RET/ PTC Gene Rearrangements in Thyroid Carcinogenesis: Assessment and Clinico-Pathological Correlations

Abstract

Rearranged during transfection (RET) is a proto oncogene implicated in thyroid carcinogenesis of papillary type (PTC). The RET proto-oncogene in PTC is constitutively activated by fusion of its tyrosine kinase domain with the 5 ´region of another gene thereby generating chimeric products collectively named RET/PTCs. RET/PTC1 and RET/PTC3 are best characterized among all RET/PTC rearrangements. Kashmir valley has witnessed an alarming increase in thyroid cancer incidence in young women. Therefore, we investigated the occurrence of RET/PTC 1 & 3 rearrangements by semi quantitative and qPCR in thyroid cancer patients (n = 48) of Kashmiri population and interrelated results with various clinicopathological characteristics. We observed that all the RET/PTC rearrangements were confined to PTC cases (10/40). Presence of RET/PTC rearrangement significantly correlated with gender, elevated TSH levels and lymph node metastasis. Overall, our study advocates that RET/PTC3 rearrangement is a frequent event in the carcinogenesis of thyroid gland in Kashmiri population although a study with a larger sample size is needed to get a clear scenario.

https://ift.tt/2PMczBC

Failed Early Intervention of Pyomyositis in an Immunocompetent Individual

Pyomyositis is a purulent infection of striated muscle tissue that usually leads to an abscess, commonly due to S. aureus. Pyomyositis is typically found in tropic regions, but it is increasingly being recognized in temperate climates, especially in immunocompromised individuals. Patient presentation ranges from afebrile with mildly elevated WBC to frank sepsis. In many reported cases, patients may develop multiple abscesses at different sites. We report a case of a 54-year-old male with a history of chronic obstructive pulmonary disease (COPD) presenting with right pectoral infection. This case demonstrates the possibility that antibiotic therapy in early presentations may not effectively prevent abscess formation, contrary to treatment suggestions found in the literature.

https://ift.tt/2FAR4PM

FDA Updates on Angiotensin II Receptor Blocker (ARB) Recalls

Audience: Consumer, Health Professional, Pharmacy Investigation ongoing – This page to be updated as more information is available FDA alerts patients and health care professionals to Mylan's recall of valsartan products due to NDEAUpdate...

https://ift.tt/2zhqt4A

Association and Interaction Analysis of Body Mass Index and Triglycerides Level with Blood Pressure in Elderly Individuals in China

Objectives. To assess the extent of interaction between body mass index (BMI) and triglyceride (TG) level and its effects on blood pressure (BP) in elderly individuals in China. Design. Cross-sectional study. Setting. Data were taken from a cross-sectional study called the China Health and Retirement Longitudinal Study. Participants. The analytic sample included 3629 subjects aged 45 to 96 years. Main Outcome Measurements. Data were obtained from the China Health and Retirement Longitudinal Study, which is a cross-sectional study. Age-adjusted partial Pearson's correlation test was used to compare various characteristics and BP. Adjusted associations were first used as linear regression models, as appropriate. Then, general linear models adjusted for related potential confounders were used to examine the synergistic effects of BMI and TG level on BP. Finally, a binary logistic regression model adjusted for confounding factors was used to examine the association between BMI or TG level and hypertension. Results. Age-adjusted partial Pearson's correlation coefficient showed that the TG level was positively correlated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in both men and women with BMI

https://ift.tt/2zv5N9B

FDA Updates on Angiotensin II Receptor Blocker (ARB) Recalls

Audience: Consumer, Health Professional, Pharmacy Investigation ongoing – This page to be updated as more information is available FDA alerts patients and health care professionals to Mylan's recall of valsartan products due to NDEAUpdate...

https://ift.tt/2zhqt4A

Dynamic prediction of childhood high blood pressure in a population-based birth cohort: a model development study

Objectives

To develop a dynamic prediction model for high blood pressure at the age of 9–10 years that could be applied at any age between birth and the age of 6 years in community-based child healthcare.

Design, setting and participants

Data were used from 5359 children in a population-based prospective cohort study in Rotterdam, the Netherlands.

Outcome measure

High blood pressure was defined as systolic and/or diastolic blood pressure ≥95th percentile for gender, age and height. Using multivariable pooled logistic regression, the predictive value of characteristics at birth, and of longitudinal information on the body mass index (BMI) of the child until the age of 6 years, was assessed. Internal validation was performed using bootstrapping.

Results

227 children (4.2%) had high blood pressure at the age of 9–10 years. Final predictors were maternal hypertensive disease during pregnancy, maternal educational level, maternal prepregnancy BMI, child ethnicity, birth weight SD score (SDS) and the most recent BMI SDS. After internal validation, the area under the receiver operating characteristic curve ranged from 0.65 (prediction at age 3 years) to 0.73 (prediction at age 5–6 years).

Conclusions

This prediction model may help to monitor the risk of developing high blood pressure in childhood which may allow for early targeted primordial prevention of cardiovascular disease.

https://ift.tt/2FyFGUk

Reliability and accuracy of delirium assessments among investigators at multiple international centres

Introduction

Delirium is a common, serious postoperative complication. For clinical studies to generate valid findings, delirium assessments must be standardised and administered accurately by independent researchers. The Confusion Assessment Method (CAM) is a widely used delirium assessment tool. The objective was to determine whether implementing a standardised CAM training protocol for researchers at multiple international sites yields reliable inter-rater assessment and accurate delirium diagnosis.

Methods

Patients consented to video recordings of CAM delirium assessments for research purposes. Raters underwent structured training in CAM administration. Training entailed didactic education, role-playing with intensive feedback, apprenticeship with experienced researchers and group discussions of complex cases. Raters independently viewed and scored nine video-recorded CAM interviews. Inter-rater reliability was determined using Fleiss kappa. Accuracy was judged by comparing raters' scores with those of an expert delirium researcher.

Results

Twenty-seven raters from eight international research centres completed the study and achieved almost perfect agreement for overall delirium diagnosis, kappa=0.88 (95% CI 0.85 to 0.92). Agreement of the four core CAM features ranged from fair to substantial. The sensitivity and specificity for identifying delirium were 72% (95% CI 60% to 81%) and 99% (95% CI 96% to 100%), considering an expert rater's scores as the reference standard (delirious, n=3; non-delirious, n=6). Delirium severity ratings were tightly clustered, with most scores within 5% of the median.

Conclusion

Our results demonstrate that, with appropriate training and ongoing scoring discussions, researchers at multiple sites can reliably detect delirium in postsurgical patients. These results support the premise that methodologically rigorous multi-centre studies can yield standardised and accurate determinations of delirium.

https://ift.tt/2qYJYKE

Use of multiple antidiabetic medications in patients with diabetes and its association with hypoglycaemic events: a case-crossover study in Jordan

Objective

To assess whether the use of multiple antidiabetic medications is associated with an increased risk of hypoglycaemia in patients with type 2 diabetes mellitus.

Design

A case-crossover study.

Setting

Cases were enrolled from the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan.

Participants

Patients were those with diabetes mellitus and reported incident of a hypoglycaemic event in their medical records during the period January 2007 to July 2017. Patients with multiple antidiabetic medications were those with at least two antidiabetic medications.

Primary outcome

History of antidiabetic medication use was extracted from the pharmacy records. The use of multiple antidiabetic medications during the risk window (before hypoglycaemia) was compared with a control window(s) (earlier time) of the same length after a washout period. Conditional logistic regression was applied to evaluate the OR of hypoglycaemia between the treatment groups. A secondary analysis was performed in patients with a blood glucose measurement of ≤70 mg/dL.

Results

182 patients (106 females, 58.2%) were included in the study with an average age of 59.9 years (SD=9.9). The patients' average body mass index was 31.7 kg/m² (SD=6.2). Compared with monotherapy, the OR of hypoglycaemic events for patients with multiple antidiabetic medications was 5.00 (95% CI 1.10 to 22.82). The OR was 6.00 (95% CI 0.72 to 49.84) for the secondary analysis patient group (n=94). Ten-fold increased risk was found in patients (n=155) with insulin and sulfonylurea-based combination therapy (OR 10.00;95% CI 1.28 to 78.12).

Conclusion

This study shows that the use of multiple antidiabetic medications appears to increase the risk of hypoglycaemic events. Patients and healthcare professionals should be extra vigilant when patients are on multiple antidiabetic medications therapy, especially the combination of sulfonylurea and insulin.

https://ift.tt/2FD6S4t

Fathers roles and perspectives on healthcare seeking for children with pneumonia: findings of a qualitative study in a rural community of the Philippines

Objectives

Pneumonia remains a primary cause of death for under-five children. It is possible to reduce the mortality impact from childhood pneumonia if caregivers recognise the danger signs of pneumonia and obtain appropriate healthcare. Among caregivers, research on fathers' healthcare-seeking behaviours and perceptions are limited, whereas research on mothers is available. This study aims to reveal fathers' roles and perspectives with respect to the selection of care and treatment for children with pneumonia in a remote island of the Philippines.

Design

A qualitative research was carried out using semistructured interviews.

Setting and participants

The interviews were conducted with 12 fathers whose children had pneumonia-like episodes in the 6 months prior to the interview. Data analysis was performed using the concept analysis method to identify codes which were merged into subcategories and categories. Finally, the themes were identified.

Results

Three themes were identified as part of fathers' roles, and two were identified as fathers' perspectives on various treatment options. Fathers took care of their sick children by not entrusting care only to mothers because they considered this as part of their role. Notably, fathers considered that arranging money for the child's treatment was a matter of prime importance. They selected a particular treatment based on their experiences and beliefs, including herbal medicine, home treatment, and visiting traditional healers and health facilities. Their decision was influenced by not only their perception of the severity of illness but also cultural beliefs on the cause of illness. Visiting health facilities, particularly during hospital admissions, causes significant financial burden for the family which was the main concern of fathers.

