Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts

Purpose: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC.

Experimental Design: The study population includes 190 patients with stage I–III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m²) given every 21 days x 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated.

Results: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event.

Conclusions: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline–taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649–57. ©2016 AACR.

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Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas

Purpose: Despite various differences, nontranslocation-related sarcomas (e.g., comprising undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma) are unified by their complex genetics. Extensive analysis of the tumor genome using molecular cytogenetic approaches showed many chromosomal gains, losses, and translocations per cell. Genomic quantitative alterations and expression variations have been extensively studied by adapted high-throughput approaches, yet translocations still remained unscreened. We therefore analyzed 117 nontranslocation-related sarcomas by RNA sequencing to identify fusion genes.

Experimental design: We performed RNA sequencing and applied a bioinformatics pipeline dedicated to the detection of fusion transcripts. RT-PCR and Sanger sequencing were then applied to validate predictions and to search for recurrence and specificity.

Results: Among the 6,772 predicted fusion genes, 420 were in-frame. One recurrent rearrangement, consistently involving TRIO with various partners, was identified in 5.1% of cases. TRIO translocations are either intrachromosomal with TERT or interchromosomal with LINC01504 or ZNF558. Our results suggest that all translocations led to a truncated TRIO protein either directly or indirectly by alternative splicing. TRIO rearrangement is associated with a modified transcriptomic program to immunity/inflammation, proliferation and migration, and an increase in proliferation.

Conclusions: TRIO fusions have been identified in four different sarcoma histotypes, likely meaning that they are not related to a primary oncogenic event but rather to a secondary one implicated in tumor progression. Moreover, they appear to be specific to nontranslocation-related sarcomas, as no such rearrangement was identified in sarcomas with simple genetics. More cases could lead to a significant association of these fusions to a specific clinical behavior. Clin Cancer Res; 23(3); 857–67. ©2016 AACR.

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Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy

Purpose: Severe skeletal muscle (SM) loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first-line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes.

Experimental Design: Using computerized tomography (CT) images taken for the evaluation of disease burden, skeletal muscle area (SMA), and density (SMD) were measured at the third lumbar vertebrae. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height²) ≤ 41. Skeletal muscle gauge (SMG) was created by multiplying SMI x SMD. Fisher exact tests, t tests, the Kaplan–Meier method, and Cox regression modeling were used.

Results: MBC patients (N = 40), median age 55 (range, 34–80), 58% sarcopenic, median SMG 1296 AU (SD, 522). Grade 3–4 toxicity was found in 57% of sarcopenic versus 18% of non-sarcopenic patients (P = 0.02). Toxicity-related hospitalizations were also higher in sarcopenic patients (39% vs. 0%, P = 0.005) as were any adverse events—defined as any grade 3–4 toxicities, hospitalizations, dose reductions, or dose delay—(74% vs. 35%, P = 0.02). Low SMG was associated with grade 3–4 toxicity (P = 0.04), hospitalization (P = 0.01), and time to treatment failure (for progression or toxicity; P = 0.03). Low SMG had a borderline significant association with any adverse event (P = 0.06) and overall survival (P = 0.07).

Conclusions: SM measures are associated with toxicity outcomes and survival in MBC patients receiving first-line taxane-based chemotherapy. Further studies are needed to explore how routinely obtained CT scans can be used to individualize dosing and improve treatment planning. Clin Cancer Res; 23(3); 658–65. ©2016 AACR.

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Highlights of This Issue

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Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases

Purpose: Bone marrow–derived progenitor cells, including VEGFR2⁺ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.

Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.

Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II–III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).

Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666–76. ©2016 AACR.

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Explant culture: An advantageous method for isolation of mesenchymal stem cells from human tissues

Abstract

Mesenchymal stem cell (MSC) research progressively moves towards clinical phases. Accordingly, a wide range of different procedures were presented in the literature for MSC isolation from human tissues; however, there is not yet any close focus on the details to offer precise information for best method selection. Choosing a proper isolation method is a critical step in obtaining cells with optimal quality and yield in companion with clinical and economical considerations. In this concern, current review widely discusses advantages of omitting proteolysis step in isolation process and presence of tissue pieces in primary culture of MSCs, including removal of lytic stress on cells, reduction of in vivo to in vitro transition stress for migrated/isolated cells, reduction of price, processing time and labour, removal of viral contamination risk, and addition of supporting functions of extracellular matrix and released growth factors from tissue explant. In next sections, it provides an overall report of technical highlights and molecular events of explant culture method for isolation of MSCs from human tissues including adipose tissue, bone marrow, dental pulp, hair follicle, cornea, umbilical cord and placenta. Focusing on informative collection of molecular and methodological data about explant methods can make it easy for researchers to choose an optimal method for their experiments/clinical studies and also stimulate them to investigate and optimize more efficient procedures according to clinical and economical benefits.

