Objectives Early recognition and appropriate bystander response has proven effect on the outcome of many critically ill patients, including those in cardiac arrest. We wanted to audit prehospital bystander response in our region and identify areas for improvement. Patients and methods We prospectively collected data, including Emergency Medical Services dispatch center audio files, on all patients with a decreased level of consciousness presenting to the Ghent University Hospital prehospital emergency care unit (n=151). Three trained emergency physicians reviewed the bystander responses, both before and after dispatcher advice was given. Suboptimal actions (SAs) were only withheld if there was 100% consensus. Results SAs were recognized in 54 (38%) of the 142 cases, and most often related to delayed (n=35) or inaccurate (n=12) alerting of the dispatch center. In seven cases, the aid given was considered suboptimal in itself. Importantly, in 21 (25.9%) of the 81 cases where a clear advice was given by the dispatcher, this advice was ignored. In 12 cases, a general practitioner was present at scene. We recognized SAs in 80% of these cases (8/10; insufficient information, n=2). Cardiopulmonary resuscitation was started in only 29 (43.3%) of the 67 cases of cardiac arrest where dispatcher-assisted cardiopulmonary resuscitation was indicated at the moment of first Emergency Medical Services call. Conclusion We audited bystander response for unconscious patients in our region and found a high degree of suboptimal actions. These results should inform policy makers and healthcare professionals and force them to urgently reflect on how to improve the first parts of the chain of survival. Correspondence to Patrick Van de Voorde, MD, PhD, FERC, Department of Emergency Medicine, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium Tel: +32 93 324 906/+32 48 842 0841; e-mails: patrick.vandevoorde@uzgent.be, patrick.vandevoorde@health.belgium.be Received March 5, 2018 Accepted December 17, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
http://bit.ly/2VQkv4b
Σάββατο 12 Ιανουαρίου 2019
Evaluation of three “beyond Baveno VI” criteria to safely spare endoscopies in compensated advanced chronic liver disease
Liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm3 exclude varices needing treatment (VNT) in viral compensated advanced chronic liver disease (cACLD), saving-up to 20-25% endoscopies (Baveno VI criteria). Refinements of such criteria to further reduce endoscopies and an approach without LSM (Platelet 150/MELD 6) were later proposed.
http://bit.ly/2QJeX7R
Nonalcoholic fatty liver disease is associated with breast cancer in nonobese women
Growing evidence supports that nonalcoholic fatty liver disease (NAFLD) is associated with extrahepatic cancers. Nonalcoholic fatty liver disease (NAFLD) and breast cancer share similar risk factors, including obesity.
http://bit.ly/2QG5iyZ
Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease
Vitamin D has promising anti-proliferative and anti-fibrotic properties, but its clinical utility in nonalcoholic fatty liver disease (NAFLD) is unclear.
http://bit.ly/2VRjSaD
Impact of the direct-acting antiviral agents (DAAs) on chronic hepatitis C in Sardinian patients with transfusion-dependent Thalassemia major
Direct antiviral agents (DAAs) have revolutionised the standard of care for the treatment of hepatitis even in patients with hemoglobinopathies. The aim of this study is to show how, thanks to DAAs, HCV infection has been substantially eradicated in one of the biggest Centres for the management of Thalassemia in Europe.
http://bit.ly/2QIRlQI
Epidemiological features and disease-related concerns of a large cohort of Italian patients with active Crohn’s disease
The SOLE study was conducted on a large cohort of Italian patients with moderate-severe Crohn's disease (CD) to assess epidemiological and disease characteristics and their correlation with disease-related worries, treatment satisfaction and adherence, workability.
http://bit.ly/2VRTBJc
Feasibility and reproducibility of liver and pancreatic stiffness in patients with alcohol-related liver disease
To date no studies evaluated liver stiffness and pancreatic stiffness by shear-wave elastography, in alcoholic liver disease setting.
http://bit.ly/2QFUr8k
A neonate with pneumoperitoneum and cyanosis of lower limbs skin during esophagogastroduodenoscopy
A girl at 16 h after birth who was born in Week 39 of pregnancy, with a height, body weight, and hemoglobin level of 51 cm, 3400 g, and 14 g/dL, respectively, was referred to our hospital with fresh hematemesis and melena. Two mg of Vitamin K was intravenously injected, and gastrolavage was conducted. However, the hematemesis and melena persisted and laboratory tests showed a hemoglobin level of 5.9 g/dL. Erythrocyte transfusion at 150 mL was administered, and the hemoglobin level was increased to 12.1 g/dL.
http://bit.ly/2QJ6K3E
Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models.
http://bit.ly/2VNR7Mg
Meta-analysis of circulating microRNAs for the diagnosis of hepatocellular carcinoma
There are no existing biomarkers that demonstrate very reliable performance in the diagnosis of hepatocellular carcinoma (HCC), especially in the early stage. Studies have shown that numerous aberrantly expressed circulating microRNAs (miRNAs) can be used as a diagnostic tool for HCC; however, these studies have produced inconsistent results.
http://bit.ly/2VRuuqj
Comparison of asymmetric (low morning-dose) and standard split-dose regimen of PEG plus bisacodyl for bowel preparation: A randomized controlled trial
Reducing the morning dose of PEG solution may be a reliable strategy to improve the patient compliance of split-dose regimens without affecting efficacy of bowel cleansing.
http://bit.ly/2QFzJpb
Colon stenting as “Bridge-to-surgery”: A further piece of the puzzle toward…?
The incidence of acute colorectal obstruction due to colorectal cancer (CRC) requiring urgent decompression has been reported to be up to 13%, with approximately 70% of cases occurring in the left side of the colon [1].
http://bit.ly/2VOG719
“Are the Expanded Baveno VI Criteria really safe to screen compensated cirrhotic patients for high-risk varices?”
The Expanded Baveno VI criteria [1] have been recently proposed as a new screening strategy for high-risk varices (HRV), able to increase the rate of spared upper endoscopies (EGDs) and improve upon the original Baveno VI Criteria [2]. To date, few studies have investigated the performance and safety of these criteria [3,4]. The recent work by Bae et al. [4] is the first one to report a high rate (>5%) of missed HRV by the expanded criteria, questioning their efficiency in safely ruling out HRV (sensitivity 81%, NPV 93%, LR- 0.30).
http://bit.ly/2QMUMpW
Genetic depletion of Soat2 diminishes hepatic steatosis via genes regulating de novo lipogenesis and by GLUT2 protein in female mice
Depletion of the cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2, encoded by Soat2) protects mice from atherosclerosis, diet-induced hypercholesterolemia, and hepatic steatosis when fed high-cholesterol diet. The glucose transporter 2 (GLUT2) represents the main gate of glucose uptake by the liver. Lipid synthesis from glucose (de novo lipogenesis; DNL) plays a pivotal role in the development of hepatic steatosis. Inhibition of DNL is a successful approach to reverse hepatic steatosis, as shown by different studies in mice and humans.
http://bit.ly/2VMpumx
HepaDisk – A new Quality of Life Questionnaire for HCV patients
Since most patients with hepatitis C virus (HCV) infection now receive treatment irrespective of liver disease severity, special attention to patient quality of life (QoL), including psycho-social aspects, is required. No QoL questionnaire is specific for patients with HCV.
http://bit.ly/2QIdy1A
Association of Time to Colonoscopy after a Positive Fecal Test Result and Fecal Hemoglobin Concentration with Risk of Advanced Colorectal Neoplasia
We evaluated the risk of advanced colorectal neoplasia (ACRN) and colorectal cancer (CRC) according to time to colonoscopy after positive fecal immunochemical test (FIT), fecal hemoglobin concentration, and combination of both.
http://bit.ly/2VMpva5
Early metabolic response to chemoradiotherapy by interim FDG PET/CT is associated with better overall survival and histological response in esophageal cancers
Early assessment of response to neoadjuvant chemoradiotherapy (CRT) is crucial in determining the most suitable treatment strategy in locally advanced oesophageal cancer (LAEC).
http://bit.ly/2QFHxXL
Deep remission on magnetic resonance imaging impacts outcomes of perianal fistulizing Crohn’s disease
The long-term management of perianal Crohn's disease for patients on anti-TNF-α therapy remains challenging.