Conclusion

It is crucial to consider the cultural background and also imperative to address issues related to medical cost and the credibility of health facilities to improve fathers' healthcare-seeking behaviour.

https://ift.tt/2qY8A6b

Protocol for a phase II, open-label exploratory study investigating the efficacy of fesoterodine for treatment of adult patients with spinal cord injury suffering from neurogenic detrusor overactivity for amelioration of autonomic dysreflexia

Introduction

Managing and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals. However, individuals with spinal cord injury (SCI) at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from neurogenic detrusor overactivity (NDO). Treatment of NDO would not only improve lower urinary tract function but could also reduce the severity and frequency of life-threatening episodes of AD. Fesoterodine, an antimuscarinic drug, has been successfully employed as a first-line treatment for detrusor overactivity in individuals without an underlying neurological disorder. Thus, our aim is to investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI.

Methods and analysis

This phase II, open-label exploratory, non-blinded, non-randomised, single-centre study will investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6. During screening, we will interview potential candidates (with a previous history of NDO and AD) and assess their injury severity. At baseline, we will perform cardiovascular and cerebrovascular monitoring (blood pressure (BP), heart rate and cerebral blood flow velocity) during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to assess severity and frequency of AD episodes (ie, maximum increase in systolic BP). The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy. To answer this, we will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, ie, three cycles of 4 weeks each). At the end of each treatment cycle, participants will be asked to answer standardised questionnaires (AD symptoms and quality of life) and present bladder and bowel diaries, which will provide additional subjective information.

Ethics and dissemination

The University of British Columbia Research Ethics Boards (H15-02364), Vancouver Coastal Health Research Institute (V15-02364) and Health Canada (205857) approved this study. The findings of the study will be published in peer-reviewed journals and presented at national and international scientific meetings. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials and CONsolidated Standards Of Reporting Trials statements.

Trial registration number

NCT02676154; Pre-results.

https://ift.tt/2FAV56Q

Rehabilitation via HOMe Based gaming exercise for the Upper-limb post Stroke (RHOMBUS): protocol of an intervention feasibility trial

Introduction

Effective interventions to promote upper-limb recovery poststroke are characterised by intensive and repetitive movements. However, the repetitive nature of practice may adversely impact on adherence. Therefore, the development of rehabilitation devices that can be used safely and easily at home, and are motivating, enjoyable and affordable is essential to the health and well-being of stroke survivors.

The Neurofenix platform is a non-immersive virtual reality device for poststroke upper-limb rehabilitation. The platform uses a hand controller (a NeuroBall) or arm bands (NeuroBands) that facilitate upper-limb exercise via games displayed on a tablet. The Rehabilitation via HOMe Based gaming exercise for the Upper-limb post Stroke trial aims to determine the safety, feasibility and acceptability of the Neurofenix platform for home-based rehabilitation of the upper-limb poststroke.

Methods and analysis

Thirty people poststroke will be provided with a Neurofenix platform, consisting of a NeuroBall or NeuroBands (dependent on impairment level), seven specially designed games, a tablet and handbook to independently exercise their upper limb for 7 weeks. Training commences with a home visit from a research therapist to teach the participant how to safely use the device. Outcomes assessed at baseline and 8 weeks and 12 weeks are gross level of disability, pain, objectively measured arm function and impairment, self-reported arm function, passive range of movement, spasticity, fatigue, participation, quality of life (QOL) and health service use. A parallel process evaluation will assess feasibility, acceptability and safety of the intervention through assessment of fidelity to the intervention measured objectively through the Neurofenix platform, a postintervention questionnaire and semistructured interviews exploring participants' experiences of the intervention. The feasibility of conducting an economic evaluation will be determined by collecting data on QOL and resource use.

Ethics and dissemination

Ethics approval granted from Brunel University London (10249-MHR-Mar/2018-12322-2). Trial results will be submitted for publication in journals, presented at national and international conferences and distributed to people with stroke.

Trial registration number

ISRCTN60291412; Pre-results.

https://ift.tt/2r7yeG1

Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review

Purpose

To evaluate persistence and adherence of oral pharmacotherapy used in the treatment of overactive bladder (OAB) in a real-world setting.

Materials and methods

Systematic literature searches of six electronic publication databases were performed to identify observational studies of patients with OAB treated with antimuscarinics and/or mirabegron. Studies obtaining persistence and adherence data from sources other than electronic prescription claims were excluded. Reference lists of identified studies and relevant systematic reviews were assessed to identify additional relevant studies.

Results

The search identified 3897 studies, of which 30 were included. Overall, persistence ranged from 5% to 47%. In studies reporting data for antimuscarinics and mirabegron (n=3), 1-year persistence was 12%–25% and 32%–38%, respectively. Median time to discontinuation was <5 months for antimuscarinics (except one study (6.5 months)) and 5.6–7.4 months for mirabegron. The proportion of patients adherent at 1 year varied between 15% and 44%. In studies reporting adherence for antimuscarinics and mirabegron, adherence was higher with mirabegron (mean medication possession ratio (MPR): 0.59 vs 0.41–0.53; mean proportion of days covered: 0.66 vs 0.55; and median MPR: 0.65 vs 0.19–0.49). Reported determinants of persistence and adherence included female (sex), older age group, use of extended-release formulation and treatment experience.

Conclusion

Most patients with OAB discontinued oral OAB pharmacotherapy and were non-adherent 1 year after treatment initiation. In general, mirabegron was associated with greater persistence and adherence compared with antimuscarinics. Combined with existing clinical trial evidence, this real-world review merits consideration of mirabegron for first-line pharmacological treatment among patients with OAB.

PROSPERO registration number

CRD42017059894.

https://ift.tt/2FCrkCJ

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer

Future Oncology, Ahead of Print.


https://ift.tt/2R89hFO

PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28–8 and E1L3N)

Immunohistochemistry (IHC) for programmed cell death ligand 1 (PD-L1) displays staining diversity. We compared IHC staining of PD-L1 in gastric cancer (GC) by using three commercially available antibody clones...

https://ift.tt/2OZb7qF

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27⁺ B cells from CVID patients

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27⁺ B cells from CVID patients, Published online: 21 November 2018; doi:10.1038/s41419-018-1191-8

IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27⁺ B cells from CVID patients

https://ift.tt/2TwnGNk

miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2

miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2

miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2, Published online: 21 November 2018; doi:10.1038/s41419-018-1182-9

miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2

https://ift.tt/2A9DKMg

LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer

LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer

LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer, Published online: 21 November 2018; doi:10.1038/s41419-018-1170-0

LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer

https://ift.tt/2Tz24jp

Mylan Initiates Voluntary Nationwide Recall of 15 Lots of Valsartan Tablets, USP, Amlodipine and Valsartan Tablets, USP, and Valsartan and Hydrochlorothiazide Tablets, USP, Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient

Audience: Consumer, Health Professional, Pharmacy Mylan N.V. (NASDAQ: MYL) today announced that its U.S. based Mylan Pharmaceuticals business is conducting a voluntary nationwide recall to the consumer level of select lots of Valsartan-containing...

https://ift.tt/2FBIwYL

Mylan Initiates Voluntary Nationwide Recall of 15 Lots of Valsartan Tablets, USP, Amlodipine and Valsartan Tablets, USP, and Valsartan and Hydrochlorothiazide Tablets, USP, Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient

Audience: Consumer, Health Professional, Pharmacy Mylan N.V. (NASDAQ: MYL) today announced that its U.S. based Mylan Pharmaceuticals business is conducting a voluntary nationwide recall to the consumer level of select lots of Valsartan-containing...

https://ift.tt/2FBIwYL

The Inclusion of Spillover Effects in Economic Evaluation: A Public Health Economics Perspective

https://ift.tt/2BotYaW

Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal

Abstract

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba^®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

https://ift.tt/2KnjTOh

Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal

The title of the article should read:

https://ift.tt/2BoXP2S

Radiotherapy May Sensitize to CTLA4 Blockade in Patients with NSCLC [Research Watch]

When combined with ipilimumab, radiotherapy may induce an abscopal response in metastatic NSCLC.

https://ift.tt/2Aec4FQ

Osteogenic Cells Supply Calcium to Tumor Cells to Enhance Bone Metastasis [Research Watch]

Calcium signaling and mTOR signaling drive bone metastasis progression.

https://ift.tt/2TymXLO

Targeting BCMA Achieves Deep and Durable Responses in Multiple Myeloma [Research Watch]

Targeting BCMA with the antibody–drug conjugate GSK2857916 is well tolerated in a phase I trial.

https://ift.tt/2Ah2a6q

PD-L1 Inhibitor Improves Survival in TNBC [News in Brief]

For subgroup of patients with metastatic triple-negative breast cancer, atezolizumab could become treatment of choice.

https://ift.tt/2TyFEPd

Anti-CD47 Agent Boosts Macrophage Activity in NHL [News in Brief]

In some non-Hodgkin lymphomas, Hu5F9-G4 plus rituximab yields high overall response rate, few side effects.

https://ift.tt/2Ah2br0

The Metabolite BH4 Drives T-cell Growth in Autoimmunity and Cancer [Research Watch]

BH4, which is involved in the production of neurotransmitters and NO, promotes mature T-cell growth.

https://ift.tt/2Tz4dvJ

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer [Research Briefs]

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase 2 study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with co-amplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET co-amplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intra- and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer.

https://ift.tt/2A8qzLw

First CAR to Pass the Road Test: Tisagenlecleucel's Drive to FDA Approval

In August 2017, the U.S. Food and Drug Administration (FDA) took historic action in granting the first approval of gene therapy to tisagenlecleucel. This landmark step brought CAR T-cell therapy to the commercial space and heralded a new era in managing refractory B-cell malignancies and FDA oversight of gene-modified therapies.

https://ift.tt/2FAzbk6

Biological Consequences of Major Histocompatibility Class-II Expression by Tumor Cells in Cancer

Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of anti-tumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through Major Histocompatibility Complexes (MHCs). Though tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen presenting complex traditionally associated with professional antigen presenting cells (APCs). MHC-II is critical for antigen presentation to CD4+ T-lymphocytes, whose role in anti-tumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.

https://ift.tt/2qYAz5K

Cancer associated fibroblasts-promoted LncRNA DNM3OS confers radioresistance by regulating DNA damage response in esophageal squamous cell carcinoma

Purpose: Our study aimed to investigate whether CAFs (cancer associated fibroblasts) were involved in lncRNAs regulated radioresponse in ESCC Experimental Design: By use of lncRNAs PCR array, 38 lncRNAs were screened in esophageal cancer cells and in normal esophageal epithelial cells Het-1A. LncRNA DNM3OS was detected in tumor tissues of ESCC patients and in matched normal esophageal epithelial tissues by qRT-PCR analysis and in situ hybridization assay. The association of DNM3OS and tumor radioresistance was investigated in vitro and in vivo. The influences of DNM3OS on DNA damage response was investigated by western blotting, immunofluorescence imaging and comet assay. The mechanisms by which CAFs promoted DNM3OS expression was investigated by kinase inhibitors screening, luciferase assay and chromatin immunoprecipitation. Results:Among the 38 lncRNAs tested, DNM3OS was found to have a much higher expression level in esophageal cancer cells than in Het-1A. In tumor tissues of 16 ESCC patients, the expression level of DNM3OS showed an average increase of 6.3429-fold compared with that in matched normal tissues. DNM3OS conferred significant radioresistance in vitro and in vivo by regulating DNA damage response. CAFs promoted the expression of DNM3OS with a 39.2554-fold and 38.3163-fold increase in KYSE-30 and KYSE-140, respectively. CAFs promoted the expression of DNM3OS in a PDGFb/PDGFRb/FOXO1 signaling pathway-dependent manner. FOXO1, a transcription factor downstream of PDGFb/PDGFRb signaling pathway initiated the transcription of DNM3OS by binding to DNM3OS promoter. Conclusions: Our study highlighted CAFs-promoted DNM3OS as an attractive target to reverse tumor radioresistance in ESCC.

https://ift.tt/2FzCdF3

Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase

The low investment in research, diagnosis and treatment are factors that contribute to the continuity of Chagas' disease as a neglected tropical diseases (NTDs). In this context, the repositioning of drugs rep...

https://ift.tt/2Q8eG2j

Mismatch between student and tutor evaluation of training needs: a study of traumatology rotations

An e-portfolio was used to determine the optimal number of times students need to repeat a procedure before they are fully capable of performing it without supervision. The results were compared with the actua...

https://ift.tt/2DDdtcp

Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe

The Kinesin-5 motor Cut7 in Schizosaccharomyces pombe plays essential roles in spindle pole separation, leading to the assembly of bipolar spindle. In many organisms, simultaneous inactivation of Kinesin-14s neutralizes Kinesin-5 deficiency. To uncover the molecular network that counteracts Kinesin-5, we have conducted a genetic screening for suppressors that rescue the cut7-22 temperature sensitive mutation, and identified 10 loci. Next generation sequencing analysis reveals that causative mutations are mapped in genes encoding α-, β-tubulins and the microtubule plus-end tracking protein Mal3/EB1, in addition to the components of the Pkl1/Kinesin-14 complex. Moreover, the deletion of various genes required for microtubule nucleation/polymerization also suppresses the cut7 mutant. Intriguingly, Klp2/Kinesin-14 levels on the spindles are significantly increased in cut7 mutants, whereas these increases are negated by suppressors, which may explain the suppression by these mutations/deletions. Consistent with this notion, mild overproduction of Klp2 in these double mutant cells confers temperature sensitivity. Surprisingly, treatment with a microtubule-destabilizing drug not only suppresses cut7 temperature sensitivity but also rescues the lethality resulting from the deletion of cut7, though a single klp2 deletion per se cannot compensate for the loss of Cut7. We propose that microtubule assembly and/or dynamics antagonize Cut7 functions, and that the orchestration between these two factors is crucial for bipolar spindle assembly.

https://ift.tt/2Brtxg9

Perturbations of Transcription and Gene Expression-Associated Processes Alter Distribution of Cell Size Values in Saccharomyces cerevisiae

The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild type Saccharomyces cerevisiae cells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains in Saccharomyces cerevisiae. We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population.

https://ift.tt/2Ko7Ss3

New Drosophila Long-Term Memory Genes Revealed by Assessing Computational Function Prediction Methods

A major bottleneck to our understanding of the genetic and molecular foundation of life lies in the ability to assign function to a gene and, subsequently, a protein. Traditional molecular and genetic experiments can provide the most reliable forms of identification, but are generally low-throughput, making such discovery and assignment a daunting task. The bottleneck has led to an increasing role for computational approaches. The Critical Assessment of Functional Annotation (CAFA) effort seeks to measure the performance of computational methods. In CAFA3, we performed selected screens, including an effort focused on long-term memory. We used homology and previous CAFA predictions to identify 29 key Drosophila genes, which we tested via a long-term memory screen. We identify 11 novel genes that are involved in long-term memory formation and show a high level of connectivity with previously identified learning and memory genes. Our study provides first higher-order behavioral assay and organism screen used for CAFA assessments and revealed previously uncharacterized roles of multiple genes as possible regulators of neuronal plasticity at the boundary of information acquisition and memory formation.

https://ift.tt/2BpeG5V

A randomized trial to assess retention rates using mobile phone reminders versus physical contact tracing in a potential HIV vaccine efficacy population of fishing communities around Lake Victoria, Uganda

High retention (follow-up) rates improve the validity and statistical power of outcomes in longitudinal studies and the effectiveness of programs with prolonged administration of interventions. We assessed par...

https://ift.tt/2FCbbNs

Investigation of a Carbapenemase-producing Acinetobacter baumannii outbreak using whole genome sequencing versus a standard epidemiologic investigation

The standard epidemiologic investigation of outbreaks typically relies on spatiotemporal data and pulsed-field gel electrophoresis (PFGE), but whole genome sequencing (WGS) is becoming increasingly used. This ...

https://ift.tt/2r0wwGg

Nudge to better care - blood cultures and catheter-related bloodstream infections in Germany at two points in time (2006, 2015)

Blood cultures (BCs) are the gold standard for diagnosing sepsis and are prerequisite for a targeted antibiotic treatment and essential for patient outcomes. Aim of the study was to analyze the frequency of BC...

https://ift.tt/2FK73uG

In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase–producing Klebsiella pneumoniae

In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infe...

https://ift.tt/2r14f2i

FDA Approves Drug to Treat Rare Immune Disease

WEDNESDAY, Nov. 21, 2018 -- The U.S. Food and Drug Administration on Monday approved Gamifant (emapalumab-lzsg) for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) in pediatric (as young as newborn) and adult patients who have...

https://ift.tt/2zpceuB

FDA Warns Two Companies About Bogus Opioid Addiction Treatment

WEDNESDAY, Nov. 21, 2018 -- Warning letters about products illegally marketed as treatments for opioid addiction, pain, and anxiety have been sent to two companies, the U.S. Food and Drug Administration said Tuesday. The agency has received reports...

https://ift.tt/2ORm79n

U of Maryland Student Dies of Adenovirus-Related Illness

WEDNESDAY, Nov. 21, 2018 -- An 18-year-old University of Maryland student has died from an adenovirus-related illness, and there have been reports of five other cases among students. Recently, at least 11 children at a New Jersey rehab facility died...

https://ift.tt/2zpcdXz

FDA Approves Drug for Treatment of Travelers' Diarrhea

WEDNESDAY, Nov. 21, 2018 -- The U.S. Food and Drug Administration on Friday announced it has approved Aemcolo (rifamycin), an antibacterial drug indicated for treating adult patients with travelers' diarrhea caused by noninvasive strains of...

https://ift.tt/2OWZAbg

CDC: U.S. Abortion Rate Declined 24 Percent From 2006 to 2015

WEDNESDAY, Nov. 21, 2015 -- The abortion rate in the United States fell 24 percent between 2006 and 2015, according to research published in the Nov. 23 issue of the U.S. Centers for Disease Control and Prevention Morbidity and Mortality Weekly...

https://ift.tt/2zoEfCv

Bromocriptine Use in Peripartum Cardiomyopathy: Review of Cases

AJP Rep 2018; 08: e335-e342
DOI: 10.1055/s-0038-1675832

Objective This study is to review published cases of peripartum cardiomyopathy (PPCM) treated with bromocriptine and outline pros and cons of the treatment strategy. Data Sources Data were collected from PubMed/MedLine, ClinicalTrials.gov; the years 2007 to 2018 were searched for English-language articles. Search terms: "bromocriptine and peripartum cardiomyopathy", "bromocriptine and cardiomyopathy." Methods of Study Selection This search strategy yielded 171 articles. After excluding duplicates, 86 studies were reviewed. Sixty-one articles involving the treatment of PPCMP were included, and of these, 17 were case reports of patients with PPCMP treated with bromocriptine; these studies were included in this review. Tabulation, Integration, and Results Seventeen of these articles were case reports of patients with peripartum cardiomyopathy treated with bromocriptine that were included. Conclusion Bromocriptine seems to be a promising treatment, there is currently insufficient evidence for universal utilization of bromocriptine for all patients with PPCMP. Addition of bromocriptine to the standard heart failure therapy should be individualized.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Natural Compounds for the Management of Parkinson’s Disease and Attention-Deficit/Hyperactivity Disorder

