Medicine by Alexandros G.Sfakianakis: 11/27/18

Τρίτη 27 Νοεμβρίου 2018

Adherence to Subcutaneous IFN β-1a in Multiple Sclerosis: Final Analysis of the Non-Interventional Study READOUTsmart Using the Dosing Log and Readout Function of RebiSmart ®

Abstract

Introduction

Patient adherence is a key determinant of treatment success in multiple sclerosis (MS). The RebiSmart^® autoinjector facilitates patient self-injection of subcutaneous interferon β-1a (sc IFN β-1a) and allows quantitative measurement of adherence via its automated dosing log. We evaluated patient adherence and patient-reported cognitive and health-economic outcomes over 2 years in patients using RebiSmart^®.

Methods

In this non-interventional, single-arm study, enrolled patients were 12–65 years of age, had relapsing–remitting MS or a single demyelinating event, and had been prescribed 44 or 22 μg sc IFN β-1a. Quantitative adherence (proportion of scheduled injections administered) and qualitative adherence (proportion of weeks with treatment schedule correctly followed) were monitored over 2 years. Other end points included self-assessed adherence, patient-reported outcomes (fatigue, depression and quality of life), cognitive outcomes and health-economic outcomes.

Results

A total of 368 of 392 (93.9%) enrolled patients were analyzed. Mean quantitative adherence was 85.3% overall (months 1–24), 89.6% for months 1–12 and 83.3% for months 13–24. No major impact on quantitative adherence was observed for sex, age (< 37 years vs. ≥ 37 years), prior medication or participation in the patient support program RebiSTAR^®. Mean qualitative adherence was 67.0% overall (months 1–24). Self-assessed adherence was reported as being higher than RebiSmart^®-monitored adherence. There was a trend toward more MS-related visits to physicians among patients with high adherence.

Conclusions

Patients using RebiSmart^® demonstrated high adherence to treatment that was associated with a slight improvement in information processing speed and working memory and an overall tendency for more intensive self-management.

Funding

Merck Serono GmbH, Germany, an affiliate of Merck KGaA, Darmstadt, Germany.

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Canaloplasty in the Treatment of Open-Angle Glaucoma: A Review of Patient Selection and Outcomes

Abstract

Canaloplasty is a relatively new non-penetrating surgery for the reduction of intraocular pressure in patients affected by glaucoma. The technique uses a microcatheter to perform a 360 º cannulation of Schlemm's canal and leaves in place a tension suture providing an inward distension. It aims to restore the physiological outflow pathways of the aqueous humour and is independent of external wound healing. Several studies have shown that canaloplasty is effective in reducing intraocular pressure and has a low rate of complications, especially compared with trabeculectomy, the gold standard for glaucoma surgery. Currently, canaloplasty is indicated in patients with open-angle glaucoma, having a mild to moderate disease, and the combination with cataract phacoemulsification may provide further intraocular pressure reduction. This article reviews canaloplasty indications, results and complications and analyses its outcomes compared with traditional penetrating and non-penetrating techniques.

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Orthodontics in Growing Patients: Clinical/Biological Evidence and Technological Advancement 2018

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Corrigendum #2 to “Effects of Chronic Exposure to Sodium Arsenite on Expressions of VEGF and VEGFR2 Proteins in the Epididymis of Rats”

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Corrigendum to “Polymorphisms in the Chicken Growth Differentiation Factor 9 Gene Associated with Reproductive Traits”

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Corrigendum to “Selective Progesterone Receptor Modulators for the Medical Treatment of Uterine Fibroids with a Focus on Ulipristal Acetate”

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Diagnostic Assessment of septin9 DNA Methylation for Colorectal Cancer Using Blood Detection: A Meta-Analysis

Abstract

This meta-analysis aimed to assess the diagnostic efficiency of blood-based septin 9 (SEPT9) methylation assay for the detection of colorectal cancer (CRC). Studies were searched in the Springer, Wiley, Cochrane Library, PubMed, Ovid, Embase, Web of Science, China BioMedicine, Wanfang and China National Knowledge Infrastructure databases until July 2017. Methodological quality assessment was performed based on the guidelines of the Quality Assessment of Diagnostic Accuracy Studies. According to 1/3 and 2/3 algorithms, the meta-analyses for the diagnostic effect of SEPT9 in CRC were compared with healthy subjects and subjects with polyps, adenoma, and non-CRC, respectively. The random effects model was applied and publication bias was evaluated. The included 29 studies comprised 10,486 subjects (3202 patients with CRC and 7284 controls). In comparison with healthy subjects, the pooled sensitivity with 95% confidence intervals (CIs) of SEPT9 methylation for the diagnosis of CRC was 0.74 (95% CI: 0.61–0.84) in the 1/3 algorithm group, whereas the specificity was 0.96 (95% CI: 0.95–0.97) in the 2/3 algorithm group. Additionally, positive likelihood ratio was less than 10 and negative likelihood ratio more than 0.1 in the 2/3 algorithm group for patients with CRC vs. polyps and adenoma. The P value of Deeks' funnel plot was 0.36, suggesting that there was no publication bias. SEPT9 methylation can be used to diagnose CRC in healthy individuals under the 2/3 algorithm. The determination of SEPT9 methylation does not distinguish well between CRC and polyps or adenoma.

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Spatial overlaps in the distribution of HIV/AIDS and malaria in Zimbabwe

In most developing economies particularly in Africa, more people are likely to die of HIV/AIDS and malaria compared to other diseases. HIV/AIDS tends to be superimposed on the long standing malaria burden part...

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Emotional release and physical symptom improvement: a qualitative analysis of self-reported outcomes and mechanisms in patients treated with neural therapy

Neural Therapy (NT) is a common complementary treatment approach using injections with short-acting local anesthetics to treat pain and chronic diseases. However, little is known about the underlying mechanism...

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Determinants of late initiation for antenatal care follow up: the case of northern Ethiopian pregnant women

Early antenatal care follow-up is the main strategy of preventing pregnancy related adverse outcomes; in which World Health Organization recommends first antenatal care visit should be offered within the first...

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Teva Pharmaceuticals USA Issues Voluntary Nationwide Recall of All Amlodipine/Valsartan Combination Tablets and Amlodipine/Valsartan/Hydrochlorothiazide Combination Tablets That Are Within Expiry

Audience: Consumer, Health Professional, Pharmacy Teva Pharmaceuticals has initiated a voluntary recall in the United States, to the patient level, of all lots of Amlodipine / Valsartan combination tablets and Amlodipine / Valsartan /...

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The Anti-malarial Drug Artesunate Blocks Wnt/β-catenin Pathway and Inhibits Growth, Migration and Invasion of Uveal Melanoma Cells

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. So far, there have been no effective targeted therapeutic agents in patients with uveal melanoma. Artesunate is a semi-synthetic derivative of artemisinin extracted from traditional Chinese medicine Artemisia annua L for treatment of severe and multidrug-resistant malaria. Besides its antimalarial activity, artesunate is identified as an anti-cancer drug due to the inhibition of Wnt/β- catenin pathway in multiple types of cancer. However, the effect of artesunate on uveal melanoma remains unknown.

Objective: We evaluated the anti-tumor effects of artesunate on uveal melanoma cells, and analyzed in terms of Wnt/β-catenin pathway, cell growth, cell death, cell migration, invasion and cancer stemlike cells (CSCs) properties.

Methods: Primary (92.1, Mel270) and metastatic (Omm1 and Omm2.3) uveal melanoma cells were used. Immunofluorescence staining, dual luciferase reporter assay, Western blotting, MTS, soft agar cloning technique, Annexin V/PI analyses, wound healing scratch assay, in vitro transwell migration and invasion assays, aldehyde dehydrogenase (ALDH) analyses and melanosphere formation assay et al. were carried out.

Results: Artesunate suppressed the phosphorylation of GSK3β at S9, and lowered the protein level of β-catenin and its downstream targets (c-Myc, cyclin D1). Artesunate potently inhibited cell viability and colony formation ability. Treatment with artesunate significantly induced apoptosis. In addition, artesunate significantly reduced the migration and invasion of uveal melanoma cells, impaired the traits of CSCs in vitro.

Conclusion: Artesunate may be a potential interest for the therapy of uveal melanoma.

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High spatial resolution identification of hematoma in inhomogeneous head phantom using broadband fNIR system

This paper presents a novel method for early detection of hematomas using highly sensitive optical fNIR imaging methods based on broadband photon migration. The NIR experimental measurements of inhomogeneous m...

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Metal artifact reduction on cervical CT images by deep residual learning

Cervical cancer is the fifth most common cancer among women, which is the third leading cause of cancer death in women worldwide. Brachytherapy is the most effective treatment for cervical cancer. For brachyth...

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Teva Pharmaceuticals USA Issues Voluntary Nationwide Recall of All Amlodipine/Valsartan Combination Tablets and Amlodipine/Valsartan/Hydrochlorothiazide Combination Tablets That Are Within Expiry

Discovery platform for inhibitors of IgH gene enhancer activity

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LncRNA TATDN1 contributes to the cisplatin resistance of non-small cell lung cancer through TATDN1/miR-451/TRIM66 axis

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Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis

Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis

Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis, Published online: 28 November 2018; doi:10.1038/s41416-018-0273-9

Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis

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Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells

Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells

Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells, Published online: 28 November 2018; doi:10.1038/s41416-018-0287-3

Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells

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PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.

