Socioeconomic status and geographical factors associated with active listing in primary care: a cross-sectional population study accounting for multimorbidity, age, sex and primary care

Background

Socioeconomic status and geographical factors are associated with health and use of healthcare. Well-performing primary care contributes to better health and more adequate healthcare. In a primary care system based on patient's choice of practice, this choice (listing) is a key to understand the system.

Objective

To explore the relationship between population and practices in a primary care system based on listing.

Methods

Cross-sectional population-based study. Logistic regressions of the associations between active listing in primary care, income, education, distances to healthcare and geographical location, adjusting for multimorbidity, age, sex and type of primary care practice.

Setting and subjects

Population over 15 years (n=123 168) in a Swedish county, Blekinge (151 731 inhabitants), in year 2007, actively or passively listed in primary care. The proportion of actively listed was 68%.

Main outcome measure

Actively listed in primary care on 31 December 2007.

Results

Highest ORs for active listing in the model including all factors according to income had quartile two and three with OR 0.70 (95% CI 0.69 to 0.70), and those according to education less than 9 years of education had OR 0.70 (95% CI 0.68 to 0.70). Best odds for geographical factors in the same model had municipality C with OR 0.85 (95% CI 0.85 to 0.86) for active listing. Akaike's Information Criterion (AIC) was 124 801 for a model including municipality, multimorbidity, age, sex and type of practice and including all factors gave AIC 123 934.

Conclusions

Higher income, shorter education, shorter distance to primary care or longer distance to hospital is associated with active listing in primary care.

Multimorbidity, age, geographical location and type of primary care practice are more important to active listing in primary care than socioeconomic status and distance to healthcare.

http://ift.tt/2s75xL3

Global prevalence of diabetes mellitus in patients with tuberculosis: a systematic review and meta-analysis protocol

Introduction

Diabetes mellitus (DM) is an important risk factor for active tuberculosis (TB), which also adversely affect TB treatment outcomes. The escalating global DM epidemic is fuelling the burden of TB and should therefore be a major target in the strategy for ending TB. This review aims to estimate the global prevalence of DM in patients with TB.

Methods and analysis

This systematic review will include cross-sectional, case–control or cohort studies of populations including patients diagnosed with TB that have reported the prevalence of DM using one of the fourth standard recommendations for screening and diagnosis. This protocol is written in accordance with recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Relevant abstracts published in English/French from inception to 31 December 2016 will be searched in PubMed, Excerpta Medica Database and online journals. Two investigators will independently screen, select studies, extract data and assess the risk of bias in each study. The study-specific estimates will be pooled through a random-effects meta-analysis model to obtain an overall summary estimate of the prevalence of diabetes across the studies. Heterogeneity will be assessed, and we will pool studies judged to be clinically homogenous. On the other hand, statistical heterogeneity will be evaluated by the ² test on Cochrane's Q statistic. Funnel-plots analysis and Egger's test will be used to investigate publication bias. Results will be presented by continent or geographic regions.

Ethics and dissemination

This study is based on published data. An ethical approval is therefore not required. This systematic review and meta-analysis is expected to inform healthcare providers as well as general population on the co-occurrence of DM and TB. The final report will be published as an original article in a peer-reviewed journal, and will also be presented at conferences and submitted to relevant health authorities. We also plan to update the review every 5 years.

Protocolregistration number

PROSPERO International Prospective Register of Systematic Reviews (CRD42016049901).

http://ift.tt/2s7pKQF

The organisational value of diagnostic strategies using high-sensitivity troponin for patients with possible acute coronary syndromes: a trial-based cost-effectiveness analysis

Objectives

To evaluate hospital-specific health economic implications of different protocols using high-sensitivity troponin I for the assessment of patients with chest pain.

Design

A cost prediction model and an economic microsimulation were developed using a cohort from a single centre recruited as part of the (ADAPT) trial, a prospective observational trial conducted from 2008 to 2011. The model was populated with 40 000 bootstrapped samples in five high-sensitivity troponin I-enabled algorithms versus standard care.

Setting

Adult emergency department (ED) of a tertiary referral hospital.

Participants

Data were available for 938 patients who presented to the ED with at least 5 min of symptoms suggestive of acute coronary syndrome. The analyses included 719 patients with complete data.

Main outcome(s)/measure(s)

This study examined direct hospital costs, number of false-negative and false-positive cases in the assessment of acute coronary syndrome.

Results

High-sensitivity troponin I-supported algorithms increased diagnostic accuracy from 90.0% to 94.0% with an average cost reduction per patient compared with standard care of $490. The inclusion of additional criteria for accelerated rule-out (limit of detection and the modified 2-hour ADAPT trial rules) avoided 7.5% of short-stay unit admissions or 25% of admissions to a cardiac ward. Protocols using high-sensitivity troponin I alone or high-sensitivity troponin I within accelerated diagnostic algorithms reduced length of stay by 6.2 and 13.6 hours, respectively. Overnight stays decreased up to 43%. Results were seen for patients with non-acute coronary syndrome; no difference was found for patients with acute coronary syndrome.

Conclusions

High-sensitivity troponin I algorithms are likely to be cost-effective on a hospital level compared with sensitive troponin protocols. The positive effect is conferred by patients not diagnosed with acute coronary syndrome. Implementation could improve referral accuracy or facilitate safe discharge. It would decrease costs and provide significant hospital benefits.

Trial registration

The original ADAPT trial was registered with the Australia-New Zealand Clinical trials Registry, ACTRN12611001069943.

http://ift.tt/2t4Tefh

Serum fibrinogen and cardiovascular events in Chinese patients with type 2 diabetes and stable coronary artery disease: a prospective observational study

Objectives

The aim of this study was to investigate the association of serum fibrinogen with cardiovascular events (CVE) in Chinese patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD).

Design

An observational study.

Setting

FuWai Hospital in Beijing, China.

Participants

A cohort of 1466 patients with T2DM and angiographic-proven stable CAD was evaluated.

Outcome measures

Baseline serum fibrinogen levels were measured and trisected into 'low', 'middle' and 'high'. Their association with CVE was explored using Cox proportional hazard models.

Results

With 20.2 months (average) follow-up, 44 (3%) were lost to follow-up and 96 patients developed CVE. Compared with the patients without CVE, the ones who developed CVE had higher levels of fibrinogen. Univariable regression revealed a significant relation of fibrinogen to CVE (HR (HR) 1.25, 95% CI 1.06 to 1.47, p=0.010) per SD increase of fibrinogen at baseline. After adjusting for multiple established cardiovascular disease (CVD) risk factors, the association persisted (HR 1.30, 95% CI 1.02 to 1.66, p=0.037). Moreover, after adjusting for CVD risk factors, the HRs for middle-serum and high-serum fibrinogen concentration, using 'low' group as reference, were 1.23 (95% CI 0.69 to 2.20) and 2.20 (95% CI 1.11 to 3.36, p=0.049).

Conclusions

We first indicated that elevated fibrinogen level was independently associated with increased CVE in Chinese patients with T2DMand stable CAD.

http://ift.tt/2s7gTOO

Protocol for a qualitative synthesis of barriers and facilitators in implementing guidelines for diagnosis of tuberculosis

Introduction

Despite the introduction of new tests and guidelines for diagnosis of tuberculosis (TB), worldwide case detection rate of TB is still suboptimal. This could be in part explained by the poor implementation of TB diagnostic guidelines. We aim to identify, appraise and synthesise qualitative evidence exploring the barriers and facilitators to implementing TB diagnostic guidelines.

Methods and analysis

A systematic review of qualitative studies will be conducted. Relevant electronic databases will be searched and studies included based on predefined inclusion criteria. We will also search reference lists, grey literature, conduct forward citation searches and contact relevant content experts. An adaptation of the Critical Appraisal Skills Programme tool will be used to assess the methodological quality of included studies. Two authors will review the search output, extract data and assess methodological quality independently, resolving any disagreements by consensus. We will use the thematic framework analysis approach based on the Supporting the Use of Research Evidence thematic framework to analyse and synthesise our data. We will apply the Confidence in the Evidence from Reviews of Qualitative research approach to transparently assess our confidence in the findings of the systematic review.

Ethics and dissemination

This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42016039790

Trial registration number

PROSPERO 2016: CRD42016039790. Available from http://ift.tt/1syiOpX

http://ift.tt/2t5mAKt

Contextual and individual inequalities of multimorbidity in Brazilian adults: a cross-sectional national-based study

Objectives

The study aims to evaluate the magnitude of multimorbidity in Brazilian adults, as well to measure their association with individual and contextual factors stratified by Brazilian states and regions.