Parkinson's disease (PD) is the second most common neurodegenerative disorder with an unknown aetiology. The pathogenic mechanisms include oxidative stress, mitochondrial dysfunction, protein dysfunction, inflammation, autophagy, apoptosis, and abnormal deposition of α-synuclein. Currently, the existing pharmacological treatments for PD cannot improve fundamentally the degenerative process of dopaminergic neurons and have numerous side effects. On the other hand, attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and is characterised by hyperactivity, impulsivity, and inattention. The aetiology of ADHD remains unknown, although it has been suggested that its pathophysiology involves abnormalities in several brain regions, disturbances of the catecholaminergic pathway, and oxidative stress. Psychostimulants and nonpsychostimulants are the drugs prescribed for the treatment of ADHD; however, they have been associated with increased risk of substance use and have several side effects. Today, there are very few tools available to prevent or to counteract the progression of such neurological disorders. Thus, therapeutic approaches with high efficiency and fewer side effects are needed. This review presents a brief overview of the two neurological disorders and their current treatments, followed by a discussion of the natural compounds which have been studied as therapeutic agents and the mechanisms underlying the beneficial effects, in particular, the decrease in oxidative stress.

https://ift.tt/2qZxlPK

The Chinese Medicinal Formulation Guzhi Zengsheng Zhitongwan Modulates Chondrocyte Structure, Dynamics, and Metabolism by Controlling Multiple Functional Proteins

Traditional Chinese medicine is one of the oldest medical systems in the world and has its unique principles and theories in the prevention and treatment of human diseases, which are achieved through the interactions of different types of materia medica in the form of Chinese medicinal formulations. GZZSZTW, a classical and effective Chinese medicinal formulation, was designed and created by professor Bailing Liu who is the only national medical master professor in the clinical research field of traditional Chinese medicine and skeletal diseases. GZZSZTW has been widely used in clinical settings for several decades for the treatment of joint diseases. However, the underlying molecular mechanisms are still largely unknown. In the present study, we performed quantitative proteomic analysis to investigate the effects of GZZSZTW on mouse primary chondrocytes using state-of-the-art iTRAQ technology. We demonstrated that the Chinese medicinal formulation GZZSZTW modulates chondrocyte structure, dynamics, and metabolism by controlling multiple functional proteins that are involved in the cellular processes of DNA replication and transcription, protein synthesis and degradation, cytoskeleton dynamics, and signal transduction. Thus, this study has expanded the current knowledge of the molecular mechanism of GZZSZTW treatment on chondrocytes. It has also shed new light on possible strategies to further prevent and treat cartilage-related diseases using traditional Chinese medicinal formulations.

https://ift.tt/2FAfHfx

I Am a Fake Loop: the Effects of Advertising-Based Artificial Selection

Abstract

Mimicry is common among animals, plants, and other kingdoms of life. Humans in late capitalism, however, have devised an unique method of mimicking the signs that trigger evolutionarily-programmed instincts of their own species in order to manipulate them. Marketing and advertising are the most pervasive and sophisticated forms of known human mimicry, deliberately hijacking our instincts in order to select on the basis of one dimension only: profit. But marketing and advertising also strangely undermine their form of mimicry, deceiving both the intended targets and the signaler simultaneously. Human forms of mimicry have the regular consequence of deceiving the imitator, reducing meta-cognitive awareness of the act and intentions surrounding such deception. Therefore, the deceiver in the end deceives himself as well as intended targets. Drawing on scholarship applying Niko Tinbergen's ethological discovery of supernormal stimuli in animals to humans, this article analyzes sophisticated mass mimicry in contemporary culture, in both intended and unintended forms.

https://ift.tt/2OXszM7

Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria

In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US.

https://ift.tt/2Kn8DS1

Accuracy of Non-invasive Scoring Systems in Assessing Risk of Death and Liver-related Endpoints in Patients With Non-alcoholic Fatty Liver Disease

Several non-invasive scoring systems have been developed to determine risk of advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the association between 4 scoring systems and incident severe liver disease and overall mortality in a large cohort of patients with biopsy-proven NAFLD.

https://ift.tt/2BpVPHG

Differences in Outcomes Reported by Patients With Inflammatory Bowel Diseases vs Their Health Care Professionals

Inflammatory bowel disease (IBD) scoring systems combine patient-reported data with physicians' observations to determine patient outcomes, but these systems are believed to have limitations. We used real-world data from a large IBD cohort in Switzerland to compare results between patients and healthcare professionals' from scoring systems for Crohn's disease (CD) and ulcerative colitis (UC).

https://ift.tt/2KnCTMv

Association Between Black Race and Presentation and Liver-related Outcomes of Patients With Autoimmune Hepatitis

& Aims: Small studies have found that black patient with autoimmune hepatitis (AIH) patients present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH.

https://ift.tt/2Bp46LX

Histologic Analysis of Endoscopic Ultrasound-guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts

It is a challenge to accurately assess pancreatic cystic lesions (PCLs) and determine their risk. We compared the yield of tissue acquired with endoscopic ultrasound (EUS)-guided microforceps (through the needle tissue biopsy, or TTNB) with that of samples collected by EUS-guided fine-needle-aspiration (EUS-FNA), and the accuracy of analyses of each sample type in the diagnosis of mucinous PCLs.

https://ift.tt/2KpBPYP

Predictive capacity for mortality and severe liver disease of the relative fat mass algorithm

The relative fat mass (RFM) is a new tool that estimates body fat composition better than body mass index (BMI). However, it is unknown if this new scoring system is better than currently available alternatives to BMI in predicting incident outcomes.

https://ift.tt/2BqPtIl

Modified Genomic Self-DNA Influences In Vitro Survival of HT29 Tumor Cells via TLR9- and Autophagy Signaling

Abstract

In relation of immunobiology, the consequence of the crosstalk between TLR9-signaling and autophagy is poorly documented in HT29 cancer cells. To assess the TLR9-mediated biologic effects of modified self-DNA sequences on cell kinetics and autophagy response HT29 cells were incubated separately with intact genomic (g), hypermethylated (m), fragmented (f), and hypermethylated/fragmented (m/f) self-DNAs. Cell viability, apoptosis, cell proliferation, colonosphere-formation were determined. Moreover, the relation of TLR9-signaling to autophagy response was assayed by real-time RT-PCR, immunocytochemistry and transmission electron microscopy (TEM). After incubation with g-, m-, and m/f-DNAs cell viability and proliferation decreased, while apoptosis increased. F-DNA treatment resulted in an increase of cell survival. Methylation of self-DNA resulted in decrease of TLR9 expression, while it did not influence the positive effect of DNA fragmentation on MyD88 and TRAF6 overexpression, and TNFα downregulation. Fragmentation of DNA abrogated the positive effect of methylation on IRAK2, NFκB and IL-8 mRNA upregulations. In case of the autophagy genes and proteins, g- and f-DNAs caused significant upregulation of Beclin1, Atg16L1, and LC3B. According to TEM analyses, autophagy was present in each group of tumor cells, but to a varying degree. Incubation with m-DNA suppressed tumor cell survival by inducing features of apoptotic cell death, and activated mitophagy. F-DNA treatment enhanced cell survival, and activated macroautophagy and lipophagy. Colonospheres were only present after m-DNA incubation. Our data provided evidence for a close existing interplay between TLR9-signaling and the autophagy response with remarkable influences on cell survival in HT29 cells subjected to modified self-DNA treatments.

https://ift.tt/2S4D1mQ

Hemorrhage from Metastasis of a 5-mm Renal Cell Carcinoma Lesion to the Gallbladder Detected by Contrast-Enhanced Endoscopic Ultrasonography

https://ift.tt/2DTV7EY

What are the benefits of licorice root?

Licorice root may offer potential health benefits, such as fighting infection, preventing tooth decay, and relieving stomach discomfort. Learn more about the possible benefits of licorice root here.

https://ift.tt/2BpDuud

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants.

https://ift.tt/2S5aLjV

Chromatin Immunoprecipitation of Murine Brown Adipose Tissue

Here we describe a protocol for efficient chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) of brown adipose tissue (BAT) isolated from a mouse. This protocol is suitable for both mapping histone modifications and investigating genome-wide localization of non-histone proteins of interest in vivo.

https://ift.tt/2DR7xh5

Unraveling Key Players of Humoral Immunity: Advanced and Optimized Lymphocyte Isolation Protocol from Murine Peyer's Patches

In this study, we present a novel and effective protocol for the isolation of lymphocytes from Peyer's Patches (PPs), which can be subsequently used for in vivo and in vitro functional assays as well as flow cytometric studies of follicular T helper and germinal center B cells.

https://ift.tt/2DQVsbB

Deficiency of AMPAR-Palmitoylation Aggravates Seizure Susceptibility

Synaptic AMPAR expression controls the strength of excitatory synaptic transmission and plasticity. An excess of synaptic AMPARs leads to epilepsy in response to seizure-inducible stimulation. The appropriate regulation of AMPARs plays a crucial role in the maintenance of the excitatory/inhibitory synaptic balance; however, the detailed mechanisms underlying epilepsy remain unclear. Our previous studies have revealed that a key modification of AMPAR trafficking to and from postsynaptic membranes is the reversible, posttranslational S-palmitoylation at the C-termini of receptors. To clarify the role of palmitoylation-dependent regulation of AMPARs in vivo, we generated GluA1 palmitoylation-deficient (Cys811 to Ser substitution) knock-in mice. These mutant male mice showed elevated seizure susceptibility and seizure-induced neuronal activity without impairments in synaptic transmission, gross brain structure, or behavior at the basal level. Disruption of the palmitoylation site was accompanied by upregulated GluA1 phosphorylation at Ser831, but not at Ser845, in the hippocampus and increased GluA1 protein expression in the cortex. Furthermore, GluA1 palmitoylation suppressed excessive spine enlargement above a certain size after LTP. Our findings indicate that an abnormality in GluA1 palmitoylation can lead to hyperexcitability in the cerebrum, which negatively affects the maintenance of network stability, resulting in epileptic seizures.