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Ribosomal lesions promote oncogenic mutagenesis.

Ribosomopathies are congenital disorders caused by mutations in ribosomal proteins (RP) or assembly factors and are characterized by cellular hypo-proliferation at an early stage. Paradoxically, many of these disorders have an elevated risk to progress to hyper-proliferative cancer at a later stage. Additionally, somatic RP mutations have recently been identified in various cancer types e.g. the recurrent RPL10-R98S mutation in T-cell acute lymphoblastic leukemia (T-ALL) and RPS15 mutations in chronic lymphocytic leukemia (CLL). We previously showed that RPL10-R98S promotes expression of oncogenes but also induces a proliferative defect due to elevated oxidative stress. In this study, we demonstrate that this proliferation defect is eventually rescued by RPL10-R98S mouse lymphoid cells that acquire 5-fold more secondary mutations than RPL10-WT cells. The presence of RPL10-R98S and other RP mutations also correlated with a higher mutational load in T-ALL patients, with an enrichment in NOTCH1-activating lesions. RPL10-R98S-associated cellular oxidative stress promoted DNA damage and impaired cell growth. Expression of NOTCH1 eliminated these phenotypes in RPL10-R98S cells, in part via downregulation of PKC-θ, with no effect on RPL10-WT cells. RP-mutant CLL patients also demonstrated a higher mutational burden, enriched for mutations that may diminish oxidative stress. We propose that oxidative stress due to ribosome dysfunction causes hypo-proliferation and cellular insufficiency in ribosomopathies and RP-mutant cancer. This drives surviving cells, potentiated by genomic instability, to acquire rescuing mutations which ultimately promote transition to hyper-proliferation.

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Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors

Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt CAR T cell therapies to treat heterogeneous solid tumors. Here we utilized a cocktail of low molecular weight bispecific adapters, each comprised of fluorescein linked to a different tumor-specific ligand, to bridge between an anti-fluorescein CAR on the engineered T cell and a unique antigen on the cancer cell. This formation of an immunological synapse between the CAR T cell and cancer cell enabled use of a single anti-fluorescein CAR T cell to eradicate a diversity of antigenically different solid tumors implanted concurrently in NSG mice. Based on these data, we suggest that a carefully designed cocktail of bispecific adapters in combination with anti-fluorescein CAR T cells can overcome tumor antigen escape mechanisms that lead to disease recurrence following many CAR T cell therapies.

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Super-enhancer-associated long non-coding RNA HCCL5 is activated by ZEB1 and promotes the malignancy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most dominant causes of neoplasm-related deaths worldwide. In this study, we identify and characterize HCCL5, a novel cytoplasmic lncRNA, as a crucial oncogene in HCC. HCCL5 promoted cell growth, G1/S transition, invasion, and metastasis while inhibiting apoptosis of HCC cells both in vitro and in vivo. Moreover, HCCL5 was upregulated in TGF-β1-induced classical epithelial-mesenchymal transition (EMT) models, and this lncRNA in turn accelerated the EMT phenotype by upregulating the expression of transcription factors Snail, Slug, ZEB1, and Twist1. HCCL5 was transcriptionally driven by ZEB1 via a super-enhancer and was significantly and frequently overexpressed in human HCC tissues, correlating with worse overall survival of HCC patients. Together, this study characterizes HCCL5 as a super-enhancer-driven lncRNA promoting HCC cell viability, migration, and EMT. Our data also suggest that HCCL5 may serve as a novel prognostic biomarker and therapeutic target in HCC.

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STING promotes homeostasis via regulation of cell proliferation and chromosomal stability

Given the integral role of Stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared to wild-type controls. Microarray analysis revealed genes involved in cell cycle regulation are differentially expressed in STINGko compared to WT MEFs. STING-mediated regulation of the cell cycle converged on NF-κB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset S phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation (IR). These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress.

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OCMA: Fast, Memory-Efficient Factorization of Prohibitively Large Relationship Matrices

Matrices representing genetic relatedness among individuals (i.e., Genomic Relationship Matrices, GRMs) play a central role in genetic analysis. The eigen-decomposition of GRMs (or its alternative that generates fewer top singular values using genotype matrices) is a necessary step for many analyses including estimation of SNP-heritability, Principal Component Analysis (PCA), and genomic prediction. However, the GRMs and genotype matrices provided by modern biobanks are too large to be stored in active memory. To accommodate the current and future "bigger-data", we develop a disk-based tool, Out-of-Core Matrices Analyzer (OCMA), using state-of-the-art computational techniques that can nimbly perform eigen and Singular Value Decomposition (SVD) analyses. By integrating memory mapping (mmap) and the latest matrix factorization libraries, our tool is fast and memory-efficient. To demonstrate the impressive performance of OCMA, we test it on a personal computer. For full eigen-decomposition, it solves an ordinary GRM (N=10,000) in 55 seconds. For SVD, a commonly used faster alternative of full eigen-decomposition in genomic analyses, OCMA solves the top 200 singular values (SVs) in half an hour, top 2,000 SVs in 0.95 hour, and all 5,000 SVs in 1.77 hours based on a very large genotype matrix (N=1,000,000, M=5,000) on the same personal computer. OCMA also supports multi-threading when running in a desktop or HPC cluster. Our OCMA tool can thus alleviate the computing bottleneck of classical analyses on large genomic matrices, and make it possible to scale up current and emerging analytical methods to big genomics data using lightweight computing resources.

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Dosage Compensation and Gene Expression of the X Chromosome in Sheep

Ohno's hypothesis predicts that the expression of the single X chromosome in males needs compensatory upregulation to balance its dosage with that of the diploid autosomes. Additionally, X chromosome inactivation ensures that quadruple expression of the two X chromosomes is avoided in females. These mechanisms have been actively studied in mice and humans but lag behind in domestic species. Using RNA sequencing data, we analyzed the X chromosome upregulation in sheep fetal tissues from day 135 of gestation under control, over or restricted maternal diets (100%, 140% and 60% of National Research Council Total Digestible Nutrients), and in conceptuses, juvenile, and adult somatic tissues. By computing the mean expression ratio of all X-linked genes to all autosomal genes (X:A), we found that all samples displayed some levels of X chromosome upregulation. The degrees of X upregulation were not significant (P-value = 0.74) between ovine females and males in the same somatic tissues. Brain, however, displayed complete X upregulation. Interestingly, the male and female reproduction-related tissues exhibited divergent X dosage upregulation. Moreover, expression upregulation of the X chromosome in fetal tissues was not affected by maternal diets. Maternal nutrition, however, did change expression levels of several X-linked genes, such as sex determination genes SOX3 and NR0B1. In summary, our results showed that X chromosome upregulation occurred in nearly all sheep somatic tissues analyzed, thus support Ohno's hypothesis in a new species. However, the levels of upregulation differed by different subgroups of genes such as those that are house-keeping and "dosage-sensitive".

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Medaka Population Genome Structure and Demographic History Described via Genotyping-by-Sequencing

Medaka is a model organism in medicine, genetics, developmental biology and population genetics. Lab stocks composed of more than 100 local wild populations are available for research in these fields. Thus, medaka represents a potentially excellent bioresource for screening disease-risk- and adaptation-related genes in genome-wide association studies. Although the genetic population structure should be known before performing such an analysis, a comprehensive study on the genome-wide diversity of wild medaka populations has not been performed. Here, we performed genotyping-by-sequencing (GBS) for 81 and 12 medakas captured from a bioresource and the wild, respectively. Based on the GBS data, we evaluated the genetic population structure and estimated the demographic parameters using an approximate Bayesian computation (ABC) framework. The genome-wide data confirmed that there were substantial differences between local populations and supported our previously proposed hypothesis on medaka dispersal based on mitochondrial genome (mtDNA) data. A new finding was that a local group that was thought to be a hybrid between the northern and the southern Japanese groups was actually an origin of the northern Japanese group. Thus, this paper presents the first population-genomic study of medaka and reveals its population structure and history based on chromosomal genetic diversity.

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High Efficiency Targeting of Non-coding Sequences Using CRISPR/Cas9 System in Tilapia

The CRISPR/Cas9 has been successfully applied for disruption of protein coding sequences in a variety of organisms. The majority of the animal genome is actually non-coding sequences, which are key regulators associated with various biological process. In this study, to understand the biological significance of these sequences, we used one or dual gRNA guided Cas9 nuclease to achieve specific deletion of non-coding sequences including microRNA and 3' untranslated region (UTR) in tilapia, which is an important fish for studying sex determination and evolution. Co-injection of fertilized eggs with single gRNA targeting seed region of miRNA and Cas9 mRNA resulted in indel mutations. Further, co-injection of fertilized eggs with dual gRNAs and Cas9 mRNA led to the removal of the fragment between the two target loci, yielding maximum efficiency of 11%. This highest genomic deletion efficiency was further improved up to 19% using short ssDNA as a donor. The deletions can be transmitted through the germline to the next generation at average efficiency of 8.7%. Cas9-vasa 3'-UTR was used to increase the efficiency of germline transmission of non-coding sequence deletion up to 14.9%. In addition, the 3'-UTR of the vasa gene was successfully deleted by dual gRNAs. Deletion of vasa 3'-UTR resulted in low expression level of vasa mRNA in the gonad when compared with the control. To summarize, the improved CRISPR/Cas9 system provided a powerful platform that can assist to easily generate desirable non-coding sequences mutants in non-model fish tilapia to discovery their functions.

