Medicine by Alexandros G.Sfakianakis: 05/12/17

Παρασκευή 12 Μαΐου 2017

The ICUC® app: Can it pave the way for quality control and transparency in medicine?

Publication date: June 2017
Source:Injury, Volume 48, Issue 6
Author(s): Pietro Regazzoni, Peter V. Giannoudis, Simon Lambert, Alberto Fernandez, Stephan M. Perren

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Editorial Board/Publication Information

Publication date: June 2017
Source:Injury, Volume 48, Issue 6

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Molecular Simulation and Biochemical Studies Support an Elevator-Type Transport Mechanism in EIIC

Enzyme IIC (EIIC) is a membrane-embedded sugar transport protein that is part of the phosphoenolpyruvate-dependent phosphotransferases. Crystal structures of two members of the glucose EIIC superfamily, bcChbC in the inward-facing conformation and bcMalT in the outward-facing conformation, were previously solved. Comparing the two structures led us to the hypothesis that sugar translocation could be achieved by an elevator-type transport mechanism in which a transport domain binds to the substrate and, through rigid body motions, transports it across the membrane.

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The relationship between job satisfaction, work stress, work-family conflict, and turnover intention among physicians in Guangdong, China: a cross-sectional study

Objective

To investigate the relationship between job satisfaction, work stress, work–family conflict and turnover intention, and explore factors associated with turnover intention, among physicians in Guangdong Province, China.

Methods

From August to October 2013, physicians completed questionnaires and scales with regard to their job satisfaction, work stress, work–family conflict, and turnover intention. Binary logistic regression and structural equation modelling (SEM) were used in data analysis.

Results

A total of 3963 physicians were approached, with 3563 completing the questionnaire. The mean score of the overall perception of turnover intention of physicians who worked in Guangdong was 2.71 on a scale ranging from 1 to 6. Hours worked per week, working in an urban/rural area, type of institution, and age significantly impacted on turnover intention. Turnover intention was directly and negatively related to job satisfaction, and it was directly, indirectly and positively related to work stress and work–family conflict.

Conclusion

Job satisfaction, work stress, work–family conflict, hours worked per week, working in an urban/rural area, types of institution and age are influencing factors of turnover intention. Reducing working hours, raising salary, providing more opportunities for career development and training, supporting and encouraging physicians by senior managers could potentially contribute to the reduction in turnover intention.

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Integrating culturally informed approaches into the physiotherapy assessment and treatment of chronic pain: protocol for a pilot randomised controlled trial

Introduction

There is strong evidence that biopsychosocial approaches are efficacious in the management of chronic pain. However, implementation of these approaches in clinical practice is known not to account for the beliefs and values of culturally and linguistically diverse (CALD) patients. This limitation in translation of research contributes to the disparities in outcomes for CALD patients with chronic pain adding to the socioeconomic burden of this prevalent condition. Cultural adaptation of chronic pain assessment and management is urgently required. Thus, the aim of this pilot randomised controlled trial (RCT) is to determine the feasibility, participant acceptance with and clinical effectiveness of a culturally adapted physiotherapy assessment and treatment approach when contrasted with 'usual evidence based physiotherapy care' for three CALD communities.

Methods and analysis

Using a participant-blinded and assessor-blinded randomised controlled pilot design, patients with chronic pain who self-identify as Assyrian, Mandaean or Vietnamese will be randomised to either 'culturally adapted physiotherapy assessment and treatment' or 'evidence informed usual physiotherapy care'. We will recruit 16 participants from each ethnocultural community that will give a total of 24 participants in each treatment arm. Both groups will receive physiotherapy treatment for up to 10 sessions over 3 months. Outcomes including feasibility data, acceptance with the culturally adapted intervention, functional and pain-related measures will be collected at baseline and 3 months by a blinded assessor. Analysis will be descriptive for feasibility outcomes, while measures for clinical effectiveness will be explored using independent samples t-tests and repeated measures analysis of variance. This analysis will inform sample size estimates while also allowing for identification of revisions in the protocol or intervention prior to a larger scale RCT.

Ethics and dissemination

This trial has full ethical approval (HREC/16/LPOOL/194). The results from this pilot RCT will be presented at scientific meetings and published in peer-reviewed journals.

Trial registration number

ACTRN12616000857404

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A scoping review protocol on social participation of indigenous elders, intergenerational solidarity and their influence on individual and community wellness

Introduction

Indigenous elders have traditionally played an important role in maintaining social cohesion within their communities. Today, part of this role has been taken over by government social and healthcare services, but they are having limited success in addressing social challenges. Increasing elders' social participation and intergenerational solidarity might foster community development and benefit young people, families, communities and the elders themselves. However, knowledge of the contribution of elders' social participation and intergenerational solidarity to wellness is scattered and needs to be synthesised. This protocol presents a scoping review on the social participation of indigenous elders, intergenerational solidarity and their influence on individual and community wellness.

Methods and analysis

This scoping review protocol is based on an innovative methodological framework designed to gather information from the scientific and grey literature and from indigenous sources. It was developed by an interdisciplinary team including indigenous scholars/researchers, knowledge users and key informants. In addition to searching information databases in fields such as public health and indigenous studies, an advisory committee will ensure that information is gathered from grey literature and indigenous sources.

Ethics

The protocol was approved by the Ethics Review Board of the Université du Québec en Abitibi-Témiscamingue and the First Nations of Quebec and Labrador Health and Social Services Commission.

Discussion

The comprehensive synthesis of the scientific and grey literature and indigenous sources proposed in this protocol will not only raise awareness within indigenous communities and among healthcare professionals and community organisations, but will also enable decision-makers to better meet the needs of indigenous people.

Conclusion

The innovative methodological framework proposed in this scoping review protocol will yield richer information on the contribution of elders to community wellness. This work is an essential preliminary step towards developing research involving indigenous communities, drawing on the social participation of elders and intergenerational solidarity.