SIGNIFICANCE STATEMENT AMPARs predominantly mediate excitatory synaptic transmission. AMPARs are regulated in a posttranslational, palmitoylation-dependent manner in excitatory synapses of the mammalian brain. Reversible palmitoylation dynamically controls synaptic expression and intracellular trafficking of the receptors. Here, we generated GluA1 palmitoylation-deficient knock-in mice to clarify the role of AMPAR palmitoylation in vivo. We showed that an abnormality in GluA1 palmitoylation led to hyperexcitability, resulting in epileptic seizure. This is the first identification of a specific palmitoylated protein critical for the seizure-suppressing process. Our data also provide insight into how predicted receptors such as AMPARs can effectively preserve network stability in the brain. Furthermore, these findings help to define novel key targets for developing anti-epileptic drugs.

https://ift.tt/2qYYJNO

RSNA: Mammography Has Value in Women Age 75 or Older

WEDNESDAY, Nov. 21, 2018 -- Women aged 75 years and older can still benefit from routine mammography, with a cancer detection rate of 8.4 per 1,000 exams, according to a study scheduled to be presented at the annual meeting of the Radiological...

https://ift.tt/2QXsYzT

Bone Erosions More Frequent With Old Age at Onset of Early RA

WEDNESDAY, Nov. 21, 2018 -- Old age at onset of early rheumatoid arthritis (RA) is associated with more frequent bone erosions, according to a study published online Nov. 11 in the International Journal of Rheumatic Diseases. Koichi Murata, from...

https://ift.tt/2R2KpPI

ED Utilization Up for Pediatric mTBI After TBI Legislation

WEDNESDAY, Nov. 21, 2018 -- Implementation of state youth traumatic brain injury (TBI) legislation correlated with an increase in pediatric emergency department utilization for youth sports- and recreation-related mild TBI (mTBI) evaluation,...

https://ift.tt/2PMO5bx

Arterial Stiffness May Predict Dementia Risk

WEDNESDAY, Nov. 21, 2018 -- Arterial stiffness may predict dementia risk, independent of subclinical brain damage, according to a study recently published in the Journal of Alzheimer's Disease. Chendi Cui, from the University of Pittsburgh Graduate...

https://ift.tt/2QWg9FY

Switching to High-Deductible Insurance Delays Diabetes Care

WEDNESDAY, Nov. 21, 2018 -- For patients with diabetes, those switching from low-deductible to high-deductible insurance have increased delays in seeking care and diagnostic testing for macrovascular symptoms and for first procedure-based treatment,...

https://ift.tt/2PIQ0xS

Novel Scoring System Can Up Access to Biologics in Psoriasis

WEDNESDAY, Nov. 21, 2018 -- A new scoring system that accounts for "not relevant" responses (NRRs) on the Dermatology Life Quality Index (DLQI) for patients with psoriasis is valid for avoiding bias and can improve access to biologics, according to...

https://ift.tt/2PIQ6po

Smoke-Free Policies Linked to Lower Systolic Blood Pressure

WEDNESDAY, Nov. 21, 2018 -- Smoke-free policies are associated with small reductions in blood pressure (BP), according to a study published online Nov. 21 in the Journal of the American Heart Association. Stephanie L. Mayne, Ph.D., from the...

https://ift.tt/2PIQ00Q

Few Mandatory Pediatric Postmarketing Studies Completed

WEDNESDAY, Nov. 21, 2018 -- During a median follow-up of 6.8 years, only 33.8 percent of mandatory pediatric postmarketing studies were completed, according to a study published online Nov. 19 in JAMA Pediatrics. Thomas J. Hwang, from Boston...

https://ift.tt/2R2VX5e

AI-Based Smartphone App Can Help Cut Cancer Pain Severity

WEDNESDAY, Nov. 21, 2018 -- An artificial intelligence (AI)-based smartphone app can reduce the severity of cancer patients' reported pain and hospital admissions, according to a study presented at the annual Palliative and Supportive Care in...

https://ift.tt/2QZH17Z

IBD Disability Index for Self-Report Reliable, Valid

WEDNESDAY, Nov. 21, 2018 -- The Inflammatory Bowel Disease Disability Index (IBD-DI) for self-report (IBD-DI-SR) is reliable and valid for measuring disability in inflammatory bowel disease (IBD), according to a study recently published online in...

https://ift.tt/2PKJUgi

Assessment of the Metabolic Profile of Primary Leukemia Cells

Here we present a protocol for the isolation of leukemic cells from leukemia patients bone marrow and analysis of their metabolic state. Assessment of the metabolic profile of primary leukemia cells could help to better characterize the demand of primary cells and could lead up to more personalized medicine.

https://ift.tt/2Kqz8WO

Unusual endoscopic treatment of recurrent cough and pneumonia

Clinical presentation

A 51-year-old male patient presented to our emergency department with fever, aggravating coughing and orthopnoea. Clinical evaluation revealed pneumonia in the right lower lobe of the lung and due to typical radiological hallmarks, aspiration pneumonia was suspected. During the last months, he had suffered from several pneumonias. The patient's history showed that he suffered from alveolar soft tissue sarcoma which was first diagnosed in 1985. He was treated with right-sided hemihepatectomy for resection of liver metastases, further liver resections, 12 sessions of radiation therapy and seven transarterial chemoembolisation sessions. Moreover, the patient developed a stenosis of the left hepatic bile duct and required repeated biliary stenting (10F stent) by endoscopic retrograde cholangiopancreaticography (ERCP; 24 ERCPS within 3.5 years).

The patient still suffered from persisting coughing with yellow sputum, although inflammation parameters were decreasing under antibiotic treatment. Further, due to elevated bilirubin levels, a bile duct stent dysfunction was suspected and an ERCP was performed showing the following picture (figure 1).

Figure 1

Due to suspected bile duct stent dysfunction, an endoscopic retrograde cholangiopancreaticography was performed. Multiple surgical clips were detectable following extensive hepatic and thoracic surgery for alveolar soft tissue sarcoma.

Question

What is your diagnosis? What would be an appropriate treatment approach?

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Gut microbiota dynamics and uraemic toxins: one size does not fit all

In the recent paper by Chu and colleagues,1 the potential role of microbiota-related metabolites in the progression of non-alcoholic fatty liver disease is discussed. This topic has been studied in the context of chronic kidney disease (CKD), characterised by changes in gut microbiota composition,2 accumulation of microbiota-derived metabolites,3 interruption of intestinal barrier function and chronic inflammation.4 In line with this, we focused, in a cohort of 17 patients with end-stage kidney disease (ESKD), on the role of gut microbiota in the generation of precursors of specific uraemic toxins which are associated with negative outcomes in these patients.5 By collecting multiple samples over time, assessment of variability within and between patients in relation to disease progress and clinical variables was possible. Faecal and serum samples were collected at eight time-points over a 4-month period (online ). Uraemic metabolites and microbial profiling...

https://ift.tt/2qXjr0j

Animal protein intake and hepatic steatosis in the elderly: authors' response

We would like to thank Tang and Mann for their interest in our study in which we showed that animal protein intake was independently associated with higher prevalence of non-alcoholic fatty liver disease (NAFLD) in an overweight, predominantly aged Caucasian population.1 2

Rightfully so, the authors express their concerns regarding the generalisability of our findings towards younger patients with clinically significant non-alcoholic steatohepatitis (NASH).1 Indeed, our results only pertain to our study population, consisting of an elderly and presumably healthy population in which the vast majority will have NAFLD, not NASH. Nonetheless, we believe that aiming for a healthy lifestyle, such as adherence to a healthy diet, is key across the entire spectrum of NAFLD and is not reserved for advanced disease only.3 Also, Tang and Mann question the clinical significance of NAFLD as a liver disease at the age of 70 years, but patients...

https://ift.tt/2FvdD8m

Visual Evidence Accumulation Guides Decision-Making in Unrestrained Mice

The ability to manipulate neural activity with precision is an asset in uncovering neural circuits for decision-making. Diverse tools for manipulating neurons are available for mice, but their feasibility remains unclear, especially when decisions require accumulating visual evidence. For example, whether mice' decisions reflect leaky accumulation is unknown, as are the relevant/irrelevant factors that influence decisions. Further, causal circuits for visual evidence accumulation are poorly understood. To address this, we measured decisions in mice judging the fluctuating rate of a flash sequence. An initial analysis (>500,000 trials, 29 male and female mice) demonstrated that information throughout the 1000 ms trial influenced choice, with early information most influential. This suggests that information persists in neural circuits for ~1000 ms with minimal accumulation leak. Next, in a subset of animals, we probed strategy more extensively and found that although animals were influenced by stimulus rate, they were unable to entirely suppress the influence of stimulus brightness. Finally, we identified anteromedial (AM) visual area via retinotopic mapping and optogenetically inhibited it using JAWS. Light activation biased choices in both injected and uninjected animals, demonstrating that light alone influences behavior. By varying stimulus–response contingency while holding stimulated hemisphere constant, we surmounted this obstacle to demonstrate that AM suppression biases decisions. By leveraging a large dataset to quantitatively characterize decision-making behavior, we establish mice as suitable for neural circuit manipulation studies. Further, by demonstrating that mice accumulate visual evidence, we demonstrate that this strategy for reducing uncertainty in decision-making is used by animals with diverse visual systems.