http://bit.ly/2VNN7v3
MiRNA-195-5p Functions as a Tumor Suppressor and a Predictive of Poor Prognosis in Non-small Cell Lung Cancer by Directly Targeting CIAPIN1
Abstract
Accumulating evidence suggests that microRNAs (miRNAs) has been proven to be a critical regulator in the tumor progression, of which miR-195-5p was reported to function as tumor suppressor in prostate cancer and oral squamous cell carcinoma. However, studies on the clinical significance and biological function of miR-195-5p in non-small cell lung cancer (NSCLC) were still unavailable. Here, we reported that the expression of miR-195-5p was decreased in NSCLC tissues and cell lines. Downregulation of miR-195-5p was significantly associated with TNM stage, tumor size and lymph node metastasis. The Kaplan-Meier survival analysis demonstrated that the survival time of NSCLC patients with high expression of miR-195-5p was longer than those with low expression during the 5-year follow up period (p = 0.0410). COX regression analysis indicated that miR-195-5p expression was an independent prognostic indicator for the survival of NSCLC patients (HR = 2.45, 95% CI: 1.53–4.63; p = 0.007). Results of functional analyses revealed that overexpression of miR-195-5p in A549 cells inhibited cell proliferation, induced cell cycle G0/G1 phase arrest and apoptosis using MTT and flow cytometry analysis. Furthermore, bioinformatics and luciferase reporter assays demonstrated that cytokine-induced apoptosis inhibitor 1 (CIAPIN1), an anti-apoptotic molecule was a direct target of miR-195-5p in NSCLC cells. Meta-analysis based on Oncomine database showed CIAPIN1 was significantly up-regulated in human lung cancer tissues. Consistently, knockdown of CIAPIN1 phenocopied the inhibitory effects of miR-195-5p overexpression in NSCLC cell function. These findings suggest that miR-195-5p could be used as a potential prognostic predictor and tumor suppressor in NSCLC.
http://bit.ly/2softP5
Uncertainty in cardiac myofiber orientation and stiffnesses dominate the variability of left ventricle deformation response
Summary
Computational cardiac modelling is a mature area of biomedical computing, and is currently evolving from a pure research tool to aiding in clinical decision making. Assessing the reliability of computational model predictions is a key factor for clinical use, and uncertainty quantification (UQ) and sensitivity analysis are important parts of such an assessment. In this study, we apply UQ in computational heart mechanics to study uncertainty both in material parameters characterizing global myocardial stiffness and in the local muscle fiber orientation that governs tissue anisotropy. The uncertainty analysis is performed using the polynomial chaos expansion (PCE) method, which is a non‐intrusive meta‐modeling technique that surrogates the original computational model with a series of orthonormal polynomials over the random input parameter space. In addition, in order to study variability in the muscle fiber architecture, we model the uncertainty in orientation of the fiber field as an approximated random field using a truncated Karhunen‐Loéve expansion. The results from the UQ and sensitivity analysis identify clear differences in the impact of various material parameters on global output quantities. Furthermore, our analysis of random field variations in the fiber architecture demonstrate a substantial impact of fiber angle variations on the selected outputs, highlighting the need for accurate assignment of fiber orientation in computational heart mechanics models.
http://bit.ly/2H76RGN
Predicting locally advanced rectal cancer response to neoadjuvant therapy with 18 F-FDG PET and MRI radiomics features
Abstract
Purpose
Pathological complete response (pCR) following neoadjuvant chemoradiotherapy or radiotherapy in locally advanced rectal cancer (LARC) is reached in approximately 15–30% of cases, therefore it would be useful to assess if pretreatment of 18F-FDG PET/CT and/or MRI texture features can reliably predict response to neoadjuvant therapy in LARC.
Methods
Fifty-two patients were dichotomized as responder (pR+) or non-responder (pR-) according to their pathological tumor regression grade (TRG) as follows: 22 as pR+ (nine with TRG = 1, 13 with TRG = 2) and 30 as pR- (16 with TRG = 3, 13 with TRG = 4 and 1 with TRG = 5). First-order parameters and 21 second-order texture parameters derived from the Gray-Level Co-Occurrence matrix were extracted from semi-automatically segmented tumors on T2w MRI, ADC maps, and PET/CT acquisitions. The role of each texture feature in predicting pR+ was assessed with monoparametric and multiparametric models.
Results
In the mono-parametric approach, PET homogeneity reached the maximum AUC (0.77; sensitivity = 72.7% and specificity = 76.7%), while PET glycolytic volume and ADC dissimilarity reached the highest sensitivity (both 90.9%). In the multiparametric analysis, a logistic regression model containing six second-order texture features (five from PET and one from T2w MRI) yields the highest predictivity in distinguish between pR+ and pR- patients (AUC = 0.86; sensitivity = 86%, and specificity = 83% at the Youden index).
Conclusions
If preliminary results of this study are confirmed, pretreatment PET and MRI could be useful to personalize patient treatment, e.g., avoiding toxicity of neoadjuvant therapy in patients predicted pR-.
http://bit.ly/2RozDqZ
Electroacupuncture for Women with Chronic Severe Functional Constipation: Subgroup Analysis of a Randomized Controlled Trial
Background. Acupuncture has been found to be effective for treating chronic constipation. Objective. The objective of this exploratory study was to evaluate the efficacy of electroacupuncture (EA) in the subgroup of women with chronic severe functional constipation. Methods. This is a subgroup analysis of the multicenter, randomized, sham-acupuncture (SA) controlled trial. The efficacy of 822 (76%) female patients of the 1075 randomized patients with chronic severe functional constipation was evaluated. Patients were randomly assigned to receive 28 sessions of EA or SA over 8 weeks with 12 weeks' follow-up. This study focused on sustained complete spontaneous bowel movements (CSBMs) responders over the 8-week treatment. Results. The primary outcome which was percentage of the sustained CSBMs responders for the subset of women with severe constipation was significantly higher in the EA group (24.3%) than in the SA group (8.1%) with difference of 13.1% (95%CI, 6.5% to 19.7%; P
http://bit.ly/2spGCBc
C4d detection and histological patterns in the diagnosis of antibody‐mediated rejection after lung transplantation: a single‐centre study
Abstract
Aims
Antibody‐mediated rejection (AMR) is an emerging and challenging issue in transplantation. Endothelial deposition of C4d and microvascular inflammation (MI) are reliable markers of AMR in renal and cardiac transplantation (Tx), but remain controversial in lung.
Methods and results
In order to assess C4d immunohistochemistry and histological patterns for the diagnosis of lung AMR, we reviewed 158 transbronchial biopsies (TBBs) (n=85 clinically indicated, and n=73 surveillance TBBs) from 48 recipients, blindly of clinical and serological data. C4d was scored as 0, 1+ (<10%), 2+ (10% to 50%) or 3+ (>50%). TBBs were reassessed for MI and acute lung injury (ALI). Donor‐specific antibodies (DSAs), acute and chronic graft dysfunction (CLAD) were recorded.
C4d3+, C4d2+, C4d1+ and C4d0 occurred respectively in 4 (2.5%), 6 (3.8%), 28 (17.7%) and 120 (75.9%) TBBs. MI and ALI were rare but more frequent in C4d1‐3+ TBBs than in the absence of C4d.C4d2+ was frequently observed with concomitant infection. Among the surveillance TBBs, only 2 (2.7%) displayed MI. Neither ALI nor C4d3+ was diagnosed on surveillance TBBs. No significant association was found between histopathological findings and DSAs. All 4 patients with C4d3+ could retrospectively be diagnosed with AMR and developed CLAD.
Conclusion
Although rare, diffuse C4d deposition appears as a strong argument for acute clinical AMR in lung transplantation, whereas intermediate C4d2+ requires more investigations. In stable patients, histopathology and C4d may lack sensitivity to diagnose sub‐clinical AMR. This emphasizes the need of a multidisciplinary evaluation of each suspected AMR case, and of complementary diagnostic tools.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Rq19nZ
Neoadjuvant chemoradiation for patients with advanced esophageal cancer‐ Which response grading system best impacts prognostic discrimination?
Abstract
Aim
Neoadjuvant chemoradiation reduces tumor volume and improves R0 resection rate, followed by extended survival for patients with advanced esophageal cancer. The degree of tumor regression has high prognostic relevance. To date, there is still no generally accepted tumor regression grading system. The aim of this study was to compare the prognostic discrimination power of different histological regression grading systems: a. the fibrosis/tumor ratio within the primary tumor (Mandard), b. the percentage of residual vital tumor cells (VTC) compared to the original primary tumor (Cologne Regression), and c. the ypT Category, in patients with cT3 carcinoma of the esophagus after neoadjuvant chemoradiation.
Methods and results
This study included 216 patients with esophageal cancer clinically staged as cT3NxM0 and treated from 2009 to 2012 with standardized chemoradiation followed by esophagectomy (median age 62 years, 176 (81%) male and 138 (64%) adenocarcinoma patients). The subgroup frequencies of the three classification systems were ypT‐category: ypT0=18%, ypT1=14%, ypT2=23%, ypT3=44%, ypT4=1%; Mandard Classification: TRG1=18%, TRG2=26%, TRG3=24%, TRG4=30%, TRG5=2%; and Cologne Regression Scale: no tumor=18%, 1‐10% VTC=27%, 10‐50% VTC=26% and >50% VTC=29%. The Mandard and Cologne Regression classifications showed better prognostic differentiation for the subgroups than ypT‐category. The four‐tiered Cologne Regression system had a good prognostic relevance.