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Entrectinib Effective across NTRK Fusion-Positive Cancers [News in Brief]

The tyrosine kinase inhibitor had a high ORR in 10 different cancers and shrank metastatic brain tumors.

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Tumor-contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine-Paracrine Loop

Purpose: The different prognostic values of tumor-infiltrating neutrophils (TINs) in different tissue compartments are unknown. In this study, we investigated their different prognostic roles and the underlying mechanism. Experimental Design: We evaluated CD66b⁺ neutrophils in primary tumors from 341 breast cancer patients from Sun Yat-Sen Memorial Hospital by immunohistochemistry. The association between stromal and parenchymal neutrophil counts and clinical outcomes was assessed in training set (170 samples), validated in internal validation set (171 samples), and further confirmed in external validation set (105 samples). In addition, we isolated TINs from clinical samples and screened the cytokine profile by antibody microarray. The interaction between neutrophils and tumor cells was investigated in transwell and 3D-matrigel co-culture systems. The therapeutic potential of indicated cytokines was evaluated in tumor-bearing immunocompetent mice. Results: We observed neutrophils in tumor parenchyma, rather than those in stroma, was an independent poor prognostic factor in training (95%CI HR=2.88-8.68, p<0.001), internal validation (95%CI HR=2.07-6.14, p<0.001) and external validation set (95%CI HR=2.27-11.33, p<0.001). The mechanistic study revealed that neutrophils induced breast cancer epithelial-mesenchymal transition (EMT) via TIMP-1. Reciprocally, breast cancer cells undergoing EMT enhanced neutrophils TIMP-1 secretion by CD90 in a cell-contact manner. In vivo, TIMP-1 neutralization or CD90 blockade significantly reduced metastasis. More importantly, TIMP-1 and CD90 were positively correlated in breast cancer (r²=0.6079, p<0.001) and associated with poor prognosis of patients. Conclusions: Our findings unravel a location-dictated interaction between tumor cells and neutrophils and provide a rationale for new anti-metastasis treatments.

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Serum miRNA-based prediction of axillary lymph node metastasis in breast cancer

Purpose: Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum microRNAs (miRNAs) and clinicopathological factors as a novel less-invasive biomarker. Experimental design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. Results: An optimal diagnostic model was identified using a combination of four miRNAs (miR-629-5p, miR-629-3p, miR-4710, and miR-4492) and three clinicopathological factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.876, a specificity of 0.712, an accuracy of 0.824, and an area under the receiver operating characteristic curve of 0.86 in the test set. Conclusions: Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.

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Fulfilling States’ Duty to Evaluate Medicaid Waivers

Nearly 75 million U.S. residents have health insurance coverage through Medicaid. Benefits and program designs vary from state to state. One source of state-based variation is Section 1115 projects, which are defined as "experimental, pilot, or demonstration" programs that are "likely to assist in…

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An Industry Experience with Data Sharing

To the Editor: Availability of the data that underlie reports of clinical trials for analysis by third parties serves a number of goals as outlined by the International Committee of Medical Journal Editors. Here we describe the experience of Boehringer Ingelheim (BI) in listing studies on the…

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Beyond Evidence-Based Medicine

Evidence-based medicine (EBM) was an important advance over the intuition-based medicine that preceded it, but its limitations are becoming clear even as it's increasingly accepted as an aspiration. Guidelines based on clinical research are being hardwired into our operational norms, incentive…

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Reducing Protections for Noncitizen Children — Exacerbating Harm and Trauma

On June 26, 2018, a federal judge ordered the Trump administration to reunite families that it had separated at the U.S.–Mexico border. As of mid-October, however, an analysis by the American Civil Liberties Union showed that 245 children were still in government custody. About half those children…

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FDA to Update Medical Device Approvals Process

TUESDAY, Nov. 27, 2018 -- A major update of the United States' system for approving medical devices was announced yesterday by the Food and Drug Administration. Experts have long criticized the decades-old process for its failure to identify...

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USPSTF: Evidence Lacking for Prevention of Child Maltreatment

TUESDAY, Nov. 27, 2018 -- The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence on the benefits and harms of primary care interventions for preventing child maltreatment is currently inadequate. These findings form the basis...

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FDA: Safe to Eat Romaine Lettuce Again, but Check Labels

TUESDAY, Nov. 27, 2018 -- In a statement released late yesterday, the U.S. Food and Drug Administration Commissioner Scott Gottlieb, M.D., announced that the agency was lifting its advisory against eating romaine lettuce, first put in place last...

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Men Should Avoid 'Rhino' Sexual Enhancement Products, FDA Says

TUESDAY, Nov. 27, 2018 -- The U.S. Food and Drug Administration is warning men that "Rhino" products promising better sex may pose serious health risks. Since 2007, the FDA has identified more than 25 products marketed with variations of the name...

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FDA Approves Vitrakvi for Cancers With Certain Genetic Trait

TUESDAY, Nov. 27, 2018 -- Vitrakvi (larotrectinib) has been approved by the U.S. Food and Drug Administration to treat adult and pediatric patients whose cancers have a specific genetic feature. The approval marks the second drug sanctioned to treat...

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Take It with a Grain of Salt

A 56-year-old woman presented to the emergency department with a 1-week history of frontotemporal headaches and nausea. She also noted mild upper respiratory symptoms and cough, which she had treated with codeine. When her headaches had progressed to what she described as "the worst pain in her…

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Take It with a Grain of Salt

Portal Venous Gas

Figure 1.

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Take It with a Grain of Salt

Doctor Sahib

Many of my father's patients, Pakistanis who migrated to Britain to save dying manufacturing industries (which were starved for laborers), did not take their medications. His most memorable patient was Mr. Khan, a good-natured Pathan (Pashtun) who hailed from the border zone between Pakistan and…

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Take It with a Grain of Salt

Pneumococcal Bacteremia and Meningitis

Figure 1.

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Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass

Presentation of Case. Dr. Keyan Salari (Urology): A 29-year-old man was seen at this hospital because of an incidentally discovered renal mass. The patient had been well until 6 weeks before this evaluation, when he identified a painless lump above his left testicle during a monthly…

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Portal Venous Gas

Figure 1.

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Beyond Evidence-Based Medicine

Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass

Iron Wars — The Host Strikes Back

Almost all forms of life, from bacteria to mammals, have an absolute requirement for iron, and a range of mechanisms — sometimes quite elaborate — have evolved for ensuring that they obtain enough iron to survive. An effective strategy used by bacteria, fungi, and some plants is the secretion of…

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Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer

The discovery of phosphatidylinositol 3-kinase (PI3K) changed the way we view and understand growth-factor signaling. From early on, it became clear that PI3K plays an important role in many disease states. However, its discovery as an oncogene in an age when cancer biology was coming to the fore…

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Probiotics for Children with Gastroenteritis

In clinical practices for adults and children, probiotics — live bacteria that are intended to have a beneficial effect in the host — are frequently recommended to treat a wide variety of diarrheal diseases. The results of thousands of studies of probiotics have been published, and most of them…

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Pneumococcal Bacteremia and Meningitis

Figure 1.

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Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis

Acute gastroenteritis accounts for approximately 1.7 million emergency department (ED) visits among children in the United States every year. Although health care providers traditionally have had little to offer to modify the disease course, probiotics are an expanding multibillion-dollar industry…

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Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children

Acute gastroenteritis causes substantial complications and is the second leading cause of death worldwide in children younger than 5 years of age. Although rarely lethal in the United States, acute gastroenteritis in children is burdensome, accounting for approximately 1.7 million visits to the…

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Disease and Famine as Weapons of War in Yemen

How can the medical community take stock of the humanitarian disaster in Yemen? The 3-year-old war intermittently garners attention from Western media — for example, in August, when an air strike on a school bus killed more than 50 civilians, mostly children — but is woefully underreported relative…

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Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass

Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer

Take It with a Grain of Salt

Pneumococcal Bacteremia and Meningitis

Figure 1.

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Take It with a Grain of Salt

Portal Venous Gas

Figure 1.

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Diagnostic routes and time intervals for patients with colorectal cancer in 10 international jurisdictions; findings from a cross-sectional study from the International Cancer Benchmarking Partnership (ICBP)

Objective

International differences in colorectal cancer (CRC) survival and stage at diagnosis have been reported previously. They may be linked to differences in time intervals and routes to diagnosis. The International Cancer Benchmarking Partnership Module 4 (ICBP M4) reports the first international comparison of routes to diagnosis for patients with CRC and the time intervals from symptom onset until the start of treatment. Data came from patients in 10 jurisdictions across six countries (Canada, the UK, Norway, Sweden, Denmark and Australia).

Design

Patients with CRC were identified via cancer registries. Data on symptomatic and screened patients were collected; questionnaire data from patients' primary care physicians and specialists, as well as information from treatment records or databases, supplemented patient data from the questionnaires. Routes to diagnosis and the key time intervals were described, as were between-jurisdiction differences in time intervals, using quantile regression.

Participants

A total of 14 664 eligible patients with CRC diagnosed between 2013 and 2015 were identified, of which 2866 were included in the analyses.

Primary and secondary outcome measures

Interval lengths in days (primary), reported patient symptoms (secondary).