SIGNIFICANCE STATEMENT To connect behaviors to their underlying neural mechanism, a deep understanding of behavioral strategy is needed. This understanding is incomplete for mice. To surmount this, we measured the outcome of >500,000 decisions made by 29 mice trained to judge visual stimuli and performed behavioral/optogenetic manipulations in smaller subsets. Our analyses offer new insights into mice' decision-making strategies and compares them with those of other species. We then disrupted neural activity in a candidate neural structure and examined the effect on decisions. Our findings establish mice as suitable for visual accumulation of evidence decisions. Further, the results highlight similarities in decision-making strategies across very different species.

https://ift.tt/2r0vjia

Sleep and Wakefulness Are Controlled by Ventral Medial Midbrain/Pons GABAergic Neurons in Mice

Sleep–wake behavior is controlled by a wide range of neuronal populations in the mammalian brain. Although the ventral midbrain/pons (VMP) area is suggested to participate in sleep–wake regulation, the neuronal mechanisms have remained unclear. Here, we found that nonspecific cell ablation or selective ablation of GABAergic neurons by expressing diphtheria toxin fragment A in the VMP in male mice induced a large increase in wakefulness that lasted at least 4 weeks. In contrast, selective ablation of dopaminergic neurons in the VMP had little effect on wakefulness. Chemogenetic inhibition of VMP GABAergic neurons also markedly increased wakefulness. The wake-promoting effect of the VMP GABAergic neuron ablation or inhibition was attenuated to varying degrees by the administration of dopamine D1 or D2/3 receptor antagonists and abolished by the administration of both antagonists together. In contrast, chemogenetic activation of VMP GABAergic neurons very strongly increased slow-wave sleep and reduced wakefulness. These findings suggest that VMP GABAergic neurons regulate dopaminergic actions in the sleep–wake behavior of mice.

SIGNIFICANCE STATEMENT Current understanding of the neuronal mechanisms and populations that regulate sleep–wake behavior is incomplete. Here, we identified a GABAergic ventral midbrain/pons area that is necessary for controlling the daily amount of sleep and wakefulness in mice. We also found that these inhibitory neurons control wakefulness by suppressing dopaminergic systems. Surprisingly, activation of these neurons strongly induced slow-wave sleep while suppressing wakefulness. Our study reveals a new brain mechanism critical for sleep–wake regulation.

https://ift.tt/2FJFqCm

A Multicomponent Neuronal Response Encodes the Larval Decision to Pupariate upon Amino Acid Starvation

Organisms need to coordinate growth with development, particularly in the context of nutrient availability. Thus, multiple ways have evolved to survive extrinsic nutrient deprivation during development. In Drosophila, growth occurs during larval development. Larvae are thus critically dependent on nutritional inputs; but after critical weight, they pupariate even when starved. How nutrient availability is coupled to the internal metabolic state for the decision to pupariate needs better understanding. We had earlier identified glutamatergic interneurons in the ventral ganglion that regulate pupariation on a protein-deficient diet. Here we report that Drosophila third instar larvae (either sex) sense arginine to evaluate their nutrient environment using an amino acid transporter Slimfast. The glutamatergic interneurons integrate external protein availability with internal metabolic state through neuropeptide signals. IP₃-mediated calcium release and store-operated calcium entry are essential in these glutamatergic neurons for such integration and alter neuronal function by reducing the expression of multiple ion channels.

SIGNIFICANCE STATEMENT Coordinating growth with development, in the context of nutrient availability is a challenge for all organisms in nature. After attainment of "critical weight," insect larvae can pupariate, even in the absence of nutrition. Mechanism(s) that stimulate appropriate cellular responses and allow normal development on a nutritionally deficient diet remain to be understood. Here, we demonstrate that nutritional deprivation, in postcritical weight larvae, is sensed by special sensory neurons through an amino acid transporter that detects loss of environmental arginine. This information is integrated by glutamatergic interneurons with the internal metabolic state through neuropeptide signals. These glutamatergic interneurons require calcium-signaling-regulated expression of a host of neuronal channels to generate complex calcium signals essential for pupariation on a protein-deficient diet.

https://ift.tt/2qZ2uT9

Temporal Contingencies Determine Whether Adaptation Strengthens or Weakens Normalization

A fundamental and nearly ubiquitous feature of sensory encoding is that neuronal responses are strongly influenced by recent experience, or adaptation. Theoretical and computational studies have proposed that many adaptation effects may result in part from changes in the strength of normalization signals. Normalization is a "canonical" computation in which a neuron's response is modulated (normalized) by the pooled activity of other neurons. Here, we test whether adaptation can alter the strength of cross-orientation suppression, or masking, a paradigmatic form of normalization evident in primary visual cortex (V1). We made extracellular recordings of V1 neurons in anesthetized male macaques and measured responses to plaid stimuli composed of two overlapping, orthogonal gratings before and after prolonged exposure to two distinct adapters. The first adapter was a plaid consisting of orthogonal gratings and led to stronger masking. The second adapter presented the same orthogonal gratings in an interleaved manner and led to weaker masking. The strength of adaptation's effects on masking depended on the orientation of the test stimuli relative to the orientation of the adapters, but was independent of neuronal orientation preference. Changes in masking could not be explained by altered neuronal responsivity. Our results suggest that normalization signals can be strengthened or weakened by adaptation depending on the temporal contingencies of the adapting stimuli. Our findings reveal an interplay between two widespread computations in cortical circuits, adaptation and normalization, that enables flexible adjustments to the structure of the environment, including the temporal relationships among sensory stimuli.

SIGNIFICANCE STATEMENT Two fundamental features of sensory responses are that they are influenced by adaptation and that they are modulated by the activity of other nearby neurons via normalization. Our findings reveal a strong interaction between these two aspects of cortical computation. Specifically, we show that cross-orientation masking, a form of normalization, can be strengthened or weakened by adaptation depending on the temporal contingencies between sensory inputs. Our findings support theoretical proposals that some adaptation effects may involve altered normalization and offer a network-based explanation for how cortex adjusts to current sensory demands.

https://ift.tt/2FB2eUv

Specificity of Primate Amygdalar Pathways to Hippocampus

The amygdala projects to hippocampus in pathways through which affective or social stimuli may influence learning and memory. We investigated the still unknown amygdalar termination patterns and their postsynaptic targets in hippocampus from system to synapse in rhesus monkeys of both sexes. The amygdala robustly innervated the stratum lacunosum-moleculare layer of cornu ammonis fields and uncus anteriorly. Sparser terminations in posterior hippocampus innervated the radiatum and pyramidal layers at the prosubicular/CA1 juncture. The terminations, which were larger than other afferents in the surrounding neuropil, position the amygdala to influence hippocampal input anteriorly, and its output posteriorly. Most amygdalar boutons (76–80%) innervated spines of excitatory hippocampal neurons, and most of the remaining innervated presumed inhibitory neurons, identified by morphology and label with parvalbumin or calretinin, which distinguished nonoverlapping neurochemical classes of hippocampal inhibitory neurons. In CA1, amygdalar axons innervated some calretinin neurons, which disinhibit pyramidal neurons. By contrast, in CA3 the amygdala innervated both calretinin and parvalbumin neurons; the latter strongly inhibit nearby excitatory neurons. In CA3, amygdalar pathways also made closely spaced dual synapses on excitatory neurons. The strong excitatory synapses in CA3 may facilitate affective context representations and trigger sharp-wave ripples associated with memory consolidation. When the amygdala is excessively activated during traumatic events, the specialized innervation of excitatory neurons and the powerful parvalbumin inhibitory neurons in CA3 may allow the suppression of activity of nearby neurons that receive weaker nonamygdalar input, leading to biased passage of highly charged affective stimuli and generalized fear.

SIGNIFICANCE STATEMENT Strong pathways from the amygdala targeted the anterior hippocampus, and more weakly its posterior sectors, positioned to influence a variety of emotional and cognitive functions. In hippocampal field CA1, the amygdala innervated some calretinin neurons, which disinhibit excitatory neurons. By contrast, in CA3 the amygdala innervated calretinin as well as some of the powerful parvalbumin inhibitory neurons and may help balance the activity of neural ensembles to allow social interactions, learning, and memory. These results suggest that when the amygdala is hyperactive during emotional upheaval, it strongly activates excitatory hippocampal neurons and parvalbumin inhibitory neurons in CA3, which can suppress nearby neurons that receive weaker input from other sources, biasing the passage of stimuli with high emotional import and leading to generalized fear.

https://ift.tt/2qZ3SFl

Instantaneous Midbrain Control of Saccade Velocity

The ability to interact with our environment requires the brain to transform spatially represented sensory signals into temporally encoded motor commands for appropriate control of the relevant effectors. For visually guided eye movements, or saccades, the superior colliculus (SC) is assumed to be the final stage of spatial representation, and instantaneous control of the movement is achieved through a rate code representation in the lower brain stem. We investigated whether SC activity in nonhuman primates (Macaca mulatta, 2 male and 1 female) also uses a dynamic rate code, in addition to the spatial representation. Noting that the kinematics of amplitude-matched movements exhibit trial-to-trial variability, we regressed instantaneous SC activity with instantaneous eye velocity and found a robust correlation throughout saccade duration. Peak correlation was tightly linked to time of peak velocity, the optimal efferent delay between SC activity and eye velocity was constant at ~12 ms both at onset and during the saccade, and SC neurons with higher firing rates exhibited stronger correlations. Moreover, the strong correlative relationship and constant efferent delay observation were preserved when eye movement profiles were substantially altered by a blink-induced perturbation. These results indicate that the rate code of individual SC neurons can control instantaneous eye velocity and argue against a serial process of spatial-to-temporal transformation. They also motivated us to consider a new framework of saccade control that does not incorporate traditionally accepted elements, such as the comparator and resettable integrator, whose neural correlates have remained elusive.

SIGNIFICANCE STATEMENT All movements exhibit time-varying features that are under instantaneous control of the innervating neural command. At what stage in the brain is dynamical control present? It is well known that, in the skeletomotor system, neurons in the motor cortex use dynamical control. In the oculomotor system, in contrast, instantaneous velocity control of saccadic eye movements is not thought to be enforced until the lower brainstem. Using correlations between residual signals across trials, we show that instantaneous control of saccade velocity is present earlier in the visuo-oculomotor neuraxis, at the level of superior colliculus. The results require us to consider alternate frameworks of the neural control of saccades.

https://ift.tt/2FBHkF3

Electrophysiological Recording of The Central Nervous System Activity of Third-Instar Drosophila Melanogaster

This protocol describes a method to record the descending electrical activity of the Drosophila melanogaster central nervous system to enable the cost-efficient and convenient testing of pharmacological agents, genetic mutations of neural proteins, and/or the role of unexplored physiological pathways.

https://ift.tt/2BnKlEG

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer; a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS

Abstract

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

https://ift.tt/2zno8Fe

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

Abstract

Background

Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox).