Methods

A national-based cross-sectional study was carried out in 2013 with Brazilian adults. Multimorbidity was evaluated by a list of 22 physical and mental morbidities (based on self-reported medical diagnosis and Patient Health Questionnaire-9 for depression). The outcome was analysed taking ≥2 and ≥3 diseases as cut-off points. Factor analysis (FA) was used to identify disease patterns and multilevel models were used to test association with individual and contextual variables.

Results

The sample comprised 60 202 individuals. Multimorbidity frequency was 22.2% (95% CI 21.5 to 22.9) for ≥2 morbidities and 10.2% (95% CI 9.7 to 10.7) for ≥3 morbidities. In the multilevel adjusted models, females, older people, those living with a partner and having less schooling presented more multiple diseases. No linear association was found according to wealth index but greater outcome frequency was found in individuals with midrange wealth index. Living in states with higher levels of education and wealthier states was associated with greater multimorbidity. Two patterns of morbidities (cardiometabolic problems and respiratory/mental/muscle–skeletal disorders) explained 92% of total variance. The relationship of disease patterns with individual and contextual variables was similar to the overall multimorbidity, with differences among Brazilian regions.

Conclusions

In Brazil, at least 19 million adults had multimorbidity. Frequency is similar to that found in other Low and and Middle Income Countries. Contextual and individual social inequalities were observed.

http://ift.tt/2t59nBE

Prevalence characteristics of cervical human papillomavirus (HPV) genotypes in the Taizhou area, China: a cross-sectional study of 37 967 women from the general population

Objectives

High-risk human papillomaviruses (hrHPVs) are highly prevalent worldwide, and HPV genotypes differ between geographical regions; however, sexually transmitted HPV may lead to cervical carcinogenesis. The objective of this cross-sectional study was to estimate the prevalence characteristics of cervical HPV genotypes in Taizhou, Southeast China.

Setting and participants

A population-based sample of 37 967 eligible women (median age: 41.6; range: 15–90 years) visiting the Taizhou ENZE Medical Center in Taizhou (2012–2016) was analysed. HPV genotyping was performed on the collected specimens using a GP5+/bioGP6+-PCR/MPG assay by Luminex 200, which simultaneously identifies 27 different HPV genotypes and the β-globin gene (internal control).

Results

The overall HPV infection rate was 22.8% in the Taizhou-based population, and the prevalence of high-risk HPV, low-risk HPV and mixed high-risk and low-risk HPV infection was 14.2%, 5.7% and 3.0%, respectively. The most prevalent genotypes were HPV52 (19.7%), 16 (11.9%), 58 (11.5%), 39 (7.2%), 18 (6.6%) and 56 (5.6%). The rate of multiple-type HPV infection was 5.7% in the whole population, and the HPV52+58, HPV16+52 and HPV16+18 mixed genotypes were most common in women with multiple infections. The age-specific HPV prevalence showed a bimodal curve, with a first peak below the age of 21 years (41.6%), followed by a second peak in the age group of 56–60 years (28.5%). Moreover, the HPV infection rate differed significantly between the outpatient and physical examination groups (24.0% vs 19.5%, p<0.0001). Further data comparisons showed that the distribution of HPV genotypes varied markedly between the two groups.

Conclusions

Data from this study could be valuable for HPV-based cervical cancer screening efforts in certain areas, support the local vaccination programme in the Taizhou region and facilitate future diagnosis and treatment of HPV diseases.

http://ift.tt/2s7gXy2

Colorectal cancer with Synchronous liver-limited Metastases: the protocol of an Inception Cohort study (CoSMIC)

Introduction

Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome.

Methods and analysis

Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care.

Ethics and dissemination

The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences.

Trial registration number

NCT02456285, pre-results.

http://ift.tt/2t5g3Q1

Diagnostic value of the antiglycoprotein-2 antibody for Crohns disease: a PRISMA-compliant systematic review and meta-analysis

Objectives

To perform a meta-analysis to evaluate the diagnostic performance of the antiglycoprotein-2 (GP2) antibody for Crohn's disease (CD).

Methods

Three databases (EMBASE, ISI Web of Knowledge and PubMed) were systematically searched. There were 17 eligible studies included in the meta-analysis. A total of 2439 patients with CD and 3184 controls were involved in these studies. STATA V.11.2 and Meta-DiSc V.1.4 were used to perform the meta-analysis.

Results

The area under the summary receiver operating characteristic curve was 0.68–0.72. The pooled diagnostic sensitivity of the anti-GP2 antibody ranged from 14% to 24%, and the specificity was 96%–98%.

Conclusions

The anti-GP2 antibody is a specific biomarker for CD, and further exploration of its prevalence among different clinical phenotypes of CD will provide a better understanding of its diagnostic performance.

http://ift.tt/2s7kXi7

Interfacility transfer of pregnant women using publicly funded emergency call centre-based ambulance services: a cross-sectional analysis of service logs from five states in India

Objective

To estimate the proportion of interfacility transfers (IFTs) transported by '108' ambulances and to compare the characteristics of the IFTs and non-IFTs to understand the pattern of use of '108' services for pregnant women in India.

Design

A cross-sectional analysis of '108' ambulance records from five states for the period April 2013 to March 2014. Data were obtained from the call centre database for the pregnant women, who called '108'.

Main outcomes

Proportion of all pregnancies and institutional deliveries in the population who were transported by '108', both overall and for IFT. Characteristics of the women transported; obstetric emergencies, the distances travelled and the time taken for both IFT and non-IFT.

Results

The '108' ambulances transported 6 08 559 pregnant women, of whom 34 993 were IFTs (5.8%) in the five states. We estimated that '108' transferred 16.5% of all pregnancies and 20.8% of institutional deliveries. Only 1.2% of all institutional deliveries in the population were transported by '108' for IFTs—lowest 0.6% in Gujarat and highest 3.0% in Himachal Pradesh. Of all '108' IFTs, only 8.4% had any pregnancy complication. For all states combined, on adjusted analysis, IFTs were more likely than non-IFTs to be for older and younger women or from urban areas, and less likely to be for women from high-priority districts, from backward or scheduled castes, or women below the poverty line. Obstetric emergencies were more than twice as likely to be IFTs as pregnant women without obstetric emergencies (OR=2.18, 95% CI 2.09 to 2.27). There was considerable variation across states.

Conclusion

Only 6% institutional deliveries made use of the '108' ambulance for IFTs in India. The vast majority did not have any complication or emergency. The '108' service may need to consider strategies to prioritise the transfer of women with obstetric emergency and those requiring IFT, over uncomplicated non-IFT.

http://ift.tt/2t5teAi

Defining and measuring suspicion of sepsis: an analysis of routine data

Objectives

To define the target population of patients who have suspicion of sepsis (SOS) and to provide a basis for assessing the burden of SOS, and the evaluation of sepsis guidelines and improvement programmes.

Design

Retrospective analysis of routinely collected hospital administrative data.

Setting

Secondary care, eight National Health Service (NHS) Acute Trusts.

Participants

Hospital Episode Statistics data for 2013–2014 was used to identify all admissions with a primary diagnosis listed in the 'suspicion of sepsis' (SOS) coding set. The SOS coding set consists of all bacterial infective diagnoses.

Results

We identified 47 475 admissions with SOS, equivalent to a rate of 17 admissions per 1000 adults in a given year. The mortality for this group was 7.2% during their acute hospital admission. Urinary tract infection was the most common diagnosis and lobar pneumonia was associated with the most deaths. A short list of 10 diagnoses can account for 85% of the deaths.

Conclusions

Patients with SOS can be identified in routine administrative data. It is these patients who should be screened for sepsis and are the target of programmes to improve the detection and treatment of sepsis. The effectiveness of such programmes can be evaluated by examining the outcomes of patients with SOS.

http://ift.tt/2s700ns

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

Introduction

Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable.

Methods and analysis

The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals.

Ethics and dissemination

Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals.

Discussion

Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation.

Trial registration number

The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry.

http://ift.tt/2t5myCl

Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

Introduction

Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD), are chronic, progressive and disabling disorders of the gastrointestinal tract. Although data from randomised controlled trials (RCTs) provide the foundation of evidence that validates medical therapy for IBD, considerable heterogeneity exists in the measured outcomes used in these studies. Furthermore, in recent years, there has been a paradigm shift in IBD treatment targets, moving from symptom-based scoring to improvement or normalisation of objective measures of inflammation such as endoscopic appearance, inflammatory biomarkers and histological and radiographic end points. The abundance of new treatment options and evolving end points poses opportunities and challenges for all stakeholders involved in drug development. Accordingly, there exists a need to harmonise measures used in clinical trials through the development of a core outcome set (COS).