Results

The main route to diagnosis for patients was symptomatic presentation and the most commonly reported symptom was 'bleeding/blood in stool'. The median intervals between jurisdictions ranged from: 21 to 49 days (patient); 0 to 12 days (primary care); 27 to 76 days (diagnostic); and 77 to 168 days (total, from first symptom to treatment start). Including screen-detected cases did not significantly alter the overall results.

Conclusion

ICBP M4 demonstrates important differences in time intervals between 10 jurisdictions internationally. The differences may justify efforts to reduce intervals in some jurisdictions.

https://ift.tt/2AqzZSM

Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells

https://ift.tt/2P6QfgX

Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis

https://ift.tt/2ztczg2

Effects of Dialysate Acidification With Citrate Versus Acetate on Cell Damage, Uremic Toxin Levels, and Inflammation in Patients Receiving Maintenance Hemodialysis

The introduction of bicarbonate-based dialysate in the 1980s decreased hemodynamic instability and improved acidosis compared to the previous acetate-based dialysate.1 Because it still contained small amounts of acetate, concern about possible deleterious effects remained. In the last decade, citric acid has been introduced as an alternative acidifying agent, with several beneficial effects, including improvement in inflammation2-5 and dialysis efficiency.6

https://ift.tt/2P6fEYa

HPV‐associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity

Abstract

Background

The majority of human papillomavirus (HPV)–associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV–associated neuroendocrine carcinomas (HPV‐NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine‐needle aspiration (FNA) cases of head and neck HPV‐NEC.

Methods

Cytology cases of HPV‐NEC were identified over a 3‐year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated.

Results

Five FNA cases of HPV‐NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV‐18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5).

Conclusions

Head and neck HPV‐NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV‐NEC is also important because of its worse prognosis in comparison with HPV‐associated squamous cell carcinoma.

https://ift.tt/2FIN1AX

Influence of solvent and a supplementary step with a finishing instrument on filling material removal from canals connected by an isthmus

Abstract

Aim

To evaluate the effectiveness of a solvent (eucalyptol) in improving filling material removal from canals connected by isthmuses, and the additional cleaning effect of a finishing instrument.

Methodology

The mesial canals from 32 mandibular molars (Vertucci's type II morphology) were instrumented and filled with the single‐cone technique using Reciproc R25 gutta‐percha points (VDW, Munich, Germany) combined with Sealer 26 (Dentsply, Petrópolis, RJ, Brazil). Each root was then subjected to retreatment using the Mtwo instrument system (VDW), with or without a solvent (n=16 per group). The volume of filling material in the canals was assessed by micro‐computed tomographic (micro‐CT) scans taken before and after retreatment. Canals with remnants of filling material received a supplementary procedure with the XP‐endo Finisher R instrument (FKG Dentaire, La Chaux‐de‐Fonds, Switzerland), with or without eucalyptol, and another micro‐CT scan was taken. All retreatment procedures were performed inside a cabinet under a controlled temperature (37°C). Filling material removal was evaluated in the 5‐mm apical canal system for the canal+isthmus space or the isthmus alone. Statistical analyses were performed to compare the removal of filling material with and without eucalyptol, and after a supplementary approach with XP‐endo Finisher R. The level of significance was set at 5% for all statistical tests (P<0.05).

Results

The amount of filling material removed from the canal+isthmus with Mtwo instruments was 83.2% when no solvent was used and 83.8% using the solvent (P>0.05). When the isthmus area was evaluated separately, most specimens were associated with a reduction in the filling material, with no significant difference between the groups with or without using a solvent (P>0.05). The supplementary step with XP‐endo Finisher R significantly improved removal of filling material from both canal and isthmus area (P<0.05), regardless of the use of a solvent (P>0.05).

Conclusion

The use of eucalyptol did not improve filling material removal from Vertucci's type II molar mesial canals and isthmi. XP‐endo Finisher R significantly enhanced removal of filling material from the canals and isthmi.

https://ift.tt/2E19abT

Messages from the auricle ‐ limiting progression of heart failure with preserved ejection fraction through transcutaneous nerve stimulation of nerves in the external ear

https://ift.tt/2Sej1yg

Four Principles Underlie Patient and Family Partnership in Care

TUESDAY, Nov. 27, 2018 -- Patient and family partnership in care should include treatment of patients and families with dignity and respect, their active engagement in all aspects of care, and their contribution to the improvement of health care...

https://ift.tt/2ztxAXH

Prevalence of Eating Disorders 1.4 Percent in Preteens

TUESDAY, Nov. 27, 2018 -- The prevalence of eating disorders among 9- to 10-year-olds in the United States is 1.4 percent, with no difference in prevalence between boys and girls, according to a research letter published online Nov. 26 in JAMA...

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Vitamin D Levels Linked to Cardiorespiratory Fitness

TUESDAY, Nov. 27, 2018 -- Serum vitamin D levels are associated with cardiorespiratory fitness (CRF), according to a study recently published in the European Journal of Preventive Cardiology. Amr Marawan, M.D., from the Virginia Commonwealth...

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RSNA: Refractory Back Pain Responds to CT-Guided Pulsed RF

TUESDAY, Nov. 27, 2018 -- Computed tomography (CT)-guided pulsed radiofrequency (pRF) is effective for patients with acute or subacute neuroradicular low back pain that is refractory to usual care, according to a study presented at the annual...

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One in Five Readmitted After Head, Neck Cancer Reconstruction

TUESDAY, Nov. 27, 2018 -- Nearly one in five patients undergoing head and neck cancer surgery reconstruction is readmitted within 30 days of surgery, according to a study published online Nov. 8 in JAMA Facial Plastic Surgery. Alexander N. Goel,...

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Pregnancy-Associated Mortality Involving Opioids Up

TUESDAY, Nov. 27, 2018 -- From 2007 to 2016, there was a sharp increase in pregnancy-associated mortality involving opioids, according to a research letter recently published in the American Journal of Obstetrics & Gynecology. Alison Gemmill,...

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Less Pediatric Screen Time Tied to Better Well-Being

TUESDAY, Nov. 27, 2018 -- A higher amount of screen time per day is associated with decreased psychological well-being in children and adolescents, according to a study published in the December issue of Preventive Medicine Reports. Jean M. Twenge,...

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Recommended Therapies for Polycythemia Vera Underused

TUESDAY, Nov. 27, 2018 -- Among older patients with polycythemia vera (PV), therapeutic phlebotomy and hydroxyurea (HU) are associated with improved overall survival and decreased risk for thrombosis but are underused, according to a study recently...

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Food Assistance May Help Older Adults Adhere to Diabetes Meds

TUESDAY, Nov. 27, 2018 -- Participation in the Supplemental Nutrition Assistance Program (SNAP) may reduce the number of low-income older adults with diabetes forgoing medications because of cost, according to a study published online Nov. 19 in...

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Risks of Trazodone Similar to Those of Atypical Antipsychotics

TUESDAY, Nov. 27, 2018 -- For older adults with dementia, trazodone is associated with a comparable risk for falls and fractures as that of atypical antipsychotics, according to a study published online Nov. 26 in CMAJ, the Journal of the Canadian...

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Temporal trends and patterns in carbamazepine use, related severe cutaneous adverse reactions, and HLA‐B*15:02 screening: A nationwide study

Summary

Objective

After discovering the association between the HLA‐B*15:02 allele and carbamazepine‐related severe cutaneous adverse reactions (SCARs), particularly in Southeastern Asian populations, clinical strategies to prevent carbamazepine‐related SCARs have changed. We aimed to investigate 10‐year trends in carbamazepine use and carbamazepine‐related SCARs and to examine the patterns and determinants of HLA‐B*15:02 screening in Taiwan.

Methods

A nationwide study was performed using Taiwan's National Health Insurance Research Database. In the first part of the study, new users of carbamazepine were included, and those who experienced SCAR‐related admissions were further identified. In the second part of the study, recipients of HLA‐B*15:02 screening (reimbursed by Taiwan's National Health Insurance since June 2010) were included and multivariate logistic regression was used to explore factors associated with the use of screening.

Results

The numbers of new users of carbamazepine and SCAR cases decreased remarkably during the 10‐year period (−82.6% and −87.1%, respectively), and the incidence rates of SCARs showed a downward trend after 2011. The screening rate of the HLA‐B*15:02 allele increased to 24.9% in 2014. Neurologists (odds ratio 12.33, 95% confidence interval 9.30‐16.35), psychiatrists (9.97, 7.31‐13.61), and neurosurgeons (3.23, 2.42‐4.32) were more likely to perform screening tests than other specialties were. Physicians practicing in medical centers (6.00, 5.51‐6.54) were more likely to perform screening tests than those practicing in other hospitals, whereas the screening rates in clinics remained at 0.0% throughout the study period.

Significance

In recent years, the number of carbamazepine‐related SCAR cases has decreased substantially in Taiwan. However, only one‐fourth of new users of carbamazepine received HLA‐B*15:02 screening, and there were considerable disparities in the screening rates across different physician groups. Policymakers should consider solutions to barriers to implementing screening tests in clinical practice and should not neglect the value of other safety communications and regulations to complement the limitations of pharmacogenomic testing.

https://ift.tt/2zsK5To

Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

Summary

Objective

To gain insight into the mechanisms underlying KCNQ2 encephalopathy by examining the electrophysiologic properties of mutant Kv7.2 channels in different multimeric configurations.