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Haemodynamic analysis for recanalisation of intracranial aneurysms after endovascular treatment: an observational registry study in China

Introduction

Recanalisation of intracranial aneurysms following endovascular treatment is a major issue. Many factors, including aneurysm morphology, the method of treatment, and haemodynamics, are considered to be associated with recanalisation. However, the underlying haemodynamic mechanisms are not completely understood.

Methods and analysis

This is a prospective, observational, registry study for patients with intracranial aneurysms who are treated endovascularly. It will enrol 200 eligible patients. Data on morphological, haemodynamic, and treatment factors will be collected prospectively. The advanced virtual stenting technique and porous media method will be used in haemodynamic simulations. The clinical and angiographic outcomes at 6 months will be measured and analysed. This observational study will determine the haemodynamic factors that affect the recanalisation of aneurysms.

Ethics and dissemination

Both the study protocol and written informed consent were reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital (KY2016-023-01). The results of study will be disseminated in professional printed media.

Trial registration number

NCT02812108; Pre-results.

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Molecular Simulation and Biochemical Studies Support an Elevator-Type Transport Mechanism in EIIC

Issue Highlights

Cross-sectional studies and clinical experience suggest there is a higher prevalence of depression and anxiety in patients with functional gastrointestinal diseases (FGID). To what extent this reflects the impact of disease symptoms on mood and whether mood disorders precede and may indeed be causally implicated in the pathogenesis of FGID has not been well established. In this issue of Clinical Gastroenterology and Hepatology, Jones et al present a study that examined the bidirectional association between mood disorders and FGID in two population-based databases.

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Foundation Chairman Takes Stage at Milken Global Conference

On May 3, Foundation Chairman Neal F. Kassell, MD, was invited to speak about focused ultrasound at the Milken Institute Global Conference in Beverly Hills.

In his first appearance of the day, Dr. Kassell was introduced by Foundation Council member Michael Milken. He spoke to the 4,500 attendees about the promise of focused ultrasound technology and introduced Vice President Joe Biden.

Please watch the first 15 minutes of the video below to see Dr. Kassell's part of the program. The remainder of the clip includes Vice President Biden's inspirational and entertaining talk, as well as a Q&A at the end with Milken and Biden.

Later that morning, Dr. Kassell also participated in a panel entitled "Things That Will Blow Your Mind." The video is available below.
Please note that Dr. Kassell is the fourth and final speaker, and he goes on stage at the 44 minute mark.

"We were grateful for the opportunity to share the story of focused ultrasound with the distinguished and entrepreneurial group of thought leaders assembled at the Milken Conference," said Kassell.

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Combination radiotherapy and cantharidin inhibits lung cancer growth through altering tumor infiltrating lymphocytes

Future Oncology Ahead of Print.

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Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial

We read with interest the article by Bruix et al1 on currently available treatment options for hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) is now the first-line technique for HCC ablation. RFA produces tumour necrosis in situ through temperature modification. Compared with RFA, microwave ablation (MWA) is one relatively recent advancement of thermoablative technology, which shows multiple theoretical advantages over RFA.2–4 We wish to report the results of a phase III randomised controlled trial (RCT) by comparing ultrasound-guided percutaneous cooled-probe MWA and RFA in ≤5 cm HCC (NCT 02539212).

From October 2008 to June 2015, 203 (265 nodules) subjects were randomised to MWA and 200 (251 nodules) were randomised to RFA. The indications were as follows: tumour size ≤5 cm in diameter, tumour number ≤3, Child–Pugh class A or B classification, no evidence of extrahepatic metastasis, vein or bile duct tumour embolus, lesions...

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UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.

These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;

1. Patient populations involved in AYP transition

2. Risks of failing transition or poor transition

3. Models of AYP transition

4. Patient and carer/parent perspective in AYP transition

5. Surgical perspective

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The {gamma}-glutamyl transpeptidase to platelet ratio (GPR) in HBV patients: just adding up?

We read with interest the article by Lemoine et al evaluating routine tests as non-invasive markers of fibrosis in patients with chronic hepatitis B (CHB).1 The -glutamyl transpeptidase to platelet ratio (GPR) has been proposed as a new fibrosis test, allegedly more accurate than classical biomarkers like the Aspartate Aminotransferase to Platelet Ratio Index (APRI) and FIB-4 in African cohorts. Therefore, we performed a validation analysis of GPR in 147 patients with untreated CHB from two Brazilian reference centres. The mean age was 40.6±13.7 years and 68% were male. Hepatitis B e antigen (HBeAg) was positive in 53% of cases and median HBV-DNA level was 107 700 IU/mL. Median aspartate aminotransferase and alanine aminotransferase (ALT) levels (and IQR) were 42 (30–76) IU/L and 58 (42–106) IU/L, respectively. The distribution of fibrosis stages was as follows: METAVIR F0–22%, F1–27%, F2–22%, F3–16% and F4–13%.

Table 1 exhibits the diagnostic performances of...

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RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis

Objective

The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel.

Design

We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-Cre^ERT2 mice.

Results

Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5⁺ stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4⁺ cells, thus promoting both intestinal stem cell and niche compartments. Wnt/β-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth.

Conclusions

We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions.

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Putting the Wnt up colon cancer

If there is one cancer signalling pathway that Gut readers should be comfortable with, it is the Wnt pathway. Central to this pathway is the adenomatous polyposis coli (APC) gene responsible for familial adenomatous polyposis. Identification of the APC gene in 1991 heralded the start of an ongoing period of exponential growth in our understanding of the molecular basis of cancer, particularly of the large bowel. Clinicians can perhaps be forgiven for finding the ever-expanding list of genes and interacting pathways with their inaccessible names and acronyms daunting. For many, the paper in this issue by Elvira Bakker and coworkers at the Netherlands Cancer Institute revealing the detailed role of RSPO3 in colorectal carcinogenesis may only serve to widen the expanding clinician–researcher divide. However, those brave enough to dive deeper into this paper will be rewarded with an insight into the current state of the art of molecular research...

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Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory 'milieu' initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD.

