Octreotide protects against hepatic ischemia/reperfusion injury via HO-1-mediated autophagy

http://ift.tt/2Eg8a0M

C-reactive protein is associated with the development of tongue squamous cell carcinoma

Abstract

C-reactive protein (CRP) acts as a biomarker reflecting different degrees of inflammation. Accumulating reports have suggested that there is a close relationship between CRP and various cancers. However, the influence of CRP on the development of tongue squamous cell carcinoma (TSCC) remains unclear. The purpose of this study was to investigate the role of CRP in TSCC. The results of immunohistochemical staining and statistical analyses showed that CRP expression was associated with TSCC tumor size, lymph node metastasis and pathological differentiation. Cell Counting Kit-8 (CCK-8) assay revealed that CRP could enhance TSCC cell proliferation in a dose- and time-dependent manner. Moreover, with CRP stimulation, proliferating cell nuclear antigen (PCNA) expression patterns presented a notable time-dependent up-regulation. In addition, CRP could enhance the invasion and migration of TSCC cells, as revealed by transwell and wound-healing assays, respectively. Annexin V-FITC/PI staining showed that CRP could protect TSCC cells from starvation- and drug-induced apoptosis. With CRP stimulation, the protein expression levels of phosphorylated protein kinase B (pAkt), phosphorylated mammalian target of rapamycin (pmTOR) and phosphorylated S6 ribosomal protein (pS6) were significantly increased, as demonstrated by western blot analysis. Our data suggest that CRP may play an important role in the development of TSCC. Moreover, the biological effects of CRP on TSCC cells might be related to Akt, mTOR, and S6.

http://ift.tt/2DCUg7W

Pilose antler polypeptides ameliorates hypoxic-ischemic encephalopathy by activated neurotrophic factors and SDF1/CXCR4 axis in rats

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a complex condition which is associated with high mortality and morbidity. However, few promising treatments for HIE exist. In the present study, the central objective was to identify the therapeutic effect of pilose antler polypeptides (PAP) on HIE in rats. Sprague-Dawley (SD) rats (14 days old) were used and divided into three groups, including control group, hypoxic-ischemia (HI) group and PAP group. After 21 days of treatment, locomotor activity was improved in PAP-treated rats, brain atrophy was decreased and cerebral edema was mitigated to some extent. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis indicated that PAP administration decreased the expressions of inflammatory cytokines and apoptosis genes in hippocampus compared with HI group. Furthermore, the mRNA expressions of genes related to neurotrophic factors were significantly increased in the hippocampus. In addition, the expressions of oxidative stress markers were all down-regulated after PAP administration. Moreover, PAP up-regulated both the mRNA and protein levels of SDF1 and CXCR4, which may activate the SDF1/CXCR4 axis to moderate brain injury. These results suggest that PAP may be potentially used in the treatment of HIE.

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A selection of abstracts presented at the 43rd annual conference of the anatomical society of Southern Africa (ASSA), 9–13 May 2015, Khaya iBHUBESI Conference Venue, Parys, Free State, South Africa

http://ift.tt/2DFBZqv

The hemodynamic response to incremental increases in negative intrathoracic pressure in healthy humans

Abstract

Negative intrathoracic pressure (nITP) generally augments venous return and left ventricular (LV) stroke volume (LVSV), though large increases in nITP, commonly seen in respiratory disease, attenuate LVSV. Despite this consistent finding, the degree of nITP required to reduce LVSV and the contributions of series and direct ventricular interaction (DVI) in mediating this response remain unclear. We hypothesized that nITP ≤−15 cmH₂0 would augment LVSV, while nITP ≥-20 cmH₂o would reduce LVSV via DVI and increased afterload.

Twenty-three healthy subjects were randomly given inspiratory loads during spontaneous breathing to generate −5, −10, −15, −20 and −25 cmH₂O. LV volumes, LV geometry, inferior vena cava collapsibility (cIVC) and LV meridional end-systolic wall-stress (LVESMWS) were assessed in the supine position using tri-plane echocardiography.

LVSV remained unchanged up to −15 cmH₂O, but was significantly reduced at nITP ≥−20 cmH₂O (−12 ± 8% and −15 ± 11% at −20 and −25 cmH2o, respectively, P < 0.05) due to significant reductions in LV end-diastolic volume (LVEDV), while end-systolic volume (LVESV) was unchanged. cIVC on inspiration was significantly increased at all levels of nITP, while LVESMWS only increased at −25cmH₂O (P < 0.05). DVI, as indicated by a significant increase in the radius of septal curvature, occurred at nITP ≥−10 cmH₂O.

In supine healthy humans, nITP ≤−15 cmH₂O does not significantly affect LV function, despite increased DVI. In contrast, nITP ≥−20 cmH₂O causes significant reductions in LVSV and LVEDV, which appear to be mediated by DVI and increased afterload at −25 cmH₂O. The impact of cIVC during nITP remains unclear.

This article is protected by copyright. All rights reserved

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Empiric antibiotic therapy in urinary tract infection in patients with risk factors for antibiotic resistance in a German emergency department

The aim of this study was to identify clinical risk factors for antimicrobial resistances and multidrug resistance (MDR) in urinary tract infections (UTI) in an emergency department in order to improve empiric...

http://ift.tt/2EftNi6

Cysteamine hydrochloride eye drop solution for the treatment of corneal cystine crystal deposits in patients with cystinosis: an evidence-based review

http://ift.tt/2Ef7toz

Chronic intermittent hypoxia and renovascular hypertension: A case of one plus one equals one-half!

Abstract

The homeostatic regulation of blood pressure depends on an exquisite interplay between multimodal sensors, several brain regions and long-range control systems that serve to maintain and defend cardiovascular constancy.

This article is protected by copyright. All rights reserved

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Epidurals in Pancreatic Resection Outcomes (E-PRO) study: protocol for a randomised controlled trial

Introduction

Epidural analgesia provides an important synergistic method of pain control. In addition to reducing perioperative opioid consumption, the deliverance of analgesia into the epidural space, effectively creating a sympathetic blockade, has a multitude of additional potential benefits, from decreasing the incidence of postoperative delirium to reducing the development of persistent postsurgical pain (PPSP). Prior studies have also identified a correlation between the use of epidural analgesia and improved oncological outcomes and survival. The aim of this study is to evaluate the effect of epidural analgesia in pancreatic operations on immediate postoperative outcomes, the development of PPSP and oncological outcomes in a prospective, single-blind, randomised controlled trial.

Methods

The Epidurals in Pancreatic Resection Outcomes (E-PRO) study is a prospective, single-centre, randomised controlled trial. 150 patients undergoing either pancreaticoduodenectomy or distal pancreatectomy will be randomised to receive an epidural bupivacaine infusion following anaesthetic induction followed by continued epidural bupivacaine infusion postoperatively in addition to the institutional standardised pain regimen of hydromorphone patient-controlled analgesia (PCA), acetaminophen and ketorolac (intervention group) or no epidural infusion and only the standardised postoperative pain regimen (control group). The primary outcome was the postoperative opioid consumption, measured in morphine or morphine-equivalents. Secondary outcomes include patient-reported postoperative pain numerical rating scores, trend and relative ratios of serum inflammatory markers (interleukin (IL)-1β, IL-6, tumour necrosis factor-α, IL-10), occurrence of postoperative delirium, development of PPSP as determined by quantitative sensory testing, and disease-free and overall survival.

Ethics and dissemination

The E-PRO trial has been approved by the institutional review board. Recruitment began in May 2016 and will continue until the end of May 2018. Dissemination plans include presentations at scientific conferences and scientific publications.

Trial registration number

NCT02681796.

http://ift.tt/2EbzcGJ

Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia

Introduction

Australia's National Cervical Screening Program (NCSP) currently recommends 2-year cytology in women aged 18–69 years. Following a review of the NCSP prompted by the implementation of human papillomavirus (HPV) vaccination, the programme will transition in 2017 to 5-year primary HPV screening with partial genotyping for HPV16/18 in women aged 25–74 years. Compass is a sentinel experience for the renewed NCSP and the first prospectively randomised trial of primary HPV screening compared with cytology to be conducted in a population with high uptake of HPV vaccination. This protocol describes the main Compass trial, which commenced after a pilot study of ~5000 women completed recruitment.

Methods and analysis

Women aged 25–69 years will be randomised at a 1:2 allocation to (1) 2.5-year image-read, liquid-based cytology (LBC) screening with HPV triage of low-grade smears (active control Arm A) or (2) 5-year HPV screening with partial genotyping and referral of HPV16/18-positive women to colposcopy (intervention Arm B). Women in Arm B positive for other oncogenic HPV (not 16/18) will undergo secondary randomisation at a 1:1 allocation to either LBC or dual-stained (p16^INK4a and Ki-67) cytology testing (dual-stained cytology). The primary outcome is cumulative CIN3+ (CIN3, adenocarcinoma in situ and invasive cervical cancer) following a 5-year HPV exit testing round in both arms, in women randomised to the HPV arm versus women randomised to the LBC arm, based on an intention-to-treat analysis. The primary outcome will first be tested for non-inferiority and if declared, the primary outcome will be tested for superiority. A total of 36 300 women in birth cohorts not offered vaccination and 84 700 women in cohorts offered vaccination will be recruited, bringing the final sample size to 121 000. The trial is powered for the secondary outcome of cumulative CIN3+ in screen-negative women, adjusted for censoring after CIN2+ treatment and hysterectomy.

Ethics and dissemination

Approved by the Bellberry Ethics Committee (2014-11-592). Findings will be reported in peer-reviewed journals and presented at scientific meetings.