Comparing results of the reevaluated Cologne Regression classification with the classification by routine pathological report showed very good inter‐rater agreement, with kappa value 0.891.
Conclusion
Tumor regression grading system using the percentage of residual vital tumor compared to the original primary tumor has prognostic relevance.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Ch9joo
A phenotypic map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites
Abstract
Background
Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterization of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages and paired primary‐metastatic comparisons between samples from the same patient are difficul.
Methods
We report the evaluation of 88 patients with HCC who underwent autopsy, including multi‐regional sampling of primary and metastatic sites totaling 230 nodules analyzed. The study included morphologic assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC.
Results
We confirm a strong predilection of HCC for lung dissemination, including sub‐clinical micro‐metastases (unrecognized during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumor nodule, multi‐nodularity, macrovascular invasion, high histological, nuclear and architectural grades, and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significant higher K19 and EpCAM expression than primary liver tumors. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumor, sometimes to a specific hepatic nodule.
Conclusions
This study suggest limited heterogeneity in metastatic sites compared to primary tumor sites.
This article is protected by copyright. All rights reserved.
http://bit.ly/2RlYgVn
Hypoxia related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma
Abstract
Aims
The present study evaluates the impact of hypoxia related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralize intracellular acidosis in classical Hodgkin's lymphoma (cHL).
Methods
81 primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analyzed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia related histological and functional data with survival characteristics.
Results
Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin‐Reed‐Sternberg (HRS) cells in 39/81 samples (48.1%) while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS‐cells could be demonstrated in only 18/77 samples (23.4%) with significant stromal positivity (50/77, 64.9%). The CAIX+ phenotype was strongly associated with lymphocyte depletion (4/4, 100%) and nodular sclerosis (29/51, 56.9%) subtypes. CAIX/Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX+ compared to CAIX‐ HRS‐cells (p<0.001). 72 months progression free survival (PFS) was significantly lower for the CAIX+ group (0.192) compared with the CAIX‐ group (0.771)(p<0.001) while the overall survival (OS) did not differ (p=0.097).
Conclusion
Hypoxic stress related adaptation ‐ highlighted by CAIX expression ‐ results in cellular quiescence in HRS‐cells potentially contributing to the short term failure of the standard chemotherapy in cHL.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Ckj9pL
DNA Damage Repair Alterations are Frequent in Prostatic Adenocarcinomas with Focal Pleomorphic Giant Cell Features
Abstract
Aims
Prostatic adenocarcinomas with focal pleomorphic giant cell features are a rare tumour subtype with abysmal clinical outcomes. More than one third of cases with this histology die within a year of the initial diagnosis of prostate cancer. Potential targeted therapies are desperately needed, however the molecular features of these tumours remain unknown.
Materials and Methods
Here, we performed next generation sequencing using a highly validated targeted panel (UW‐Oncoplex) on somatic tumour DNA extracted from 8 cases of prostatic adenocarcinomas with focal pleomorphic giant cell features, including cases with and without prior treatment for prostate cancer.
Results
We find that DNA damage repair mutations are common in this rare subset of prostate tumours, with 2 of 8 having bi‐allelic pathogenic mutations in homologous DNA repair genes (including BRCA2 and NBN) and 2 of 8 having bi‐allelic pathogenic mutations in mismatch repair genes (including MSH2 and MLH1).
Conclusion
These data are consistent with emerging data that DNA repair alterations are enriched among castration resistant prostate cancer and aggressive subsets of primary tumours. Given that these patients are potential candidates for PARP inhibitor and/or immune checkpoint blockade and have poor prognosis with standard therapy, we recommend tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant cell features.
This article is protected by copyright. All rights reserved.
http://bit.ly/2RlQGdr
SMAD4 alteration associates with invasive‐front pathological markers and poor prognosis in colorectal cancer
Abstract
Objective
SMAD4 acts as a tumor suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC). Although next‐generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC.
Methods
We retrospectively investigated 201 patients with Stage I‐IV CRC, using a 415‐gene panel. To analyze the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables including invasive‐front pathological markers: tumor budding, poorly differentiated cluster, and Crohn‐like lymphoid reaction.
Results
Fifty‐six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive‐front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn‐like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I‐III disease, SMAD4 alteration was significantly associated with poor prognosis on relapse‐free and overall survivals (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival.
Conclusion
SMAD4 alteration is associated with invasive‐front pathological markers and poor prognosis in Stage I‐III CRC.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Cgr0EL
Cefuroxime Plasma and Tissue concentrations in Patients Undergoing Elective Cardiac Surgery: Continuous versus Bolus Application A Pilot Study
Abstract
Aim
Surgical site infections contribute to morbidity and mortality after surgery. The authors hypothesized that higher antibiotic tissue concentrations can be reached for a prolonged time span by continuous administration of prophylactic cefuroxime compared to bolus administration.
Methods
Twelve patients undergoing elective cardiac surgery were investigated. Group A received 1.5 g cefuroxime as bolus infusions before surgery, and 12 and 24 hours thereafter. In group B, a continuous infusion of 3.0 g cefuroxime was started after a bolus of 1.5 g. Cefuroxim levels were determined in blood and tissue (microdialysis). T‐test, Wilcoxon Signed Rank test, and chi‐square test were used for statistical analysis.
Results
The area under the curve (AUC) of plasma cefuroxime concentrations was greater in group B (399 [333‐518]) as compared to group A (257 [177‐297] h•mg•L‐1, (median and IQR), P = 0.026). Furthermore, a significantly longer percentage of time > minimal inhibitory concentrations of 2 mg•L‐1 (100% vs. 50%), 4 mg•L‐1 (100% vs. 42%), 8 mg•L‐1 (100% vs. 17%), and 16 mg•L‐1 (83% vs. 8%) was found for free plasma cefuroxime in group B. In group B AUC in subcutaneous tissue (78 [61‐113] h•mg•L‐1) and median peak concentration (33 [26‐38] mg•L‐1) were markedly higher compared to group A (P = 0.041 and P = 0.026, respectively).
Conclusions
Higher cefuroxime concentrations were measured in plasma and subcutaneously over a prolonged period of time when cefuroxime was administered continuously. The clinical implication of this finding still has to be elucidated.
http://bit.ly/2RGlkxz
Volume of motor area predicts motor impulsivity
Abstract
Impulsivity is a personality trait associated with many maladaptive behaviors. Trait impulsivity is typically divided into three different dimensions, including attentional impulsiveness, motor impulsiveness, and non‐planning impulsiveness. The present work aimed to investigate the neuroanatomical basis of the multidimensional impulsivity trait. Eighty‐four healthy subjects were studied with structural magnetic resonance imaging. Multiple regression analyses revealed that the score of motor impulsiveness was negatively correlated with gray matter volumes of the right supplementary motor area and paracentral lobule. A machine‐learning based prediction analysis indicated that decreased gray matter volumes of the supplementary motor area and paracentral lobule strongly predicted deficits in motor impulsiveness control. Our findings provide insights into the predictive role of motor brain structures in motor impulsivity and inhibition control.
This article is protected by copyright. All rights reserved.
http://bit.ly/2D7VZV1
Residual LCMV antigen in transiently CD4+ T cell‐depleted mice induces high levels of virus‐specific antibodies but only limited B cell memory
Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (Arm) induces an acute infection with rapid virus clearance by CD8+ T cells independently of CD4+ T cell help. Residual viral antigen may, however, persist for a prolonged time. Here, we demonstrate that mice that had been transiently depleted of CD4+ T cells during acute LCMV Arm infection generated high levels of virus‐specific IgG antibodies (Ab) after viral clearance. Robust induction of LCMV‐specific IgG after transient CD4+ T cell depletion was dependent on Fcγ receptors but not on the complement receptors CD21/CD35. In contrast to the potent production of LCMV‐specific IgG, the generation of LCMV‐specific isotype‐switched memory B cells after transient CD4+ T cell depletion was considerably reduced. Moreover, mice depleted of CD4+ T cells during acute infection were strongly impaired in generating a secondary LCMV‐specific B cell response upon LCMV rechallenge. In conclusion, our data indicate that LCMV antigen depots after viral clearance were capable of inducing high levels of virus‐specific IgG. They failed, however, to induce robust virus‐specific B cell memory revealing a previously unappreciated dichotomy of specific Ab production and memory cell formation after priming with residual antigen.
