access memory, an on/off ratio of 10⁵ is maintained under 0–1% strain showing that devices can be applicable for flexible memristors.

http://ift.tt/2yEn11U

Large-Area All-Textile Pressure Sensors for Monitoring Human Motion and Physiological Signals

Abstract

Wearable pressure sensors, which can perceive and respond to environmental stimuli, are essential components of smart textiles. Here, large-area all-textile-based pressure-sensor arrays are successfully realized on common fabric substrates. The textile sensor unit achieves high sensitivity (14.4 kPa⁻¹), low detection limit (2 Pa), fast response (≈24 ms), low power consumption (<6 µW), and mechanical stability under harsh deformations. Thanks to these merits, the textile sensor is demonstrated to be able to recognize finger movement, hand gestures, acoustic vibrations, and real-time pulse wave. Furthermore, large-area sensor arrays are successfully fabricated on one textile substrate to spatially map tactile stimuli and can be directly incorporated into a fabric garment for stylish designs without sacrifice of comfort, suggesting great potential in smart textiles or wearable electronics.

Large-area all-textile pressure-sensor arrays are successfully fabricated on a woven fabric substrate for monitoring human motion and personal healthcare. High sensitivity, excellent mechanical flexibility, low detection limit, and power consumption are achieved for applications in wearable electronics or smart textiles.

http://ift.tt/2wROPTq

From clinical epidemiology to practice recommendations: Knowledge gaps and uncertainty in the management of anal precancers

This editorial discusses the existing data on anal precancers and demonstrates the impact of evidence gaps and uncertainty on a clinical decision model developed to provide clinical guidance for the management of anal precancers. See also pages 000-000.

http://ift.tt/2xDczJI

Antifungal Activity of Essential Oils against Candida albicans Strains Isolated from Users of Dental Prostheses

Objective. The objective of this study was to analyze the antifungal activity of citral, selected by screening natural products, against Candida albicans isolates from subjects who use dental prostheses. Methodology. Screening of essential oils, including those from Mentha piperita L. (Briq), Origanum vulgare, and Zingiber officinale L., and the phytoconstituents citral and limonene, to select an appropriate natural product. Citral, which mediated the best antifungal response, was selected for biological assays. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) for citral and nystatin were determined by the microdilution method. Micromorphological analyses, time-kill curve, and modulation tests were performed. Results. The MIC and MFC of citral were established as 32 μg/mL, consistent with fungicidal activity. The clinical strains were resistant to nystatin. Citral caused micromorphological alteration in the strains. In the time-kill curve, the growth of the clinical strain was reduction in growth equal to 3 log10 colony-forming units per milliliter after exposure to the MIC and of citral for 2 h. Citral did not modulate the resistance of the studied strains to nystatin. Conclusion. This study revealed the potential of citral as a fungicidal agent and highlighted the resistance of clinical strains of C. albicans to nystatin.

http://ift.tt/2xyxmg1

Antidepressant Mechanism Research of Acupuncture: Insights from a Genome-Wide Transcriptome Analysis of Frontal Cortex in Rats with Chronic Restraint Stress

Major depressive disorder (MDD) is a chronic disease that adversely affects mood and cognition. In this study, we randomly divided the rats into control group (C), model group (M), fluoxetine group (F), and acupuncture group (A), used open-field test to ascertain whether acupuncture affects chronic restraint stress (CRS) induced depression-like behaviors of rats, and explored the antidepressant mechanism of acupuncture at the molecular level of transcriptome in the frontal cortex of CRS rats by RNA-sequencing (RNA-seq). According to differentially expressed genes (DEG) analysis, we identified 134, 46, and 89 response genes differentially expressed in C versus M, F versus M, and A versus M, respectively. Through Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we identified the gene sets involved in extracellular space, inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway, and TNF signaling pathway. In this study, RNA-seq technology was used to investigate the frontal cortex genome-wide transcriptomes in depression rats under CRS, which suggested that the antidepressant effect of acupuncture is effective and has a multitarget characteristic, which may be related to amino acid metabolism and inflammatory pathways, especially the Toll-like receptor signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway.

http://ift.tt/2yoO2FS

Group-sequential analysis may allow for early trial termination: illustration by an intra-observer repeatability study

Abstract

Background

Group-sequential testing is widely used in pivotal therapeutic, but rarely in diagnostic research, although it may save studies, time, and costs. The purpose of this paper was to demonstrate a group-sequential analysis strategy in an intra-observer study on quantitative FDG-PET/CT measurements, illuminating the possibility of early trial termination which implicates significant potential time and resource savings.

Methods

Primary lesion maximum standardised uptake value (SUVmax) was determined twice from preoperative FDG-PET/CTs in 45 ovarian cancer patients. Differences in SUVmax were assumed to be normally distributed, and sequential one-sided hypothesis tests on the population standard deviation of the differences against a hypothesised value of 1.5 were performed, employing an alpha spending function. The fixed-sample analysis (N = 45) was compared with the group-sequential analysis strategies comprising one (at N = 23), two (at N = 15, 30), or three interim analyses (at N = 11, 23, 34), respectively, which were defined post hoc.

Results

When performing interim analyses with one third and two thirds of patients, sufficient agreement could be concluded after the first interim analysis and the final analysis. Other partitions did not suggest early stopping after adjustment for multiple testing due to one influential outlier and our small sample size.