Methods and analysis

The development of an IBD-specific COS includes four steps. First, a systematic literature review is performed to identify outcomes previously used in IBD RCTs. Second, semistructured qualitative interviews are conducted with key stakeholders, including patients, clinicians, researchers, pharmaceutical industry representatives, healthcare payers and regulators to identify additional outcomes of importance. Using the outcomes generated from literature review and stakeholder interviews, an international two-round Delphi survey is conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting is held to ratify the COS and disseminate findings for application in future IBD trials.

Ethics and dissemination

Given that over 30 novel therapeutic compounds are in development for IBD treatment, the design of robust clinical trials measuring relevant and standardised outcomes is crucial. Standardising outcomes through a COS will reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies and improve clinical trial quality.

http://ift.tt/2t5mx1f

Associations between self-rated health and health behaviour among older adults in Estonia: a cross-sectional analysis

Objectives

The population of Estonia has one of the lowest life expectancies and health statuses in Europe. This is reflected in a lower perception of health among older adults. This study focuses on the role of health behaviour (smoking, alcohol consumption, physical activity and nutrition) in self-rated health, accounting for sociodemographic characteristics, activity limitations and long-term illnesses as well as satisfaction with life of older Estonian men and women.

Design

We use representative cross-sectional data from Wave 4 of the Estonian Survey of Health, Ageing and Retirement in Europe, conducted mainly in 2011.

Participants

Frequencies, ² tests and logistic regression models include respondents aged 50 years and older, with no upper age limit (n=6660).

Results

Men have 20% higher odds (CI 1.02 to 1.43) of poor self-rated health. Being of foreign origin (OR 1.48; CI 1.24 to 1.77), having a basic (2.50; CI 2.06 to 3.00) or secondary (1.71; CI 1.43 to 2.04) education, being retired (2.00; CI 1.65 to 2.44) or staying at home (1.49; CI 1.16 to 1.93) and having activity limitations (3.25; CI 2.77 to 3.80) or long-term illnesses (4.78; CI 4.08 to 5.60) are related to poor self-rated health. Never being involved in vigorous (2.30; CI 1.90 to 2.79) or moderate physical activity (1.41; CI 1.02 to 1.94), and consuming legumes and eggs less frequently (1.25; CI 1.08 to 1.45) is associated with poorer self-rated health. Lower satisfaction with life accounts for some of the variation (2.28; CI 1.92 to 2.71).

Conclusions

There is a strong cumulative effect of one's previous life course on the self-rated health of older adults in Estonia, suggesting that public health policies have long-term consequences rather than immediate consequences. Health services supporting health behaviours and targeting vulnerable population groups with specific sociodemographic characteristics and health problems may influence self-rated health for some. Public health services emphasising social activities or psychological aspects may be most successful in improving self-rated health of older Estonians through satisfaction with life.

http://ift.tt/2s7iGnp

The quality of reports of medical and public health research from Palestinian institutions: a systematic review

Objective

Over the past decade, there has been an increase in reports of health research from Palestine, but no assessment of their quality. We have assessed the quality of reports of Palestinian health research and factors associated with it.

Design

This is a systematic review.

Inclusion criteria

We searched Medline and Scopus for reports of original research relevant to human health or healthcare authored by researchers affiliated with Palestinian institutions and published between January 2000 and August 2015 inclusive.

Outcomes

We used international guidelines to assess report quality, classifying as adequate those with ≥50% of items completely addressed.

Results

Of 2383 reports identified, 497 met our inclusion criteria. Just over half (264; 55%) of these were published after 2010. 354 (71%) of first authors were affiliated with Palestinian institutions; 261 (53%) reports had coauthors from outside Palestine. The majority of the reports in our study were inadequately reported (342; 69%), and none had adequately reported all items. Of 439 observational studies, 11 (2.5%) reports provided adequate descriptions of eligibility criteria and selection procedures; 35 (8%) reported efforts to address potential sources of bias; 50 (11.4%) reported the basis for the study sample size; and funding sources were mentioned in 74 reports (17%). Higher reporting quality was associated with international affiliation of the first author (prevalence ratio (PR) 1.6 (95% CI 1.2 to 2.1)), international collaboration (PR 2.9 (95% CI 1.7 to 5.0)), international funding (PR 1.9 (95% CI1.5 to 2.5)), publication after 2005 (PR 3.9 (95% CI 1.8 to 8.5)) and four or more coauthors (PR 1.5 (95% CI 1.1 to 2.1)).

Conclusion

Although the quality of reports of Palestinian research has improved in recent years, it remains well below an acceptable standard. International reporting guidelines should be used to guide research design and improve the quality of reports of research.

Trial registration number

The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) registery (registration number: CRD42015027553).

http://ift.tt/2t5gf1H

Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2snXk5C

Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2r4jgig

Editorial

Publication date: June 2017
Source:Women and Birth, Volume 30, Issue 3
Author(s): Linda Sweet




http://ift.tt/2rVYCSv

Guest Editorial

Publication date: June 2017
Source:Women and Birth, Volume 30, Issue 3
Author(s): Ann Kinnear




http://ift.tt/2rbePX5

Aims and scope

Publication date: June 2017
Source:Women and Birth, Volume 30, Issue 3





http://ift.tt/2rVZK8V

Some pathological and clinical factors are important to describe association between Ki67 expression and recurrences in breast cancer patients receiving neoadjuvant chemotherapy—reply

We very much appreciate Dr. Altundag's careful reading and comments on our manuscript in the Letter to the Editor.

http://ift.tt/2r4e9P6

Differential Gene Expression Profiles According to the IASLC/ATS/ERS Histopathological Classification in Lung Adenocarcinoma Subtypes

The current lung cancer classification from the Association for the Study of Lung Cancer (IASLC) / the American Thoracic Society (ATS)/ the European Respiratory Society (ERS) has considerably changed the pathologic diagnosis of lung invasive adenocarcinoma, identifying disease subtypes with substantial implications for medical practice, such as clinical, radiological, molecular and prognostic differences. We analyzed the differences in the genetic expression of adenocarcinoma subtypes according to the new classification.

http://ift.tt/2snNnFa

A decision tree-based combination of ezrin-interacting proteins to estimate the prognostic risk of patients with esophageal squamous cell carcinoma

Our previous studies have highlighted the importance of ezrin in esophageal squamous cell carcinoma (ESCC). Here our objective was to explore the clinical significance of ezrin-interacting proteins, which would provide a theoretical basis for understanding the function of ezrin and potential therapeutic targets for ESCC. We employed affinity purification and mass spectrometry to identify PDIA3, CNPY2 and STMN1 as potential ezrin-interacting proteins. Confocal microscopy and co-immunoprecipitation analysis further confirmed the colocalization and interaction of ezrin with PDIA3, CNPY2 and STMN1.

http://ift.tt/2r4KnJQ

Overexpression of phosphoprotein phosphatase 2A predicts worse prognosis in patients with breast cancer: a 15-year follow-up

Breast cancer subtypes can be stratified by immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2). The signaling pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form phosphoprotein phosphatase 2A (p-PP2A).

http://ift.tt/2snHGXK

Early stage minor salivary gland adenoid cystic carcinoma has favourable prognosis

Abstract

The purpose of the study was to evaluate the long-term outcome of minor salivary and mucous gland (MiSG) adenoid cystic carcinoma (ACC) of the head and neck and to compare the results with earlier reports including our recently published series on major salivary gland (MaSG) ACC. The study comprised 68 MiSG ACCs operated during 1974–2012 at the Helsinki University Hospital, Helsinki, Finland. Medical records and histological samples were reviewed. Our previously published cohort comprising 54 MaSG ACCs during the years from 1974 to 2009 was used for comparison. The most common locations were the oral cavity and sinonasal cavities. Most patients presented stages IV (33.8%) and I (23.5%) disease. Primary treatment with curative intent, mainly surgery, was offered for 64 patients. Thirty-three (51.6%) of these patients developed a disease recurrence and 22 (66.7%) patients in less than 5 years. The difference in the length of recurrence-free time (<5 vs. >5 years) had an impact on OS and DSS (p < 0.001) showing worse prognosis for the earlier recurring group. T classes 2–4 (p = 0.005, p < 0.001, and p = 0.001, respectively) and stages II–IV (p = 0.019, p < 0.001, and p = 0.002, respectively) were associated with worse OS, DSS, and DFS. MiSG ACC had a similar long-term survival compared to MaSG ACC. Patients with stage I MiSG ACC seem to carry a favourable prognosis compared with those with stages II, III, and IV tumours. It is thus noteworthy that stage II tumours represent a truly advanced disease entity warranting a more aggressive treatment approach.