This article is protected by copyright. All rights reserved
http://bit.ly/2TL0b2t
Diagnostic manifestations of total hemispheric glucose metabolism ratio in neuronal network diaschisis: diagnostic implications in Alzheimer’s disease and mild cognitive impairment
Abstract
Purpose
We tested the hypothesis that lateralized hemispheric glucose metabolism may have diagnostic implications in Alzheimer's disease (AD) and mild cognitive impairment (MCI).
Methods
We performed FDG-PET/CT in 23 patients (mean age 63.7 years, range 50–78, 17 females) diagnosed with AD (n = 15) or MCI (n = 8) during a six-month period in 2014. Ten neurologically healthy individuals (HIs) (mean age 62.5 years, range 43–75, 5 females) served as controls. A neuroimaging expert provided visual assessment of diaschisis. The total hemispheric glucose metabolism ratio (THGr) was calculated, and with area-under the curve of receiver operating characteristics (AUC-ROC) we generated a "Network Diaschisis Test (NDT)".
Results
The qualitative detection of cerebral (Ce) and cerebellar (Cb) diaschisis was 7/15 (47%), 0/8 (0%), and 0/10 (0%) in AD, MCI, and HI groups, respectively. Median cerebral THGr was 0.68 (range 0.43–0.99), 0.86 (range 0.64–0.98), and 0.95 (range 0.65–1.00) for AD, MCI, and HI groups, respectively (p = 0.04). Median cerebellar THGr was, respectively, 0.70 (range 0.18–0.98), 0.70 (range 0.48–0.81), and 0.84 (range 0.75–0.96) (p = 0.0138). A positive NDT yielded a positive predictive value of 100% for the presence of AD or MCI and a 86% negative predictive value for healthy brain. Moreover, the diagnostic manifestation of THGr between MCI and AD led to a positive predictive value of 100% for AD, but a negative predictive value of 42.9% for MCI.
Conclusion
Patients with AD or MCI had more pronounced diaschisis, lateralized hemispheric glucose metabolism and lower THGr compared to healthy controls. The NDT distinguished AD and MCI patients from HIs, and AD from MCI patients with a high positive predictive value and moderate and low negative predictive values. THGr can be a straightforward source of investigating neuronal network diaschisis in AD and MCI and in other cerebral diseases, across institutions.
http://bit.ly/2D6A9RS
Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice
Abstract
Purpose
REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy.
Methods
Radium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated.
Results
This interim analysis included 583 patients. Median duration of observation was 7 months (range, 0–20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group.
Conclusions
The short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.
http://bit.ly/2TKrjig
Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy
http://bit.ly/2HhYVmi
Mitochondria-driven elimination of cancer and senescent cells
Journal Name: Biological Chemistry
Issue: Ahead of print
http://bit.ly/2RqOjGi
Visualizing Cellular Gibberellin Levels Using the NlsGPS1 Förster Resonance Energy Transfer (FRET) Biosensor
Gibberellin Perception Sensor 1 (GPS1) is the first Förster resonance energy transfer-based biosensor for measuring the cellular levels of gibberellin phytohormones with a high spatiotemporal resolution. This protocol reports on the method to visualize and quantify cellular gibberellin levels using the genetically encoded nlsGPS1 biosensor in Arabidopsis hypocotyls and root tips.
http://bit.ly/2D5PmT7
A Novel Approach to Monitoring Graft Neovascularization in the Human Gingiva
http://bit.ly/2RLpNPn
Normothermic Ex Situ Heart Perfusion in Working Mode: Assessment of Cardiac Function and Metabolism
http://bit.ly/2HcvqlB
Distribution of Migraine Attacks over the Days of the Week: Preliminary Results from a Web‐Based Questionnaire
Abstract
Objectives
The purpose of this work is the analysis of migraine attack reports collected online within the project Migraine Radar in respect to the distribution of the migraine attacks over the week on a single‐participant level.
Materials & Methods
Recording data using a web app as well as smartphone apps made it possible to collect data of 44,639 migraine attacks of 1,085 participants who reported 7 or more attacks over a participation period of at least 90 days. This allows the investigation of attack distributions on a single‐participant level. Considering the day of the week with the highest attack frequency for each participant – the mode of the individual distribution – allows identifying participants suffering from weekend migraines. Namely, a weekend pattern is assumed if the mode falls on a Saturday or Sunday.
Results
For 15.9% of the participants, the attacks were not distributed equally (p < 0.05) over the days of the week. Instead, participants show different individual patterns for the distribution of their migraine attacks. Furthermore, the modes of the individual distributions are not distributed equally over the week. In fact, Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1,085).
Conclusions
Concerning the individual attack distributions, we found that participants show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while other participants show accumulations of their attacks on other days of the week.
This article is protected by copyright. All rights reserved.
http://bit.ly/2FsHIno
Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis
Abstract
Introduction
Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5 years' treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population.
Methods
Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5.
Results
Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2 years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5.
Conclusion
In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2 years in patients with methotrexate-naïve RA are required.
Plain Language Summary
Plain language summary available for this article.
http://bit.ly/2Rrxon1
Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases
Abstract
Background
In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.
Methods
All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.
Results
In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.
Conclusions
The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.
http://bit.ly/2RJgKOR
Variations in right colic vascular anatomy observed during laparoscopic right colectomy
Abstract
Background
This study aimed to analyze right colonic vascular variability.
Methods
The study included 60 consecutive patients who underwent laparoscopic radical right colectomy and D3 lymph node dissection for malignant colonic cancer on the ileocecal valve, ascending colon or hepatic flexure (March 2013 to October 2016). The videos of the 60 surgical procedures were collected. Variations of right colonic vascular anatomy were retrospectively analyzed based on 60 high-resolution surgical videos of laparoscopic surgery.
Results
The superior mesenteric artery and vein were present in all cases; 95.0% (57/60) had the superior mesenteric artery on the left side of the superior mesenteric vein. The ileocolic artery and vein occurred in 96.7% (58/60) and 100% (60/60) of cases, respectively; 50.0% (29/58) had the ileocolic artery passing the superior mesenteric vein anteriorly. Thirty-three (55.0%) cases had a right colic artery, and 2 (3.33%) had a double right colic artery; 90.9% (30/36) had the right colic vein passing anterior to the superior mesenteric artery. Fifty-six (93.3%) cases had a right colic vein; 7 (12.5%) had a right colic vein accompanied by a right colic artery, 66.1% (37/56) had the right colic vein draining into the gastrocolic trunk of Henle, 23.2% (13/56) had the right colic vein directly draining into superior mesenteric vein, and 10.7% (6/56) had one right colic vein draining into the superior mesenteric vein and the other into the gastrocolic trunk of Henle. Fifty-three (88.3%) cases had a gastrocolic trunk of Henle: a gastrocolic trunk in 35.8% (19/53), a gastropancreatic trunk in 9.4% (5/53), and a gastropancreaticocolic trunk in 54.7% (29/53). The frequencies of middle colic artery and vein were respectively 100% (60/60) and 93.3% (56/60).
Conclusions
Right colonic vascular variations were classified in Chinese patients. Notable findings included a superior mesenteric artery positioned to the right of the superior mesenteric vein and variation in middle colic artery length. This knowledge may be helpful to colorectal surgeons and could potentially help to improve safety by reducing vascular complications during minimally invasive procedures.
http://bit.ly/2VQtjYa
Correction to: MiRNA-126 expression inhibits IL-23R mediated TNF-α or IFN-γ production in fibroblast-like synoviocytes in a mice model of collagen-induced rheumatoid arthritis
The authors would like to add an article note stating that "The authors Jie Gao and Ruina Kong have equally contributed to the article".
http://bit.ly/2RnMY2N
Peri‐implantitis and its prevention
Abstract
This perspective article on peri‐implantitis and its prevention was produced as a supplement to a 3‐D, computer‐animated film aiming at presenting key characteristics of peri‐implant health, the build‐up of a biofilm and the ensuing host‐response resulting in peri‐implant mucositis and, subsequently, peri‐implantitis. Treatment concepts for peri‐implantitis were briefly reviewed and prevention of the condition was brought to attention as a priority in implant dentistry. The overview also highlighted the 2017 World Workshop on Classification of Periodontal and Peri‐implant diseases and Conditions, in which new disease definitions and case definitions were presented for peri‐implant health, peri‐implant mucositis and peri‐implantitis.
This article is protected by copyright. All rights reserved.
http://bit.ly/2D6xHL9
Missed Injuries in Combat Casualties: Lessons from Iraq and Afghanistan
Publication date: Available online 11 January 2019
Source: Injury
Author(s): Vicente J. Undurraga Perl, Connie Johnson, Sean Kelley, Pam Woods, Kathleen Martin, David Zonies
Abstract
Introduction
Once injured in the battlefield in Iraq and Afghanistan, U.S. and NATO troops receive medical treatment through tiered echelons of care with varying resources, from austere to state-of-the-art. Similar to civilian trauma systems, the aim is to provide rapid and safe patient movement toward definitive management. A consequence of the rapid transfer of patients is the possibility of missed or delayed diagnosis of injuries. With the new injury patterns seen during these conflicts, we aimed to identify and characterize which injuries are missed and what consequences do they have on our troops' road to recovery.