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Apicobasal polarity and Ras/Raf/MEK/ERK signalling in cancer

Many glandular epithelia such as the GI tract are composed of a sheet of cells polarised along their apicobasal axes with the apical membrane facing the lumen of the tube and the basolateral membrane binding to neighbouring cells and the basal extracellular matrix (ECM). Generation of these two membrane domains with distinct cellular macromolecular contents (including proteins and lipids) provides the basic building blocks that support tissue architecture and their various functions.1

The apicobasal polarisation of epithelial cells is a complex and multistage programme controlled by a network of proteins and lipids. It is initiated by cues from the ECM and cell–cell contacts that trigger changes to the cytoskeleton and hence the polarised organisation of endosomal trafficking that sort and deliver proteins and lipids to the apical and basolateral membrane domains. These events lead to the establishment of cell–cell junctional complexes comprising tight and adherens junctions

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Telomere length and pancreatic cancer risk: breaking down the evidence

Telomeres, located at the ends of chromosomes and composed of a protein complex and tandem repeats of TTAGGG nucleotides, function to protect chromosomes from end-to-end fusions, breakage and degradation in dividing cells. Due to the inherent nature of DNA replication ('the end replication problem') and oxidative stress—telomeres gradually shorten with age. This has been demonstrated cross-sectionally in most tissues examined including the pancreas, and especially in cells with extensive proliferation (eg, leucocytes).12 Cells with critically short telomeres enter growth arrest, or senescence, and may remain viable for extended periods. Premalignant cells can avoid senescence and continue to proliferate by upregulating telomerase or elongating telomeres by alternative mechanisms.1

Shortened telomeres are thought to contribute to chromosomal instability and age-related diseases in humans, including cancer. Up to 90% of human tumours reactivate telomerase, which is epigenetically silenced in most adult somatic cells.1...

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Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer

Objective

Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer.

Design

We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively.

Results

Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; p_trend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r²<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023).

Conclusions

Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.

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Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis

Objective

We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue.

Design

Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors.

Results

Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth.

Conclusions

Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach.

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GI highlights from the literature

Basic scienceRedefining liver zonation

Bahar Halpern K, Shenhav R, Matcovitch–Natan O, et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver Nature 2017;542:352–6.

Hepatocytes in distinct anatomical locations within the liver lobule are thought to have specialised functions, a paradigm termed liver zonation. In this study, the authors use singlemolecule fluorescence in situ hybridisation and single-cell RNA sequencing (scRNA-seq) to define exhaustively the zonation profiles of all liver genes in mice. Using a panel of six zonally distributed genes (Glul, Cyp2e1, Ass1, Asl, Alb, Cyp2f2), they defined a 'spatial barcode', whereby the relative expression of these zonal genes could infer the location of a given cell within one of nine lobule layers between the central vein and portal node. They proceeded to perform scRNA-seq on freshly isolated hepatocytes and used expression levels of the spatial barcode genes to assign each sequenced hepatocyte to...

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Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids

Background

Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.

Objective

To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.

Design

The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27^Kip1 was tested on the human human gastric adenocarcinoma cell line stably expressing CCKBR (AGSE) and mouse small intestinal neuroendocrine carcinoma (STC)-1 cell lines.

Results

The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27^Kip1 both in vivo and in gastrin-treated cell lines. Loss of p27^Kip1 was also observed in human gastric carcinoids arising in the setting of atrophic gastritis.

Conclusions

Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27^Kip1 cellular location and stability.

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The learning curve to achieve satisfactory completion rates in upper GI endoscopy: an analysis of a national training database

Objective

The aim of this study was to determine the number of OGDs (oesophago-gastro-duodenoscopies) trainees need to perform to acquire competency in terms of successful unassisted completion to the second part of the duodenum 95% of the time.

Design

OGD data were retrieved from the trainee e-portfolio developed by the Joint Advisory Group on GI Endoscopy (JAG) in the UK. All trainees were included unless they were known to have a baseline experience of >20 procedures or had submitted data for <20 procedures. The primary outcome measure was OGD completion, defined as passage of the endoscope to the second part of the duodenum without physical assistance. The number of OGDs required to achieve a 95% completion rate was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine which factors were independently associated with OGD completion, a mixed effects logistic regression model was constructed with OGD completion as the outcome variable.

Results

Data were analysed for 1255 trainees over 288 centres, representing 243 555 OGDs. By moving average method, trainees attained a 95% completion rate at 187 procedures. By LC-Cusum analysis, after 200 procedures, >90% trainees had attained a 95% completion rate. Total number of OGDs performed, trainee age and experience in lower GI endoscopy were factors independently associated with OGD completion.

Conclusions

There are limited published data on the OGD learning curve. This is the largest study to date analysing the learning curve for competency acquisition. The JAG competency requirement for 200 procedures appears appropriate.

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{alpha}-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors

Objective

α-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown.

Design

We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined -aminobutyric acid receptor B (GABA_BR) and voltage-gated calcium channel (Ca_V2.2, Ca_V2.3) expression in human and mouse DRG neurons.

Results

Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABA_BR did not. Human DRG neurons expressed GABA_BR and its downstream effector channels Ca_V2.2 and Ca_V2.3. Mouse colonic DRG neurons exhibited high GABA_BR, Ca_V2.2 and Ca_V2.3 expression, with upregulation of the Ca_V2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABA_BR antagonist prevented Vc1.1-induced inhibition, whereas blocking both Ca_V2.2 and Ca_V2.3 caused inhibition comparable with Vc1.1 alone.

Conclusions

Vc1.1-mediated activation of GABA_BR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABA_BR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.

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The effect of heritability and host genetics on the gut microbiota and metabolic syndrome

Objective

Metabolic syndrome (MetS) arises from complex interactions between host genetic and environmental factors. Although it is now widely accepted that the gut microbiota plays a crucial role in host metabolism, current knowledge on the effect of host genetics on specific gut microbes related to MetS status remains limited. Here, we investigated the links among host genetic factors, gut microbiota and MetS in humans.