http://ift.tt/2rfmIWG

Ptosis as a complication of Kawasaki disease

Kawasaki disease is an acute febrile exanthematous disease that affects children younger than 5 years of age. It is regarded as the most common cause of childhood acquired heart disease, but ocular and neurological problems are among the other important clinical findings. We present a 3-year-old boy who developed bilateral ptosis on day 21, 5 days after intravenous immunoglobulin. The ptosis was due to bilateral paralysis of the levator palpebrae superioris muscles and resolved spontaneously on day 25. There were no cardiac sequelae.

http://ift.tt/2rbbbwl

Extensive cutaneous involvement due to herpes simplex virus infection

Description

A 39-year-old woman, with a medical history of oligofrenia, obesity and varicella at 8 years of age, presented to the emergency department (ED) with multiple skin lesions of upper limb, which began with the appearance of vesicles, associated with intense pain and pruritus and with 3 days of evolution. No fever was reported. She was discharged home medicated with acyclovir and hydroxyzine.

Three days later, she returned to the ED with worsening complaints of pain and itching, and extension of cutaneous lesions throughout the body.

On physical examination, she was febrile (T: 38.5°C), with erythematous-pruriginous lesions, some of which were typically targeted, associated with numerous bullae dispersed throughout the body with oral mucosa involvement (figure 1A–C).

Figure 1

(A) Erythematous lesions associated with numerous bullae dispersed throughout the right upper limb. (B) Erythematous lesions associated with numerous bullae dispersed throughout the left upper limb. (C) Erythematous lesions some of which were...

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A rare case of Ludwigs angina after viper bite

Description

A previously healthy 20-year-old woman presented to our Accident and Emergency Department of Degehbur Hospital, a small district hospital in Somali region of Ethiopia, with complaints of rapidly progressive swelling in her neck and difficulty in swallowing for the past 2 days (figures 1 and 2). She was bitten by a snake, which was later identified as a viper, over her right lower jaw while sleeping on the floor. She did not seek any medical treatment until day 3 when the swelling became worse and involved both submandibular region and the tongue. She also complained of rapidly increase shortness of breath for the past 24 hours.

Figure 1

The patient presented to emergency department with severe swelling of her tongue, neck and submandibular area.

Figure 2

Lateral view of the patient showing severe submandibular swelling that obscuring the airway.

...

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Constraints on eQTL Fine Mapping in the Presence of Multi-site Local Regulation of Gene Expression

Expression QTL (eQTL) detection has emerged as an important tool for unraveling of the relationship between genetic risk factors and disease or clinical phenotypes. Most studies use single marker linear regression to discover primary signals, followed by sequential conditional modeling to detect secondary genetic variants affecting gene expression. However, this approach assumes that functional variants are sparsely distributed and that close linkage between them has little impact on estimation of their precise location and magnitude of effects. We describe a series of simulation studies designed to evaluate the impact of linkage disequilibrium on the fine-mapping of causal variants with typical eQTL effect sizes. In the presence of multi-site regulation, even though between 80% and 90% of modeled eSNPs associate with normally distributed traits, up to 10% of all secondary signals could be statistical artefacts, and at least 5% but up to one quarter of credible intervals of SNPs within r2>0.8 of the peak may not even include a causal site. The Bayesian methods eCAVIAR and DAP provide only modest improvement in resolution. Given the strong empirical evidence that gene expression is commonly regulated by more than one variant, we conclude that the fine-mapping of causal variants needs to be adjusted for multi-site influences, as conditional estimates can be highly biased by interference among linked sites, but ultimately experimental verification of individual effects is needed. Presumably similar conclusions apply not just to eQTL mapping, but to multi-site influences on fine mapping of most types of quantitative trait.

http://ift.tt/2rfDHI5

A High-Density Genetic Linkage Map and QTL Fine Mapping for Body Weight in Crucian Carp (Carassius auratus) Using 2b-RAD Sequencing

A high-resolution genetic linkage map is essential for a wide range of genetics and genomics studies such as comparative genomics analysis and QTL fine mapping. Crucian carp (Carassius auratus) widely distributes in Eurasia and is an important aquaculture fish worldwide. In this study, a high-density genetic linkage map was constructed for crucian carp using 2b-RAD technology. The consensus map contains 8,487 SNP markers assigning on 50 linkage groups (LGs) and spanned 3,762.88 cM with an average marker interval of 0.44 cM and genome coverage of 98.8 %. The female map had 4,410 SNPs and spanned 3,500.42 cM (0.79 cM/marker), while the male map had 4,625 SNPs and spanned 3,346.33 cM (0.72 cM/marker). The average recombination ratio of female to male was 2.13:1, and significant male-biased recombination suppressions were observed in LG47 and LG49. Comparative genomics analysis revealed a clear 2:1 syntenic relationship between crucian carp LGs and chromosomes of zebrafish and grass carp, and a 1:1 correspondence but extensive chromosomal rearrangement between crucian carp and common carp, providing an evidence that crucian carp had experienced the fourth round of whole genome duplication (4R-WGD). Eight chromosome-wide QTL for body weight at two months after hatch were detected on five LGs, explaining 10.1-13.2% of the phenotypic variations. Potential candidate growth-related genes, such as EGF-like domain and TGF-beta, were identified within the QTL intervals. This high-density genetic map and QTL analysis supply a basis for genome evolutionary studies in cyprinid fishes, genome assembly and QTL fine mapping for complex traits in crucian carp.

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Unique Allelic eQTL Clusters in Human MHC Haplotypes

The control of gene regulation within the MHC remains poorly understood despite several eQTL studies revealing an association of MHC gene expression with independent tag-SNPs. MHC haplotype variation may exert a greater effect on gene expression phenotype than specific single variants. To explore the effect of MHC haplotype sequence diversity on gene expression phenotypes across the MHC, we examined the MHC transcriptomic landscape at haplotype-specific resolution for three prominent MHC haplotypes (A2-B46-DR9, A33-B58-DR3, and A1-B8-DR3) derived from MHC-homozygous B-lymphoblastoid cell lines. We demonstrate that MHC-wide gene expression patterns are dictated by underlying haplotypes, and identify 36 differentially expressed genes. By mapping these haplotype sequence variations to known eQTL, we provide evidence that unique allelic combinations of eQTL, embedded within haplotypes, are correlated with the level of expression of 17 genes. Interestingly, the influence of haplotype sequence on gene expression is not homogenous across the MHC. We show haplotype sequence polymorphisms within or proximate to HLA-A, HLA-C, C4A, and HLA-DRB regions exert haplotype-specific gene regulatory effects, whereas the expression of genes in other parts of the MHC region are not affected by the haplotype sequence. Overall, we demonstrate that MHC haplotypes sequence diversity can impact phenotypic outcome via the alteration of transcriptional variability, indicating that a haplotype-based approach is fundamental for the assessment of trait associations in the MHC.

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Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer

Purpose: We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.<br /><br />Experimental Design: In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period.<br /><br />Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 months post-surgery. All six later relapsed compared to four of the remaining patients (Hazard ratio (HR), 37.7, 95% confidence interval (CI), 4.2-335.5; P<0.001). The ability of a 3 month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95%CI, 1.5-15.7; P=0.007). Changes in ctDNA levels induced by relapse intervention (n=19) showed good agreement with changes in tumor volume (Kappa=0.41, Spearman's rho=0.4).<br /><br />Conclusions: Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the post-operative management of CRC patients.

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Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity

Purpose: <br /> <p>This study investigated the safety, clinical activity and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.</p> <br />Experimental Design: <br /> <p>The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2000 mg plus cetuximab or erlotinib according to standard posology, respectively. The impact of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of sqNSCLC patients treated with lumretuzumab and erlotinib.</p> <br />Results: <br /> <p>Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and 2 DLTs in the erlotinib part were reported. The most frequent adverse events (AEs) were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with numerically higher disease control rate but not ORR.</p> <br />Conclusions:<br />The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels.