Trial registration number

NCT02328872; Pre-results.

http://ift.tt/2DDQewf

Thread embedding acupuncture for musculoskeletal pain: a systematic review and meta-analysis protocol

Introduction

Thread embedding acupuncture (TEA) is a special type of acupuncture that inserts certain medical threads (eg, catgut or polydioxanone) into subcutaneous tissue or muscles at specific points. Although TEA has been widely used for the treatment of musculoskeletal pain in Korea, China and Taiwan, evidence regarding its efficacy is lacking. The aim of this protocol is to evaluate the effectiveness and safety of TEA in the treatment of musculoskeletal pain, by conducting a systematic review and meta-analysis.

Methods and analysis

The following 16 databases will be searched from their inception to 14 May 2017: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, three Chinese database (China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database and the Wanfang database) and eight Korean databases (Korean Medical Database, Korean Association of Medical Journal Editors, Korean Studies Information Service System, Korean National Assembly Digital Library, National Digital Science Library, Oriental Medicine Advanced Searching Integrated System, 'Database Periodical Information Academic and Korean Traditional Knowledge Portal'). The WHO International Clinical Trials Registry Platform will also be searched to retrieve the recently completed studies.

All randomised controlled studies in which TEA was used on specific points for the treatment of musculoskeletal pain will be included and no restrictions on language will be applied. The risk of bias of each study will be evaluated by the Cochrane risk of bias tool.

Mean difference or standardised mean difference for continuous data and risk ratio for dichotomous data will be calculated with 95% CIs using a random effects model or a fixed effects model. Additional subgroup and sensitivity analyses will be conducted according to a predefined protocol.

Ethics and dissemination

No ethical issues are predicted. The systematic review will be published in a peer-reviewed journal or conference presentation. These findings will summarise the current evidence of TEA for the treatment of musculoskeletal pain and may provide guidance for clinicians and patients to select TEA for musculoskeletal pain.

PROSPERO registration number

CRD42015019046.

http://ift.tt/2EdHduF

Impact of hepatitis C virus infection on long-term mortality after acute myocardial infarction: a nationwide population-based, propensity-matched cohort study in Taiwan

Introduction

The influence of hepatitis C virus (HCV) infection on long-term outcomes of patients with acute myocardial infarction (AMI) is unclear. Therefore, this study aimed to analyse the impact of HCV infection on 12-year mortality rates after AMI using data from the Taiwan National Health Insurance Research Database (NHIRD).

Methods

NHIRD data for approximately 23 000 000 patients between January 2000 and December 2012 were analysed. A total of 186 112 cases of first AMI admission were identified. A total of 4659 patients with HCV infection not receiving interferon therapy were enrolled and divided into those with (n=107) or without (n=4552) cirrhosis. Using one-to-one matching, 4552 matched controls were included in the final analysis.

Results

The 12-year mortality rate was significantly higher in patients with AMI with HCV infection and cirrhosis than in those with HCV infection but without cirrhosis (P<0.0001) or controls (P<0.0001). Patients with HCV infection but without cirrhosis had significantly higher long-term mortality rates than the matched controls (P<0.0001). The HR for mortality was higher in patients with HCV infection (HR 1.12; 95% CI 1.06 to 1.18). HCV influenced outcomes among the subgroups of patients who were male (HR 1.15) and those who had hypertension (HR 1.14).

Conclusions

HCV infection influenced the 12-year mortality rates of patients with AMI, especially those who were male and those who had hypertension. Cirrhosis further increased the long-term mortality rates of patients with AMI with HCV infection.

http://ift.tt/2DCZ9xQ

Recommendations for successful sensory screening in older adults with dementia in long-term care: a qualitative environmental scan of Canadian specialists

Objectives

This study aimed to identify screening tools, technologies and strategies that vision and hearing care specialists recommend to front-line healthcare professionals for the screening of older adults in long-term care homes who have dementia.

Setting

An environmental scan of healthcare professionals took place via telephone interviews between December 2015 and March 2016. All interviews were audio recorded, transcribed, proofed for accuracy, and their contents thematically analysed by two members of the research team.

Participants

A convenience sample of 11 professionals from across Canada specialising in the fields of vision and hearing healthcare and technology for older adults with cognitive impairment were included in the study.

Outcome measures

As part of a larger mixed-methods project, this qualitative study used semistructured interviews and their subsequent content analysis.

Results

Following a two-step content analysis of interview data, coded citations were grouped into three main categories: (1) barriers, (2) facilitators and (3) tools and strategies that do or do not work for sensory screening of older adults with dementia. We report on the information offered by participants within each of these themes, along with a summary of tools and strategies that work for screening older adults with dementia.

Conclusions

Recommendations from sensory specialists to nurses working in long-term care included the need for improved interprofessional communication and collaboration, as well as flexibility, additional time and strategic use of clinical intuition and ingenuity. These suggestions at times contradicted the realities of service provision or the need for standardised and validated measures.

http://ift.tt/2Ef3Uib

Multicentre validation of a sepsis prediction algorithm using only vital sign data in the emergency department, general ward and ICU

Objectives

We validate a machine learning-based sepsis-prediction algorithm (InSight) for the detection and prediction of three sepsis-related gold standards, using only six vital signs. We evaluate robustness to missing data, customisation to site-specific data using transfer learning and generalisability to new settings.

Design

A machine-learning algorithm with gradient tree boosting. Features for prediction were created from combinations of six vital sign measurements and their changes over time.

Setting

A mixed-ward retrospective dataset from the University of California, San Francisco (UCSF) Medical Center (San Francisco, California, USA) as the primary source, an intensive care unit dataset from the Beth Israel Deaconess Medical Center (Boston, Massachusetts, USA) as a transfer-learning source and four additional institutions' datasets to evaluate generalisability.

Participants

684 443 total encounters, with 90 353 encounters from June 2011 to March 2016 at UCSF.

Interventions

None.

Primary and secondary outcome measures

Area under the receiver operating characteristic (AUROC) curve for detection and prediction of sepsis, severe sepsis and septic shock.

Results

For detection of sepsis and severe sepsis, InSight achieves an AUROC curve of 0.92 (95% CI 0.90 to 0.93) and 0.87 (95% CI 0.86 to 0.88), respectively. Four hours before onset, InSight predicts septic shock with an AUROC of 0.96 (95% CI 0.94 to 0.98) and severe sepsis with an AUROC of 0.85 (95% CI 0.79 to 0.91).

Conclusions

InSight outperforms existing sepsis scoring systems in identifying and predicting sepsis, severe sepsis and septic shock. This is the first sepsis screening system to exceed an AUROC of 0.90 using only vital sign inputs. InSight is robust to missing data, can be customised to novel hospital data using a small fraction of site data and retains strong discrimination across all institutions.

http://ift.tt/2DFtMTd

Quality of life, sleep and rheumatoid arthritis (QUASAR): a protocol for a prospective UK mHealth study to investigate the relationship between sleep and quality of life in adults with rheumatoid arthritis

Introduction

People with rheumatoid arthritis (RA) frequently report reduced health-related quality of life (HRQoL), the impact one's health has on physical, emotional and social well-being. There are likely numerous causes for poor HRQoL, but people with RA have identified sleep disturbances as a key contributor to their well-being. This study will identify sleep/wake rhythm-associated parameters that predict HRQoL in patients with RA.

Methods and analysis

This prospective cohort study will recruit 350 people with RA, aged 18 years or older. Following completion of a paper-based baseline questionnaire, participants will record data on 10 symptoms including pain, fatigue and mood two times a day for 30 days using a study-specific mobile application (app). A triaxial accelerometer will continuously record daytime activity and estimate evening sleep parameters over the 30 days. Every 10 days following study initiation, participants will complete a questionnaire that measures disease specific (Arthritis Impact Measurement Scale 2-Short Form (AIMS2-SF)) and generic (WHOQOL-BREF) quality of life. A final questionnaire will be completed at 60 days after entering the study. The primary outcomes are the AIMS2-SF and WHOQOL-BREF. Structural equation modelling and latent trajectory models will be used to examine the relationship between sleep/wake rhythm-associated parameters and HRQoL, over time.

Ethics and dissemination

Results from this study will be disseminated at regional and international conferences, in peer-reviewed journals and Patient and Public Engagement events, as appropriate.

http://ift.tt/2EasP6t

Evaluating sickness absence duration by musculoskeletal and mental health issues: a retrospective cohort study of Scottish healthcare workers

Objectives

Sickness absence (SA) among healthcare workers is associated with occupational and non-occupational risk factors and impacts employee health, healthcare delivery and patient health. At the same time, healthcare is one of the employment sectors with the highest rates of work-related ill health in the UK. Musculoskeletal (MSK) and mental health (MH) issues are leading causes of SA, but there is a lack of research on how certain MSK/MH conditions impact on SA duration. The study aim is to determine differences in SA duration by MH and MSK disorders in healthcare employees.

Methods

Survival analyses were used to estimate SA duration due to MSK and MH problems over 6 years, and Cox's proportional hazards models to determine the HRs of returning to work, using a bespoke Scottish health board database with over 53 000 SA events. SA duration and time to return-to-work (RTW) were estimated for employees by age, gender, job and health conditions.

Results

MSK and MH conditions accounted for 27% and 6% of all SA events and 23.7% and 19.5% of all days lost, respectively. Average SA duration was 43.5 days for MSK and 53.9 days for MH conditions. For MSK conditions, employees with low back or neck pain had the fastest RTW (median P₅₀: 7 days), whereas employees absent due to depression took the longest (P₅₀: 54 days). The most influential sociodemographic variables affecting RTW were age, gender and job category.