Methods

We analyzed the genotype‐phenotype relationship in 4 patients with KCNQ2 encephalopathy and performed electrophysiologic analysis of M‐currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels.

Results

Negligible or no current was recorded in cells expressing homomeric E130K, W270R, or G281R de novo mutants, and it was reduced by more than 90% for the L243F maternally inherited mutant. The E130K and G281R mutants presented a marked dominant‐negative behavior, whereas the current density was partially reduced (L243F) or not affected (W270R) when coexpressed with wild‐type Kv7.2 subunits. In contrast, the extent of Kv7.3 "rescue," which yields negligible currents on its own, followed the sequence E130K > L243F > W270R, whereas no rescue was observed with the G281R mutant. No significant effects on current density were observed when subunits were expressed in a 0.5:0.5:1.0 (Kv7.2:mutant:Kv7.3) DNA ratio to mimic the genetic balance. There was an increase in sensitivity to phosphatidylinositol 4,5‐bisphosphate (PIP₂) depletion for W270R/Kv7.3, but no substantial differences were observed when the mutated subunits were coexpressed with Kv7.2 or both Kv7.2 and Kv7.3.

Significance

There was a marked disparity of the impact of these mutations on Kv7.2 function, which varied on association with Kv7.2 or Kv7.3 subunits. Current density of homomeric channels was the most reliable property relating Kv7.2 function to encephalopathy, but other factors are required to explain the milder phenotype for some individuals carrying the maternally inherited L243F mutation. We hypothesize that the role of homomeric Kv7.2 channels for fine‐tuning neuronal connections during development is critical for the severity of the KCNQ2 encephalopathy.

https://ift.tt/2P5OCjH

Epidemiology of status epilepticus in adults: A population‐based study on incidence, causes, and outcomes

Summary

Objective

In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic–clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population‐based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome.

Methods

We conducted a retrospective population‐based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015.

Results

We identified 221 patients with a median age of 69 years (range 20‐99 years). The age‐ and sex‐adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2‐48.5), 12.1 (95% CI 6.8‐20.0), and 24.0 (95% CI 16.0‐34.5; including CSE 15.8 [95% CI 9.4‐24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic–clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%).

Significance

This first population‐based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

https://ift.tt/2zwlvkz

Alterations in the hippocampal‐thalamic pathway underlying secondarily generalized tonic–clonic seizures in mesial temporal lobe epilepsy: A diffusion tensor imaging study

Summary

Objective

The epileptogenic network underlying secondarily generalized tonic–clonic seizures (sGTCS) in mesial temporal lobe epilepsy (mTLE) is not well understood. Here, we investigated alterations in the probabilistic hippocampal‐thalamic pathway (pHTP) underlying sGTCS using diffusion tensor imaging and resting‐state functional magnetic resonance imaging in a cohort of TLE patients with hippocampal sclerosis (HS).

Methods

We consecutively recruited 51 unilateral TLE‐HS patients (26 with and 25 without sGTCS) and 22 healthy controls. Probabilistic tractography was used to track the pHTP. Raw fractional anisotropy (FA) and mean diffusivity (MD) of the pHTP were corrected by the FA/MD of the hemispheric white matter on the same side. The volume of the thalamic subregion connected to the hippocampus (TSCH) was investigated. Fractional amplitude of low‐frequency fluctuations of the hippocampus, the TSCH, and the thalamic subregion unconnected to the hippocampus in resting‐state functional magnetic resonance imaging were also calculated.

Results

After correction, the sGTCS group showed lower FA than the non‐sGTCS group (P = 0.03), and lower FA as well as higher MD than controls in the ipsilateral pHTP. The non‐sGTCS group only showed higher corrected MD in the ipsilateral pHTP relative to controls. Corrected FA or MD in the contralateral pHTP did not differ among groups. The TSCH was located in the mesial aspect of the thalamus, and it was atrophied in the sGTCS group compared to the non‐sGTCS group and controls. The sGTCS group had lower fractional amplitude of low‐frequency fluctuations in the ipsilateral hippocampus and TSCH compared to controls.

Significance

In TLE‐HS, sGTCS was associated with impaired integrity of the pHTP as well as structural and functional abnormalities in the medial thalamus. The medial thalamus is important in seizure generalization in mTLE.

https://ift.tt/2P6rQbx

Unveiling the Genetic Architecture of Human Disease for Precision Medicine

https://ift.tt/2Rgf1Nx

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

Background

Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis.

Methods

To understand the molecular bases of aneuploid acute myeloid leukemia (A‐AML), this study examined the genomic profile in 42 A‐AML cases and 35 euploid acute myeloid leukemia (E‐AML) cases.

Results

A‐AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E‐AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A‐AML, which was associated with a 3‐gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A‐AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E‐AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression.

Conclusions

These findings indicate that aneuploidy‐related and leukemia‐specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.

https://ift.tt/2PYt3Hf

Safety and survival outcomes for bloodless transplantation in patients with myeloma

High‐dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL‐ASCT) are examined among patients with myeloma. This retrospective case‐control study included patients who underwent BL‐ASCT and Transfusion‐supported ASCT (TS‐ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL‐ASCT and 70 who underwent TS‐ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant‐related cardiovascular complications or mortality in either the BL‐ASCT group or the TS‐ASCT group. The median progression‐free survival was 36 months and 44 months in the BL‐ASCT and TS‐ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow‐up of 59 months after ASCT (P = .627). There was no transplant‐related mortality at the 100‐day or 1‐year mark in either group. BL‐ASCT is safe and feasible; transplant‐related mortality, cardiovascular and hematologic complications are similar to those associated with TS‐ASCT. Furthermore, BL‐ASCT can yield similar engraftment and survival parameters comparable to those observed with TS‐ASCT.

https://ift.tt/2RiDS3c

Trends in liver cancer mortality in the United States: Dual burden among foreign‐ and US‐born persons

Background

Since the mid‐1980s, the burden of liver cancer in the United States has doubled, with 31,411 new cases and 24,698 deaths occurring in 2014. Foreign‐born individuals may be more likely to die of liver cancer than individuals in the general US‐born population because of higher rates of hepatitis B infection, a low socioeconomic position, and language barriers that limit the receipt of early cancer detection and effective treatment.

Methods

To determine whether liver cancer mortality rates were higher among foreign‐born individuals versus US‐born individuals in the United States, population‐based cancer mortality data were obtained from the National Center for Health Statistics of the Centers for Disease Control and Prevention. Annual population estimates were obtained from the US Census Bureau's American Community Survey. Age‐adjusted mortality rates and rate ratios (RRs) for liver cancer stratified by birth place were calculated, and the average annual percent change (AAPC) was used to evaluate trends.

Results

A total of 198,557 deaths from liver and intrahepatic bile duct cancer were recorded during 2005‐2014, and 16% occurred among foreign‐born individuals. Overall, foreign‐born individuals had a 24% higher risk of liver cancer mortality than US‐born individuals (RR, 1.24; 95% confidence interval [CI], 1.22‐1.25). Foreign‐born individuals did not have any significant changes in liver cancer mortality rates overall, but among US‐born individuals, liver cancer mortality rates significantly increased (AAPC, 2.7; 95% CI, 2.1‐3.3).

Conclusions

Efforts that address the major risk factors for liver cancer are needed to help to alleviate the health disparities observed among foreign‐born individuals and reverse the increasing trend observed in the US‐born population.

https://ift.tt/2PYsYDr

Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

Background

Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time‐efficient and cost‐efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors' knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer‐associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment.

Methods

The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non‐BRCA1/2 cancer‐associated genes.

Results

A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non‐BRCA1/2 cancer‐associated gene. Non‐BRCA1/2 cancer‐associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC).

Conclusions

Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.

https://ift.tt/2RcRrkO

STAR act expected to improve care for pediatric patients with cancer

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Cancer centers issue call to action regarding the human papillomavirus vaccine

https://ift.tt/2RcRixM

First Person: Hyman Muss, MD

https://ift.tt/2PUKBnv

Issue Information

https://ift.tt/2Rk8RfA

Clinical Snippets

https://ift.tt/2Q09TRe

Issue Information

https://ift.tt/2ReiRqx

Membrane‐enriched solute carrier family 2 member 1 (SLC2A1/GLUT1) in psoriatic keratinocytes confers sensitivity to 2‐deoxy‐D‐glucose (2‐DG) treatment

Abstract

Psoriasis is a common chronic disease with accelerated epidermal cell growth. Solute carrier family 2 member 1 (SLC2A1), also named GLUT1, transports glucose and its analogues into cells. With elevated membrane‐bound GLUT1, psoriatic keratinocytes uptake more glucose with increased glucose metabolism. Competition between glucose and its analogues can serve as a strategy to inhibit glycolysis as well as proliferation. In this study, we investigated the expression patterns of GLUT1 in keratinocytes in the human psoriasis vulgaris and imiquimod‐induced psoriasis model, and determined that the glucose metabolism inhibitor 2‐deoxyglucose (2‐DG) can relieve the psoriatic lesions. We found membrane‐enriched GLUT1 in psoriasis keratinocytes, which suggested some potential for glucose metabolic target therapy based on the glycolytic microenvironment. Furthermore, 2‐DG was able to relieve the psoriatic lesions in an in vivo animal model which provides a new possible therapeutic strategy.

https://ift.tt/2PZReVy

Student Elective Competition 2018/19: A call for entries

We are now launching the 2018/19 competition for students and interns. Write up your experiences as a global health case report and you could be the winner of a position as a Global Health Associate Editor for BMJ Case Reports.