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miR-193a-3p is a key tumor suppressor in ulcerative colitis-associated colon cancer and promotes carcinogenesis through up-regulation of IL17RD

Purpose: Patients with ulcerative colitis (UC) are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.   <p>Experimental Design: Tissue from 12 controls, 9 UC patients without neoplasia, and 11 UC patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.</p> <p>Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in UC-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of UC-cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in UC-cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in UC-cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared to cells expressing IL17RD with mutant 3'UTR.</p> <p>Conclusions: miR-193a-3p is down-regulated in UC-neoplasia, and its loss promotes carcinogenesis through up-regulation of IL17RD. These findings provide novel insight into inflammation-driven CRC and could suggest new therapeutic targets in this high-risk population.

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Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies: a major breakthrough for K-RAS mutated colorectal cancer treatment

Purpose: <p>Patients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct b-catenin/Tcf4 target gene. In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling, CSCs and reduce relapses.</p> Experimental Design: <p>Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of CRC cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSCs self-renewal capacity, tumor recurrence and Wnt signaling.</p> Results: <p>We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of CRC cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.</p> Conclusions:<br /><br />All together, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS mutated colorectal patients, for which there is a crucial unmet medical need.

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Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma

Purpose: Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. <br /><br />Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts.<br /><br />Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

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TRABECTEDIN OVERRIDES OSTEOSARCOMA DIFFERENTIATIVE BLOCK AND REPROGRAMS THE TUMOR IMMUNE ENVIRONMENT ENABLING EFFECTIVE COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS

Purpose: Osteosarcoma (OS), the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. <p>Experimental Design: We have developed immuno-competent OS models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human OS. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.</p> <p>Results: Trabectedin, as monotherapy, significantly inhibited OS primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling OS progression.</p> <p>Conclusion: These results demonstrate the therapeutic efficacy of trabectedin in OS treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

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Dual Inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 inhibits thyroid cancer growth and metastases

PURPOSE: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDACs) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent, and to evaluate biomarkers of treatment response. <p>EXPERIMENTAL DESIGN: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its anti-proliferative effect in vitro and in vivo.</p> <p>RESULTS: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2/M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase 3/7 activity and decreased survivin levels, and decreased cellular migration and invasion.  CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Lastly, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.</p> <p>CONCLUSIONS: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer.

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Human Papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose <p>Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61% respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.</p> <p>Experimental design</p> <p>DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV positive cases were identified using: Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing.</p> <p>Results</p> <p>Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n=30), median E2 methylation was significantly higher in patients who responded (p = <0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n=33), median E2 methylation was lower in patients who responded to treatment (p = 0.03 (not significant after Bonferroni correction)); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.</p> <p>Conclusions</p> <p>These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial.

http://ift.tt/2sn9An2

Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies

Survival of children with cancers has dramatically improved over the past several decades.  This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents.  Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities.  In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically-defined subsets of pediatric leukemias, solid tumors, and brain tumors.

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The Structure of ABCG2 Provides Insight into Multidrug Resistance [Research Watch]

The ABCG2 structure reveals the multidrug-binding pocket and suggests a multidrug transport mechanism.

http://ift.tt/2t4yqEX

BCR Loss Reduces the Fitness of MYC-Driven Lymphoma Cells [Research Watch]

BCR-proficient lymphoma cells exhibit a competitive growth advantage in vitro and in vivo.

http://ift.tt/2s6kKvF

Alectinib Superior to Crizotinib for ALK+ NSCLC [News in Brief]

Next-generation ALK inhibitor more than doubles progression-free survival, reduces brain and CNS metastases.

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Loss of Vhl, Trp53, and Rb1 Induces Clear Cell Renal Carcinoma in Mice [Research Watch]

An autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) recapitulates the human disease.

http://ift.tt/2s6Ol8u

Aldehydes Promote BRCA2 Haploinsufficiency and Genomic Instability [Research Watch]

Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.

http://ift.tt/2t4xsZe

Biallelic Mutations in TRIP13 Increase the Risk of Wilms Tumor [Research Watch]

Mutations resulting in loss of TRIP13 expression induce chromosome missegregation and SAC impairment.

http://ift.tt/2s71zli

Issue highlights

Patients with cirrhosis have been shown to have a decrease in health-related quality of life (HRQOL). These patients also report sleep disturbances, which can negatively affect HRQOL. In this issue of Clinical Gastroenterology and Hepatology, Ghabril and colleagues measured the prevalence of disturbed sleep and its impact on HRQOL in 193 ambulatory patients with cirrhosis. Of these, 154 patients had decompensated cirrhosis but did not have any evidence of overt hepatic encephalopathy. The authors also compared neurocognitive function, actigraphy (measuring sleep time, latency, awakenings), and non-targeted serum metabolic profiling in subsets of patients with normal and disturbed sleep.

http://ift.tt/2rVGIiU

New tests identify patterns of vestibular loss

For the last century, the caloric test of horizontal canal function has been the standard test of vestibular function and, as a result, many deficits of peripheral and central vestibular function have gone undetected. Clinicians have puzzled about patients showing what are manifestly vestibular symptoms at the bedside examination, in whom the calorics were within the normal range. The introduction of the new vestibular tests – video head impulse test of all six semicircular canals (reviewed in (Halmagyi et al., 2017) and vestibular evoked myogenic potentials (VEMP) testing of utricular and saccular function (reviewed in (Curthoys et al., 2017) has solved this puzzle.

http://ift.tt/2rKvuiG

Precision Oncology and Genomically Guided Radiation Therapy, A Report From the ASTRO/AAPM/NCI Precision Medicine Conference

Radiation therapy is an incredibly precise and increasingly adaptable therapeutic modality. There is a significant amount of data showing that genomic metrics can significantly influence the outcomes for numerous malignancies treated with radiation therapy. Despite this, current standards of care do little to adapt radiation therapy based on genomic or tumor specific biological factors. This manuscript summarizes the current state of integrating genomic and biologic data into management strategies with radiation therapy.

http://ift.tt/2r4yx2q

The results of Low dose Total Skin Electron Beam Radiotherapy (TSEB), in patients with mycosis fungoides from the UK cutaneous lymphoma group

30Gy in 20 fractions is the standard schedule of TSEB in the UK for mycosis fungoides with excellent results but causes significant toxicity. Results of a low dose 12Gy in 8 fractions schedule from 3 centres in the UK were prospectively collected. The results show the complete response rate is lower, the overall response rate and response duration are similar, and the toxicity is less making it an effective option for patients.

http://ift.tt/2rbcjQI

Effects of Community Screening for Helicobacter pylori: 13-Year Follow-up of a Randomized Controlled Trial (HEP-FYN)

Helicobacter pylori (Hp) eradication improves the prognosis of peptic ulcer disease (PUD), dyspepsia, and possibly gastric cancer. Hp screening tests are accurate and eradication therapy is effective. Hp population screening seems attractive.The aim of this study was to evaluate the long-term effect of Hp population screening and eradication on dyspepsia prevalence and the incidence of PUD, and as secondary outcomes to assess the effect on health-care consumption and quality of life.

http://ift.tt/2rVQ26t

Occurrence of IgG4 in Esophageal Lichen Planus

http://ift.tt/2raUDoi

Agreement Between Home-based Measurement of Stool Calprotectin and ELISA Results for Monitoring Inflammatory Bowel Disease Activity

An increasing number of physicians use repeated measurements of stool calprotectin to monitor intestinal inflammation in patients with inflammatory bowel diseases (IBD). A lateral flow-based rapid test allows patients to measure their own stool calprotectin values at home. The test comes with a software application (IBDoc) that turns a smartphone camera into a results reader. We compared results from this method with those from the hospital-based reader (Quantum Blue) and ELISA analysis.

http://ift.tt/2rVTu0N

Association between Endoscopist and Center ERCP Volume with Procedure Success and Adverse Outcomes: A Systematic Review and Meta-Analysis

ERCP has become a predominantly therapeutic intervention with a resultant increase in complexity. The relationship between ERCP volume and outcomes is unclear. We aimed to conduct a systematic review and meta-analysis assessing the relationship between endoscopist and center ERCP volume with (i) ERCP success; and (ii) adverse event (AE) rates.

http://ift.tt/2rbjBUr

Societal perspectives and patient/public involvement in DAAs coverage of hepatitis C treatment in the U.S.

http://ift.tt/2rW1YVU

Estimating the accuracy of a reduced-order model for the calculation of fractional flow reserve (FFR)