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Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wnt^liver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt, and metM-Wnt^liver cells, 12, 29, and 25 metabolites, respectively, were significantly different (P < 0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration, and invasion occurred in M-Wnt and metM-Wnt^liver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype.

Implications: Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer. Mol Cancer Res; 15(2); 189–200. ©2016 AACR.

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Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation

Deubiquitinases (DUB) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressor signaling. Here, evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non–small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1 isoform is inhibitory, while the short OTUD6B-2 isoform stimulates protein synthesis. These properties affect NSCLC cell proliferation, because OTUD6B-1 represses DNA synthesis while OTUD6B-2 promotes it. Mutational analysis and downstream mediators suggest that the two OTUD6B isoforms modify different cellular targets. OTUD6B-2 influences the expression of cyclin D1 by promoting its translation while regulating (directly or indirectly) c-Myc protein stability. This phenomenon appears to have clinical relevance as NSCLC cells and human tumor specimens have a reduced OTUD6B-1/OTUD6B-2 mRNA ratio compared with normal samples. The global OTUD6B expression level does not change significantly between nonneoplastic and malignant tissues, suggesting that modifications of splicing factors during the process of transformation are responsible for this isoform switch.

Implications: Because protein synthesis inhibition is a viable treatment strategy for NSCLC, these data indicate that OTUD6B isoform 2, being specifically linked to NSCLC growth, represents an attractive, novel therapeutic target and potential biomarker for early diagnosis of malignant NSCLC. Mol Cancer Res; 15(2); 117–27. ©2016 AACR.

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Highlights of This Issue

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The Efflux Transporter ABCG2 Maintains Prostate Stem Cells

Prostate stem cells (PSC) are characterized by their intrinsic resistance to androgen deprivation therapy (ADT), possibly due to the lack of androgen receptor (AR) expression. PSCs resistance to ADT and PSC expansion in castration resistant prostate cancer (CRPC) has sparked great interest in using differentiation therapy as an adjuvant to ADT. Understanding the mechanisms, by which PSCs maintain their undifferentiated phenotype, thus has important implications in differentiation therapy. In the prostate, the ATP binding cassette sub-family G member 2 (ABCG2) transporters, which enrich for AR-positive, ADT-resistant PSCs, play an important role in regulating the intracellular androgen levels by effluxing androgens. We hypothesized that the ABCG2-mediated androgen efflux is responsible for maintaining PSCs in an undifferentiated state. Using the HPr-1-AR (nontumorigenic) and CWR-R1 (tumorigenic) prostate cell lines, it was demonstrated that inhibiting the ABCG2-mediated androgen efflux, with Ko143 (ABCG2 inhibitor), increased the nuclear AR expression due to elevated intracellular androgen levels. Increased nuclear translocation of AR is followed by increased expression of AR regulated genes, a delayed cell growth response, and increased luminal differentiation. Furthermore, Ko143 reduced tumor growth rates in mice implanted with ABCG2-expressing CWR-R1 cells. In addition, Ko143-treated mice had more differentiated tumors as evidenced by an increased percentage of CK8⁺/AR⁺ luminal cells and decreased percentage of ABCG2-expressing cells. Thus, inhibiting ABCG2-mediated androgen efflux forces the PSCs to undergo an AR-modulated differentiation to an ADT-sensitive luminal phenotype.

Implications: This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128–40. ©2016 AACR.

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MYC Mediates mRNA Cap Methylation of Canonical Wnt/{beta}-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase

MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here, it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational capacity, elevated protein levels, and enhanced Wnt signaling activity. Mechanistic evidence indicates that MYC promotes recruitment of RNA methyltransferase (RNMT) to Wnt signaling gene promoters by enhancing phosphorylation of serine 5 on the RNA polymerase II carboxy-terminal domain, mediated in part through an interaction between the TIP60 acetyltransferase complex and TFIIH.

Implications: MYC enhances mRNA cap methylation above and beyond transcriptional induction. Mol Cancer Res; 15(2); 213–24. ©2016 AACR.