Design

We characterised the gut microbial community composition of 655 monozygotic (n=306) and dizygotic (n=74) twins and their families (n=275), of which approximately 18% (121 individuals) had MetS. We evaluated the association of MetS status with the gut microbiota and estimated the heritability of each taxon. For the MetS-related and heritable taxa, we further investigated their associations with the apolipoprotein A-V gene (APOA5) single nucleotide polymorphism (SNP) rs651821, which is known to be associated with triglyceride levels and MetS.

Results

Individuals with MetS had a lower gut microbiota diversity than healthy individuals. The abundances of several taxa were associated with MetS status; Sutterella, Methanobrevibacter and Lactobacillus were enriched in the MetS group, whereas Akkermansia, Odoribacter and Bifidobacterium were enriched in the healthy group. Among the taxa associated with MetS status, the phylum Actinobacteria, to which Bifidobacterium belongs, had the highest heritability (45.7%). Even after adjustment for MetS status, reduced abundances of Actinobacteria and Bifidobacterium were significantly linked to the minor allele at the APOA5 SNP rs651821.

Conclusions

Our results suggest that an altered microbiota composition mediated by a specific host genotype can contribute to the development of MetS.

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Inhibition of RAF1 kinase activity restores apicobasal polarity and impairs tumour growth in human colorectal cancer

Background and aim

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death. Novel therapeutics are urgently needed, especially for tumours with activating mutations in KRAS (~40%). Here we investigated the role of RAF1 in CRC, as a potential, novel target.

Methods

Colonosphere cultures were established from human tumour specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma. The role of RAF1 was tested by generating knockdowns (KDs) using three independent shRNA constructs or by using RAF1-kinase inhibitor GW5074. Clone-initiating and tumour-initiating capacities were assessed by single-cell cloning and injecting CRC cells into immune-deficient mice. Expression of tight junction (TJ) proteins, localisation of polarity proteins and activation of MEK-ERK pathway was analysed by western blot, immunohistochemistry and immunofluorescence.

Results

KD or pharmacological inhibition of RAF1 significantly decreased clone-forming and tumour-forming capacity of all CRC cultures tested, including KRAS-mutants. This was not due to cytotoxicity but, at least in part, to differentiation of tumour cells into goblet-like cells. Inhibition of RAF1-kinase activity restored apicobasal polarity and the formation of TJs in vitro and in vivo, without reducing MEK-ERK phosphorylation. MEK-inhibition failed to restore polarity and TJs. Moreover, RAF1-impaired tumours were characterised by normalised tissue architecture.

Conclusions

RAF1 plays a critical role in maintaining the transformed phenotype of CRC cells, including those with mutated KRAS. The effects of RAF1 are kinase-dependent, but MEK-independent. Despite the lack of activating mutations in RAF1, its kinase domain is an attractive therapeutic target for CRC.

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Fungal microbiota dysbiosis in IBD

Objective

The bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD.

Design

Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearman's test and distance correlation.

Results

We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohn's disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations.

Conclusions

Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis.

http://ift.tt/2puowyZ

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Objective

Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.

Design and results

Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl₄-injected Opn^Hep transgenic yet it was less in wild type and almost absent in Opn^–/– mice. Hmgb1 ablation in hepatocytes (Hmgb1^Hep) protected mice from CCl₄-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K–pAkt1/2/3 pathway to upregulate collagen-I.

Conclusions

During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

http://ift.tt/2qf4h5o

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Objective

Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD).

Design

We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.

Results

180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.

Conclusions

Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.

Trial registration numbers

NCT01393626 and NCT01393899.

http://ift.tt/2puHLZ6

Drug-induced liver injury: recent advances in diagnosis and risk assessment

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption–distribution–metabolism–elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public–private partnerships.

http://ift.tt/2puu10x

Primary Seminal Vesicle Carcinoma. The Usefulness of Pax8 Immunohistochemical Expression for the Differential Diagnosis

Primary seminal vesicle carcinoma is a rare entity whose diagnosis can be achieved ruling out the main carcinomas that commonly invade the seminal vesicles. Although a panel of immunohistochemical markers (CA125, CK7, CK20, PSA and PSAP) has been proposed as unique for primary seminal vesicle carcinoma, a reliable positive marker is lacking. In this article, we report a case of primary seminal vesicle carcinoma in a 57-years-old man. The tumor was localized to the left seminal vesicle and histologically characterized by papillae lined by broad eosinophilic cells with pleomorphic nuclei.

http://ift.tt/2pI0w7k

mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi Sarcoma

Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (n=274), most (90%) associated with human immunodeficiency virus (HIV).

http://ift.tt/2r3aLHA

Variant morphology in upper urinary tract urothelial carcinoma: a fourteen-year case series of biopsy and resection specimens

Upper urinary tract urothelial carcinoma exhibiting variant morphology, especially in higher-grade tumors, is a recognized phenomenon but has not been comparatively studied in biopsy versus resection material. We studied the morphologic patterns and clinicopathological features, and provide a comparison between biopsy and resection specimens. Consultation cases were evaluated separately to investigate for possible consultation bias. A total of 383 in-house cases from 352 patients including 314 resection specimens and 69 biopsies from 2001–2014 were reviewed from a single institution.

http://ift.tt/2pHIjXQ

Identification of potential Campylobacter jejuni genes involved in biofilm formation by EZ-Tn5 Transposome mutagenesis

Biofilm formation has been suggested to play a role in the survival of Campylobacter jejuni in the environment and contribute to the high incidence of human campylobacteriosis. Molecular studies of biofilm format...

http://ift.tt/2qcrKpu

SAR1a promoter polymorphisms are not associated with fetal hemoglobin in patients with sickle cell disease from Cameroon

Reactivation of adult hemoglobin (HbF) is currently a dominant therapeutic approach to sickle cell disease (SCD). In this study, we have investigated among SCD patients from Cameroon, the association of HbF le...

http://ift.tt/2pHn2g8

Radiotherapeutic care for brain metastases within the Veterans Health Administration (VHA): Practice patterns and guideline correlation

Abstract

Objective

Brain metastases are common and complex to manage. Our goal was to determine practice patterns and adherence to guidelines among VHA Radiation Oncologists (ROs) regarding management of veterans with brain metastases.