Methods

FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1^N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1^Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting.

Results

Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1^Hi myeloma cells caused partial resistance to Bz (1.9–5.6 fold) and Dox (1.5–2.9 fold) in vitro, using FOXM1^N myeloma as control. Reduced sensitivity of FOXM1^Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively.

Conclusions

These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1^Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.

https://ift.tt/2S75j05

The feasibility, acceptability and outcomes of exergaming among individuals with cancer: a systematic review

Abstract

Background

Individuals with cancer have reduced quality of life, functionality, range of motion, strength, and an increase in pain and fatigue. Exergaming appears to be an effective rehabilitation tool for Parkinson's disease, multiple sclerosis and post-stroke patients to improve functionality, balance and quality of life; however, the usefulness of exergaming in individuals with cancer is unknown. The aim of this systematic review is to describe exergaming interventions delivered to adults with a current or previous cancer diagnosis and to report the feasibility, acceptability and outcomes of such interventions.

Methods

Studies reporting on exergaming interventions delivered to individuals with a current or previous cancer diagnosis were included. 12 electronic databases were searched. Eight articles (seven interventions) were identified. Data were extracted and assessed for quality by two reviewers.

Results

Three interventions were delivered at hospital, two at home, one at a clinical laboratory, and one did not report. Two interventions were delivered by a physiotherapist, two by an occupational therapist, and one by a nurse, research staff and an exercise physiologist. The Nintendo Wii was used in four of seven studies, whilst the remaining three used the IREX system, BrightArm Duo Rehabilitation System or a custom made exergame. Studies showed that most participants enjoyed the exergaming intervention, and would recommend their use, with some preferring exergaming over standard care interventions. Adherence rates and enjoyment appear greater during exergaming than standard care. Exergaming interventions appear to support improvements balance, function, physical activity levels, strength, fatigue, emotions, cognition and pain.

Conclusion

Exergaming interventions delivered to individuals with cancer show great heterogeneity; differing in duration, frequency and gaming platform. The disease stage and severity of those included, and the outcome measures assessed also vary widely making it difficult to conclude its effectiveness at this time. However, adherence rates and enjoyment appear greater during exergaming compared to standard care, supporting the feasibility and acceptability of this type of intervention delivery for adults with cancer.

https://ift.tt/2DP8KW9

Effects of PKM2 on global metabolic changes and prognosis in hepatocellular carcinoma: from gene expression to drug discovery

Abstract

Background

Hepatocellular carcinoma (HCC) is a malignant tumor that threatens global human health. High PKM2 expression is widely reported in multiple cancers, especially in HCC. This study aimed to explore the effects of PKM2 on global gene expression, metabolic damages, patient prognosis, and multiple transcriptional regulation relationships, as well as to identify several key metabolic genes and screen some small-molecule drugs.

Methods

Transcriptome and clinical HCC data were downloaded from the NIH-GDC repository. Information regarding the metabolic genes and subsystems was collected from the Recon 2 human metabolic model. Drug-protein interaction data were obtained from the DrugBank and UniProt databases. We defined patients with PKM2 expression levels ≥11.25 as the high-PKM2 group, and those with low PKM2 expression (< 11.25) were defined as the low-PKM2 group.

Results

The results showed that the global metabolic gene expression levels were obviously divided into the high- or low-PKM2 groups. In addition, a greater number of affected metabolic subsystems were observed in the high-PKM2 group. Furthermore, we identified 98 PKM2-correlated deregulated metabolic genes that were associated with poor overall patient survival. Together, these findings suggest more comprehensive influences of PKM2 on HCC. In addition, we screened several small-molecule drugs that target these metabolic enzymes, some of which have been used in antitumor clinical studies.

Conclusions

HCC patients with high PKM2 expression showed more severe metabolic damage, transcriptional regulation imbalance and poor prognosis than low-PKM2 individuals. We believe that our study provides valuable information for pathology research and drug development for HCC.

https://ift.tt/2S75hoZ

Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: axillary dissection versus no axillary dissection in patients with involved sentinel node

Abstract

Background

Three randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial (ClinicalTrials.gov, number NCT01717131) to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included.

Methods

SERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement.

Results

Of the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria.

Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy.

Conclusion

The main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed.

Trial registration

This study is registered with ClinicalTrials.gov, number NCT01717131 October 19, 2012.

https://ift.tt/2DSXTdZ

Cancers, Vol. 10, Pages 462: Liquid Crystals: A Novel Approach for Cancer Detection and Treatment

Cancers, Vol. 10, Pages 462: Liquid Crystals: A Novel Approach for Cancer Detection and Treatment

Cancers doi: 10.3390/cancers10110462

Authors: Jayalakshmi Vallamkondu Edwin Bernard Corgiat Gollapelli Buchaiah Ramesh Kandimalla P. Hemachandra Reddy

Liquid crystals are defined as the fourth state of matter forming between solid and liquid states. Earlier the applications of liquid crystals were confined to electronic instruments, but recent research findings suggest multiple applications of liquid crystals in biology and medicine. Here, the purpose of this review article is to discuss the potential biological impacts of liquid crystals in the diagnosis and prognosis of cancer along with the risk assessment. In this review, we also discussed the recent advances of liquid crystals in cancer biomarker detection and treatment in multiple cell line models. Cases reviewed here will demonstrate that cancer diagnostics based on the multidisciplinary technology and intriguingly utilization of liquid crystals may become an alternative to regular cancer detection methodologies. Additionally, we discussed the formidable challenges and problems in applying liquid crystal technologies. Solving these problems will require great effort and the way forward is through the multidisciplinary collaboration of physicists, biologists, chemists, material-scientists, clinicians, and engineers. The triumphant outcome of these liquid crystals and their applications in cancer research would be convenient testing for the detection of cancer and may result in treating the cancer patients non-invasively.

https://ift.tt/2DQzANy

Benefits of oil pulling with coconut oil

Oil pulling is a method of cleansing the mouth by swishing oil around for up to 20 minutes. Learn about the possible benefits oil pulling with coconut oil here.

https://ift.tt/2Qj7DE9

Extracellular membrane vesicles (EVs) in the three domains of life and beyond

Abstract

Cells from all three domains of life, Archaea, Bacteria and Eukarya, produce extracellular vesicles (EVs) which are sometimes associated to filamentous structures known as nanopods or nanotubes. The mechanisms of EV biogenesis in the three domains remain poorly understood, although studies in Bacteria and Eukarya indicate that the regulation of lipid composition plays a major role in initiating membrane curvature. EVs are increasingly recognized as important mediators of intercellular communication via transfer of a wide variety of molecular cargoes. They have been implicated in many aspects of cell physiology such as stress response, inter-cellular competition, lateral gene transfer (via RNA or DNA), pathogenicity, and detoxification. Their role in various human pathologies and aging has aroused much interest in recent years. EVs can be used as decoys against viral attack but virus infected cells also produce EVs that boost viral infection. Here, we review current knowledge on EVs in the three domains of life and their interactions with the viral world.

https://ift.tt/2FzzX0P

Nitrogen availability facilitates phosphorus acquisition by bloom-forming cyanobacteria

Abstract

Cyanobacterial blooms are threatening freshwater ecosystems. The physiological basis involved in the onset of cyanobacterial bloom is fundamental to advance in bloom predictions. Generally, cyanobacteria grow until the availability of nitrogen (N), phosphorus (P), or both nutrients becomes limited. Population survival may depend on physiological adjustments to nutrient deficiency as well as on the efficient use of episodic N and P inputs. This study investigated the effect of N inputs on phosphate uptake affinity and activity of N-deficient bloom-forming cyanobacteria. Lake samples dominated by filamentous cyanobacteria were preincubated with and without nitrate addition, and the uptake of [³²P] phosphate pulses was measured in the following days. Phosphate uptake kinetics were analyzed with a flow-force model that provides the threshold concentration, reflecting phosphate uptake affinity, and the membrane conductivity coefficient that corresponds to the activity of uptake systems. After 24 h of nitrate preincubation, phosphate uptake kinetics showed a progressive increase in affinity (nanomolar [P_e]_A) and activity (25-fold) concomitant with cyanobacterial growth. It was demonstrated that the alleviation of N-deficiency by N inputs boosts the activation of phosphate uptake systems of non-N₂-fixing cyanobacteria to sustain growth. Therefore, reduction of dissolved inorganic N levels in lakes is also mandatory to limit cyanobacterial phosphate uptake affinity and activity capabilities.

https://ift.tt/2BpUX5X

Planctomycetes in boreal and subarctic wetlands: diversity patterns and potential ecological functions

Abstract

Members of the phylum Planctomycetes are common inhabitants of boreal Sphagnum peat bogs and lichen-dominated tundra wetlands. These bacteria colonize both oxic and anoxic peat layers and reach the population size of 10⁷ cells per gram of wet peat. The 16S rRNA gene sequences from planctomycetes comprise 5–22% of total 16S rRNA gene reads retrieved from peat samples. Most abundant peat-inhabiting planctomycetes affiliate with the families Isosphaeraceae and Gemmataceae, and with as-yet-uncultured Phycisphaera-related group WD2101. The use of metatranscriptomics to assess the functional role of planctomycetes in peatlands suggested the presence of versatile hydrolytic capabilities in these bacteria. This evidence was further confirmed by the analysis of genome-encoded capabilities of isolates from wetlands. Large (up to 12 Mbp) genomes of planctomycetes encode wide repertoires of carbohydrate-active enzymes including many unclassified putative glycoside hydrolases, which suggests the presence of extremely high glycolytic potential in these bacteria. Experimental tests confirmed their ability to grow on xylan, pectin, starch, lichenan, cellulose, chitin, and polysaccharides of microbial origin. These results provide an insight into the ecological roles of peat-inhabiting planctomycetes and suggest their participation in degradation of plant-derived polymers, exoskeletons of peat-inhabiting arthropods as well as exopolysaccharides produced by other bacteria.