Conclusions

Using a unique and rich database, we found significant differences in SA duration by presenting condition in healthcare workers. MH conditions, and depression specifically, accounted for the most working days' absence. Significant variations in duration were also observed for MSK conditions. Our findings can inform public health practitioners and healthcare managers of the most significant factors impacting MSK-related and MH-related SA to develop and implement tailored and targeted workplace interventions.

http://ift.tt/2DEoV4G

Healthy Foundations Study: a randomised controlled trial to evaluate biological embedding of early-life experiences

Introduction

Adverse early experiences are associated with long-lasting disruptions in physiology, development and health. These experiences may be 'biologically embedded' into molecular and genomic systems that determine later expressions of vulnerability. Most studies to date have not examined whether preventive interventions can potentially reverse biological embedding. The Nurse-Family Partnership (NFP) is an evidence-based intervention with demonstrated efficacy in improving prenatal health, parenting and child functioning. The Healthy Foundations Study is an innovative birth cohort which will evaluate the impact of the NFP on biological outcomes of mothers and their infants.

Methods and analysis

Starting in 2013, up to 400 pregnant mothers and their newborns were recruited from the British Columbia Healthy Connections Project—a randomised controlled trial of the NFP, and will be followed to child aged 2 years. Women were recruited prior to 28 weeks' gestation and then individually randomised to receive existing services (comparison group) or NFP plus existing services (intervention group). Hair samples are collected from mothers at baseline and 2 months post partum to measure physiological stress. Saliva samples are collected from infants during all visits for analyses of stress and immune function. Buccal swabs are collected from infants at 2 and 24 months to assess DNA methylation. Biological samples will be related to child outcome measures at age 2 years.

Ethics and dissemination

The study received ethical approval from seven research ethics boards. Findings from this study will be shared broadly with the research community through peer-reviewed publications, and conference presentations, as well as seminars with our policy partners and relevant healthcare providers. The outcomes of this study will provide all stakeholders with important information regarding how early adversity may lead to health and behavioural disparities and how these may be altered through early interventions.

Trial registration number

NCT01672060; Pre-results.

http://ift.tt/2EcG1I6

Cross-sectional study assessing the addition of contrast sensitivity to visual acuity when testing for fitness to drive

Objectives

The aim of this study is to quantify the importance of loss of contrast sensitivity (CS) and its relationship to loss of visual acuity (VA), driving restrictions and daytime, on-road driving evaluations in drivers aged 70+.

Design

A predictive cross-sectional study.

Setting

Volunteer participants to a drivers' refresher course for adults aged 70+ delivered by the Swiss Automobile Club in western Switzerland from 2011 to 2013.

Participants

162 drivers, male and female, aged 70 years or older.

Clinical predictors

We used a vision screener to estimate VA and the The Mars Letter Contrast Sensitivity Test to test CS.

Outcomes

We asked drivers to report whether they found five driving restrictions useful for their condition; restrict driving to known roads, avoid driving on highways, avoid driving in the dark, avoid driving in dense traffic and avoid driving in fog. All participants also underwent a standardised on-road evaluation carried out by a driving instructor.

Results

Moderate to severe loss of CS for at least one eye was frequent (21.0% (95% CI 15.0% to 28.1%)) and often isolated from a loss of VA (11/162 cases had a VA ≥0.8 decimal and a CS of ≤1.5 log(CS); 6.8% (95% CI 3.4% to 11.8%)). Drivers were more likely (R²=0.116, P=0.004) to report a belief that self-imposed driving restrictions would be useful if they had reduced CS in at least one eye. Daytime evaluation of driving performance seems limited in its ability to correctly identify difficulties related to CS loss (VA: R²=0.004, P=0.454; CS: R²=0.006, P=0.332).

Conclusion

CS loss is common for older drivers. Screening CS and referring for cataract surgery even in the absence of VA loss could help maintain mobility. Reduced CS and moderate reduction of VA were both poor predictors of daytime on-road driving performances in this research study.

http://ift.tt/2DCmKPm

Randomised controlled trial of the sliding hip screw versus X-Bolt Dynamic Hip Plating System for the fixation of trochanteric fractures of the hip in adults: a protocol study for WHiTE 4 (WHiTE4)

Introduction

Sliding hip screw fixation is well established in the treatment of trochanteric fractures of the hip. The X-Bolt Dynamic Hip Plating System builds on the successful design features of the sliding hip screw but differs in the nature of the fixation in the femoral head. A randomised pilot study suggested that the X-bolt Dynamic Hip Plating System might provide similar health-related quality of life while reducing the risk of revision surgery when compared with the sliding hip screw. This is the protocol for a multicentre randomised trial of sliding hip screw versus X-Bolt Dynamic Hip Plating System for patients 60 years and over treated for a trochanteric fracture of the hip.

Methods and analysis

Multicentre, multisurgeon, parallel, two-arm, randomised controlled trial. Patients aged 60 years and older with a trochanteric hip fracture are potentially eligible. Participants will be randomly allocated on a 1:1 basis to either sliding hip screw or X-Bolt Dynamic Hip Plating System. Otherwise, all care will be in accordance with National Institute for Health and Care Excellence guidance. A minimum of 1128 patients will be recruited to obtain 90% power to detect a 0.075-point difference in EuroQol-5D health-related quality of life at 4 months postrandomisation. Secondary outcomes include mortality, residential status, revision surgery and radiographic measures. The treatment effect will be estimated using a two-sided t-test adjusted for age, gender and cognitive impairment based on an intention-to-treat analysis.

Ethics and dissemination

National Research Ethics Committee approved this study on 5 February 2016 (16/WM/0001). The study is sponsored by the University of Oxford and funded through an investigator initiated grant by X-Bolt Orthopaedics. A manuscript for a high-impact peer-reviewed journal will be prepared, and the results will be disseminated to patients through local mechanisms at participating centres.

Trial registration number

ISRCTN92825709.

http://ift.tt/2EfVPtu

Simple surgical solution: scaphoid type congenital megalourethra

Description

Congenital megalourethra (CM) is an uncommon paediatric urogenital problem with less than 80 reported cases1 and may go ignored for years. It is defined as dilatation and elongation of the penile urethra associated with the deficiency of the corpora cavernosa and/or spongiosum. It may be of scaphoid or fusiform variety. However, surgery in most cases may be challenging.

A 10-year-old boy presented with the complaint of a swelling appearing on the under-surface of the penis during voiding since birth. This persisted even after micturation and had to be milked out post voiding. His urinary stream was of good calibre and normal volume. There was no associated history of urinary tract infection or obstruction. External genital examination was normal with bilateral descended testes, stretched penile length=4.5 cm, normal prepuce and normally positioned urethral meatus. However, dilatation of the dorsal penile shaft was observed during micturation. A retrograde cum voiding...

http://ift.tt/2DHrZRU

Cryptococcal meningitis in a daily cannabis smoker without evidence of immunodeficiency

Cryptococcal meningitis is a life-threatening condition most commonly observed in immunocompromised individuals. We describe a daily cannabis smoker without evidence of immunodeficiency presenting with confirmed Cryptococcus neoformans meningitis. An investigation of cannabis samples from the patient's preferred dispensary demonstrated contamination with several varieties of Cryptococcus, including C. neoformans, and other opportunistic fungi. These findings raise concern regarding the safety of dispensary-grade cannabis, even in immunocompetent users.

http://ift.tt/2nfyujz

Hemiparesis in spontaneous spinal epidural haematoma: a potential stroke imitator

Spontaneous spinal epidural haematoma (SSEH) is a rare condition that requires urgent surgical intervention in order to prevent permanent neurological deficit. SSEH commonly presents as a paraparesis or tetraparesis. SSEH presenting as a hemiparesis is less common and in such situations, it can be mistaken for a cerebrovascular accident (CVA). Thrombolytic or anticoagulant treatment for CVA can potentially worsen the neurological deficit. We report one such case of SSEH misdiagnosed as a CVA. Treatment with tissue plasminogen activator led to worsening of his condition. On a subsequent cervical spine MRI, an epidural haematoma extending from C3 to C5 was detected and treated with laminectomy and evacuation. Surgical intervention led to significant improvement from American Spinal Injury Association Scale (ASIA) B to ASIA E. Presence of clinical features such as Horner's syndrome, Brown-Sequard syndrome and the absence of cranial nerve palsies in acute hemiparesis are indicative of SSEH rather than CVA.

http://ift.tt/2DFaIZm

Desmoplastic fibroblastoma of the left upper arm

An elderly female patient presented to the clinic with a several-week history of a mass in her left upper arm that was tender to the touch. The mass was initially thought to be a schwannoma of the left radial nerve based on imaging and was surgically removed. The pathology report revealed an uncommon diagnosis of desmoplastic fibroblastoma.

http://ift.tt/2nhtDP1

Delayed diagnosis of dermal leiomyosarcoma mimicking keloid scar

A 43-year-old man developed an abnormal scar 6 months following excision of a leiomyoma from his left shoulder. The scar was elevated, irregular in shape, pink-red in colour, hard in consistency and it was extending beyond the margins of the original wound. A diagnosis of a keloid scar was considered and the patient was managed as such. He underwent a planned procedure for intralesional excision of the keloid scar. The histopathological examination showed a diagnosis of leiomyosarcoma. This case report presents a delayed diagnosis of dermal leiomyosarcoma mimicking a keloid scar. The patient subsequently underwent wider excision of the tumour with curative intention.

http://ift.tt/2DG9PzU

Neurogenic pulmonary oedema secondary to vertebral artery dissection while playing tennis

We present a case of a patient who developed vertebral artery dissection (VAD) while playing tennis and presented with neurogenic pulmonary oedema. The case highlights two important points: acute pulmonary oedema as an unusual presenting feature of VAD and VAD, an important cause of stroke in young people, as being associated with playing low-impact sports such as tennis. These associations, independent of each other, are under-recognised and can lead to a delay in diagnosis.