Patients and Methods
A retrospective review of a PI database (established 2007) for consecutively admitted combat casualties was performed between 2007-2013. Baseline patient characteristics, injury year, admitting service, injury type, and subsequent management decisions were categorized and analyzed.
Results
There were 301 missed injuries (MI) identified in 248 patients. The annual missed injury rate was 25 per 1000 admissions. Missed injuries were associated with a penetrating mechanism (82.7% vs 58.5%, p < 0.001), ICU admission (58.5% vs 27.4%, p < 0.001), higher ISS (median 14 vs 8, p < 0.001), and a longer length of stay (median 3 versus 2 days, p < 0.001). 194 (64.5%) missed injuries led to a change in management, with 68 (22.6%) requiring a surgical procedure. 1.3% of missed injuries were life threatening, 28.2% major and 65.4% minor. The most common injuries were distal extremity fractures (23.9%), followed by spine fractures (13.3%) and traumatic tympanic membrane rupture (12.6%), There were no deaths attributed to a missed injury.
Discussion
Missed injuries during combat operations occur on a low but consistent basis. Most injuries are orthopedic in nature and typically occur in critically ill patients admitted to the ICU. It is rare that a missed injury results in a life-threatening condition.
Conclusion
As healthcare practitioners prepare for future deployments, this analysis may serve as a resource to focus on frequently missed injuries and possibly improve their detection.
http://bit.ly/2RrnUIr
HIV infection in Xi’an, China: epidemic characterization, risk factors to false positives and potential utility of the sample-to-cutoff index to identify true positives using Architect HIV Ag/Ab combo
In China, although tremendous efforts has been made, the HIV/AIDS is still not controlled.
http://bit.ly/2FsHw7J
Correction to: Non-prescribed sale of antibiotics for acute childhood diarrhea and upper respiratory tract infection in community pharmacies: a 2 phase mixed-methods study
The original article [1] contains a minor omission.
http://bit.ly/2FpTWxO
Correction to: Efficacy of intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B for post-neurosurgical intracranial infections due to MDR/XDR Acinectobacter baumannii: a retrospective cohort study
The original article [1] contains an error in the Safety analysis sub-section of the results regarding the reported mean creatinine level.
http://bit.ly/2FoZfxv
Is Use of Warning Lights and Sirens Associated With Increased Risk of Ambulance Crashes? A Contemporary Analysis Using National EMS Information System (NEMSIS) Data
We compare reported crash rates for US ambulances responding to or transporting patients from a 911 emergency scene with or without lights and sirens. Our null hypothesis is that there will be no difference in the rate of ambulance crashes whether lights and sirens are used.
http://bit.ly/2Rpbi4v
Clostridium difficile infections in teaching hospital in northern Finland
The aim of this study to compare the incidence of Clostridium difficile (CD) infections in the five university hospital districts in Finland based on national register. The clinical findings of CD cases in the...
http://bit.ly/2RI6yGA
Rates of hospitalization and death for all-cause and rotavirus acute gastroenteritis before rotavirus vaccine introduction in Kenya, 2010–2013
Rotavirus vaccine was introduced in Kenya immunization program in July 2014. Pre-vaccine disease burden estimates are important for assessing vaccine impact.
http://bit.ly/2HaGWOp
Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae isolated from the nasopharynx of children with acute otitis media
Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae has been implicated in the pathogenesis of otitis media, mainly in chronic and recurrent cases. We studied the "in vitro" biofilm producti...
http://bit.ly/2RKQIef
Using clinical practice guidelines to manage dengue: a qualitative study in a Malaysian hospital
Malaysia has rising dengue incidence. World Health Organization clinical practice guidelines for managing dengue have been adapted by the Ministry of Health in Malaysia, with evidence of good awareness by clin...
http://bit.ly/2H86Mm1
Prevalence, genotype and antimicrobial resistance of Clostridium difficile isolates from healthy pets in Eastern China
Clostridium difficile (C. difficile) is a main cause of antibiotic-associated diarrhoea in humans. Several studies have been performed to reveal the prevalence rate of C. difficile in cats and dogs. However, litt...
http://bit.ly/2RNcNsw
Plant growth-promoting rhizobacterium Pseudomonas PS01 induces salt tolerance in Arabidopsis thaliana
Plant growth-promoting rhizobacteria (PGPR) may contribute to sustainable crop production by improving plant growth and/or plant tolerance to abiotic stresses. Soil salinity, which limits the productivity of c...
http://bit.ly/2VMXrUb
Association of objective sedentary behaviour and self-rated health in English older adults
Reducing sedentary behaviour (SB) might improve the health of older adults. However, we know little about how objectively measured SB impacts on self-rated health in older adults. We aimed to explore the assoc...
http://bit.ly/2QFhyzO
PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA
Abstract
Background
Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression.
Methods
We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels.
Results
We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer.
Conclusions
These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.
http://bit.ly/2H6tgDV
LPS-induced CXCR7 expression promotes gastric Cancer proliferation and migration via the TLR4/MD-2 pathway
Lipopolysaccharide (LPS) from Helicobacter pylori (HP) plays an important role in gastric cancer occurrence and development. Toll-like receptor 4 (TLR4) and myeloid differential protein-2 (MD-2) are also reported...
http://bit.ly/2RPjSJm
Miliary pattern MRSA sepsis following clandestine intravenous infusion
Abstract
Intravascular devices aid in drug administration and fluid replacement for hospitalized patients and are thus an integral part of modern medical care; however, poor aseptic technique and improper manipulation of infusion devices increase the risk of infections secondary to catheterization that can progress to sepsis and septic shock. We report the case of a woman who presented with altered mental status after receiving normal saline through an intravenous catheter placed by a medically untrained individual. Less than 24 h following her initial presentation to emergency medical services the patient became unresponsive to multiple vasopressors and broad-spectrum antibiotics and succumbed to septic shock. At autopsy, the decedent had enumerable hemorrhagic lesions consistent with septic emboli, and microscopic examination revealed clusters of coccoid-appearing bacteria. Cultures of the intravenous fluid and IV tubing collected at the decedent's home grew methicillin-resistant Staphylococcus aureus (MRSA), which was consistent with ante-mortem cultures. This case highlights the rapid clinical deterioration and autopsy presentation of MRSA sepsis due to contamination of the intravenous delivery system.
http://bit.ly/2RPk4Z6
Histological characteristics of the largest and secondary tumors in radical prostatectomy specimens and implications for focal therapy
Pathological features of prostate cancer in Korean men were analyzed to determine whether identification of tumor volume, Gleason score (GS), focality, and location using radical prostatectomy (RP) specimens c...
http://bit.ly/2H832Rv
Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia
In this study, we present the mutation profile of 25 genes and the mRNA expression pattern of 107 genes in a cohort of atypical chronic myeloid leukemia cases (aCML, n = 26) in comparison with a cohort of chronic myelomonocytic leukemia cases (CMML, n = 59). Our aim was to identify molecular markers which may contribution to the discrimination of aCML and CMML, two entities of hematopoietic neoplasms which display a combination of myelodysplastic and myeloproliferative features (MDS/MPN). Employing a machine learning classification approach using linear discriminant analysis of the mutation data, we were able to classify more than 85% of aCML and CMML cases correctly In addition, a statistically significant negative correlation of SETBP1 mutation (in aCML) and TET2 mutation (in CMML) with the presence of a blast excess in the bone marrow was found.
Abstract
Atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) represent two histologically and clinically overlapping myelodysplastic/myeloproliferative neoplasms. Also the mutational landscapes of both entities show congruencies. We analyzed and compared an aCML cohort (n = 26) and a CMML cohort (n = 59) by next‐generation sequencing of 25 genes and by an nCounter approach for differential expression in 107 genes. Significant differences were found with regard to the mutation frequency of TET2, SETBP1, and CSF3R. Blast content of the bone marrow revealed an inverse correlation with the mutation status of SETBP1 in aCML and TET2 in CMML, respectively. By linear discriminant analysis, a mutation‐based machine learning algorithm was generated which placed 19/26 aCML cases (73%) and 54/59 (92%) CMML cases into the correct category. After multiple correction, differential mRNA expression could be detected between both cohorts in a subset of genes (FLT3, CSF3R, and SETBP1 showed the strongest correlation). However, due to high variances in the mRNA expression, the potential utility for the clinic is limited. We conclude that a medium‐sized NGS panel provides a valuable assistance for the correct classification of aCML and CMML.
http://bit.ly/2Rl6xZH
Three inflammation‐related genes could predict risk in prognosis and metastasis of patients with breast cancer
This study revealed an important novel finding by reporting a mRNA‐based classifier developed by Cox proportional hazards regression algorithm with a three‐mRNA signature to predict prognosis of breast cancer with or without metastasis in 1938 patients. The robustness and the independence of the prognostic model were successfully validated in training and test datasets.