Methods

A survey was e-mailed to all VHA ROs. Information queried included employment status, academic appointment, and years in practice. Number of patients with brain metastases seen per year, steroid usage/dosage, use of prognostic scores, and availability of stereotactic radiosurgery (SRS) and palliative care services was asked. ROs were presented with three scenarios involving patients with brain metastases and asked to choose optimal management.

Results

Sixty-four of 82 ROs responded to the questionnaire. All ROs had palliative care services at their facility. Prognostic scores were routinely calculated by 40.6% of ROs. Thirty-one percent of VA facilities performed SRS, and the remaining facilities referred patients out for this technology.

The responses to management of each of the clinical scenarios follows:

(Uncontrolled cancer with hemiplegia, >10 brain metastases, poor Karnofsky Performance Score (KPS), and short life-expectancy (LE)): Sixty-six percent of respondents chose whole-brain radiation (WBRT) and 34% percent chose no intervention/supportive care or steroids only.
(Controlled cancer with hemiplegia, 4–6 metastases, KPS 70, and LE >4 months): Ninety-five percent of ROs recommended WBRT.
(Newly diagnosed cancer without symptoms, 2 brain lesions, KPS 90, and LE >6 months): Forty-four percent would recommend SRS alone while 35.9% would combine SRS with WBRT.

Conclusion

Veterans with brain metastases treated at VHA radiation oncology centers receive evidence-based care and have access to advanced technologies and palliative care services.

http://ift.tt/2pHE8Kt

Insight into the Recent Genome Duplication of the Halophilic Yeast Hortaea werneckii: Combining an Improved Genome with Gene Expression and Chromatin Structure

Extremophilic organisms demonstrate the flexibility and adaptability of basic biological processes by highlighting how cell physiology adapts to environmental extremes. Few eukaryotic extremophiles have been well studied and only a small number are amenable to laboratory cultivation and manipulation. A detailed characterisation of the genome architecture of such organisms is important to illuminate how they adapt to environmental stresses. One excellent example of a fungal extremophile is the halophile Hortaea werneckii (Pezizomycotina; Dothideomycetes, Capnodiales), a yeast-like fungus able to thrive at near-saturating concentrations of sodium chloride and which is also tolerant to both UV irradiation and desiccation. Given its unique lifestyle and its remarkably recent whole genome duplication, H. werneckii provides opportunities for testing the role of genome duplications and adaptability to extreme environments. We previously assembled the genome of H. werneckii using short-read sequencing technology and found a remarkable degree of gene duplication. Technology limitations, however, precluded high-confidence annotation of the entire genome. We therefore revisited the H. wernickii genome using long-read single molecule sequencing and provide an improved genome assembly, which combined with transcriptome and nucleosome analysis, provides a useful resource for fungal halophile genomics. Remarkably, the ~50 MB H. wernickii genome contains 15,974 genes of which 90% (7608) are duplicates formed by a recent WGD, with an average of 5% protein sequence divergence between them. We found that the WGD is extraordinarily recent, and compared to S. cerevisiae, the majority of the genome's ohnologs have not diverged at the level of gene expression of chromatin structure.

http://ift.tt/2pHBWTj

Metabolic Adaptation to Nutrients Involves Co-regulation of Gene Expression by the RNA Helicase Dbp2 and the Cyc8 Co-repressor in Saccharomyces cerevisiae

Cells fine-tune their metabolic programs according to nutrient availability in order to maintain homeostasis. This is achieved largely through integrating signaling pathways and the gene expression program, allowing cells to adapt to nutritional change. Dbp2, a member of the DEAD-box RNA helicase family in Saccharomyces cerevisiae, has been proposed to integrate gene expression with cellular metabolism. Prior work from our laboratory has reported the necessity of DBP2 in proper gene expression, particularly for genes involved in glucose-dependent regulation. Here, by comparing differentially expressed genes in dbp2 to those of 700 other deletion strains from other studies, we find that CYC8 and TUP1, which form a complex and inhibit transcription of numerous genes, co-repress a common set of genes with DBP2. GO annotations reveal that these co-repressed genes are related to cellular metabolism, including respiration, gluconeogenesis, and alternative carbon source utilization genes. Consistent with a direct role in metabolic gene regulation, loss of either DBP2 or CYC8 results in increased cellular respiration rates. Furthermore, we find that co-repressed genes have a propensity to be associated with overlapping long non-coding RNAs and that up-regulation of these genes in the absence of DBP2 correlates with decreased binding of Cyc8 to these gene promoters. Taken together, this suggests that Dbp2 integrates nutrient availability with energy homeostasis by maintaining repression of glucose-repressed, Cyc8-targeted genes across the genome.

http://ift.tt/2qcCSme

A Pathway-Centered Analysis of Pig Domestication and Breeding in Eurasia

Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9,000 years ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome-windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated, and shared a variable percentage of genes. There were 12 genes present in more than 10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), an important target trait as well during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably in the case of pig, behavior played an important role, among other physiological and developmental processes.

http://ift.tt/2pHlnqU

Exploring the Impact of Cleavage and Polyadenylation Factors on Pre-mRNA Splicing Across Eukaryotes

In human, mouse and Drosophila, the spliceosomal complex U1 snRNP (U1) protects transcripts from premature cleavage and polyadenylation at proximal intronic polyadenylation signals (PAS). These U1-mediated effects preserve transcription integrity and are known as telescripting. The watchtower role of U1 throughout transcription is clear. What is less clear is whether cleavage and polyadenylation factors (CPFs) are simply patrolled or if they may actively antagonize U1 recruitment. In addressing this question, we found that in the introns of human, mouse and Drosophila and of 14 other eukaryotes, including multi- and single-celled species, the conserved AATAAA PAS — a major target for CPFs — is selected against. This selective pressure, approximated using DNA strand asymmetry, is detected for peripheral and internal introns alike. It is surprisingly more pronounced within — rather than outside — the action range of telescripting and particularly intense in the vicinity of weak 5' splice sites. Our study uncovers a novel feature of eukaryotic genes: that the AATAAA PAS is universally counter-selected in spliceosomal introns. This pattern implies that CPFs may attempt to access introns at any time during transcription. However, natural selection operates to minimize this access. By corroborating and extending previous work, our study further indicates that CPF access to intronic PASs might perturb the recruitment of U1 to the adjacent 5' splice sites. These results open the possibility that CPFs may impact the splicing process across eukaryotes.