Summary

Image-based non-invasive fractional flow reserve (FFR) is an emergent approach to determine the functional relevance of coronary stenoses. The present work aimed to determine the feasibility of using a method based on coronary computed tomography angiography (CCTA) and reduced-order models (0D-1D) for the evaluation of coronary stenoses. The reduced-order methodology (cFFR_ro) was kept as simple as possible and did not include pressure drop or stenosis models. The geometry definition was incorporated into the physical model used to solve coronary flow and pressure. cFFR_ro was assessed on a virtual cohort of 30 coronary artery stenoses in 25 vessels and compared with a standard approach based on 3D computational fluid dynamics (cFFR_3D). In this proof-of-concept study, we sought to investigate the influence of geometry and boundary conditions on the agreement between both methods. Performance on a per-vessel level showed a good correlation between both methods (Pearson's product-moment R = 0.885, P < 0.01), when using cFFR_3D as the reference standard. The 95% limits of agreement were -0.116 and 0.08, and the mean bias was -0.018 (SD =0.05). Our results suggest no appreciable difference between cFFR_ro and cFFR_3D with respect to lesion length and/or aspect ratio. At a fixed aspect ratio, however, stenosis severity and shape appeared to be the most critical factors accounting for differences in both methods. Despite the assumptions inherent to the 1D formulation, asymmetry did not seem to affect the agreement. The choice of boundary conditions is critical in obtaining a functionally significant drop in pressure. Our initial data suggest that this approach may be part of a broader risk assessment strategy aimed at increasing the diagnostic yield of cardiac catheterisation for in-hospital evaluation of hæmodynamically significant stenoses. This article is protected by copyright. All rights reserved.

http://ift.tt/2rKDJLL

Dengue type 4 in Rio de Janeiro, Brazil: case characterization following its introduction in an endemic region

Due to the populations' susceptibility, DENV-4 introduction in 2010 led to the occurrence of explosive epidemics in the following years in Brazil. In 2011, DENV-4 was identified in Rio de Janeiro (RJ) and it w...

http://ift.tt/2rb2hir

Seasonality of acquisition of respiratory bacterial pathogens in young children with cystic fibrosis

Seasonal variations are often observed for respiratory tract infections; however, limited information is available regarding seasonal patterns of acquisition of common cystic fibrosis (CF)-related respiratory ...

http://ift.tt/2rVDsEd

Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue

A previous genome-wide association study identified 2 susceptibility loci for severe dengue at MICB rs3132468 and PLCE1 rs3740360 and further work showed these mutations to be also associated with less severe cli...

http://ift.tt/2rbaCCv

Hybrid 18 F–FDG PET/MRI might improve locoregional staging of breast cancer patients prior to neoadjuvant chemotherapy

Abstract

Purpose

Our purpose in this study was to assess the added clinical value of hybrid ¹⁸F–FDG-PET/MRI compared to conventional imaging for locoregional staging in breast cancer patients undergoing neoadjuvant chemotherapy (NAC).

Methods

In this prospective study, primary invasive cT2-4 N0 or cT1-4 N+ breast cancer patients undergoing NAC were included. A PET/MRI breast protocol was performed before treatment. MR images were evaluated by a breast radiologist, blinded for PET images. PET images were evaluated by a nuclear physician. Afterwards, a combined PET/MRI report was written. PET/MRI staging was compared to conventional imaging, i.e., mammography, ultrasound and MRI. The proportion of patients with a modified treatment plan based on PET/MRI findings was analyzed.

Results

A total of 40 patients was included. PET/MRI was of added clinical value in 20.0% (8/40) of patients, changing the treatment plan in 10% and confirming the malignancy of suspicious lesions on MRI in another 10%. In seven (17.5%) patients radiotherapy fields were extended because of additional or affirmative PET/MRI findings being lymph node metastases (n = 5) and sternal bone metastases (n = 2). In one (2.5%) patient radiotherapy fields were reduced because of fewer lymph node metastases on PET/MRI compared to conventional imaging. Interestingly, all treatment changes were based on differences in number of lymph nodes suspicious for metastasis or number of distant metastasis, whereas differences in intramammary tumor extent were not observed.

Conclusion

Prior to NAC, PET/MRI shows promising results for locoregional staging compared to conventional imaging, changing the treatment plan in 10% of patients and potentially replacing PET/CT or tissue sampling in another 10% of patients.

http://ift.tt/2rVBAeJ

Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

British Journal of Cancer advance online publication, June 8 2017. doi:10.1038/bjc.2017.168

Authors: Muhammad A Alvi, Maurice B Loughrey, Philip Dunne, Stephen McQuaid, Richard Turkington, Marc-Aurel Fuchs, Claire McGready, Victoria Bingham, Brendan Pang, Wendy Moore, Perry Maxwell, Mark Lawler, Jacqueline A James, Graeme I Murray, Richard H Wilson & Manuel Salto-Tellez

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KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

British Journal of Cancer advance online publication, June 8 2017. doi:10.1038/bjc.2017.165

Authors: Jie Wang, Xingjun Guo, Chencheng Xie & Jianxin Jiang

http://ift.tt/2rRDVHA

Gender differences in colorectal cancer survival: A Meta-analysis

Abstract

A meta-analysis was conducted to determine the influence of gender on overall survival (OS) and cancer-specific survival (CSS) in colorectal cancer patients. Major databases were searched for clinical trials, which compare survival differences between male and female for colorectal cancer patients. A list of these studies and references, published in English and Chinese from 1960 to 2017, was obtained independently by two reviewers from databases such as PubMed, Medline, ScienceDirect, the China National Knowledge Infrastructure (CNKI) and Web of Science. Overall survival and cancer-specific survival were compared using Review Manager 5.3. Females had significantly better OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]=0.85–0.89) and CSS (HR = 0.92; 95% CI=0.89–0.95) than males after meta-analysis. These results suggest that gender seems to be a significant factor influencing survival results among colorectal cancer patients. This article is protected by copyright. All rights reserved.

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Acrinol: a dye with potential for nuclear staining in confocal laser endomicroscopy

Abstract

Confocal laser endomicroscopy (CLE)¹⁾ and endocytoscopy system (ECS)²⁾ have made optical biopsy in the digestive tract a reality. However, for omission of biopsy histology, visualization of nuclei is essential. In ECS, nuclei can be observed after vital staining with methylene blue, toluidine blue etc.³⁾, and vital staining in CLE requires venous injection or spraying of fluorescein into the gastrointestinal lumen⁴⁾. However, fluorescein does not stain nuclei. Acriflavin, a topical antiseptic drug, can stain nuclei for CLE observation⁵⁾, but it has not been widely used because of associated adverse events.

This article is protected by copyright. All rights reserved.

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A case of colonic adenoma involving a diverticulum resected by a traction-assisted endoscopic submucosal dissection technique

Abstract

A 76-year-old man with positive fecal occult blood tests underwent colonoscopy, which revealed a laterally spreading tumor completely surrounding a diverticulum in the ascending colon. He was referred to our hospital for further examination and treatment. A second colonoscopy revealed that the laterally spreading tumor involved an entire diverticulum in the posterior wall of the ascending colon.

This article is protected by copyright. All rights reserved.

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In Vitro Evaluation of 188Re-HEDP: A Mechanistic View of Bone Pain Palliations

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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External adjustment of unmeasured confounders in a case-control study of benzodiazepine use and cancer risk

Summary

Introduction

Previous studies have reported diverging results on the association between benzodiazepine use and cancer risk.

Methods

We investigated this association in a matched case–control study including incident cancer cases during 2002-2009 in the Danish Cancer Registry (n=94,923) and age and sex-matched (1:8) population controls (n=759,334). Long-term benzodiazepine use was defined as ≥500 defined daily doses 1-5 years prior to the index date. We implemented propensity score (PS) calibration using external information on confounders available from a survey of the Danish population. Two PSs were used: The error-prone PS using register-based confounders and the calibrated PS based on both register- and survey-based confounders, retrieved from the Health Interview Survey.

Results

Register-based data showed that cancer cases had more diagnoses, higher comorbidity score and more co-medication then population controls. Survey-based data showed lower self-rated health, more self-reported diseases, and more smokers as well as subjects with sedentary lifestyle among benzodiazepine users. By PS calibration, the odds ratio for cancer overall associated with benzodiazepine use decreased from 1.16 to 1.09 (1.00, 1.19) and for smoking-related cancers from 1.20 to 1.10 (1.00, 1.21).

Conclusion

We conclude that the increased risk observed in the solely register-based study could partly be attributed to unmeasured confounding.