All authors must be students or interns at the time of submission.

Your entry will undergo the same treatment that all our journal submissions do, including the peer review process, so be sure to check out our Instructions for Authors for guidance before you start writing. If you've never written a global health case report before, you may find our Global Health section useful to help you get started.

Winners will be selected for interview to become a Global Health Associate Editor. We welcome submissions from all over the world. Patients may be anyone seen on the ward or at home, in medical school or on elective. Winners will be announced in September 2019.

Global Health Associate Editors will have the chance to contribute to our global health blog, help manage our social media presence and collaborate on special global health projects.

The post Student Elective Competition 2018/19: A call for entries appeared first on BMJ Case Reports blog.

https://ift.tt/2RhS6BH

Characterization and regulation of MT1‐MMP cell surface‐associated activity

MT1‐MMP was stably expressed and a cell‐based FRET assay developed to quantify activity towards synthetic collagen‐model triple‐helices. Activity measurements were performed using a series of membrane‐anchored MT1‐MMP mutants and compared directly with those of soluble MT1‐MMP. Cell surface localization of MT1‐MMP was found to restrict substrate binding and protein coupled motions for catalysis. Small molecule and triple‐helical transition state analog MMP inhibitors were found to function similarly in solution and at the cell surface.

Abstract

Quantitative assessment of MT1‐MMP cell surface‐associated proteolytic activity remains undefined. Presently, MT1‐MMP was stably expressed and a cell‐based FRET assay developed to quantify activity towards synthetic collagen‐model triple‐helices. To estimate the importance of cell surface localization and specific structural domains on MT1‐MMP proteolysis, activity measurements were performed using a series of membrane‐anchored MT1‐MMP mutants and compared directly with those of soluble MT1‐MMP. MT1‐MMP activity (k_cat/K_M) on the cell surface was 4.8‐fold lower compared with soluble MT1‐MMP, with the effect largely manifested in k_cat. Deletion of the MT1‐MMP cytoplasmic tail enhanced cell surface activity, with both k_cat and K_M values affected, while deletion of the hemopexin‐like domain negatively impacted K_M and increased k_cat. Overall, cell surface localization of MT1‐MMP restricts substrate binding and protein coupled motions (based on changes in both k_cat and K_M) for catalysis. Comparison of soluble and cell surface‐bound MT2‐MMP revealed 12.9‐fold lower activity on the cell surface. The cell‐based assay was utilized for small molecule and triple‐helical transition state analog MMP inhibitors, which were found to function similarly in solution and at the cell surface. These studies provide the first quantitative assessments of MT1‐MMP activity and inhibition in the native cellular environment of the enzyme.

https://ift.tt/2TQLKL2

Determination of the binding mechanism of histone deacetylase inhibitors

The understanding of the mode of action of active substances and how this is coupled to the biological response is of utmost importance for the optimization of drug candidates. This article contains a comprehensive collection of methods and protocols that enables the elucidation of the binding mechanism of inhibitors to histone deacetylases. All available equilibrium and kinetic data can be beneficially combined in a data analysis procedure called Integrated Global Fit analysis eventually yielding the most likely binding mechanism.

Abstract

This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small molecule inhibitors or substrates, interact with zinc containing bacterial or human members of the histone deacetylase family (HDACs). These methods include biochemical and biophysical approaches and can be subdivided into equilibrium and kinetic methods. More information about the exact mode of action can be obtained by combining these methods with specific mutant variants of the enzymes and/or series of structural similar ligands. All available equilibrium and kinetic data including additional information from 3D‐structures of HDAC‐ligand complexes can be beneficially combined in a data analysis procedure called Integrated Global Fit analysis eventually providing the most likely binding mechanism.

https://ift.tt/2AqGOUf

Solid Phase Synthesis and Self‐Assembly of Higher‐Order siRNAs and their Bioconjugates

Summary: We have developed an efficient method for the production of a ribouridine branchpoint synthon that can be effectively incorporated within higher‐order RNA structures, including those adopting V‐, and Y‐shape RNA. Self‐assembly with complementary RNA produces higher‐order siRNA nanostructures that silence the Glucose Regulated Proteins in cancer cells. Moreover, we have also developed solid phase bioconjugation strategies for incorporating bio‐active probes such as fatty acids and fluorescent reporters that respectively facilitate direct transfection and tracking of siRNA activity in cancer cells

Abstract

New methods for the synthesis of higher‐order siRNA motifs and their bioconjugates have recently gained widespread attention in the development of new and improved gene therapeutics. Our efforts aim to produce new chemical tools and protocols for the generation of modified siRNAs that screen for important oncogene targets as well as silence their activity for effective gene therapy in cancer models. More specifically, we have developed an efficient solution‐phase synthesis for the production of a ribouridine branchpoint synthon that can be effectively incorporated by solid phase synthesis within higher‐order RNA structures, including those adopting V‐, and Y‐ and >‐< shape RNA templates. Self‐assembly of complementary RNA to the template strands produced higher‐order siRNA nanostructures that were characterized by a combination of PAGE, DLS and TEM techniques. In an effort to extend the repertoire of functionally diverse siRNAs, we have also developed solid phase bioconjugation strategies for incorporating bio‐active probes such as fatty acid appendages and fluorescent reporters. Taken together, these methods highlight the ability to generate higher‐order siRNAs and their bioconjugates for exploring the influence of modified siRNA structure on anti‐cancer activity.

https://ift.tt/2TPB0g7

Synthesis, anticancer activity and cytotoxicity of 7‐O‐β‐D‐galactosyl‐PEG‐epothilone B

The 7‐O‐β‐D‐galactosyl‐PEG‐epothilone B 6 was successfully synthesized by a combined chemical and enzymatic method. Activity tests showed that compound 6 was low in toxicity and had strong anticancer activity

Abstract

Epothilone, the macrolide compound produced by Sorangium cellulosum, has antitumor activity. Its anti‐tumor mechanism is similar to that of paclitaxel, which promotes the polymerization of tubulin and induces apoptosis. Herein, 7‐O‐β‐D‐galactosyl‐PEG‐epothilone B 6 was synthesized. It showed that the toxicity of the synthesized compound was 1/182 of the epothilone B. In addition, compound 6 also had significant anticancer activity under the action of enzyme.

https://ift.tt/2AoRClU

Influence of restorative margins position on one‐stage laser‐microgrooved implants‐supported single screwed crowns: A clinical, biochemical, and microbiological analysis

Abstract

Aim

To clinically, biochemically, and microbiologically evaluate the influence of crown margins position on one‐stage laser‐microgrooved implants.

Materials and Methods

Twenty‐one‐stage titanium implants with a laser‐microgrooved collar surface, supporting screwed, single crown restorations, were placed in 20 partially edentulous patients and evaluated. Clinical parameters included modified plaque index, modified gingival index, peri‐implant probing pocket depth, bleeding on probing, and distance between implant shoulder and mucosal margin. The parameters were recorded at baseline (crowns delivery) and at every 6‐month recall visit, until the end of the 3 years follow‐up period. At the same time intervals, radiographic marginal bone levels were assessed at the mesial and distal aspect of the implant sites. For biochemical analysis, the volume of the peri‐implant sulcus fluid, and its levels of interleukin‐1beta (IL‐1β), interleukin‐6 (IL‐6), and of tumor necrosis factor‐α, were utilized to evaluate the peri‐implant health conditions at the end of the 3‐year follow‐up period. At the same time, microbiological analysis, including the concentration of five putative periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Tannerella forsythensis), were assessed. The crown margins positions were classified into four groups (A = intracrevicular position >2 mm, B = intracrevicular position ≤2 mm/<1 mm, C = intracrevicular position ≤1 mm/<0 mm, and D = extracrevicular position), and the biochemical, and microbiological parameters were evaluated at 3 years.

Results

No statistical differences of clinical and biochemical parameters were found between the four groups. In group A, compared to groups B, C, and D, a statistically significant higher concentration of putative periodontal pathogens was found.

Conclusions

Results showed that the intracrevicular deeper position of the restoration margin does not influence the clinical and biochemical peri‐implant parameters. The deeper position of the crown margin is associated with a greater amount of putative periodontal pathogenic microflora colonization.

https://ift.tt/2PWIMXl

Association between breast cancer and thyroid cancer: A study based on 13 978 patients with breast cancer

In the current study, we investigated the association of thyroid cancer incidence in a cohort of 13 978 breast cancer patients. We identified that the standardized incidence ratio of secondary thyroid cancer was significantly increased and a family history of malignancy was the only independent risk factor, which provided a new insight into the association of breast cancer and thyroid cancer.

Abstract

Background

Thyroid cancer (TC) is one of the most commonly seen secondary malignancy in breast cancer (BC) survivors.

Materials and methods

A retrospective study was conducted in BC patients in our center from 1999 to 2013. Patients were divided into BC‐TC group and BC‐alone group.

Results

In total, 13 978 BC patients were identified, among whom 247 (1.8%) had TC. The standardized incidence ratio (SIR) of TC was 4.48 compared with Chinese females, and up to 98.0% of cases were thyroid papillary carcinomas. A family history of malignancy was the only independent risk factor (odds ratio = 1.457, P = 0.025) for development of TC in patients with BC. We also identified inferior survival in patients with synchronous versus metachronous BC‐TC (P = 0.016). Synchronous BC‐TC (risk ratio = 5.597, P = 0.018) was an independent prognostic factor for inferior RFS.