http://ift.tt/2qcEIDT

Effects of the Ordering of Natural Selection and Population Regulation Mechanisms on Wright-Fisher Models

We explore the effect of different mechanisms of natural selection on the evolution of populations for one- and two-locus systems. We compare the effect of viability and fecundity selection in the context of the Wright-Fisher model with selection under the assumption of multiplicative fitness. We show that these two modes of natural selection correspond to different orderings of the processes of population regulation and natural selection in the Wright-Fisher model. We find that under the Wright-Fisher model these two different orderings can affect the distribution of trajectories of haplotype frequencies evolving with genetic recombination. However, the difference in the distribution of trajectories is only appreciable when the population is in significant linkage disequilibrium. We find that as linkage disequilibrium decays the trajectories for the two different models rapidly become indistinguishable. We discuss the significance of these findings in terms of biological examples of viability and fecundity selection, and speculate that the effect may be significant when factors such as gene migration maintain a degree of linkage disequilibrium.

http://ift.tt/2pHs1xk

RNAi-Mediated Reverse Genetic Screen Identified Drosophila Chaperones Regulating Eye and Neuromuscular Junction Morphology

Accumulation of toxic proteins in neurons have been linked with the onset of neurodegenerative diseases, which in many cases, are characterized by altered neuronal function and synapse loss. Molecular chaperones help protein folding and resolubilization of unfolded proteins thereby reducing the protein aggregation stress. While most of the chaperones are expressed in neurons, their functional relevance largely remains unknown. Here, using bioinformatics analysis, we identified 95 Drosophila chaperones and classified them into seven different classes. Ubiquitous actin5C-Gal4 mediated RNAi knockdown revealed that about 50% of the chaperones are essential in Drosophila. Knocking down these genes in eyes revealed that about 30% of the essential chaperones are crucial for eye development. Using neuron-specific knockdown, immunocytochemistry and robust behavioural assays, we identified a new set of chaperones that play critical roles in the regulation of Drosophila NMJ structural organization. Together, our data presents the first classification and comprehensive analysis of Drosophila chaperones. Our screen identified new set of chaperones that regulate eye and NMJ morphogenesis. Outcome of the screen reported here provides a useful resource for further elucidating the role of individual chaperones in Drosophila eye morphogenesis and synaptic development.

http://ift.tt/2qctlvC

A Systemic Analysis of Transcriptomic and Epigenomic Data To Reveal Regulation Patterns for Complex Disease

Integrating diverse genomics data can provide a global view of the complex biological processes related to the human complex diseases. Although substantial efforts have been made to integrate different omics data, there are at least three challenges for multi-omics integration methods: (i) How to simultaneously consider the effects of various genomic factors, since these factors jointly influence the phenotypes; (ii) How to effectively incorporate the information from publicly accessible databases and omics datasets to fully capture the interactions among (epi-)genomic factors from diverse omics data; and (iii) Until present, the combination of >2 omics datasets has been poorly explored. Current integration approaches are not sufficient to address all of these challenges together. We proposed a novel integrative analysis framework by incorporating sparse model, multivariate analysis, Gaussian graphical model and network analysis to address these three challenges simultaneously. Based on this strategy, we performed a systemic analysis for GBM (Glioblastoma multiforme) integrating genome-wide gene expression, DNA methylation, and miRNA expression data. We identified three regulatory modules of genomic factors associated with GBM survival time and revealed a global regulatory pattern for GBM by combining the three modules with respect to the common regulatory factors. Our method can not only identify disease-associated dysregulated genomic factors from different omics, but also more importantly, incorporate the information from publicly accessible databases and omics datasets to infer a comprehensive interaction map of all these dysregulated genomic factors. Our work represents an innovative approach to enhance our understanding of molecular genomic mechanisms underlying human complex diseases.

http://ift.tt/2pHAGQp

Manipulating the Mitochondrial Genome To Enhance Cattle Embryo Development

The mixing of mitochondrial DNA (mtDNA) from the donor cell and the recipient oocyte in embryos and offspring derived from somatic cell nuclear transfer (SCNT) compromises genetic integrity and affects embryo development. We set out to generate SCNT embryos that inherited their mtDNA from the recipient oocyte only, as is the case following natural conception. Whilst SCNT blastocysts produced from Holstein (Bos Taurus) fibroblasts depleted of their mtDNA and oocytes derived from Angus (Bos Taurus) cattle possessed oocyte mtDNA only, the co-existence of donor cell and oocyte mtDNA resulted in blastocysts derived from non-depleted cells. Moreover, the use of the reprogramming agent, Trichostatin A (TSA), further improved the development of embryos derived from depleted cells. RNA-seq analysis highlighted 35 differentially expressed genes from the comparison between blastocysts generated from non-depleted cells and blastocysts from depleted cells, both in the presence of TSA. The only differences between these two sets of embryos were the presence of donor cell mtDNA and a significantly higher mtDNA copy number for embryos derived from non-depleted cells. Furthermore, the use of TSA on embryos derived from depleted cells positively modulated the expression of CLDN8, TMEM38A and FREM1, which affect embryonic development. In conclusion, SCNT embryos produced by mtDNA depleted donor cells have the same potential to develop to the blastocyst stage without the presumed damaging effect resulting from the mixture of donor and recipient mtDNA.

http://ift.tt/2qctsY4

Linkage Map of Lissotriton Newts Provides Insight into the Genetic Basis of Reproductive Isolation