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Papillary thyroid carcinoma metastasizing to anaplastic meningioma: an unusual case of tumor-to-tumor metastasis

Abstract

Tumor-to-tumor metastasis is a relatively uncommon entity, whereby the so-called 'recipient' tumor is involved by another biologically unrelated 'donor' tumor. Intracranially, meningioma (WHO grade 1) is the most common recipient tumor, while breast and lung cancers are the most common donor tumors. We present an unusual case of intracranial tumor-to-tumor metastasis involving papillary thyroid carcinoma (PTC) believed to have metastasized to an anaplastic meningioma (WHO grade 3). The patient is a 64-year-old female with a history of PTC, whose neuroimaging, performed as part of her staging workup, revealed a right parietal scalp lesion. The lesion was resected to reveal metastatic PTC with spindle cell component believed to represent sarcomatoid differentiation. Follow-up neuroimaging 2 months later revealed regrowth of the lesion under the previous craniotomy site. PET scan showed increased uptake in this area consistent with metastasis. Resection of this lesion revealed primarily features of an anaplastic meningioma. The combination of pathologic findings from both resections in conjunction with findings from the PET scan led to the suggestion that the PTC had metastasized into the anaplastic meningioma. To the authors' knowledge, this is the first example in the literature of a donor tumor metastasizing to a high-grade recipient tumor.

http://ift.tt/2rao7CG

Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay

Here, it is demonstrated how the in situ Proximity Ligation Assay (PLA) can be used to detect and visualize the direct protein-protein interactions between ATM and p53 in suspension cell cultures exposed to genotoxic stress.

http://ift.tt/2r3uJyC

Scorpion neurotoxin AaIT-expressing Beauveria bassiana enhances the virulence against Aedes albopictus mosquitoes

To improve the insecticidal efficacy of this entomopathogen Beauveria bassiana, the fungus was genetically modified to express an insect-specific scorpion neurotoxin AaIT. The virulence of the recombinant B. bass...

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The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes

Abstract

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

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Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing

Human induced pluripotent stem cells (hiPSCs) are considered a powerful tool for drug and chemical screening and for the development of new in vitro models for toxicity testing, including neurotoxicity. Here, a detailed protocol for the differentiation of hiPSCs into neurons and glia is described.

http://ift.tt/2s5ouxH

Rational Design of Peptide Derivatives for Inhibition of MyD88-Mediated TLR Signaling in Human PBMCs and Epithelial Cells Exposed to F. tularensis

Abstract

Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88-mediated TLR signaling by F. tularensis. Fifty-three tripeptide derivatives were synthesized to mimic a key BB-loop region involved in toll-like/interleukin-1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF-α, IFN-γ, IL-6, and IL-1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F. tularensis. From fifty-three compounds synthesized and tested, ten compounds were identified as effective inhibitors of F. tularensis LPS-induced cytokines. Compound stability testing in the presence of human liver microsomes and human serum resulted in the identification of tripeptide derivative 7 that was a potent, stable and drug-like small molecule. Target corroboration using a cell-based reporter assay and competition experiments with MyD88 TIR domain protein supported that the effect of 7 was through MyD88 TIR domain interactions. Compound 7 also attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis at a multiplicity of infection of 1:5. Small molecules that target TIR domain interactions in MyD88-dependent TLR signaling represent a promising strategy toward host-directed adjunctive therapeutics for inflammation associated with biothreat agent-induced sepsis.

This article is protected by copyright. All rights reserved.

Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88-mediated TLR signaling by F. tularensis a causative agent of tularemic sepsis. Lead compound 7 attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis. Small molecules that target TIR domain interactions in MyD88-dependent TLR signaling represent a promising strategy toward host-directed adjunctive therapeutics for inflammation associated with biothreat agent-induced sepsis.

http://ift.tt/2smY1Mj

TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Abstract

Background

Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4–6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients.

Methods/design

TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2.

Discussion

The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases.

Trial registration

TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014–004436-19, October 10, 2014.

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Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Abstract

Background

Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs.

Results

In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis.

Conclusions

Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

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Biomarker Test Could Reduce Unnecessary Biopsies to Detect Prostate Cancer

Findings from a new study show testing for two biomarkers in urine may help some men avoid an unnecessary biopsy to detect a suspected prostate cancer.

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In Ovo Electroporation in the Chicken Auditory Brainstem

Auditory brainstem neurons of avians and mammals are specialized for fast neural encoding, a fundamental process for normal hearing functions. These neurons arise from distinct precursors of embryonic hindbrain. We present techniques utilizing electroporation to express genes in the hindbrain of chicken embryos to study gene function during auditory development.

http://ift.tt/2r35Oej

Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding

Guanosine triphosphate (GTP) binding is one of the earliest events in G-Protein-Coupled Receptor (GPCR) activation. This protocol describes how to pharmacologically characterize specific GPCR-ligand interactions by monitoring the binding of the radio-labeled GTP analog, [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPγS), in response to a ligand of interest.

http://ift.tt/2smRSQx

A Silicon Nanowire as a Spectrally Tunable Light-Driven Nanomotor

Over the last decades, scientists have endeavored to develop nanoscopic machines and envisioned that these tiny machines could be exploited in biomedical applications and novel material fabrication. Here, a visible-/near-infrared light-driven nanomotor based on a single silicon nanowire is reported. The silicon nanomotor harvests energy from light and propels itself by the self-electrophoresis mechanism. Due to the high efficiency, the silicon nanowire can be readily driven by visible and near-infrared illumination at ultralow light intensity (≈3 mW cm⁻²). The experimental study and numerical simulation also show that the detailed structure around the concentrated reaction center determines the migration behavior of the nanomotor. Importantly, due to the optical resonance inside the silicon nanowire, the spectral response of the nanowire-based nanomotor can be readily modulated by the nanowire's diameter. Compared to other methods, light controlling potentially offers more freedom and flexibility, as light can be modulated not only with its intensity and direction, but also with the frequency and polarities. This nanowire motor demonstrates a step forward to harness the advantages of light, which opens up new opportunities for the realization of many novel functions such as multiple channels communication to nanorobots and controllable self-assembly.

A visible/near-infrared-light-driven nanomotor is developed based on a silicon-nanowire solar cell and the electrophoretic mechanism. The morphology influence is experimentally and theoretically investigated, which offers a new protocol for motion maneuvering. The spectral engineering to modulate optical resonance inside the silicon wire provides a new dimension for the light-controlled nanorobots and sheds light on their future biomedical applications.

http://ift.tt/2rUz9cm

Bmp Signaling Governs Biliary-Driven Liver Regeneration in Zebrafish via Tbx2b and Id2a

Abstract

Upon mild liver injury, new hepatocytes originate from pre-existing hepatocytes. However, if hepatocyte proliferation is impaired, a manifestation of severe liver injury, biliary epithelial cells (BECs) contribute to new hepatocytes through BEC dedifferentiation into liver progenitor cells (LPCs), also termed oval cells or hepatoblast-like cells (HB-LCs), and subsequent differentiation into hepatocytes. Despite the identification of several factors regulating BEC dedifferentiation and activation, little is known about factors involved in the regulation of LPC differentiation into hepatocytes during liver regeneration. Using a zebrafish model of near-complete hepatocyte ablation, we here show that Bmp signaling is required for BEC conversion to hepatocytes, particularly for LPC differentiation into hepatocytes. We found that severe liver injury led to the upregulation of genes involved in Bmp signaling, including smad5, tbx2b, and id2a, in the liver. Bmp suppression did not block BEC dedifferentiation into HB-LCs; however, the differentiation of HB-LCs into hepatocytes was impaired due to the maintenance of HB-LCs in an undifferentiated state. Later Bmp suppression did not affect HB-LC differentiation, but increased BEC number through proliferation. Notably, smad5, tbx2b, and id2a mutants exhibited similar liver regeneration defects as those observed in Bmp-suppressed livers. Moreover, BMP2 addition promoted the differentiation of a murine LPC cell line into hepatocytes in vitro. Conclusions: Bmp signaling regulates BEC-driven liver regeneration via smad5, tbx2b and id2a: it regulates HB-LC differentiation into hepatocytes via tbx2b and BEC proliferation via id2a. Our findings provide insights into promoting innate liver regeneration as a novel therapy. This article is protected by copyright. All rights reserved.