http://ift.tt/2nfBfRW

Dont put your foot in it: a case of talonavicular septic arthritis

We present the second documented case of primary septic arthritis of the talonavicular joint. This patient had a number of medical comorbidities, including chronic widespread pain including the ipsilateral limb, which made diagnosis an even greater challenge. Although a clinical diagnosis, joint fluid aspiration remains the gold standard. Prompt surgical drainage with adjuvant antibiotic treatment is recommended, and management requires a multidisciplinary team approach. The aim of treatment is to avoid the sequelae of joint destruction, pain and foot deformity.

http://ift.tt/2DIqoeI

Rare occurrence of eight-and-a-half syndrome as a clinically isolated syndrome

Eight-and-a-half syndrome is a rare condition that is described as a combination of one-and-a-half syndrome and an ipsilateral facial nucleus lesion. We present a clinical case of occurrence of eight-and-a-half syndrome that was caused by a demyelinating lesion in the dorsal pontine tegmentum. A 44-year-old man presented to the hospital with a subacute onset of horizontal diplopia and left-sided facial weakness. MRI revealed a T2 hyperintense lesion in his dorsal pons, which was consistent with a demyelinating pathology. Treatment with intravenous steroids showed significant improvement in his symptoms. In our case, it occurred due to a suspected demyelinating lesion that was this patient's first and only demyelinating event, leaving him with a diagnosis of clinically isolated syndrome. His responsiveness to steroids represents the first case report of an adult patient presenting with an eight-and-a-half syndrome secondary to a suspected demyelinating pathology.

http://ift.tt/2nh9Hvw

Sepsis Secondary to Bacteroides Fragilis Tubo-Ovarian Abscess Requiring Hysterectomy and Bilateral Salpingo-Oophorectomy

A 45-year-old, G0P0 premenopausal woman was admitted for investigation of right lower quadrant pain, fever, leucocytosis and right adnexal abscess on CT. She was started on intravenous antibiotics and underwent CT-guided percutaneous drainage from which Bacteroides fragilis was cultured. A few days later, she had an exploratory laparotomy with incision and drainage. Once stabilised, she was discharged on intravenous antibiotics. She was followed outpatient and subsequent imaging demonstrated significant improvement of the abscess. After being asymptomatic for 3 months, she again presented to the emergency department with right lower quadrant abdominal pain, fever and leucocytosis. Two days later, she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. She made a full recovery and began treatment with a herbal oestrogen derivative to prevent early menopause.

http://ift.tt/2DI9gpa

Antibiotic use in a tertiary healthcare facility in Ghana: a point prevalence survey

The global rise and spread of antibiotic resistance is limiting the usefulness of antibiotics in the prevention and treatment of infectious diseases. The use of antibiotic stewardship programs guided by local ...

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Bioaerosol concentrations generated from toilet flushing in a hospital-based patient care setting

In the United States, 1.7 million immunocompromised patients contract a healthcare-associated infection, annually. These infections increase morbidity, mortality and costs of care. A relatively unexplored rout...

http://ift.tt/2DGHXvt

Multicenter validation of cancer gene panel-based next-generation sequencing for translational research and molecular diagnostics

Abstract

The simultaneous detection of multiple somatic mutations in the context of molecular diagnostics of cancer is frequently performed by means of amplicon-based targeted next-generation sequencing (NGS). However, only few studies are available comparing multicenter testing of different NGS platforms and gene panels. Therefore, seven partner sites of the German Cancer Consortium (DKTK) performed a multicenter interlaboratory trial for targeted NGS using the same formalin-fixed, paraffin-embedded (FFPE) specimen of molecularly pre-characterized tumors (n = 15; each n = 5 cases of Breast, Lung, and Colon carcinoma) and a colorectal cancer cell line DNA dilution series. Detailed information regarding pre-characterized mutations was not disclosed to the partners. Commercially available and custom-designed cancer gene panels were used for library preparation and subsequent sequencing on several devices of two NGS different platforms. For every case, centrally extracted DNA and FFPE tissue sections for local processing were delivered to each partner site to be sequenced with the commercial gene panel and local bioinformatics. For cancer-specific panel-based sequencing, only centrally extracted DNA was analyzed at seven sequencing sites. Subsequently, local data were compiled and bioinformatics was performed centrally. We were able to demonstrate that all pre-characterized mutations were re-identified correctly, irrespective of NGS platform or gene panel used. However, locally processed FFPE tissue sections disclosed that the DNA extraction method can affect the detection of mutations with a trend in favor of magnetic bead-based DNA extraction methods. In conclusion, targeted NGS is a very robust method for simultaneous detection of various mutations in FFPE tissue specimens if certain pre-analytical conditions are carefully considered.

http://ift.tt/2BxbO3o

Enhancer-Driven Gene Expression Changes Facilitate Metastasis [Research Watch]

Altered enhancer activity allows for dynamic gene expression to promote osteosarcoma metastasis.

http://ift.tt/2DGnvXm

Blood Monocyte Frequency May Be a Biomarker for Response to Anti-PD-1 [Research Watch]

CD14⁺CD16^–HLA-DR^hi monocyte frequency was linked to response to anti–PD-1 in patients with melanoma.

http://ift.tt/2Ed3n0h

Chromosomal Instability Drives Metastasis Independent of Aneuploidy [Research Watch]

Chromosomal instability (CIN) promotes metastasis with little effect on primary tumor growth.

http://ift.tt/2DFmsXJ

Dimerization Is Critical for the Functions of Wild-type and Mutant KRAS [Research Watch]

Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.

http://ift.tt/2Ed3jO5

Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1 negative human lung cancers

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non-small-cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2. Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x and HHLA2 on human T cell proliferation and cytokine production were investigated. Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts, and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, while HHLA2 was positive in 61% and 64% of tumors in the two sets. The co-expression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1 negative cases expressed B7x, HHLA2 or both. The triple positive group had more TIL infiltration than the triple negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells. Conclusion: The majority of PD-L1 negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1 negative tumors deserves to be explored to provide the rationale for an effective immunotherapy strategy in these tumors.

http://ift.tt/2FneqDE

The strategy of PIKing a target: What is AKTually most effective?

Breast and gynecological cancers harboring PIK3CA mutations showed no significant responses to AZD5363, a pan-AKT catalytic inhibitor, in contrast with previous in vitro data showing activity of the drug in this subset of cancers. These results raise the question on how to select the most accurate predictive biomarkers of response.

http://ift.tt/2DOoYhY

Immune biomarkers predictive for disease-free survival with adjuvant sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma in the S-TRAC trial (ClinicalTrials.gov number, NCT00375674). A prospectively-designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, Receiver Operating Characteristics curves were generated. Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median (median [95% CI], not reached [6.83-not reached] vs. 3.47 years [1.73-not reached]; hazard ratio 0.40 [95% CI, 0.20-0.81]; P=0.009) treated with sunitinib (n=101), but not with placebo (n=90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1- tumors (hazard ratio 1.75; P=0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (hazard ratio 0.58; P=0.175). Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.

http://ift.tt/2FnhQGp

Small Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver.

Small cell neuroendocrine cancers often originate in the lung, but can also arise in the bladder or prostate. Phenotypically, small cell carcinoma of the bladder (SCCB) shares many similarities with small cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations.

http://ift.tt/2DOQzPR

Circulating tumor cells with stem-like phenotypes for diagnosis, prognosis and therapeutic response evaluation in hepatocellular carcinoma

Purpose: In present study, we assessed the clinical value of circulating tumor cells (CTCs) with stem-like phenotypes for diagnosis, prognosis and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized QPCR-based detection platform. Experimental Design:Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter-patient study with independent validation (total n=1006), including healthy individuals, patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL) and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of CTC panel in treatment response surveillance and its prognostic significance were further investigated. Results: The AUC of CTC panel was 0.88 in training set [sensitivity=72·5%, specificity=95.0%, positive predictive value (PPV) =92.4, negative predictive value (NPV)=77.8] and 0.93 in validation set (sensitivity=82·1%; specificity=94.2%, PPV=89.9, NPV=89.3). This panel performed equally well in detecting early-stage and α-fetoprotein (AFP)-negative HCC, as well as differentiating HCC from CHB, LC and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of CTC panel in predicting tumor recurrence was further confirmed (training: HR=2.692, 95% CI, 1.617-4.483, P<0.001; validation: HR=3.127, 95% CI, 1.360-7.190, P=0.007). Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies.

http://ift.tt/2Fmp90Z

RNF6 promotes colorectal cancer by activating the Wnt/{beta}-catenin pathway via ubiquitination of TLE3

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer (CRC). Previous whole-genome sequencing of CRC clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we show that RNF6 is upregulated in 73.5% (147/200) of CRC patients, and was positively associated with RNF6 gene amplification. Further, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of CRC patients. RNF6 promoted cell growth, cell cycle progression, and epithelial-to-mesenchymal transition in CRC cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.

http://ift.tt/2FjWF7X

MicroRNA-508 defines the stem-like/mesenchymal subtype in colorectal cancer

Colorectal cancer (CRC) includes an invasive stem-like/mesenchymal subtype but its genetic drivers, functional and clinical relevance are uncharacterized. Here we report the definition of an altered microRNA (miR) signature defining this subtype which includes a major genomic loss of miR-508. Mechanistic investigations showed that this microRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, BMI1 and BMI1. Loss of miR-508 in CRC was associated with upregulation of the novel hypoxia-induced long non-coding RNA AK000053. Ectopic expression of miR-508 in CRC cells blunted epithelial-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical CRC specimens, expression of miRNA-508 negatively correlated with stemness and EMT-associated gene expression and inversely correlated with patient survival. Overall, our results showed that miRNA-508 is a key functional determinant of the stem-like/mesenchymal CRC subtype and a candidate therapeutic target for its treatment.