Abstract
Background
Current predictive model is not developed by inflammation‐related genes to evaluate clinical outcome of breast cancer patients.
Methods
With mRNA expression profiling, we identified 3 mRNAs with significant expression between 15 normal samples and 669 breast cancer patients. Using 7 cell lines and 150 paraffin‐embedded specimens, we verified the expression pattern by bio‐experiments. Then, we constructed a three‐mRNA model by Cox regression method and approved its predictive accuracy in both training set (n = 1095) and 4 testing sets (n = 703).
Results
We developed a three‐mRNA (TBX21, TGIF2, and CYCS) model to stratify patients into high‐ and low‐risk subgroup with significantly different prognosis. In training set, 5‐year OS rate was 84.5% (78.8%‐90.5%) vs 73.1% (65.9%‐81.2%) for the low‐ and high‐risk group (HR = 1.573 (1.090‐2.271); P = 0.016). The predictive value was similar in four independent testing sets (HR>1.600; P < 0.05). This model could assess survival independently with better predictive power compared with single clinicopathological risk factors and any of the three mRNAs. Patients with both low‐risk values and any poor prognostic factors had more favorable survival from nonmetastatic status (HR = 1.740 (1.028‐2.945), P = 0.039). We established two nomograms for clinical application that integrated this model and another three significant risk factors to forecast survival rates precisely in patients with or without metastasis.
Conclusions
This model is a dependable tool to predict the disease recurrence precisely and could improve the predictive accuracy of survival probability for breast cancer patients with or without metastasis.
http://bit.ly/2CjpIc9
Fatigue, symptom burden, and health‐related quality of life in patients with myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria
Abstract
Background
Fatigue is distressing and affects quality of life (QoL) among patients with myelodysplastic syndrome (MDS), aplastic anemia (AA), and paroxysmal nocturnal hemoglobinuria (PNH). Limited data exist on the impact of fatigue, QoL, and related symptoms in these patients.
Objective
Prospectively assess fatigue (functional assessment of cancer therapy‐anemia [FACT‐An]); QoL (FACT‐An subscales); pain (brief pain inventory); and depression, anxiety, and stress (depression anxiety stress scale‐21) and strategies used to manage these symptoms in patients with MDS, AA, and PNH.
Methods
Surveys were administered via the AA and MDS International Foundation website and database from October 2014 through April 2015 in a cross‐sectional study. Results were summarized using descriptive statistics.
Results
Of 303 patients, 145 (48%) had MDS, 84 (28%) had AA, and 74 (24%) had PNH; 31 (10%) had >1 diagnosis. The mean age was 57 years, 200 (66%) were female, and 195 (92%) were white. The mean fatigue scores were 25 (range 1‐52) for the whole cohort, 28 for AA, 25 for MDS, and 24 for PNH (P = 0.117); these are all considered severe level. The mean QoL score was 68 (range 10‐104) for the whole cohort, 67 for AA, 69 for MDS, and 67 for PNH (P = 0.821). The ranges for stress were normal; pain and depression, mild; and anxiety, moderate. The most common management strategies perceived as helpful for fatigue in the past month were preserving energy, physical activity, and naps.
Conclusions
Many patients with MDS, AA, and PNH report severe fatigue. The helpfulness of fatigue management strategies may impact patients' continued use; whether these strategies are beneficial and decrease fatigue levels needs more study.
http://bit.ly/2RnwyHH
The role and molecular mechanism of Trop2 induced epithelial‐mesenchymal transition through mediated β‐catenin in gastric cancer
Trop2 as a useful marker for inducing EMT and metastasis of GC, which may help to lead a better understanding of the pathogenesis of the GC.
Abstract
The present study elucidates the potential role of Trop2 in tumor invasion and the promotion of epithelial‐mesenchymal transition (EMT) when binding β‐catenin in GC. The role of Trop2 in promoting EMT in GC cells was examined by a variety of experimental assays. Moreover, the underlying molecular mechanism of Trop2 in promoting EMT was studied by in vivo and in vitro assays. The Trop2 expression in relation to tumor metastasis status was detected by IHC in 248 cases of GC tissues and 86 cases of matched adjacent tissues. Trop2 promoted the metastasis and induces EMT in GC. Meanwhile, the elevated protein levels of Trop2 and mesenchymal markers were also found in the TGF‐β1‐induced EMT model in GC cells. Importantly, Trop2 physically bound and activated β‐catenin to promote EMT; moreover, Trop2 increased the accumulation of β‐catenin in the nucleus to accelerate metastasis in GC cells. Inhibition of Trop2 expression in GC cells prevented the migration and invasion of GC cells in vivo. Trop2+/vimentin+ expression was higher in GC tissues than that in matched adjacent tissues, and Trop2+/vimentin+ expression in GC was associated with the differentiation, TNM stage, and distant metastases. These sets of data reveal a novel regulatory network of Trop2 in EMT and GC metastasis, suggesting Trop2 as a useful marker for inducing EMT and metastasis of GC, which may help to lead a better understanding of the pathogenesis of the GC.
http://bit.ly/2CgbCIk
Human papillomavirus types in cervical high‐grade lesions or cancer among Nordic women—Potential for prevention
In this multicountry study, we present the prevalence and type distribution of human papillomavirus (HPV) in CIN2/CIN3 or cervical cancer among Nordic women. While HPV16/18 vaccination can prevent a large proportion of these cervical lesions, HPV16/18/31/33/45/52/58 vaccination could add an important protection against cervical high‐grade lesions and cancer. Our results are based on one of the largest pre‐vaccination population‐based series of HPV typing of cervical lesions and may thus assist in assessing type‐specific disease burden and population impact of HPV vaccination.
Abstract
It is valuable to establish a population‐based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high‐grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high‐grade precancerous cervical lesions (n = 1240) during 2004‐2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0‐86.4) in CIN2, 91.6% (95% CI 89.7‐93.5) in CIN3, and 86.4% (95% CI 83.7‐89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2‐40.6; CIN3: 50.2%, 95% CI 46.8‐53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8‐13.9; CIN3: 12.1%, 95% CI 9.9‐14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9‐52.7 and 15.3%, 95% CI 12.5‐18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0‐46.7) of CIN2, 57% (95% CI 53.8‐60.5) of CIN3 and 64% (95% CI 60.3‐67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0‐72.2) in CIN2, 85% (95% CI 82.4‐87.2) in CIN3 and 80% (95% CI 77.0‐83.2) in cervical cancer. This study provides large‐scale and representative baselines for assessing and evaluating the population‐based preventive impact of HPV vaccination.
http://bit.ly/2RkWuDQ
Vestibular dysfunction is a manifestation of 22q11.2 deletion syndrome
Abstract
The 22q11.2 deletion syndrome (22q11.2DS) is the second most common cause of developmental delay after Down syndrome. Impaired cognitive development is highly prevalent, but also motor abnormalities such as hypotonia and delays in achieving motor milestones are described. Instability is frequently detected in children, adolescents, and adults and is mostly attributed to their limited motor performance. Until now, vestibular function has not been investigated in these patients, despite the growing evidence that they often have inner ear malformations. The aim of this prospective study was to identify the presence and character of vestibular dysfunction in 22q11.2DS. We investigated 23 subjects with proven 22q11.2DS, older than the age of 12. We performed caloric testing and pendular rotation chair tests with videonystagmography, cervical vestibular‐evoked myogenic potential (c‐VEMP)‐testing, and posturography. Additional otoscopy and audiometry were performed on all subjects. We found a unilateral caloric hypofunction in 55% of patients, a certain absent c‐VEMP response in 15% of ears, an inconclusive c‐VEMP response in 33% of ears, and abnormal posturography in 68% of patients, of whom 42% displayed a typical vestibular pattern. Remarkably, 90% revealed uni‐ or bilateral weak caloric responses, independent of caloric symmetry. Vestibular dysfunction is frequent in subjects with 22q11.2DS. This knowledge should be taken into account when assessing motor performance in these patients. Additional larger studies are needed to determine whether this dysfunction implicates a therapeutic potential.