Linkage maps are widely used to investigate structure, function and evolution of genomes. In speciation research, maps facilitate the study of the genetic architecture of reproductive isolation by allowing identification of genomic regions underlying reduced fitness of hybrids. Here we present a linkage map for European newts of the Lissotriton vulgaris species complex, constructed using two families of F2 L. montandoni x L. vulgaris hybrids. The map consists of 1146 protein coding genes on 12 linkage groups, equal to the haploid chromosome number, with a total length of 1484 cM (1.29 cM/marker). It is notably shorter than two other maps available for salamanders, but the differences in map length are consistent with cytogenetic estimates of the number of chiasmata per chromosomal arm. Thus large salamander genomes do not necessarily, as previously suggested, translate into long linkage maps. Consequently, salamanders are an excellent model to study evolutionary consequences of recombination rate variation in taxa with large genomes and similar number of chromosomes. A complex pattern of transmission ratio distortion (TRD) was detected: TRD occurred mostly in one family, in one breeding season and clustered in two genomic segments. This is consistent with environment-dependent mortality of individuals carrying L. montandoni alleles in these two segments and suggests a role of TRD blocks in reproductive isolation. The reported linkage map will empower studies on the genomic architecture of divergence and interactions between the genomes of hybridizing newts.

http://ift.tt/2pHpUJL

Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib

Abstract

Aim

Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring (TDM) based dose optimization in daily practice.

Methods

A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using LC-MS/MS and trough levels were estimated using an predefined algorithm. Dose interventions were proposed based on trough levels.

Results

396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing. 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels.

Conclusions

Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38% to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.

http://ift.tt/2puglT7

Cytosine Methylation Alters Transcription Factor DNA Binding [Research Watch]

CpG methylation promotes binding of a subset of transcription factors and inhibits binding of others.

http://ift.tt/2r9QM6f

The HECT E3 Ubiquitin Ligase WWP2 Is Autoinhibited by a Peptide Linker [Research Watch]

Peptide linkers that tether WWP2 WW domains lock the HECT domain in an inactive conformation.

http://ift.tt/2qbtek3

Engineering CAR T Cells with Biomaterials [News in Brief]

Studies examine programming CAR T cells in situ with nanoparticles; delivering therapy to solid tumors via dissolvable sponges.

http://ift.tt/2r9WNA0

Chemotherapy-Activated Caspase 3 Cleaves GSDME to Drive Pyroptosis [Research Watch]

GSMDE promotes a switch of chemotherapy-mediated cell death from apoptosis to pyroptosis.

http://ift.tt/2qbyN1Z

Anticancer Sulfonamides Induce Splicing Factor RBM39 Degradation [Research Watch]

Anticancer sulfonamides produce aberrant splicing by inducing degradation of the splicing factor RBM39.

http://ift.tt/2ragBDj

Varlilumab Is Safe and Active in Patients with Advanced Solid Tumors [Research Watch]

Varlilumab activates the CD27 pathway in T cells to promote antitumor activity in solid tumors.

http://ift.tt/2qbqFyE

Macrodactylia lipomatosa with fibrolipomatous hamartomas: macroscopic and ultrasound clues

Although representing congenital anomaly, fibrolipomatous hamartomas often present with uni- or multifocal peripheral nerve lesions in childhood, or at latest the third and fourth decade of adulthood owing to their slowly progressive growth and consecutive peripheral nerve compression (Silverman et al., 1985, Plaza et al., 2014). In this report, we present the clinical and ultrasound clues of an unusual presentation of a male patient with multifocal fibrolipomatous hamartomas of the left ulnar, median, musculocutaneous nerves and left brachial plexus together with macrodactylia lipomatosa.

http://ift.tt/2rbzKFV

Seizure prediction in patients with focal hippocampal epilepsy

Epilepsy is a neurological disorder affecting 1% of the world's population. It causes seizures characterized by recurrent synchronous abnormal electrical discharges in the brain (Chaovalitwongse et al. 2006; Browne and Holmes 2008). Epileptic patients are often at high risk of serious injury or death (Cockerell et al. 1994). Moreover, accompanying psychological stress and helplessness can cause impaired everyday functioning (Buck et al. 1997; Baker et al. 1997). Thereby, reliable prediction of seizures can considerably improve the quality of life of epileptic patients by warning them of impeding seizures to avoid potentially dangerous situations like driving or swimming and enable administration of treatments (Cook et al., 2013; Ramgopal et al., 2014).

http://ift.tt/2qBFeMW

Flexion Synergy Overshadows Flexor Spasticity During Reaching in Chronic Moderate to Severe Hemiparetic Stroke

Clinicians will be required to quantitatively measure and directly target the contributing underlying motor impairments in individuals with hemiparetic stroke to realize advances beyond conventional care in restoring upper extremity function (Krakauer et al., 2012). In the context of reaching function, impairment in joint individuation is the best predictor of recovery outcome over other common impairments observed in chronic stroke such as weakness and spasticity (Zackowski et al., 2004). The term "spasticity" is defined traditionally as a velocity-dependent hyperactive stretch reflex (Lance, 1980; Thilmann et al., 1991) measured under passive conditions.

http://ift.tt/2rb9hrZ

Ancestral Interactions of Ribosomal RNA and Ribosomal Proteins

We have proposed that the ancient ribosome increased in size during early evolution by addition of small folding-competent RNAs. In this Accretion Model, small RNAs and peptides were subsumed onto subunit surfaces, gradually encasing and freezing previously acquired components. The model predicts that appropriate rRNA fragments have inherited local autonomy of folding and local autonomy of assembly with ribosomal proteins (rProteins), and that the rProtein and rRNA are co-chaperones. To test these predictions, we investigate the rRNA interactions of rProtein uL23 and its tail, uL23tail, which is a β-hairpin that penetrates deep into the core of the large ribosomal subunit.

http://ift.tt/2pu0sfC

How Does Mg Modulate the RNA Folding Mechanism: A Case Study of the G:C W:W Trans Basepair

Reverse Watson-Crick G:C basepairs (G:C W:W Trans) occur frequently in different functional RNAs. This is one of the few basepairs whose gas-phase-optimized isolated geometry is inconsistent with the corresponding experimental geometry. Several earlier studies indicate that through post-transcriptional modification, direct protonation, or coordination with Mg2+, accumulation of positive charge near N7 of guanine can stabilize the experimental geometry. Interestingly, recent studies reveal significant variation in the position of putatively bound Mg2+.

http://ift.tt/2qeJkr9

How Does Mg2+ Modulate the RNA Folding Mechanism: A Case Study of the G:C W:W Trans Basepair

http://ift.tt/2ps6gGz

Background

Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening.