Conclusions

We observed high co‐occurrence of TC in patients with BC. There might be different mechanisms behind synchronous and metachronous BC‐TC.

https://ift.tt/2AqFtNd

Second primary cancer after female breast cancer: Familial risks and cause of death

Abstract

Background

With continuous increases in survival rates following breast cancer (BC) diagnosis, the challenge of multiple primary cancers has become an issue. The data on familial risk of SPCs after BC diagnosis and the related mortality in BC patients are scarce.

Methods

A total of 87 752 female BC patients were followed for SPC diagnoses and records of death. Relative risks (RRs) of SPC in BC patients who had first‐degree relatives (parents or siblings) affected by the same cancer were compared to the patients without family history. Causes of death were compared between patients with and without SPC.

Results

After a median follow‐up of 5 years, 14 952 BC patients developed SPCs, among which 10 280 (68.8%) had first‐degree relatives diagnosed with cancer. Familial risks were significant for 14 site‐specific SPCs, and the highest risk was for second ovarian cancer (RR = 6.28, 95%CI: 4.50‐8.75), compared to those without family history (1.49, 1.34‐1.65). In patients with SPC, SPC was the main cause of death, including diverse cancers and BC in approximately equal proportions.

Conclusions

Family history contributed to the excess number of patients with SPCs, and SPC was the leading cause of death in patients with SPC. Taking family history at diagnosis of BC may provide warning signs with regard to possible subsequent SPCs and may offer possibilities for counseling, intervention and management.

https://ift.tt/2TSW0SW

Surgery vs. radiotherapy for locally advanced hypopharyngeal cancer in the contemporary era: A population‐based study

From 2010 to 2015, overall survival for hypopharyngeal cancer patients (T2‐T4aM0) who received total pharyngectomy with lymph node dissection (n = 209) or chemoradiotherapy (n = 648) was compared. Chemoradiotherapy for both T2‐3 and T4a hypopharyngeal cancers showed comparable OS rates to surgery. For patients with T4a category cancer with high possibility of preserving the laryngopharyngeal function, chemoradiotherapy may be a promising alternative treatment.

Abstract

Objectives

To compare overall survival (OS) in locally advanced hypopharyngeal cancer treated with surgery or definitive chemoradiotherapy in the contemporary era.

Methods

From 2010 to 2015, data for patients diagnosed with hypopharyngeal cancer (T2‐T4aM0) and treated with total pharyngectomy with lymph node dissection (surgery group) or definitive radiotherapy and chemotherapy (chemoradiotherapy group) was retrieved from the SEER database. Multivariate analyses were performed in each subgroup divided according to T category (T2‐3 or T4a).

Results

The number of patients in the surgery and chemoradiotherapy groups was 209 and 648, respectively. Among them, the number of T4a patients was 111 and 126 in each group. Three‐year OS rate in the surgery and chemoradiotherapy groups was 37.9% and 44.1%, respectively (P = 0.178). The 3‐year OS rate for the T2‐3 patients was 46.5% and 48.7% (P = 0.598), and the 3‐year OS rate for the T4a patients was 29.9% and 26.1% in the surgery and chemoradiotherapy groups, respectively (P = 0.439). On multivariate analysis, the chemoradiotherapy group was not inferior to the surgery group in T2‐T4a patients (Hazard ratio [HR] for the chemoradiotherapy group 0.889, 95% confidence interval [CI] 0.699‐1.129, P = 0.334), in T2‐3 patients (HR 0.932, 95% CI 0.699‐1.297, P = 0.675), and in T4a patients (HR 0.880, 95% CI 0.617‐1.256, P = 0.481).

Conclusions

Chemoradiotherapy for locally advanced hypophagyngeal cancer showed a comparable OS rate to surgery. For patients with T4a category cancer with high possibility of preserving the laryngopharyngeal function, chemoradiotherapy may be a promising alternative treatment.

https://ift.tt/2AqFrF5

A novel lncRNA‐miRNA‐mRNA network analysis identified the hub lncRNA RP11‐159F24.1 in the pathogenesis of papillary thyroid cancer

Cancer Medicine A novel lncRNA‐miRNA‐mRNA network analysis identified the hub lncRNA RP11‐159F24.1 in the pathogenesis of papillary thyroid cancer

This study has constructed a PTC‐related lncRNA‐miRNA‐mRNA network and identified the hub lncRNA RP11‐159F24.1 in the tumorigenesis, which provided novel insights to explore the underlying mechanism of PTC.

Abstract

Papillary thyroid cancer (PTC) is one of the most common cancers worldwide, and its carcinogenesis is influenced by a complex network of gene interactions. In this study, the microarray expression profile was re‐annotated into a lncRNA‐mRNA biphasic profile. LncRNA‐mRNA interactions were confirmed by established miRNA‐RNA data and hypergeometric test. Then, a PTC‐related lncRNA‐miRNA‐mRNA network (PTCRN) was constructed by integrating differentially expressed genes with the RNA‐RNA networks. The new network consisted of 21 lncRNAs, 241 mRNAs and 803 edges. To prioritize PTC‐related genes, we performed topological analysis and random walk with restart (PWR) algorithm analysis of PTCRN. Both analyses identified lncRNA RP11‐159F24.1 as a hub node in the network, which could interact with 47 mRNAs by sponging miR‐485. In functional enrichment analysis, these interacting mRNAs were associated with the pathways in cancer. In validation, RP11‐159F24.1 (up‐regulated; P = 0.0013) showed an opposite expression pattern with its target miR‐485 (down‐regulated; P = 0.0013) in PTC, indicating that the RP11‐159F24.1/miR‐485/mRNAs axis might play an important role in the development of PTC. In conclusion, this study has constructed a PTC‐related lncRNA‐miRNA‐mRNA network and identified the hub lncRNA RP11‐159F24.1 in the tumorigenesis, which provided novel insights to explore the underlying mechanism of PTC.

https://ift.tt/2TOat2y

CD44v9 is associated with epithelial‐mesenchymal transition and poor outcomes in esophageal squamous cell carcinoma

CD44v9 expression at the tumor invasive front is associated with the EMT, tumor invasion. Moreover, CD44v9 expression at the TIF was an independent prognostic factor of overall survival and recurrence‐free survival. We conclude that CD44v9 represents a novel prognostic biomarker and a potential therapeutic target for ESCC.

Abstract

CD44 serves as a marker of cancer stem cells. Alternative splicing generates the CD44v9 isoform. Cancer stem cells are associated with the epithelial‐mesenchymal transition in cancers, although little is known about their role in esophageal squamous cell carcinoma. Here, we aimed to clarify the relationship between CD44v9 expression, the epithelial‐mesenchymal transition, and clinicopathological features of patients with esophageal squamous cell carcinoma. CD44v9 levels were higher at the tumor invasive front compared with the center of the tumor and higher in metastatic lymph nodes compared with primary tumors. High levels of CD44v9 at the tumor invasive front were significantly associated with deeper tumor invasion and shorter overall survival and recurrence‐free survival. The expression of CD44v9 was increased by treatment with transforming growth factor‐β, which induced esophageal squamous cell carcinoma cells to undergo the epithelial‐mesenchymal transition. Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells. These results indicate that the expression of CD44v9 at the tumor invasive front induced by stemness was strongly associated with the epithelial‐mesenchymal transition and poor prognosis of patients with esophageal squamous cell carcinoma. CD44v9 may therefore serve as a novel prognostic biomarker and a potential therapeutic target for esophageal squamous cell carcinoma.

https://ift.tt/2AqFcKb

Pretreatment values of bilirubin and albumin are not prognostic predictors in patients with advanced pancreatic cancer

The baseline level of bilirubin and serum proteins were not associated with the prognosis of advanced pancreatic cancer. Although tumor location and baseline level of CA19‐9, CA 242 and CA 50 were associated with the overall survival in the univariate analysis, only tumor location and level of CA19‐9 served as independent indicators for poor prognosis in multivariate regression analysis.

Abstract

Purpose

To identify the pretreatment values of bilirubin and albumin and other serum biomarkers in predicting the prognosis for advanced pancreatic cancer.

Methods

A total of 201 consecutive patients pathologically diagnosed as advanced pancreatic cancer were retrospectively reviewed. Tumor location, TNM classification, the level of baseline total bilirubin (TBIT), direct bilirubin (DBIT), albumin (ALB), globulin (GLOB), total protein (TP), ALB to GLOB ratio (AGR), CA19‐9, CA242, and CA50 were collected. The values of CA19‐9, CA242, and CA50 were divided into two groups according to the upper limit value which were 1000 U/mL, 150 IU/mL, and 500 IU/mL, respectively. The values of TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB were divided into low and high groups according to the median. To investigate if the median was an effective discriminator in dividing these markers, the patients were divided into a test set (n = 100) and a validation set (n = 101). Kaplan‐Meier (K‐M) survival analysis and Cox regression analysis were performed to explore the potential relationship between them and overall survival (OS).