http://ift.tt/2DQE8mI

Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with OC, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+MDSC and a concomitant increase in the antitumor activities of circulating CD8+T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in OC patients.

http://ift.tt/2FijIAb

Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-{beta}-catenin signaling axis

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of GC. Using genome-wide methylation studies we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in GC. We then investigated the functional significance and clinical implication of FOXF2 in GC. FOXF2 was silenced in GC cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1-S cell cycle transition, induced apoptosis of GC cell lines and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2 binding protein like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early stage GC patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for GC patients.

http://ift.tt/2DPT30p

Distinct Presentation of a Neglected Tropical Disease on Screening Colonoscopy

A 52-year-old asymptomatic woman presented for a screening colonoscopy. Her only significant history was that she emigrated from the Republic of Burundi in East Africa 8 years prior.

http://ift.tt/2DO7vGl

LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells

Journal Name: Biological Chemistry
Issue: Ahead of print


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Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23

Journal Name: Biological Chemistry
Issue: Ahead of print


http://ift.tt/2DHrbw6

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors, Published online: 26 January 2018; doi:10.1038/s41419-017-0141-1

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors

http://ift.tt/2DGVJyd

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer, Published online: 26 January 2018; doi:10.1038/s41419-017-0143-z

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer

http://ift.tt/2ngX5oj

Human papillomavirus E7 induces p63 expression to modulate DNA damage response

Human papillomavirus E7 induces p63 expression to modulate DNA damage response

Human papillomavirus E7 induces p63 expression to modulate DNA damage response, Published online: 26 January 2018; doi:10.1038/s41419-017-0149-6

Human papillomavirus E7 induces p63 expression to modulate DNA damage response

http://ift.tt/2DJjmWP

N6-methyladenosine links RNA metabolism to cancer progression

N6-methyladenosine links RNA metabolism to cancer progression

N6-methyladenosine links RNA metabolism to cancer progression, Published online: 26 January 2018; doi:10.1038/s41419-017-0129-x

N6-methyladenosine links RNA metabolism to cancer progression

http://ift.tt/2ngquiB

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway, Published online: 26 January 2018; doi:10.1038/s41419-017-0131-3

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway

http://ift.tt/2DEQnmY

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death, Published online: 26 January 2018; doi:10.1038/s41419-017-0170-9

Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

http://ift.tt/2neVxeq

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure, Published online: 26 January 2018; doi:10.1038/s41419-017-0150-0

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

http://ift.tt/2DFJBxA

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway, Published online: 26 January 2018; doi:10.1038/s41419-017-0132-2

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

http://ift.tt/2neV63M

To Care Is Human — Collectively Confronting the Clinician-Burnout Crisis

The ethical principles that guide clinical care — a commitment to benefiting the patient, avoiding harm, respecting patient autonomy, and striving for justice in health care — affirm the moral foundation and deep meaning underlying many clinicians' view of their profession as a worthy and…

http://ift.tt/2Gh9Wzr

Case 3-2018: A 5-Month-Old Boy with Hypoglycemia

Presentation of Case. Dr. Micaela R. Atkins (Pediatrics): A 5-month-old boy was admitted to the pediatric intensive care unit (ICU) of this hospital for evaluation of suspected hypoglycemia. The patient was born at another hospital after 40 weeks 4 days of gestation. His mother had had a positive…

http://ift.tt/2DFM9LV

Monitoring Neuromuscular Function

http://ift.tt/2Fcz9tv

Monitoring Neuromuscular Function

http://ift.tt/2Fcz9tv

PEPFAR — 15 Years and Counting the Lives Saved

In the long history of successful public health initiatives, such as those leading to the eradication of smallpox, the elimination of polio throughout most of the world, and the marked reduction globally in vaccine-preventable childhood diseases, few programs have matched the impact of one that…

http://ift.tt/2EeeCp4

Visualizing Lignification Dynamics in Plants with Click Chemistry: Dual Labeling is BLISS!

BLISS, a dual labeling protocol for studying lignification dynamics, was developed. Using synthetic monolignol reporters and a sequential combination of SPAAC and CuAAC bioorthogonal click reactions, this methodology paves the way to in-depth analysis of the factors that regulate the biogenesis of lignins in planta.

http://ift.tt/2rKBDgW

Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers, Vol. 10, Pages 33: The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers doi: 10.3390/cancers10020033

Authors: Sandra Valle Laura Martin-Hijano Sonia Alcalá Marta Alonso-Nocelo Bruno Sainz Jr.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (&lt;7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

http://ift.tt/2neR5NP

PEPFAR — 15 Years and Counting the Lives Saved

In the long history of successful public health initiatives, such as those leading to the eradication of smallpox, the elimination of polio throughout most of the world, and the marked reduction globally in vaccine-preventable childhood diseases, few programs have matched the impact of one that…

http://ift.tt/2EeeCp4

To Care Is Human — Collectively Confronting the Clinician-Burnout Crisis

The ethical principles that guide clinical care — a commitment to benefiting the patient, avoiding harm, respecting patient autonomy, and striving for justice in health care — affirm the moral foundation and deep meaning underlying many clinicians' view of their profession as a worthy and…

http://ift.tt/2Gh9Wzr

Man saved by EMT as baby becomes first responder

By EMS1 Staff NEW YORK — A man who was saved by an EMT when he was born a premature baby reunited with him as he graduated from the EMS academy himself. NY Post reported that Joseph Bitetto reunited with EMT-turned NYPD detective Howard Blanck 22 years later as he walked across the stage during FDNY's EMS graduation. Bitetto's mom suffered a ruptured placenta in 1996 when she was just ...

http://ift.tt/2nf6flm

New Research From Psychological Science

Read about the latest research published in Psychological Science:

Deconstructing Rich False Memories of Committing Crime: Commentary on Shaw and Porter (2015)

Kimberley A. Wade, Maryanne Garry, and Kathy Pezdek

In a 2015 study investigating false-memory creation, Shaw and Porter found that 70% of participants constructed "rich false memories" of having committed a crime as adolescents. This false-memory rate is much higher than the central tendency (about 22%) in studies using a similar paradigm, a discrepancy that the commentary authors attribute to combining false beliefs (e.g., accepting that the event occurred) and false memories (e.g., reporting memory of the event, elaborating on the event). The authors replicated the 70% false memory finding when they used Shaw and Porter's original coding scheme. However, when they used two other established coding schemes, they found that only 26% to 30% of the reports met the criteria for false memories, and around 43% met the criteria for false beliefs. In additional experiments, lay readers reported low confidence that many of the reports originally coded as false memories showed evidence of actual remembering. The authors conclude that the rate of true false memories generated in the 2015 study is likely to be closer to the central tendency in the literature, a rate that still warrants concern about the potential for false memories in real-world contexts.

Unifying Visual Space Across the Left and Right Hemifields  

Zhimin Chen, Anna Kosovicheva, Benjamin Wolfe, Patrick Cavanagh, Andrei Gorea, and David Whitney

To examine whether the visual system uses a fixed or dynamic approach to integrate the left and right visual fields into a unified percept, the authors developed a novel adaptation paradigm. In an adaptation phase, participants saw a moving set of colored lines that was split down the middle vertically, one side appearing higher than the other. Then, a pair of dashes appeared briefly on screen, and participants reported whether the left dash was higher or lower than the right. After each set of these judgments, participants had another 1-min adaptation period. The results showed that viewing the misaligned adaptation stimulus caused a shift in the opposite direction when participants subsequently viewed the dashes. For example, if participants had adapted to a stimulus in which the left half was shifted downward, they reported that the dashes were aligned when in fact the left dash was lower. This negative aftereffect emerged with other adaptation stimuli, including movie clips, but it was specific to vertical misalignment across the two visual fields. The results suggest that the visual system continuously recalibrates alignment of elements across the visual fields to create a unified percept.

http://ift.tt/2nhWvrp

Comparative Evaluation of Using NOTA and DOTA Derivatives as Bifunctional Chelating Agents in the Preparation of 68Ga-Labeled Porphyrin: Impact on Pharmacokinetics and Tumor Uptake in a Mouse Model

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


http://ift.tt/2Ed0ooE

Single-cell Microfluidic Analysis of Bacillus subtilis

We present a method for the microfluidic analysis of individual bacterial cell lineages using Bacillus subtilis as an example. The method overcomes shortcomings of traditional analytical methods in microbiology by allowing observation of hundreds of cell generations under tightly controllable and uniform growth conditions.

http://ift.tt/2rFwlDr

Contractility Measurements of Human Uterine Smooth Muscle to Aid Drug Development

This article describes experimental protocols to study ex vivo contractions of human myometrium and their application in drug discovery. This technique is used to improve the understanding of myometrial physiology and pathophysiology as well as to validate pharmacological data from novel research probes or drug leads.

http://ift.tt/2GmMqRR

Computed tomography and magnetic resonance imaging evaluation of pelvic lymph node metastasis in bladder cancer

Accurate evaluation of lymph node metastasis in bladder cancer (BCa) is important for disease staging, treatment selection, and prognosis prediction. In this study, we aimed to evaluate the diagnostic accuracy...

http://ift.tt/2nfVfVz

A Simple Planting Technique for Re-establishing Trees Where Frequent Inundation Occurs

This protocol describes a simple, cost-effective tree planting technique for restoring degraded Everglades tree islands that experience inundation. The design creates an island (pop-up) which floats initially and adds elevation to promote tree survival and growth under flooded conditions.

http://ift.tt/2DAmErn

Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark

We present an effective and reproducible method to isolate and culture neural progenitor cells from embryonic and postnatal brain tissue for chromatin immunoprecipitation (ChIP) of histone 3 lysine 79 dimethylation (H3K79me2) - a histone mark located within the globular domain of histone 3.

http://ift.tt/2EdYx2G

Delineation of two intracranial areas and the perpendicular intracranial width is sufficient for intracranial volume estimation

Abstract

Objectives

The aim of the present study is to determine if the delineation of one or two optimally chosen intracranial areas (ICA) is enough to achieve adequate estimates of intracranial volume (ICV) in magnetic resonance imaging.