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Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-{kappa}B Activation

Balsalazide is a colon-specific prodrug of 5-aminosalicylate that is associated with a reduced risk of colon cancer in patients with ulcerative colitis. Parthenolide, a strong NF-B inhibitor, has recently been demonstrated to be a promising therapeutic agent, promoting apoptosis of cancer cells. In the current study, the antitumor effect of balsalazide combined with parthenolide in human colorectal cancer cells and colitis-associated colon cancers (CAC) was investigated. The results demonstrate that the combination of balsalazide and parthenolide markedly suppress proliferation, nuclear translocation of NF-B, IB-α phosphorylation, NF-B DNA binding, and expression of NF-B targets. Apoptosis via NF-B signaling was confirmed by detecting expression of caspases, p53 and PARP. Moreover, treatment of a CAC murine model with parthenolide and balsalazide together resulted in significant recovery of body weight and improvement in histologic severity. Administration of parthenolide and balsalazide to CAC mice also suppressed carcinogenesis as demonstrated by uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) using micro-PET/CT scans. These results demonstrate that parthenolide potentiates the efficacy of balsalazide through synergistic inhibition of NF-B activation and the combination of dual agents prevents colon carcinogenesis from chronic inflammation.

Implications: This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141–51. ©2016 AACR.

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High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV

In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls.

Implications: HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status. Mol Cancer Res; 15(2); 179–88. ©2016 AACR.

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A New Role for ER{alpha}: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes

Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα⁺) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα⁺ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα⁺ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial–mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan–Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis–free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

Implications: ERα directs DNA methylation–mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152–64. ©2016 AACR.

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Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with each other in vitro and in vivo. Mechanistically, the KRAS/ERK axis induced upregulation of MUC16 and shedding of CA125 via its effector c-Myc in SW1990 and PANC-1 pancreatic cancer cells. Notably, proto-oncogene c-Myc could bind to the promoter of MUC16 and transcriptionally activate its expression. Taken together, these data establish CA125 as a prognostic marker for pancreatic cancer, and mechanistic studies uncovered the KRAS/c-Myc axis as a driving factor for upregulation of MUC16.

Implications: The current study uncovers the contribution of oncogenic KRAS to serum marker CA125 production through a mechanism that involves the ERK/c-Myc axis. Mol Cancer Res; 15(2); 201–12. ©2016 AACR.

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Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacologic manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Coimmunoprecipitation and proximal ligation assays indicated LSR–pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that overexpress LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.

Implications: LSR functions in the promotion of aggressive breast cancer phenotypes and poor patient outcome via differential subcellular localization to alter cell signaling, bioenergetics, and gene expression. Mol Cancer Res; 15(2); 165–78. ©2016 AACR.

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Astrocyte Elevated Gene-1 Regulates {beta}-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal

Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein–protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated β-catenin translocation into the nucleus by forming a complex with LEF1 and β-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3β signaling axis, AEG-1 controlled phosphorylation levels of β-catenin that stabilized the protein.

Implications: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR.

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Intraluminal bioresorbable vascular scaffold dismantling with aneurysm formation leading to very late thrombosis

Coronary artery aneurysm formation has been described in patients after the placement of first-generation drug-eluting stents (DES), but is less common with newer generation metallic stents. In contrast, coronary artery aneurysm formation may be more common with the use of bioresorbable vascular scaffolds (BVS) due to the frequent formation of evaginations in the arterial wall seen with BVS. In this article, we describe a unique case of BVS dismantling and thrombus formation leading to an acute coronary syndrome thirty-two months after initial BVS placement. We also discuss existing literature and the pathophysiology of BVS degradation, in addition to the utility of optical coherence tomography in the identification of associated conditions, such as strut fracture, intraluminal scaffold dismantling (ILSD), under-expansion, and/or malapposition. © 2017 Wiley Periodicals, Inc.

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First in human experience of a new self-expandable percutaneous pulmonary valve implantation using knitted nitinol-wire and tri-leaflet porcine pericardial valve in the native right ventricular outflow tract

Balloon-expandable percutaneous pulmonary valve systems using the Melody and Edwards SAPIEN transcatheter heart valves have been increasingly used instead of surgically implantable pulmonary valves. However, limited patients with right ventricular outflow tract (RVOT) lesions are suitable candidates for percutaneous pulmonary valve implantation (PPVI) using these systems after surgical correction of tetralogy of Fallot. Therefore, larger self-expandable valved-stents are being developed for native RVOT lesions. We report the first-in-human case of a new self-expandable PPVI in a patient with a native RVOT lesion using a newly made knitted nitinol-wire stent mounted with a tri-leaflet porcine pericardial valve developed in South Korea. © 2017 Wiley Periodicals, Inc.