Method

DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers).

A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers).

Discussion

As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated.

http://ift.tt/2r9Q5tA

Clinical benefit of adding oxaliplatin to standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a meta-analysis

Abstract

Background

Neoadjuvant fluoropirimidine (5FU)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still debated. We conducted a meta-analysis to evaluate the role of OXP in this patient population.

Methods

Literature searches were carried out in PubMed, Medline and Scopus databases. End points were overall survival (OS), disease free survival (DFS), local failure (LF) and distant failure (DF). Odd ratio (OR) with 95% confidence interval (CI) was calculated using random effects model.

Results

Four randomized trials were included. Patients treated with OXP-5FU CRT had significantly decreased DF (OR = 0.76; 95% CI, 0.60 to 0.97; p = 0.03) compared to standard CRT. OS, DFS and LF were not significantly different between groups.

Conclusions

OXP significantly decreased DF, but does not improve OS e DFS compared to 5FU CRT. Precise role of OXP in neoadjuvant setting of LARC remains to be determined.

http://ift.tt/2qbgtGq

Systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome

Veno-venous extracorporeal membrane oxygenation (ECMO) for refractory acute respiratory distress syndrome (ARDS) is a rapidly expanding technique. We performed a systematic review and meta-analysis of the most...

http://ift.tt/2qeBy0A

Joint annual meeting 2017, Bern EXPO, Bern, Switzerland, 8-9 June 2017

http://ift.tt/2qaYIXF

The effectiveness of long-needle acupuncture at acupoints BL30 and BL35 for CP/CPPS: a randomized controlled pilot study

The chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the commonest chronic inflammatory diseases in adult men, for which acupuncture has been used to relieve related symptoms. The present s...

http://ift.tt/2r28494

Direct and indirect risk associated with the use of dietary supplements among persons with dementia in a Norwegian memory clinic

The use of dietary supplements (DS) is common among persons with dementia. Direct risks associated with DS use include adverse events and DS-drug interactions. A direct risk is a risk caused by the treatment i...

http://ift.tt/2pHbF8G

"Placebo effect is probably what we refer to as patient healing power": A qualitative pilot study examining how Norwegian complementary therapists reflect on their practice

Complementary therapists spend considerable time with their patients, especially in the first consultation. The communication between patients and their therapists is important for raising consciousness and ac...

http://ift.tt/2r2LnBv

MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor

Abstract

Purpose

Gastric cancer (GC) is one of the fatal malignancies worldwide with high occurrences but poor outcomes. bFGF has been shown to play significant roles in GC. Yet, whether bFGF affects the development of GC is less studied.

Methods

MicroRNA assays, real-time PCR, and western blot were conducted for expression analysis of miR-195-5p and basic fibroblast growth factor (bFGF). Luciferase activity was measured with mutated bFGF 3′-UTR sequence at the 3′ end of the luciferase gene. Two GC cell lines, SNU-1 and KATO-3 overexpressing miR-195-5p and bFGF were subjected to wound healing assay and transwell invasion assay. Mouse GC xenograft model was established and subjected to tumor size analysis.

Results

Expression levels of miR-195-5p and bFGF showed negative correlation in human GC tissues. MiR-195-5p directly targeted bFGF 3′-UTR as demonstrated by luciferase activity assay. MiR-195-5p, through downregulating bFGF, inhibited the migration and invasion of SNU-1 and KATO-3 cells, as well as tumorigenesis in a xenograft mouse model, which could be restored by re-introduction of bFGF.

Conclusions

MiR-195-5p inhibits tumorigenesis of GC through suppressing bFGF, which supports both miR-195-5p and bFGF as potential therapeutic targets in the treatment of GC.

http://ift.tt/2qBzFhG

Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension

Droxidopa, a prodrug of norepinephrine, was approved for treatment of neurogenic orthostatic hypotension (nOH) due to primary autonomic disorders based on 3 randomized double-blind studies. We performed safety...

http://ift.tt/2qaXonT

Frontal lobotomy

http://ift.tt/2qd04z4

Re: Srivastava A, Carter BJ; AAV Infection: Protection from Cancer; Hum Gene Ther 2017;28:323–327; DOI: 10.1089/hum.2016.147

Human Gene Therapy May 2017, Vol. 28, No. 5: 375-376.

http://ift.tt/2r9IScW

Authors' Response to Jesse D. Riordan, Hum Gene Ther 2017;28:375–376; DOI: 10.1089/hum.2017.045

Human Gene Therapy May 2017, Vol. 28, No. 5: 376-377.

http://ift.tt/2qaTxH9

AAV Capsid Engineering: Zooming in on the Target

Human Gene Therapy May 2017, Vol. 28, No. 5: 373-374.

http://ift.tt/2r9luwf

Gene Delivery of Calreticulin Anti-Angiogenic Domain Attenuates the Development of Choroidal Neovascularization in Rats

Human Gene Therapy May 2017, Vol. 28, No. 5: 403-414.

http://ift.tt/2qaKV3p

Drug development and registration: Challenges and opportunities in ovarian cancer

Many challenges and opportunities present themselves for improving the care and outcome of patients with ovarian cancer. Open, ongoing discussion between regulatory, National Cancer Institute, academic, and pharmaceutical investigators and scientists will lead to benefit and an enhanced understanding of ovarian cancer. See also pages 000-000

http://ift.tt/2qbLZUc

Regulatory considerations on endpoints in ovarian cancer drug development

Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

http://ift.tt/2pGRnLr

Brain Membrane Fractionation: An Ex Vivo Approach to Assess Subsynaptic Protein Localization

http://ift.tt/2qe1ppx

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Παρασκευή 12 Μαΐου 2017

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