Results

A K‐M survival analysis revealed that the investigated markers in test set, including TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB, were not associated with the OS. The findings from the validation set were consistent with those in the test set. Factors with P value smaller than 0.1 in the univariate analysis along with the tumor location, CA19‐9, CA242, CA50, were entered into the multivariate analysis. A Cox regression analysis suggested that the cancerization at head of pancreas (P = 0.01) and a high level of CA19‐9 (P = 0.02) were independent prognostic indicators for poor OS of pancreatic cancer.

Conclusions

Baseline bilirubin and serum proteins were not associated with the prognosis of advanced pancreatic cancer. Tumor location and level of CA19‐9 may serve as significant indicators for poor prognosis in those patients.

https://ift.tt/2TRL606

IVIg‐induced plasmablasts in patients with Guillain‐Barré syndrome

Abstract

Objective

The Guillain–Barré syndrome (GBS) is an acute, immune‐mediated disease of peripheral nerves. Plasmablasts and plasma cells play a central role in GBS by producing neurotoxic antibodies. The standard treatment for GBS is high‐dose intravenous immunoglobulins (IVIg), however the working mechanism is unknown and the response to treatment is highly variable. We aimed to determine whether IVIg changes the frequency of B‐cell subsets in patients with GBS.

Methods

Peripheral blood mononuclear cells were isolated from 67 patients with GBS before and/or 1, 2, 4, and 12 weeks after treatment with high‐dose IVIg. B‐cell subset frequencies were determined by flow cytometry and related to serum immunoglobulin levels. Immunoglobulin transcripts before and after IVIg treatment were examined by next‐generation sequencing. Antiglycolipid antibodies were determined by ELISA.

Results

Patients treated with IVIg demonstrated a strong increase in plasmablasts, which peaked 1 week after treatment. Flow cytometry identified a relative increase in IgG2 plasmablasts posttreatment. Within IGG sequences, dominant clones were identified which were also IGG2 and had different immunoglobulin sequences compared to pretreatment samples. High plasmablast frequencies after treatment correlated with an increase in serum IgG and IgM, suggesting endogenous production. Patients with a high number of plasmablasts started to improve earlier (P = 0.015) and were treated with a higher dose of IVIg.

Interpretation

High‐dose IVIg treatment alters the distribution of B‐cell subsets in the peripheral blood of GBS patients, suggesting de novo (oligo‐)clonal B‐cell activation. Very high numbers of plasmablasts after IVIg therapy may be a potential biomarker for fast clinical recovery.

https://ift.tt/2DNHtCw

OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia

Abstract

Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and β‐cell function in Friedreich ataxia patients, heterozygous FXN mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2‐ to 3.5‐fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and β‐cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.

https://ift.tt/2Qp4mDc

Validated automatic speech biomarkers in primary progressive aphasia

Abstract

Objective

To automatically extract and quantify specific disease biomarkers of prosody from the acoustic properties of speech in patients with primary progressive aphasia.

Methods

We analyzed speech samples from 59 progressive aphasic patients (non‐fluent/agrammatic = 15, semantic = 21, logopenic = 23; ages 50–85 years) and 31 matched healthy controls (ages 54–89 years). Using a novel, automated speech analysis protocol, we extracted acoustic measurements of prosody, including fundamental frequency and speech and silent pause durations, and compared these between groups. We then examined their relationships with clinical tests, gray matter atrophy, and cerebrospinal fluid analytes.

Results

We found a narrowed range of fundamental frequency in patients with non‐fluent/agrammatic variant aphasia (mean 3.86 ± 1.15 semitones) compared with healthy controls (6.06 ± 1.95 semitones; P < 0.001) and patients with semantic variant aphasia (6.12 ± 1.77 semitones; P = 0.001). Mean pause rate was significantly increased in the non‐fluent/agrammatic group (mean 61.4 ± 20.8 pauses per minute) and the logopenic group (58.7 ± 16.4 pauses per minute) compared to controls. In an exploratory analysis, narrowed fundamental frequency range was associated with atrophy in the left inferior frontal cortex. Cerebrospinal level of phosphorylated tau was associated with an acoustic classifier combining fundamental frequency range and pause rate (r = 0.58, P = 0.007). Receiver operating characteristic analysis with this combined classifier distinguished non‐fluent/agrammatic speakers from healthy controls (AUC = 0.94) and from semantic variant patients (AUC = 0.86).

Interpretation

Restricted fundamental frequency range and increased pause rate are characteristic markers of speech in non‐fluent/agrammatic primary progressive aphasia. These can be extracted with automated speech analysis and are associated with left inferior frontal atrophy and cerebrospinal phosphorylated tau level.

https://ift.tt/2DKjfJk

Hepatoprotective effects of blue honeysuckle on CCl4‐induced acute liver damaged mice

BHe 200 mg/kg showed more favorable hepatoprotective effects compared with those of silymarin 100 mg/kg on CCl4‐induced acute liver damage in mice.

Abstract

The objective of this study was to evaluate the hepatoprotective effects of blue honeysuckle (BH) on carbon tetrachloride (CCl₄)‐induced acute hepatic damage in mice. The experiment used a total of 60 ICR mice, which were divided into six groups. Except for the intact control groups, all groups received a single intraperitoneal injection of CCl₄ after a 7 day pre‐treatment period with distilled water, BH extracts, or silymarin. Twenty‐four hours after the CCl₄ injection, the following observations, representative of classical oxidative stress‐mediated centrolobular necrotic acute liver injuries, were observed: decreased body weight; small nodule formation and enlargement on the gross inspections with related liver weight increase; elevation of serum AST and ALT, increases in hepatic lipid peroxidation and related depletion of endogenous antioxidants and antioxidative enzymes; centrolobular necrosis; increases in apoptotic markers, lipid peroxidation markers, and oxidative stress markers. However, liver damage was significantly inhibited by the pre‐treatment with BH extracts. The present study demonstrated that oral administration of BH extracts prior to exposure to CCl₄ conferred favorable hepatoprotective effects. These results demonstrated that BHe possessed suitable properties for use as a potent hepatoprotective medicinal food.

https://ift.tt/2r8JHVx

Effect of processing and soybean cultivar on natto quality using response surface methodology

Bacilllus subtilis fermentation of soaked and cooked soybeans results in proteolysis of soy polypeptides, altering its digestibility, taste, and flavor, as well as improving the protein quality. Besides, it inactivates antinutritional factors, removes indigestible oligosaccharides, and increases isoflavone, proteolytic enzymes, and phytosterols that can make difference in human health.

Abstract

In an attempt to commercialize the traditional technology of fermenting soybean into natto on laboratory scale using three locally available soybean varieties, that is, white, black, and brown, response surface methodology (RSM) was used to determine the optimum combination of two factors, that is, the effect of steaming time (20–50 min) and fermentation time (12–48 hr). Thirteen samples from each variety were formulated which were packed in low‐density polyethylene for LDPE using the isolated culture from the natto sample and incubated at 37°C, and the sensory data were analyzed by using Design Expert (RSM). All the responses (taste, hardness, thread/stickiness, and overall acceptance) were significantly (p < 0.05) affected by the two variables except appearance for all three varieties of natto prepared. The optimum combinations of steaming time (min) and fermentation time (hr) were found for white soybean natto (33.4 min and 34.5 hr), for black soybean natto (34.7 min and 30.9 hr), and for brown soybean natto (33.2 min and 34.9 hr), respectively. The proximate composition of soybean and best three formulated natto obtained after sensory evaluation from 13 samples of each variety were studied, that is, moisture, crude protein, pH, calcium, and iron on dry basis found to have increased, whereas carbohydrate and crude fiber found to have slightly decreased, but crude fat and ash found to be almost equal on three varieties than the raw soybean used. Microbiologically, the product was hygienic and safe as coliform and salmonella were not detected.

https://ift.tt/2FL8cCj

In vitro antihypertensive and antioxidative properties of trypsin‐derived Moringa oleifera seed globulin hydrolyzate and its membrane fractions

$Food Science & Nutrition In vitro antihypertensive and antioxidative properties of trypsin‐derived Moringa oleifera seed globulin hydrolyzate and its membrane fractions$

Protein isolate (globulin) was isolated from Moringa oleifera seed. This was hydrolyzed with trypsin and fractionated into different MW peptides sizes. Their antioxidant abilities (DPPH, FRAP, hydroxyl radical scavenging) were tested. Their in vitro antihypertensive properties were also tested. The peptide fractions showed good antioxidant and ACE inhibition abilities.

Abstract

Moringa oleifera seed globulin was hydrolyzed with trypsin and fractionated to produce <1, 1–3, and 3–5 kDa peptide sizes. These were evaluated for antioxidant properties: DPPH, hydroxyl radical scavenging assays, FRAP, and metal chelation tests; and in vitro antihypertensive properties: ACE and renin inhibition. Membrane fractionation led to improved antioxidative properties of 29.13% (<1 kDa), 180% (<1 kDa), and 30.58% (1–3 kDa) for DPPH, FRAP, and metal iron chelation, respectively. There was however 48.77% reduction (1–3 kDa) in hydroxyl radical scavenging activity. There was also improvement in ACE inhibitory potentials of the peptides with the 1–3 kDa peptide showing significantly highest ACE inhibition (72.48%)but very low (17.64%, 1–3 kDa) inhibition against the renin. It was concluded that hydrolysis of M oleifera seed globulin with trypsin produced peptides and peptide fractions with potential antioxidant and antihypertensive properties.

https://ift.tt/2r3JrY2

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Τρίτη 27 Νοεμβρίου 2018

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