Conclusions

Group-sequential testing may enable early stopping of a trial, allowing for potential time and resource savings. The testing strategy must, though, be defined at the planning stage, and sample sizes must be reasonably large at interim analysis to ensure robustness against single outliers. Group-sequential testing may have a place in accuracy and agreement studies.

http://ift.tt/2wRxeec

Decrease in Anti-HBs Antibodies over Time in Medical Students and Healthcare Workers after Hepatitis B Vaccination

Background. Hepatitis B is one of the most important occupational hazards among healthcare workers (HCWs). This study aimed to measure the anti-HBs titres among the medical students and HCWs vaccinated against hepatitis B virus and to determine the association between anti-HBs levels and time since vaccination. Materials and Methods. In this cross-sectional study, medical students and healthcare workers who had received all three doses of hepatitis B vaccination and completed at least six months after vaccination since the last dose were included. 3 ml blood was collected from subjects () and anti-HBs titre was estimated using ELISA. Results. A total of 340/400 subjects were aged between 18 and 60 years; 204 were females and 136 males. The median and interquartile range for time since vaccination were 5 and 5 years, respectively. Duration since vaccination was ≤5 years in 223 (65.5%), 6–10 years in 84 (24.7%), and >10 years in 33 (9.70%); among them, antibody titres were >10 mIU/ml in 94.1%, 79.7%, and 72.7% subjects, respectively. There was significant decline in antibody titres as duration of postvaccination increased. Conclusion. The proportion of subjects who were unprotected after 5 and 10 years after vaccination were 20% and 27%, respectively. The need for a booster dose can be made mandatory at least for healthcare professionals.

http://ift.tt/2ypWGUE

3D Liver Tumor Segmentation in CT Images Using Improved Fuzzy C-Means and Graph Cuts

Three-dimensional (3D) liver tumor segmentation from Computed Tomography (CT) images is a prerequisite for computer-aided diagnosis, treatment planning, and monitoring of liver cancer. Despite many years of research, 3D liver tumor segmentation remains a challenging task. In this paper, an efficient semiautomatic method was proposed for liver tumor segmentation in CT volumes based on improved fuzzy C-means (FCM) and graph cuts. With a single seed point, the tumor volume of interest (VOI) was extracted using confidence connected region growing algorithm to reduce computational cost. Then, initial foreground/background regions were labeled automatically, and a kernelized FCM with spatial information was incorporated in graph cuts segmentation to increase segmentation accuracy. The proposed method was evaluated on the public clinical dataset (3Dircadb), which included 15 CT volumes consisting of various sizes of liver tumors. We achieved an average volumetric overlap error (VOE) of 29.04% and Dice similarity coefficient (DICE) of 0.83, with an average processing time of 45 s per tumor. The experimental results showed that the proposed method was accurate for 3D liver tumor segmentation with a reduction of processing time.

http://ift.tt/2yqV7Wo

Systems Study on the Antirheumatic Mechanism of Tibetan Medicated-Bath Therapy Using Wuwei-Ganlu-Yaoyu-Keli

In clinical practice at Tibetan area of China, Traditional Tibetan Medicine formula Wuwei-Ganlu-Yaoyu-Keli (WGYK) is commonly added in warm water of bath therapy to treat rheumatoid arthritis (RA). However, its mechanism of action is not well interpreted yet. In this paper, we first verify WGYK's anti-RA effect by an animal experiment. Then, based on gene expression data from microarray experiments, we apply approaches of network pharmacology to further reveal the mechanism of action for WGYK to treat RA by analyzing protein-protein interactions and pathways. This study may facilitate our understanding of anti-RA effect of WGYK from perspective of network pharmacology.

http://ift.tt/2xwOkel

Clinical and molecular characterization of patients with cancers of unknown primary in the modern era

Abstract

Background

On the basis of historical data, patients with cancers of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than one year. Treatment is typically cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next generation sequencing in the evaluation and treatment of patients with CUP.

Patients and methods

Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent two-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment.

Results

We identified 333 patients with a diagnosis of CUP evaluated at our institution from January 1^st 2014 through June 30^th 2016. 150 of these patients had targeted next generation sequencing performed on available tissue. Median overall survival in this cohort was 13 months. 45/150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15/150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21/150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco.

Conclusions

Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.

http://ift.tt/2fxmHgO

Clinical benefit of systemic treatment in patients with advanced pancreatic and gastro-intestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework

Abstract:

BackgroundAssessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumors (GEP-NET) is challenging. Recently several tools have been developed to grade clinical benefit of cancer drugs. European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review we graded systemic treatments for GEP-NET patients with both frameworks.MethodsThe electronic databases (PubMed, Embase) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by 4 independent assessors, discrepancies were discussed.ResultsThe search yielded 32 trials of which 6 trials were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F; resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F.ConclusionThe currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.

http://ift.tt/2xHYfQx

Analyzing the impact of Depth of Response on Survival in patients with metastatic non-small cell lung cancer.

http://ift.tt/2fxcBfP

Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go

Abstract

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference "Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes." There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally-anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1. establishing a working definition for alternative markers of performance; 2. defining goals for using alternative performance markers; 3. implications for measurement when using alternative markers; 4. identifying practical concerns related to the use of alternative performance markers; and 5. identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged, and are summarized in the paper.

This article is protected by copyright. All rights reserved.

http://ift.tt/2fplhkF