Methods

The correlations of 62 fully delineated ICVs with four types of ICV estimates were calculated. The estimate types were: (1) a single midsagittal ICA, (2) single ICA multiplied by the intracranial width perpendicular to the ICA, (3) sum of two ICAs multiplied by the perpendicular intracranial width and (4) shape-preserving piecewise cubic interpolation using two ICAs. For methods 2–4, the fully delineated ICVs were randomly separated into an evaluation and a validation set of equal size. Method 1 was validated against all of the fully delineated ICVs.

Results

Estimates from method 1 had a Pearson correlation of 0.904 with fully delineated ICV. For method 2, the correlation was 0.986 when delineating the sagittal ICA at 31% of the sagittal intracranial width. For methods 3 and 4, the correlations were both 0.997 when delineating the sagittal ICAs at 17.5 and 64% and at 12 and 64% respectively.

Conclusions

Delineation of two specific intracranial areas is sufficient for intracranial volume estimation.

Main messages

• Delineation of two specific intracranial areas is sufficient for intracranial volume estimation.

• The estimates had a Pearson correlation of 0.997 with intracranial volume.

• The estimation should take no more than 5 min.

http://ift.tt/2DQAsRK

Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS

International Journal of Hematologic Oncology, Ahead of Print.


http://ift.tt/2DREdGL

Ultrasound Cyclo Plasty in Eyes with Glaucoma

Glaucoma is a chronic disease with progressive degeneration of optic nerve fibers resulting in decreased visual field. Elevated intraocular pressure is considered the most important and the only treatable risk factor. This manuscript describes a simple, surgeon-friendly, non-incisional technique, named Ultrasound Cyclo Plasty, for reducing intraocular pressure in glaucoma patients.

http://ift.tt/2nfcned

Thymoma-associated multiorgan autoimmunity with exclusive gastrointestinal tract involvement: case report and review of the literature

Abstract

Thymoma-associated multiorgan autoimmunity (TAMA) is a recently delineated and rare paraneoplastic syndrome reported in patients with thymoma. The disorder is characterized by graft-versus-host disease-like pathology affecting the skin, gastrointestinal tract (GIT), and liver, and is usually associated with a poor outcome. We document a case of TAMA with exclusive GIT involvement which included the stomach, small and large bowel, presenting in a 66-year-old male patient 5 years after complete resection of a type B2 thymoma. A brief review is provided of this scarce syndrome, the GIT pathology described in the 21 TAMA cases reported to date, and the unique characteristics of patients with exclusive GIT involvement by this acquired autoimmune disorder.

http://ift.tt/2rEYpa1

Man who was saved by EMT as a baby becomes first responder

By EMS1 Staff NEW YORK — A man who was saved by an EMT when he was born a premature baby reunited with him as he graduated from the EMS academy himself. NY Post reported that Joseph Bitetto reunited with EMT-turned NYPD detective Howard Blanck 22 years later as he walked across the stage during FDNY's EMS graduation. Bitetto's mom suffered a ruptured placenta in 1996 when she was just ...

http://ift.tt/2nfeCho

ELMO and Sponge specify subapical restriction of Canoe and formation of the subapical domain in early Drosophila embryos [RESEARCH ARTICLE]

Anja Schmidt, Zhiyi Lv, and Jörg Grosshans

Canoe/Afadin and the GTPase Rap1 specify the subapical domain during cellularization in Drosophila embryos. The timing of domain formation is unclear. The subapical domain might gradually mature or emerge synchronously with the basal and lateral domains. The potential mechanism for activation of Rap1 by guanyl nucleotide exchange factors (GEFs) or GTPase activating proteins (GAPs) is unknown. Here, we retraced the emergence of the subapical domain at the onset of cellularization by in vivo imaging with CanoeYFP in comparison to the lateral and basal markers ScribbledGFP and CherrySlam. CanoeYFP accumulates at a subapical position at about the same time as the lateral marker ScribbledGFP but a few minutes prior to basal CherrySlam. Furthermore, we show that the unconventional GEF complex ELMO-Sponge is subapically enriched and is required for subapical restriction of Canoe. The localization dynamics of ELMO-Sponge suggests a patterning mechanism for positioning the subapical region adjacent to the apical region. While marking the disc-like apical regions before cellularization, ELMO-Sponge redistributes to a ring-like pattern surrounding the apical region at the onset of cellularization.

http://ift.tt/2BvYHzs

Putting Canoe in place: a tale of two GEFs [RESEARCH HIGHLIGHT]

http://ift.tt/2ndnNPn

Rap1 acts via multiple mechanisms to position Canoe and adherens junctions and mediate apical-basal polarity establishment [RESEARCH ARTICLE]

Teresa T. Bonello, Kia Z. Perez-Vale, Kaelyn D. Sumigray, and Mark Peifer

Epithelial apical-basal polarity drives assembly and function of most animal tissues. Polarity initiation requires cell-cell adherens junction assembly at the apical-basolateral boundary. Defining the mechanisms underlying polarity establishment remains a key issue. Drosophila embryos provide an ideal model, as 6000 polarized cells assemble simultaneously. Current data place the actin-junctional linker Canoe (fly homolog of Afadin) at the top of the polarity hierarchy, where it directs Bazooka/Par3 and adherens junction positioning. Here we define mechanisms regulating Canoe localization/function. Spatial organization of Canoe is multifaceted, involving membrane localization, recruitment to nascent junctions and macromolecular assembly at tricellular junctions. Our data suggest apical activation of the small GTPase Rap1 regulates all three events, but support multiple modes of regulation. The Rap1GEF Dizzy (PDZ-GEF) is crucial for Canoe tricellular junction enrichment but not apical retention. The Rap1-interacting RA domains of Canoe mediate adherens junction and tricellular junction recruitment but are dispensable for membrane localization. Our data also support a role for Canoe multimerization. These multifactorial inputs shape Canoe localization, correct Bazooka and adherens junction positioning, and thus apical-basal polarity. We integrate the existing data into a new polarity establishment model.

http://ift.tt/2BxD1mU

Protein binders and their applications in developmental biology [PRIMER]

Stefan Harmansa and Markus Affolter

Developmental biology research would benefit greatly from tools that enable protein function to be regulated, both systematically and in a precise spatial and temporal manner, in vivo. In recent years, functionalized protein binders have emerged as versatile tools that can be used to target and manipulate proteins. Such protein binders can be based on various scaffolds, such as nanobodies, designed ankyrin repeat proteins (DARPins) and monobodies, and can be used to block or perturb protein function in living cells. In this Primer, we provide an overview of the protein binders that are currently available and highlight recent progress made in applying protein binder-based tools in developmental and synthetic biology.

http://ift.tt/2ndmr7j

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Abstract

Background

Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma.

Methods

To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction.

Results

Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin.

Conclusions

Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.

http://ift.tt/2nf5GIe

Is ERAS effective and safe in laparoscopic gastrectomy for gastric carcinoma? A meta-analysis

Abstract

Background

It is still unclear whether enhanced recovery after surgery is effective and safe in laparoscopic gastrectomy for gastric carcinoma.

Methods

Cochrane library databases, Medline, Embase, and Pubmed were searched from January 1, 1986, to December 31, 2016. Randomized controlled trials (RCTs) comparing fast-track recovery with conventional recovery strategies in laparoscopic radical gastrectomy for gastric carcinoma were included. The main outcomes measured were postoperative hospital stay, time to first flatus, hospital charge, and overall complication rate.

Results

Six RCTs with 400 patients were included in this study. Fast-track surgery has shorter postoperative hospital stays (weighted mean difference (WMD) − 2.65; 95% CI, − 4.01 to − 1.29, z = 3.82, P < 0.01) and less hospitalization expenditure (WMD − 523.43; 95% CI, − 799.79 to − 247.06, z = 3.71, P < 0.01) than conventional recovery strategies. There was no significant difference with respect to duration to first flatus (WMD − 17.72; 95% CI, − 39.46–4.02, z = 1.60, P = 0.11) and complication rate (OR 1.57; 95% CI, 0.82–2.98, z = 1.37, P = 0.17).

Conclusions

Enhanced recovery after surgery is effective and safe and is thus recommended in laparoscopic radical gastrectomy for gastric carcinoma.

http://ift.tt/2DNl7kZ

Renal sympathetic nerve activity after catheter-based renal denervation

Abstract

Background

Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal ¹²³I–meta-iodobenzylguanidine (¹²³I–mIBG) scintigraphy.

Methods

In 21 RHT patients (median age 60 years), we performed ¹²³I–mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after ¹²³I–mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented ¹²³I–mIBG uptake. Renal ¹²³I–mIBG washout was calculated between 15 min and 4 h.

Results

After RDN office-based systolic BP decreased from 172 to 153 mmHg (p = 0.036), while diastolic office BP (p = 0.531), mean 24 h systolic and diastolic BP (p = 0.602, p = 0.369, respectively), PRA (p = 0.409) and plasma catecholamines (p = 0.324) did not significantly change post-RDN. Following RDN, ¹²³I–mIBG renal uptake at 15 min was 3.47 (IQR 2.26–5.53) compared to 3.08 (IQR 2.79–4.95) before RDN (p = 0.289). Renal ¹²³I–mIBG washout did not change post-RDN (p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal ¹²³I–mIBG parameters.