https://ift.tt/2Ko5PUQ

Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency

Marks and colleagues use integrative mass spectrometry to profile post-translational histone modifications and the chromatin-associated proteome in ground-state pluripotency. This reveals H3K27me3 and PRC2 as widespread hallmarks on euchromatin and heterochromatin. They show that ubiquitous chromatin-associated PRC2 protects the epigenome from priming, in particular from gaining DNA methylation.

https://ift.tt/2KnhWl3

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation

Park et al. find that IKZF2 regulates chromatin accessibility of self-renewal and differentiation genes in leukemic stem cells. Depletion of IKZF2 has preferential effect in leukemic stem cells compared to normal hematopoietic stem cells, providing a new strategy for targeting leukemic stem cells.

https://ift.tt/2BpU2lZ

Quantitative Clonal Analysis and Single-Cell Transcriptomics Reveal Division Kinetics, Hierarchy, and Fate of Oral Epithelial Progenitor Cells

Jones et al. define the organization, cycling kinetics, and clonal dynamics of oral mucosal progenitor cells. They also show, via single-cell RNA sequencing, that the basal layer contains progenitor and post-mitotic cells at various stages of maturation, demonstrating basal layer heterogeneity and providing insights into localization of cell fate decisions.

https://ift.tt/2KnSpIk

A system for the expression and release of heterologous proteins from the core of Bacillus subtilis spores

Abstract

Methodologies that exploit the durability of Bacillus subtilis spores by displaying heterologous proteins or antigenic molecules on the spore surface for mucosal vaccine delivery and other applications are well established. Here we extend the concept by engineering spores intended as oral delivery vehicles for therapeutic proteins. The method is exemplified by the expression and deposition of human growth hormone in the developing spore core, where the protein is shielded from physicochemical and biological degradation by the protective spore structure. Lysates from physically disrupted spores are shown to stimulate differentiation of a pre-adipocyte cell line to mature adipocyte cells, indicating that the spore-core located human growth hormone is folded correctly and functional. We also introduce a methodology for controlled release of heterologous proteins from the spore core, which utilises components of the PBSX prophage to lyse spores during germination and outgrowth. With further development, spore core expression, coupled with an engineered autolytic germination mechanism, may permit the use of spores as oral delivery carriers of therapeutic proteins.

https://ift.tt/2BpgrzW

Virulence factor-dependent basolateral invasion of choroid plexus epithelial cells by pathogenic Escherichia coli in vitro

Abstract

Escherichia coli (E. coli) is the most common Gram-negative causative agent of neonatal meningitis and E. coli meningitis is associated with a high morbidity and mortality. Previous research has been carried out with regards to the blood-brain barrier and thereby unveiled an assortment of virulence factors involved in E. coli meningitis. Little, however, is known about the role of the blood-cerebrospinal fluid (CSF) barrier (BCSFB), in spite of several studies suggesting that the choroid plexus (CP) is a possible entry point for E. coli into the CSF spaces. Here, we used a human CP papilloma (HIBCPP) cell line that was previously established as valid model for the study of the BCSFB. We show that E. coli invade HIBCPP cells in a polar fashion preferentially from the physiologically relevant basolateral side. Moreover, we demonstrate that deletion of outer membrane protein A, ibeA, or neuDB genes result in decreased cell infection, while absence of fimH enhances invasion, although causing reduced adhesion to the apical side of HIBCPP cells. Our findings suggest that the BCSFB might constitute an entry point for E. coli into the central nervous system and HIBCPP cells are a valuable tool for investigating E. coli entry of the BCSFB.

https://ift.tt/2KqbhGH

The impact of clinicopathologic and surgical factors on relapse and pregnancy in young patients (≤40 years old) with borderline ovarian tumors

Abstract

Background

Fertility sparing surgery has been extensively performed among patients with borderline ovarian tumors due to their age and favorable prognosis. Nevertheless, the prognosis and obstetric outcomes in these patients remain uncertain. Thus, the current study was carried out to evaluate the oncological safety and fertility benefits of different fertility sparing surgery subtypes and various clinicopathological parameters.

Methods

Young borderline ovarian tumor patients with an age of ≤40 years, who were admitted and treated in Zhejiang Cancer Hospital from January 1996 to December 2016, were enrolled in this study and reviewed retrospectively. The prognostic and obstetric effects of clinicopathological and surgical variables were evaluated using univariate/multivariate analyses and survival curves.

Results

A total of 92 eligible patients were enrolled in the analysis. Among these patients, 22 (24%) patients showed recurrence after a median follow-up of 46.5 months. Within the fertility sparing surgery group, patients at advanced stage (≥stage II), of serous type, with micropapillary and bilateral tumors were associated with a higher recurrence rate and a shorter recurrence interval. In terms of different modalities of fertility sparing surgery, adnexectomy was remarkably favored over cystectomy-including (P = 0.012); unilateral salpingo-oophorectomy had better prognosis than cystectomy and bilateral cystectomy was favored over unilateral salpingo-oophorectomy+contralateral cystectomy. Univariate Cox regression analysis indicated that the International Federation of Gynecology and Obstetrics stage (≥Stage II), the presence of bilateral and micropapillary lesions, and the application of cystectomy-including surgery were correlated with poorer disease-free survival, while the mucinous type of borderline ovarian tumors was related to improved disease-free survival. In this study, a total of 22 patients attempted to conceive and 15 (68%) of these patients achieved successful pregnancy.

Conclusions

Unilateral salpingo-oophorectomy and bilateral cystectomy should be recommended as the preferred choice of treatment for young patients with unilateral and bilateral borderline ovarian tumor who desire to preserve fertility. In addition, borderline ovarian tumor patients at advanced stage (≥stage II), of serous type, with micropapillary and bilateral tumors should pay more attention to the risk of recurrence. Therefore, these patients should choose fertility sparing surgery carefully and attempt to achieve pregnancy as soon as possible.

https://ift.tt/2AaUwul

Sleep duration and the risk of cancer: a systematic review and meta-analysis including dose–response relationship

Abstract

Background

The effect of sleep duration on cancer risk remains controversial. We aimed to quantify the available evidence on this relationship using categorical and dose–response meta-analyses.

Methods

Population-based cohort studies and case-control studies with at least three categories of sleep duration were identified by searching PubMed, EMBASE, and the Cochrane Library database up to July 2017.

Results

Sixty-five studies from 25 articles were included, involving 1,550,524 participants and 86,201 cancer cases. The categorical meta-analysis revealed that neither short nor long sleep duration was associated with increased cancer risk (short: odds ratio [OR] = 1.01, 95% confidence intervals [CI] = 0.97–1.05; long: OR = 1.02, 95% CI = 0.97–1.07). Subgroup analysis revealed that short sleep duration was associated with cancer risk among Asians (OR = 1.36; 95% CI: 1.02–1.80) and long sleep duration significantly increased the risk of colorectal cancer (OR = 1.21; 95% CI: 1.08–1.34). The dose–response meta-analysis showed no significant relationship between sleep duration and cancer risk. When treated as two linear piecewise functions with a cut point of 7 h, similar nonsignificant associations were found (per 1-h reduction: OR = 1.02, 95% CI = 0.98–1.07; per 1-h increment: OR = 1.003, 95% CI = 0.97–1.03).

Conclusion

Categorical meta-analysis indicated that short sleep duration increased cancer risk in Asians and long sleep duration increased the risk of colorectal cancer, but these findings were not consistent in the dose–response meta-analysis. Long-term randomized controlled trials and well-designed prospective studies are needed to establish causality and to elucidate the mechanism underlying the association between sleep duration and cancer risk.

https://ift.tt/2TzPa4C

Radiomics score: a potential prognostic imaging feature for postoperative survival of solitary HCC patients

Abstract

Background

Radiomics is an emerging field in oncological research. In this study, we aimed at developing a radiomics score (rad-score) to estimate postoperative recurrence and survival in patients with solitary hepatocellular carcinoma (HCC).

Methods

A total of 319 solitary HCC patients (training cohort: n = 212; validation cohort: n = 107) were enrolled. Radiomics features were extracted from the artery phase of preoperatively acquired computed tomography (CT) in all patients. A rad-score was generated by using the least absolute shrinkage and selection operator (lasso) logistic model. Kaplan-Meier and Cox's hazard regression analyses were used to evaluate the prognostic significance of the rad-score. Final nomograms predicting recurrence and survival of solitary HCC patients were established based on the rad-score and clinicopathological factors. C-index and calibration statistics were used to assess the performance of nomograms.

Results

Six potential radiomics features were selected out of 110 texture features to formulate the rad-score. Low rad-score positively correlated with aggressive tumor phenotypes, like larger tumor size and vascular invasion. Meanwhile, low rad-score was significantly associated with increased recurrence and reduced survival. In addition, multivariate analysis identified the rad-score as an independent prognostic factor (recurrence: Hazard ratio (HR): 2.472, 95% confident interval (CI): 1.339–4.564, p = 0.004;survival: HR: 1.558, 95%CI: 1.022–2.375, p = 0.039). Notably, the nomogram integrating rad-score had a better prognostic performance as compared with traditional staging systems. These results were further confirmed in the validation cohort.

Conclusions

The preoperative CT image based rad-score was an independent prognostic factor for the postoperative outcome of solitary HCC patients. This score may be complementary to the current staging system and help to stratify individualized treatments for solitary HCC patients.

https://ift.tt/2A9t4x7