http://bit.ly/2AKfLEr
Evaluation of Wearable Digital Devices in a Phase I Clinical Trial
We assessed the performance of two US Food and Drug Administration (FDA) 510(k)‐cleared wearable digital devices and the operational feasibility of deploying them to augment data collection in a 10‐day residential phase I clinical trial. The Phillips Actiwatch Spectrum Pro (Actiwatch) was used to assess mobility and sleep, and the Vitalconnect HealthPatch MD (HealthPatch) was used for monitoring heart rate (HR), respiratory rate (RR), and surface skin temperature (ST). We measured data collection rates, compared device readouts with anticipated readings and conventional in‐clinic measures, investigated data limitations, and assessed user acceptability. Six of nine study participants consented; completeness of data collection was adequate (> 90% for four of six subjects). A good correlation was observed between the HealthPatch device derived and in‐clinic measures for HR (Pearson r = 0.71; P = 2.2e‐16) but this was poor for RR (r = 0.08; P = 0.44) and ST (r = 0.14; P = 0.14). Manual review of electrocardiogram strips recorded during reported episodes of tachycardia > 180 beats/min showed that these were artefacts. The HealthPatch was judged to be not fit‐for‐purpose because of artefacts and the need for time‐consuming manual review. The Actiwatch device was suitable for monitoring mobility, collecting derived sleep data, and facilitating the interpretation of vital sign data. These results suggest the need for fit‐for‐purpose evaluation of wearable devices prior to their deployment in drug development studies.
http://bit.ly/2SOFpPl
Dose tailoring of human cell line‐derived recombinant factor VIII simoctocog alfa: using a limited sampling strategy in patients with severe haemophilia A
Summary
Background
The use of www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2607 prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK‐tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients.
Objectives
To develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples.
Patients/Methods
PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analyzed. The Factor VIII data measured using two different assays (chromogenic and the one‐stage clotting assay) were fit to separate develop population PK models using nonlinear mixed‐effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%.
Results
The PK data for chromogenic and the one‐stage clotting assays were both best described by a 2‐compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 h allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for two assay methods).
Conclusion
In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.
http://bit.ly/2SOU64V
Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway
A series of novel quinoxaline derivatives was evaluated for their cytotoxic activity. Compound 12 showed potent antiproliferative activity against three cancer cell lines, and the biological studies showed that it inhibited tubulin polymerization, induced ROS production, and led to cancer cells apoptosis. The binding mode was also probed.
Abstract
A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19–0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose‐dependent manner. Western blot analysis showed that compound 12 induced up‐regulation of p21 and affected the expression of cell cycle‐related proteins. The binding mode was also probed by molecular docking.
http://bit.ly/2TKoOwe
Genital tract tears in women giving birth on a birth seat: A cohort study with prospectively collected data
Publication date: Available online 11 January 2019
Source: Women and Birth
Author(s): Li Thies-Lagergren, Trine Uldbjerg, Rikke Maimburg Damkjær
Abstract
Background
Birth positions may influence the risk of tears in the genital tract during birth. Birth positions are widely studied yet knowledge on genital tract tears following birth on a birth seat is inconclusive.
Aim
The objective of this study was to describe the proportion of genital tract tears in women who gave birth on a birth seat compared to women who did not.
Method
An observational cohort study based on birth information collected prospectively. In total 10 629 live, singleton, non-instrumental births in cephalic presentation were studied.
Results
Fewer women who gave birth on a birth seat experienced an overall intact genital tract compared to women who gave birth in any other position. Women who gave birth on a birth seat were less likely to have an episiotomy performed. Women who gave birth vaginally on a birth seat after a previous caesarean section may have an increased risk for sustaining a sphincter tear.
Discussion
It is important to be aware of the decreased chance of an overall intact genital tract area when giving birth on a birth seat. Furthermore, there is a possibly increased risk of sphincter tear in women having a vaginal birth after caesarean. It is required and of importance to provide pregnant women with evidence-based information on factors associated with genital tract tears including birth positions.
http://bit.ly/2FoZVTM
Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet‐Containing Constructs
A coaxial bioprinting platform is developed for fabrication of islet‐containing constructs. With precision control over the location of multiple cells, the coaxial printed constructs may provide protection to the encapsulated islets in the core while simultaneously delivering multiple supporting cells into the shell. This novel strategy has the potential to improve revascularization and provide immune‐protection to the implanted islets.
Abstract
Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin‐based bioink formulation is optimized for islet and islet‐related cell encapsulation and 3D printing. In addition, a custom‐designed coaxial printer is developed for 3D printing of multicellular islet‐containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes.
http://bit.ly/2AHKUs5
Layer‐by‐Layer Cerium Oxide Nanoparticle Coating for Antioxidant Protection of Encapsulated Beta Cells
A potent nano‐scale layer‐by‐layer antioxidant coating is assembled via alternating layers of cerium oxide nanoparticles (CONP) and alginate. Ultrathin coatings on biomaterial surfaces, such as alginate microcapsules, scavenge and protect underlying encapsulated cells from reactive oxygen species (ROS) mediated damage. The high activity and versatility of this coating provides a useful approach for protecting transplanted cells from inflammation.
Abstract
In type 1 diabetes, the replacement of the destroyed beta cells could restore physiological glucose regulation and eliminate the need for exogenous insulin. Immunoisolation of these foreign cellular transplants via biomaterial encapsulation is widely used to prevent graft rejection. While highly effective in blocking direct cell‐to‐cell contact, nonspecific inflammatory reactions to the implant lead to the overproduction of reactive oxygen species, which contribute to foreign body reaction and encapsulated cell loss. For antioxidant protection, cerium oxide nanoparticles (CONPs) are a self‐renewable, ubiquitous, free radical scavenger currently explored in several biomedical applications. Herein, 2–12 alternating layers of CONP/alginate are assembled onto alginate microbeads containing beta cells using a layer‐by‐layer (LbL) technique. The resulting nanocomposite coatings demonstrate robust antioxidant activity. The degree of cytoprotection correlates with layer number, indicating tunable antioxidant protection. Coating of alginate beads with 12 layers of CONP/alginate provides complete protection to the entrapped beta cells from exposure to 100 × 10−6m H2O2, with no significant changes in cellular metabolic activity, oxidant capacity, or insulin secretion dynamics, when compared to untreated controls. The flexibility of this LbL method, as well as its nanoscale profile, provides a versatile approach for imparting antioxidant protection to numerous biomedical implants, including beta cell transplantation.
http://bit.ly/2SQLvif
Near‐Infrared‐Light Activatable Nanoparticles for Deep‐Tissue‐Penetrating Wireless Optogenetics
This review summarizes recent advances in regard to design strategies and synthetic methods for near‐infrared (NIR)‐light activatable optogenetic tools, including lanthanide‐doped upconversion nanoparticles with NIR‐to‐visible ability, and NIR absorbers with photothermal effects. These NIR‐activatable tools enable "remote control" activation and the inhibition of cellular signaling pathways for deep‐tissue‐penetrating wireless optogenetics to occur.
Abstract
Optogenetics has been developed to control the activities and functions of cells with high spatiotemporal resolution, cell‐type specificity, and flexibility. However, current optogenetic tools generally rely on visible light (e.g., blue or yellow) with shallow tissue penetration ability that does require invasive fiber‐optic probes to deliver visible light into organs and animal tissues. This often results in a series of side effects, such as tissue damage and unwanted inflammation. Fortunately, the emerging wireless optogenetic tools that can respond to deep‐tissue‐penetrating near‐infrared (NIR) light have attracted increasing attention due to their much‐reduced damage to living organisms. There are mainly two types of NIR‐activatable optogenetic tools: one uses lanthanide‐doped upconversion nanoparticles to transduce NIR light to visible light to modulate classical opsin‐expressing neurons; the other type couples with an NIR absorber to convert NIR light to heat to activate thermosensitive proteins. These NIR‐activatable optogenetic tools enable low‐invasive "remote control" activation and inhibition of cellular signaling pathways. This approach has great potential to help create more innovative therapies for diseases like cancer, diabetes, and neuronal disorders in the near future. Therefore, this review article summarizes the recent advances on design strategies and synthetic methods of NIR‐activatable nanomaterials for wireless optogenetic applications.
http://bit.ly/2ADTt79
Designing Next‐Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic
There is an unmet medical need in glioblastoma adjuvant chemotherapy for drug delivery carriers that provide sustained and local release of small molecules and combination drugs. Herein, quantitative pharmacokinetic lessons from the clinic that can inform the next generation of materials development for local treatment of glioblastoma are summarized.