Conclusions

No changes were observed in renal ¹²³I–mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy.

http://ift.tt/2naAFWI

Imaging of Spontaneous and Traumatic Cervical Artery Dissection

Abstract

Introduction

Cervical artery dissection (CAD) is an important etiology of ischemic stroke and early recognition is vital to protect patients from the major complication of cerebral embolization by administration of anticoagulants. The etiology of arterial dissections differ and can be either spontaneous or traumatic. Even though the historical gold standard is still catheter angiography, recent studies suggest a good performance of computed tomography angiography (CTA) for detection of CAD. We conducted this research to evaluate the variety and frequency of possible imaging signs of spontaneous and traumatic CAD and to guide neuroradiologists' decision making.

Methods

Retrospective review of the database of our multiple injured patients admitted to the Department of Trauma, Hand, and Reconstructive Surgery of the University Hospital Münster in Germany (a level 1 trauma center) for patients with traumatic CAD (tCAD) and of our stroke database (2008–2015) for patients with spontaneous CAD (sCAD) and CT/CTA on initial clinical work-up. All images were evaluated concerning specific and sensitive radiological features for dissection by two experienced neuroradiologists. Imaging features were compared between the two etiologies.

Results

This study included 145 patients (99 male, 46 female; 45 ± 18.8 years of age), consisting of 126 dissected arteries with a traumatic and 43 with spontaneous etiology. Intimal flaps were more frequently observed after traumatic etiology (58.1% tCADs, 6.9% sCADs; p < 0.001); additionally, multivessel dissections were much more frequent in trauma patients (3 sCADs, 21 tCADs) and only less than half (42%) of the patients with traumatic dissections showed cervical spine fractures.

Conclusion

Neuroradiologists should be aware that intimal flaps and multivessel dissections are more common after a traumatic etiology. In addition, it seems important to conduct a CTA in a trauma setting, even if no cervical spine fracture is detected.

http://ift.tt/2BwhsTp

Protein binders and their applications in developmental biology [PRIMER]

Stefan Harmansa and Markus Affolter

Developmental biology research would benefit greatly from tools that enable protein function to be regulated, both systematically and in a precise spatial and temporal manner, in vivo. In recent years, functionalized protein binders have emerged as versatile tools that can be used to target and manipulate proteins. Such protein binders can be based on various scaffolds, such as nanobodies, designed ankyrin repeat proteins (DARPins) and monobodies, and can be used to block or perturb protein function in living cells. In this Primer, we provide an overview of the protein binders that are currently available and highlight recent progress made in applying protein binder-based tools in developmental and synthetic biology.

http://ift.tt/2ndmr7j

Rap1 acts via multiple mechanisms to position Canoe and adherens junctions and mediate apical-basal polarity establishment [RESEARCH ARTICLE]

Teresa T. Bonello, Kia Z. Perez-Vale, Kaelyn D. Sumigray, and Mark Peifer

Epithelial apical-basal polarity drives assembly and function of most animal tissues. Polarity initiation requires cell-cell adherens junction assembly at the apical-basolateral boundary. Defining the mechanisms underlying polarity establishment remains a key issue. Drosophila embryos provide an ideal model, as 6000 polarized cells assemble simultaneously. Current data place the actin-junctional linker Canoe (fly homolog of Afadin) at the top of the polarity hierarchy, where it directs Bazooka/Par3 and adherens junction positioning. Here we define mechanisms regulating Canoe localization/function. Spatial organization of Canoe is multifaceted, involving membrane localization, recruitment to nascent junctions and macromolecular assembly at tricellular junctions. Our data suggest apical activation of the small GTPase Rap1 regulates all three events, but support multiple modes of regulation. The Rap1GEF Dizzy (PDZ-GEF) is crucial for Canoe tricellular junction enrichment but not apical retention. The Rap1-interacting RA domains of Canoe mediate adherens junction and tricellular junction recruitment but are dispensable for membrane localization. Our data also support a role for Canoe multimerization. These multifactorial inputs shape Canoe localization, correct Bazooka and adherens junction positioning, and thus apical-basal polarity. We integrate the existing data into a new polarity establishment model.

http://ift.tt/2BxD1mU

ELMO and Sponge specify subapical restriction of Canoe and formation of the subapical domain in early Drosophila embryos [RESEARCH ARTICLE]

Anja Schmidt, Zhiyi Lv, and Jörg Grosshans

Canoe/Afadin and the GTPase Rap1 specify the subapical domain during cellularization in Drosophila embryos. The timing of domain formation is unclear. The subapical domain might gradually mature or emerge synchronously with the basal and lateral domains. The potential mechanism for activation of Rap1 by guanyl nucleotide exchange factors (GEFs) or GTPase activating proteins (GAPs) is unknown. Here, we retraced the emergence of the subapical domain at the onset of cellularization by in vivo imaging with CanoeYFP in comparison to the lateral and basal markers ScribbledGFP and CherrySlam. CanoeYFP accumulates at a subapical position at about the same time as the lateral marker ScribbledGFP but a few minutes prior to basal CherrySlam. Furthermore, we show that the unconventional GEF complex ELMO-Sponge is subapically enriched and is required for subapical restriction of Canoe. The localization dynamics of ELMO-Sponge suggests a patterning mechanism for positioning the subapical region adjacent to the apical region. While marking the disc-like apical regions before cellularization, ELMO-Sponge redistributes to a ring-like pattern surrounding the apical region at the onset of cellularization.

http://ift.tt/2BvYHzs

Putting Canoe in place: a tale of two GEFs [RESEARCH HIGHLIGHT]

http://ift.tt/2ndnNPn

Study Identifies Potential Cause of Hearing Loss from Cisplatin

A new study has found the commonly used chemotherapy drug cisplatin is retained in the inner ear of mice and humans for long periods. The finding may explain why many patients treated with the drug develop hearing loss and could point toward potential ways to prevent it.

http://ift.tt/2Gl61ls

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation

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http://ift.tt/2ncwrhc

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway

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http://ift.tt/2BubAKD

EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

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http://ift.tt/2neu0KT

p53 expression and subcellular survivin localization improve the diagnosis and prognosis of patients with diffuse astrocytic tumors

Abstract

Purpose

Diffuse astrocytic tumors are the most frequently occurring primary central nervous system (CNS) tumors. Their histological sub-classification into diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GB) is challenging and the available prognostic factors are limited to age and tumor subtype. Biomarkers that may improve the histological sub-classification and/or serve as prognostic factors are, therefore, urgently needed. The relationship between survivin and p53 in diffuse astrocytic tumor progression and survival is currently unclear. Here, we aimed to assess the relevance of these proteins in the accuracy of the histological sub-classification of these tumors and their respective treatment responses.

Methods

One hundred and thirty-three formalin-fixed paraffin-embedded diffuse astrocytic tumor samples were included. The tumor samples were histologically reviewed and subsequently assessed for p53 and survivin expression and the presence of the IDH R132H mutation by immunohistochemistry. p53 expression levels and survivin subcellular localization patterns were correlated with histological classification and clinical outcome.

Results

We found that age and histological subtype were the only features with a prognostic impact. In addition, we found that high p53 expression levels and a nuclear survivin localization correlated with the AA subtype, whereas cytoplasmic survivin localization correlated with the GB subtype. We also found that patients carrying tumors with a high cytoplasmic survivin expression, a high nuclear survivin expression or a high p53 expression, and who did not receive radiotherapy, exhibited poorer short-term and long-term overall survival rates.

Conclusions

Our data suggest that subcellular survivin localization and p53 expression may be employed as valuable tools to improve the accuracy of the histological sub-classification of diffuse astrocytic tumors. Patients whose tumors overexpress these proteins may benefit from radiotherapy, irrespective age and/or histological classification.

http://ift.tt/2DEBNMy

miR-328 mediates a metabolic shift in colon cancer cells by targeting SLC2A1/GLUT1

Abstract

Purpose

Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells.

Methods

We performed in silico bioinformatic analyses to identify miR-328-mediated molecular pathways and targets. We also performed luciferase assays and western blot analyses in LOVO and SW480 colon cancer cell lines. In addition, we assessed miR-328 expression in 47 paired tumor and normal tissue specimens from resected colon cancer patients.

Results

Luciferase reporter assays showed that miR-328 directly targeted SLC2A1 3′-untranslated region (UTR), with a significant decrease in luciferase activity in both LOVO and SW480 cell lines. These results were validated by western blot. miR-328 expression was significantly downregulated in tumor tissue compared with paired normal tissue.