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Serum microcystins level positively linked with risk of hepatocellular carcinoma: a case-control study in Southwest China

Abstract

Microcystins have been reported carcinogenic by animal and cell experimentation, but there were no data on the linkage between serum microcystins and hepatocellular carcinoma (HCC) risk in human. We conducted a clinical case-control study to investigate the association between serum microcystins and HCC risk after controlling several known risk factors, such as hepatitis B virus (HBV), alcohol, and aflatoxin. From December 2013 to May 2016, 214 patients newly diagnosed with HCC, along with 214 controls (frequency-matched by age and sex) were recruited from three hospitals in Chongqing, Southwest China. Basic information on life style and history of disease was obtained via questionnaires. Blood samples were collected and analyzed for serum microcystin-LR (MC-LR) and aflatoxin albumin adduct (AFB-ALB adduct) by ELISA, and for HBsAg status by ECLIA. Binary logistic regression analyses were performed to assess the independent effects of MC and its joint effects with other factors on HCC risk. The adjusted OR (AOR) for HCC risk by serum MC-LR was 2.9 (95%CI, 1.5-5.5) in all patients. Notably, a clear relationship between increased MC-LR level (Q2, Q3 and Q4) and HCC risk was observed with the elevation AORs (1.3, 2.6, and 4.0, respectively). Positive interactions on the additive model were investigated between MC-LR and HBV infection (S=3.0; 95%CI, 2.0-4.5), and between MC-LR and alcohol (S=4.0; 95%CI, 1.7-9.5), while a negative interaction was found between microcystins and aflatoxin (S=0.4; 95%CI, 0.3-0.7). Additionally, serum MC-LR was significantly associated with tumor differentiation (r= -0.228, P<0.001). Conclusions: We firstly provided evidence that serum MC-LR was an independent risk factor for HCC in human, with an obvious positive interaction with HBV/alcohol but a negative interaction with aflatoxin. This article is protected by copyright. All rights reserved.

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Molecular classification of hepatocellular carcinoma: The view from metabolic zonation

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Growth charts for Australian children with achondroplasia

Achondroplasia is an autosomal dominant disorder, the most common genetic cause of short stature in humans. Reference curves for head circumference, weight, height, and BMI are needed in clinical practice but none exist for the Australian population. This study aimed to produce head circumference, height, weight, and BMI reference percentile curves for Australian children and adolescents with achondroplasia. Measurements of head circumference, height and weight taken at clinical visits were retrospectively extracted from the electronic medical record. Age was corrected for prematurity. Patients were excluded from head circumference analysis if they had significant neurosurgical complications and from the weight and BMI analysis when they had a clinical diagnosis of overweight. Measurements were available on 138 individuals (69 males and 69 females) taken between 1970 and 2015, with over 50% collected since 2005. A total of 3,352 data points were available. The LMS method was used to produce growth charts with estimated centiles (10, 25, 50, 75, and 90th) separately for males and females. For females birth weight was 3 kg (2.5–3.5 kg), birth length 48 cm (44–50 cm) and head circumference 37.5 cm (36–39 cm), adult height was 125 cm (116–132 cm), weight 42 kg (34–54 kg), and head circumference 58 cm (55.5–60.5 cm) all 50th centile (10–90th). For males birth weight was 3.5 kg (3–4 kg), length 49 cm (46–52 cm) and head circumference 38.5 cm (36–41 cm), adult height was 134 cm (125–141 cm), weight 41 kg (24.5–57 kg) and head circumference 61 cm (58–64 cm). The curves are similar to previously published reference data from the USA and have expected population wide variation from curves from an Argentinian population. Despite limitations of our curves for adolescents (12 years and older) due to data paucity, these Australian growth charts for children and adolescents with achondroplasia will be a useful reference in clinical practice.

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Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter

Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.

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Clinical and molecular cytogenetic characterization of four unrelated patients carrying 2p14 microdeletions

We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1. Here, we report three further patients carrying proximal 2p14 microdeletions not including OTX1 and one patient carrying a more distal 2p14p15 microdeletion including this gene, providing new insights into the associated phenotypic spectrum. First, our study and a review of the literature showed that 3/4 patients carrying proximal 2p14 microdeletions had sensorineural hearing loss, suggesting the presence of a previously unreported deafness-causing gene in this chromosomal region. Second, one patient developed a progressive cardiomyopathy, suggesting that a cardiac follow-up should be systematically warranted even in the absence of congenital heart disease. We speculate that ACTR2 and MEIS1 might respectively play a role in the pathogenesis of the observed deafness and cardiomyopathy. Third, we observed other previously unreported features such as glaucoma, retinopathy, and mild midline abnormalities including short corpus callosum, hypospadias and anteriorly placed anus. Finally, the patient carrying a 2p14p15 deletion including OTX1 had normal kidneys and genitalia, thus confirming that OTX1 haploinsufficiency is not invariably associated with genitourinary defects. In conclusion, our study contributes significantly to delineate the phenotypic spectrum of 2p14 microdeletions.

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Increased FDG uptake on late-treatment PET in non-tumour-affected oesophagus is prognostic for pathological complete response and disease recurrence in patients undergoing neoadjuvant radiochemotherapy

Abstract

Purpose

Early side effects including oesophagitis are potential prognostic factors in patients undergoing radiochemotherapy (RCT) for locally advanced oesophageal cancer (LAEC). We assessed the prognostic value of ¹⁸F-fluorodeoxyglucose (FDG) uptake within irradiated non-tumour-affected oesophagus (NTO) during restaging positron emission tomography (PET) as a surrogate for inflammation/oesophagitis.

Methods

This retrospective evaluation included 64 patients with LAEC who had completed neoadjuvant RCT and had successful oncological resection. All patients underwent FDG PET/CT before and after RCT. In the restaging PET scan maximum and mean standardized uptake values (SUV_max, SUV_mean) were determined in the tumour and NTO. Univariate Cox regression with respect to overall survival, local control, distant metastases and treatment failure was performed. Independence of clinically relevant parameters was tested in a multivariate Cox regression analysis.

Results

Increased FDG uptake, measured in terms of SUV_mean in NTO during restaging was significantly associated with complete pathological remission (p = 0.002) and did not show a high correlation with FDG response of the tumour (rho < 0.3). In the univariate analysis, increased SUV_max and SUV_mean in NTO was associated with improved overall survival (p = 0.011, p = 0.004), better local control (p = 0.051, p = 0.044), a lower rate of treatment failure (p < 0.001 for both) and development of distant metastases (p = 0.012, p = 0.001). In the multivariate analysis, SUV_max and SUV_mean in NTO remained a significant prognostic factor for treatment failure (p < 0.001, p = 0.004) and distant metastases (p = 0.040, p = 0.011).

Conclusions

FDG uptake in irradiated normal tissues measured on restaging PET has significant prognostic value in patients undergoing neoadjuvant RCT for LAEC. This effect may potentially be of use in treatment personalization.

http://ift.tt/2t2Karc

Salvage robotic SBRT for local prostate cancer recurrence after radiotherapy: preliminary results of the Oscar Lambret Center

Abstract

Background

Currently, there is no standard option for local salvage treatment for local prostate cancer recurrence after radiotherapy. Our objective was to investigate the feasibility and efficiency of Robotic Stereotactic Body Radiation Therapy (SBRT) in this clinical setting.

Methods/materials

We retrospectively reviewed patients who were treated at our institution with SBRT for local prostate cancer recurrence after External Beam Radiation Therapy (EBRT) or brachytherapy.

Multidisciplinary staff approved the treatment, and recurrence was biopsy-proven when feasible. A dose of 36 Gy was prescribed in six fractions. Treatment was delivered every other day.

Results

Between August 2011 and February 2014, 23 patients were treated with SBRT for intra-prostate cancer recurrence with a median follow up of 22 months (6 to 40).

Twenty patients had biopsy-proven recurrence.

For 19 patients, EBRT was the initial treatment and in four patients, brachytherapy was the initial treatment; the median relapse-time from initial treatment was 65 months (28 to 150).

At relapse, 10 patients had an extra-capsular extension.

Fourteen patients were treated with androgen deprivation that could be stopped after a median of 1 month after SBRT (range 0–24).

A PSA decrease occurred in 82.6% of the patients after SBRT.

The 2-year disease-free survival and overall survival rates were 54 and 100%, respectively.

Disease progression was observed for nine patients (39.1%) (five local, three metastatic and one nodal progression) after a median of 20 months (7–40 months).

The median nadir PSA was 0.35 ng/ml and was achieved after a median of 8 months (1 to 30) after treatment.

We observed no grade 4 or 5 toxicity. Two patients presented with grade 3 toxicities (two Cystitis and one neuralgia). Other toxicities included urinary toxicities (five grade 2 and nine grade 1) and rectal toxicities (two grade 2 and two grade 1).

Conclusion

SBRT for local prostate cancer recurrence seems feasible and well tolerated with a short follow up. Prospective evaluation is needed.

http://ift.tt/2rJ0yj1