Abstract
To date, the clinical outcomes and survival rates for patients with glioblastoma (GB) remain poor. A promising approach to disease‐modification involves local delivery of adjuvant chemotherapy into the resection cavity, thus circumventing the restrictions imposed by the blood–brain barrier. The clinical performance of the only FDA‐approved local therapy for GB [carmustine (BCNU)‐loaded polyanhydride wafers], however, has been disappointing. There is an unmet medical need in the local treatment of GB for drug delivery vehicles that provide sustained local release of small molecules and combination drugs over several months. Herein, key quantitative lessons from the use of local and systemic adjuvant chemotherapy for GB in the clinic are outlined, and it is discussed how these can inform the development of next‐generation therapies. Several recent approaches are highlighted, and it is proposed that long‐lasting soft materials can capture the value of stiff BCNU‐loaded wafers while addressing a number of unmet medical needs. Finally, it is suggested that improved communication between materials scientists, biomedical scientists, and clinicians may facilitate translation of these materials into the clinic and ultimately lead to improved clinical outcomes.
http://bit.ly/2SPQgZv
High‐Flow Oxygen Therapy for Treating Bronchiolitis in infants
Abstract
Bronchiolitis is the most common reason for hospitalization in infants worldwide. Current recommendations by the American Academy of Pediatrics are for supportive care including maintenance of hydration and oxygen support for hypoxemia. Other interventions such as the use of bronchodilators have failed to show any benefit when compared to supportive care alone. However, it has been proposed that the obstructive process of bronchiolitis that causes increased work of breathing, hypoxia and hypercapnea might respond to the moderate positive pressure provided by high flow oxygen therapy.
This article is protected by copyright. All rights reserved.
http://bit.ly/2AKtafE
Identification a novel set of 6 differential expressed genes in prostate cancer that can potentially predict biochemical recurrence after curative surgery
Abstract
Purpose
Approximately, 30% patients after radical prostatectomy (RP) will undergo post-operative biochemical recurrence (BCR). Present stratification method by TNM staging and Gleason score was not adequate to screen high-risk patients. In this study, we intended to identify a novel set of differentially expressed gene (DEG) signature that can predict BCR after RP.
Materials/patients
358 patients after RP with follow-up data were extracted from The Cancer Genome Atlas (TCGA), among which 61 patients had undergone BCR. Key DEGs were confirmed by the intersection of GSE35988 and TCGA_PCa dataset, and their gene expression data were also extracted from TCGA_PCa dataset. Kaplan–Meier plot and Cox proportion hazard regression model were applied to assess the relationship between risk score and survival outcome (BCR).
Results
310 DEGs were confirmed in two prostate cancer dataset. 6 DEGs (SMIM22, NINL, NRG2, TOP2A, REPS2, and TPCN2) were selected to construct a risk score formula. The risk score was a powerful predictive factor independent of TNM stage (HR 3.045, 95% CI 1.655–5.602, p < 0.001).
Conclusion
In this study, a novel 6-gene signature with robust predictive ability on post-operative BCR was constructed and 4 genes (SMIM22, NRG2, NINL and TPCN2) in the 6-gene signature were not reported to be associated with prostate cancer.
http://bit.ly/2FpLq1O
The role of immunotherapy in small cell lung cancer
Abstract
Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.
http://bit.ly/2FuDDir
Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma
Abstract
Objective
To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma.
Methods
Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined.
Results
There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients.
Conclusion
Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.
http://bit.ly/2FkyiLH
Constitutional mosaicism in RASA1‐related capillary malformation‐arteriovenous malformation (CM‐AVM)
Capillary malformation‐arteriovenous malformation (CM‐AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM‐AVM. High‐throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM‐AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21,5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM‐AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk, and helps to explain the great phenotypic variability in CM‐AVM.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Fq3loi
C reactive protein (CRP) rs3093059C predicts poor mizolastine response in chronic spontaneous urticaria patients with elevated serum CRP level
Abstract
Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to nonsedating H1 antihistamines treatment. CRP gene encodes the C reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4‐week nonsedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non‐effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and β‐Hexosaminidase assay were conducted in HEK293T cells or RBL‐2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55(72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype was significantly associated with good response (OR=4.20, p=0.015), had lower serum CRP, IL‐6 and TNF‐α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (p<0.001). From the β‐Hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL‐2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level.
This article is protected by copyright. All rights reserved.
http://bit.ly/2FncIWI
The HCV care continuum: linkage to HCV care and treatment among patients at an urban health network, Philadelphia, PA
Abstract
Background/Aims
Improving care and treatment for persons infected with hepatitis C virus (HCV) can reduce HCV‐related morbidity and mortality. Our primary objective was to examine the HCV care continuum among patients receiving care at five Federally Qualified Health Centers (FQHCs) in Philadelphia, PA where a testing and linkage to care program had been established.
Methods
Among the five FQHCs, one served a homeless population, two served public housing residents, one served a majority Hispanic population, and the last, a "test and treat" site, also provided HCV treatment to patients. We analyzed data from electronic health records of patients tested for HCV antibody from 2012‐2016 and calculated the percentage of patients across nine steps of the HCV care continuum ranging from diagnosis to cure. We further explored factors associated with successful patient navigation through two steps of the continuum using multivariable logistic regression.
Results
Of 885 chronically infected patients, 92.2% received their RNA positive result, 82.7% were referred to an HCV provider, 69.4% were medically evaluated by the provider, 55.3% underwent liver disease staging, 15.0% initiated treatment, 12.0% completed treatment, 8.7% were assessed for sustained virologic response (SVR), and 8.0% achieved SVR. Regression results revealed that test and treat site patients were significantly more likely to be medically evaluated (aOR=2.76; 95% CI=1.82, 4.17) and undergo liver disease staging (aOR=1.92, 95% CI=1.02, 2.86) than patients at the other FQHCs combined.
Conclusions
In this U.S. urban setting, over two‐thirds of HCV‐infected patients were linked to care. Although treatment uptake was low overall, it was highest at the test and treat site. Scaling up treatment services in HCV testing settings will be vital to improve the HCV care continuum.
This article is protected by copyright. All rights reserved.
http://bit.ly/2RnQgDq
Cholemic nephropathy causes acute kidney injury and is accompanied by loss of aquaporin 2 in collecting ducts
Abstract
Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in cirrhotic patients (HRS‐AKI, type 1). Causes of non‐HRS AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN is mostly obtained from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 to 2016 at the Department of Gastroenterology, Hepatology and Endocrinology. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent EASL criteria 45 of the 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD) (43%). Renal biopsy revealed the diagnosis of CN in 8 of the 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin and the diagnosis of CN revealed loss aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy related complications requiring medical intervention occurred in four of 79 patients (5.1%).
In conclusion, CN is a common finding in patients with liver disease, AKI and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and be in part responsible for the impairment of renal function.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Cjq9mq
Circadian Regulation of Membrane Physiology in Neural Oscillators Throughout the Brain
Abstract
Twenty‐four‐hour rhythmicity in physiology and behavior are driven by changes in neurophysiological activity that vary across the light‐dark and rest‐activity cycle. Although this neural code is most prominent in neurons of the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, there are many other regions in the brain where region‐specific function and behavioral rhythmicity may be encoded by changes in electrical properties of those neurons. In this review, we explore the existing evidence for molecular clocks and/or neurophysiological rhythms (i.e., 24‐h) in brain regions outside the SCN. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators. For example, the cerebellum expresses rhythmicity in over 2,000 gene transcripts, and yet we know very little about how circadian regulation drives 24‐h changes in the neural coding responsible for motor coordination. Finally, we conclude with a discussion of how our understanding of circadian regulation of electrical properties may yield insight into disease mechanisms which may lead to novel chronotherapeutic strategies in the future.
This article is protected by copyright. All rights reserved.
http://bit.ly/2RmUueo
Separate cortical and hippocampal cell populations target the rat nucleus reuniens and mammillary bodies
Abstract
Nucleus reuniens receives dense projections from both the hippocampus and the frontal cortices. Reflecting these connections, this nucleus is thought to enable executive functions, including those involving spatial learning. The mammillary bodies, which also support spatial learning, again receive dense hippocampal inputs, as well as lighter projections from medial frontal areas. The present study, therefore, compared the sources of these inputs to nucleus reuniens and the mammillary bodies. Retrograde tracer injections in rats showed how these two diencephalic sites receive projections from separate cell populations, often from adjacent layers in the same cortical areas. In the subiculum, which projects strongly to both sites, the mammillary body inputs originate from a homogenous pyramidal cell population in more superficial levels, while the cells that target nucleus reuniens most often originate from cells positioned at a deeper level. In these deeper levels, a more morphologically diverse set of subiculum cells contributes to the thalamic projection, especially at septal levels. While both diencephalic sites also receive medial frontal inputs, those to nucleus reuniens are especially dense. The densest inputs to the mammillary bodies appear to arise from the dorsal peduncular cortex, where the cells are mostly separate from deeper neurons that project to nucleus reuniens. Again, in those other cortical regions that innervate both nucleus reuniens and the mammillary bodies, there was no evidence of collateral projections. The findings support the notion that these diencephalic nuclei represent components of distinct, but complementary, systems that support different aspects of cognition.
This article is protected by copyright. All rights reserved.
http://bit.ly/2CjayU3
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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