Conclusions

Our results show that miR-328 targets SLC2A1/GLUT1. We suggest that miR-328 may be involved in the orchestration of the Warburg effect in colon cancer cells. Furthermore, miR‐328 expression is reduced in colon cancer patients and thus inversely correlates with the classically reported upregulated SLC2A1/GLUT1 expression in tumors.

http://ift.tt/2DCxNYT

Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model

Background: Specific immunotherapy, including agonists for Toll-like receptor 2 (TLR2), have been shown to protect from allergies and to have a high immunomodulatory capacity. Methods: A new antibody, TSP-2, reactive against an epitope of the extracellular domain of TLR2, was identified. The effect of the antibody on dendritic cells was assessed by immunohistochemistry, Western blot, and flow cytometric analysis. The effect of TSP-2 in a murine asthma model induced with ovalbumin (OVA) was assessed. The model is a form of airway hyperresponsiveness (AHR) and was analyzed by whole-body plethysmography, the measurement of Th1/Th2 cytokines in bronchial alveolar lavage fluid (BALF) and serum by ELISA, and the CCK-8 assay for lymphocyte proliferation. The effect of TSP-2 on the maturation of bone marrow-derived dendritic cells (BMDCs) was assessed by flow cytometric analysis. Results: TSP-2 promoted the maturation of dendritic cells and the proliferation of lymphocyte in vitro and in vivo. The effect of TSP-2 on T helper 1 (Th1)/Th2 cytokine secretion was slightly more powerful than that of Pam₃CSK₄. TSP-2 antibody reduced AHR and OVA-specific IgE levels in allergic asthma. TSP-2 antibody also reduced lung inflammation and decreased leukocyte numbers in an OVA-sensitized and challenged asthma model. TSP-2 antibody increased OVA-stimulated I-A, CD80, CD86, and MHC-II levels on BMDCs. Conclusions: This study identifies a novel therapeutic strategy for AHR, which uses antibodies reactive against TLR2. It also provides theoretical evidence for the control of allergic asthma by targeting TLR2.
Int Arch Allergy Immunol

http://ift.tt/2BuFJJE

Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells

Background: Bombesin receptor subtype-3 (BRS-3) is a member of the bombesin-like peptide receptor family. Our previous studies demonstrated that activation of the human BRS-3 plays a protective role in oxidation-injured human bronchial epithelial cells (HBEC). The present study was designed to determine the role of BRS-3 activation in the antigen-presenting action of HBEC and the corresponding proliferation and differentiation of T cells. Materials and Methods: In vivo, an asthma animal model was established and the expression and distribution of BRS-3 were analyzed by immunocytochemistry. In vitro, 2 kinds of B7 costimulatory molecules, i.e., B7H1 and B7DC, on HBEC were analyzed by flow cytometry. The antigen uptake by HBEC was examined by confocal microscopy and flow cytometry. The antigen-presenting-action-induced proliferation of T cells was determined by MTT assays. IFN-#x03B3; and IL-4 levels were measured by ELISA. All studies were performed in the absence or presence of the synthetic peptide P3513. Results: BRS-3 expression was induced in asthma animal models and mainly distributed in bronchial epithelial cells. HBEC express the costimulatory molecules B7H1 and B7DC. BRS-3 activation increased B7H1 expression but decreased B7DC expression on HBEC. BRS-3 activation also increased the antigen uptake by HBEC and the subsequent T cell proliferation. In addition, BRS-3 activation promoted the releases of IFN-#x03B3;, but not IL-4, in the supernatant of cocultured HBEC and T cells. Conclusion: These data suggest that HBEC can present antigen to T cells and BRS-3 activation promotes the process of antigen presentation and subsequent T cell proliferation and Th1 differentiation.
Int Arch Allergy Immunol

http://ift.tt/2neCIJ6

Sexual Orientation and Leadership Suitability: How Being a Gay Man Affects Perceptions of Fit in Gender-Stereotyped Positions

Abstract

The current set of studies examines perceptions of gay men's fitness for leadership positions in the workplace. In two between-subjects experiments we examined the effect of a male employee's sexuality on perceptions of his suitability for stereotypically feminine, masculine, and gender-neutral managerial positions, as well as potential mediators (perceptions of target agency and communion) and moderators (target out status) of these effects. In Study 1, 341 U.S. college student participants rated a gay male target as more communal and more suitable for feminine managerial positions than an otherwise identical heterosexual target, irrespective of his "out" status. Moreover, ratings of communion mediated the relationship between targets' sexuality and suitability for feminine leadership. No differences between gay and heterosexual targets in targets' agency or targets' suitability for masculine or gender-neutral managerial positions were detected. Study 2 used a sample of 439 U.S. adults and an ambiguous target's résumé to replicate and expand Study 1. This study provided participants with conflicting information on targets' agency and communion, and it assessed the same dependent variables of targets' agency, communion, and leadership suitability for various positions. Study 2 again found that ratings of communion significantly mediated the relationship between male targets' sexuality and perceived suitability for feminine managerial roles. These findings extend previous research on perceptions of gay men in the workplace and have practical implications for being "out" at work.

http://ift.tt/2DRAE3e

Prevalence and antimicrobial susceptibility pattern of Salmonella and Shigella species among asymptomatic food handlers working in Haramaya University cafeterias, Eastern Ethiopia

Salmonellosis and Shigellosis remain a major public health problem across the globe, particularly in developing countries like Ethiopia, where hand hygiene and food microbiology are still below the required st...

http://ift.tt/2GiUDWV

Trait self-awareness predicts perceptions of choice meaningfulness in a decision-making task

Seminal theorists such as Erikson, Bruner, Frankl and Rogers have underscored the importance of meaning in psychological life. However contemporary scholars interested in meaning have noted that further invest...

http://ift.tt/2rFo9D0

Breast implant-associated anaplastic large cell lymphoma in a Li-FRAUMENI patient: a case report

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare malignancy, recently recognized as a provisional entity by the World Health Organization. Although increasing data have been publis...

http://ift.tt/2DMX31F

Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2DD9Znp

Extracellular Vesicles As miRNA Nano-Shuttles: Dual Role in Tumor Progression

Abstract

Tumor-derived extracellular vesicles (EVs) have a pleiotropic role in cancer, interacting with target cells of the tumor microenvironment, such as fibroblasts, immune and endothelial cells. EVs can modulate tumor progression, angiogenic switch, metastasis, and immune escape. These vesicles are nano-shuttles containing a wide spectrum of miRNAs that contribute to tumor progression. MiRNAs contained in extracellular vesicles (EV-miRNAs) are disseminated in the extracellular space and are able to influence the expression of target genes with either tumor suppressor or oncogenic functions, depending on both parental and target cells. Metastatic cancer cells can balance their oncogenic potential by expressing miRNAs with oncogenic function, whilst exporting miRNAs with tumor suppressor roles out of the cells. Importantly, treatment of cancer cells with specific natural and chemical compounds could induce the elimination of miRNAs with oncogenic function, thereby reducing their aggressiveness. In this review, we discuss the mechanisms by which EV-miRNAs, acting as miRNAs with oncogenic or tumor suppressor functions, could contribute to cancer progression.

http://ift.tt/2DIUGO4

Establishing a Safe Administration of ASA in Cardiovascular Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity with Skin and/or Respiratory Involvement

Background: A history of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with cross-intolerance to several drugs is common in some patients with coronary artery disease. We present a series of patients with acute coronary syndrome undergoing ASA desensitization prior to a possible stent to evaluate the short- and long-term efficacy and safety. The aim was to evaluate the outcomes of an ASA desensitization protocol developed by our center based on the guidelines proposed by the EAACI drug allergy expert recommendations. Methods: We developed a desensitization protocol that was based on both the patient characteristics and onset of reaction after NSAIDs, including premedication with a leukotriene antagonist and the H1-antagonist antihistamine. The clinical entities were NSAID-induced urticaria and/or angioedema in the absence of chronic spontaneous urticaria (NIUA) and NSAID-exacerbated respiratory disease (NERD). Results: A total of 23 patients were challenged or desensitized with ASA: 19 NIUA and 4 NERD. All patients tolerated the protocol at the different times of 30, 45, 90, and 120 min. The dosages of oral ASA that were given included 10, 21, 41, 81, and 162 mg (cumulative dose 315 mg). One patient reacted during the procedure and 1 during follow-up. Symptoms were limited to the skin without manifestations in other organs. All patients tolerated the required dose of ASA within 30–120 min. Those requiring urgent catheterization were desensitized within 90 min. Conclusions: Our protocol addresses challenge or desensitization with the contribution of a specialist allergist. It provides an effective, dynamic, safe, and short administration of 81 mg or higher of ASA in patients with a history of NSAID hypersensitivity with skin involvement.
Int Arch Allergy Immunol

http://ift.tt/2Gltoer

Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients' quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease.
Int Arch Allergy Immunol

http://ift.tt/2rErx1d

Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2DD9Znp

Sepsis-Associated Coagulopathy Severity Predicts Hospital Mortality

Objectives: To assess whether sepsis-associated coagulopathy predicts hospital mortality. Design: Retrospective cohort study. Setting: One-thousand three-hundred beds urban academic medical center. Patients: Six-thousand one-hundred forty-eight consecutive patients hospitalized between January 1, 2010, and December 31, 2015. Interventions: Mild sepsis-associated coagulopathy was defined as an international normalized ratio greater than or equal to 1.2 and less than 1.4 plus platelet count less than or equal to 150,000/µL but greater than 100,000/µL; moderate sepsis-associated coagulopathy was defined with either an international normalized ratio greater than or equal to 1.4 but less than 1.6 or platelets less than or equal to 100,000/µL but greater than 80,000/µL; severe sepsis-associated coagulopathy was defined as an international normalized ratio greater than or equal to 1.6 and platelets less than or equal to 80,000/µL. Measurements and Main Results: Hospital mortality increased progressively from 25.4% in patients without sepsis-associated coagulopathy to 56.1% in patients with severe sepsis-associated coagulopathy. Similarly, duration of hospitalization and ICU care increased progressively as sepsis-associated coagulopathy severity increased. Multivariable analyses showed that the presence of sepsis-associated coagulopathy, as well as sepsis-associated coagulopathy severity, was independently associated with hospital mortality regardless of adjustments made for baseline patient characteristics, hospitalization variables, and the sepsis-associated coagulopathy-cancer interaction. Odds ratios ranged from 1.33 to 2.14 for the presence of sepsis-associated coagulopathy and from 1.18 to 1.51 for sepsis-associated coagulopathy severity for predicting hospital mortality (p

http://ift.tt/2rKnWPg