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A single center tertiary care experience utilizing the large volume mega 50cc intra-aortic balloon counterpulsation in contemporary clinical practice

Objective

Clinical outcomes and adverse events utilizing the large volume 50cc intra-aortic balloon (IAB) in contemporary clinical practice.

Background

The newer large volume 50cc IAB, recently introduced into clinical practice offers improved diastolic augmentation and better left ventricular (LV) unloading compared to the older 40cc IAB.

Methods

In 150 consecutive patients who received intra-aortic balloon counterpulsation (IABC) with a 50cc balloon from 2011 to 2015, we retrospectively analyzed demographic, clinical, laboratory, and hemodynamic variables, adverse events and survival to discharge from index hospitalization.

Results

Median LVEF was 20%. The most common indication was cardiogenic shock (CS) in 100 patients. Median duration of IABC was 92.5 hr. 95% of patients were free of any IAB device related complications. Five patients received a transfusion for bleeding causally related to IABC. 70 of the 150 patients who received MCS with IABC with no escalation of therapy, recovered and were discharged alive. Fifteen patients were stabilized on IABC and bridged to orthotopic heart transplant. All 15 were discharged alive. Thirty-four patients were initiated on IABC and escalated to VAD and/or Impella/Tandem Heart, with 24 patients surviving to hospital discharge. Overall survival to hospital discharge for the 150 patients was 72.7%.

Conclusion

IABC using a larger volume 50cc balloon appears effective as a first line percutaneous MCS strategy in a large fraction of critically ill cardiac patients with few adverse events. A large scale registry or randomized clinical trial utilizing the larger volume IAB is needed to validate our results. © 2017 Wiley Periodicals, Inc.

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Device-associated thrombus formation after left atrial appendage occlusion: A systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet

Objectives

This study aimed to provide a systematic review of device-associated thrombosis (DAT) after left atrial appendage occlusion (LAAO) with the Watchman, Amplatzer Cardiac Plug, and Amulet devices.

Background

DAT is known as a complication of LAAO but data about its clinical impact is scarce.

Methods

A systematic review of studies evaluating the incidence, treatment and clinical implications of DAT from January 2008 to September 2015 was conducted.

Results

A total of 30 studies describing DAT events were included in the analysis. The overall incidence of DAT was 3.9% (82 DAT for 2118 implanted devices). The median time from procedure to diagnosis of DAT was 1.5 months (IQR: 0–2.9). Most cases were diagnosed with transesophageal echocardiogram (TEE). The treatment consisted of low molecular weight heparin (LMWH) in 45.5% of cases, and oral anticoagulation (OAC) or other treatment modalities in 54.5%. Complete thrombus resolution was achieved in 95.0% of cases (100% with LMWH and 89.5% with OAC). Treatment duration varied greatly with a median treatment duration of 45 days (IQR: 14–135). Clinical events related to DAT consisted of neurologic events namely two transient ischemic attacks (2.4%) and four ischemic strokes (4.9%).

Conclusions

DAT is an infrequent complication of percutaneous LAAO. It occurs mainly early after the procedure and is associated with a low rate of neurological complications. In the majority of cases, diagnosis is made during follow-up imaging with TEE. Anticoagulation treatment seems to be safe and highly effective. Further studies are needed to evaluate the optimal management of DAT. © 2017 Wiley Periodicals, Inc.

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Procedural and 30-day clinical outcomes following transcatheter aortic valve replacement with lotus valve: Results of the RELEVANT study

Objectives

We report procedural and 30-day clinical outcomes following transcatheter aortic valve replacement (TAVR) with Lotus Valve system in a high-risk population.

Background

Lotus valve is a second-generation TAVR fully repositionable and retrievable device. RELEVANT (REgistry of Lotus valvE for treatment of aortic VAlve steNosis with Tavr) study is an Italian prospective multicentre registry.

Methods

Five major centers performing TAVR using Lotus participated. All high-risk symptomatic patients with severe aortic stenosis were evaluated by a heart team and screened for eligibility for TAVR. Primary end-points were procedural and 30-day mortality. Secondary endpoints included procedural and 30-day safety/effectiveness metrics according to Valve Academic Research Consortium (VARC)−2 criteria.

Results

Two hundred and twenty-five patients undergoing TAVR with Lotus were enrolled. Mean age was 82.6 ± 6.3 years, 51.6% females. Mean STS score for mortality was 8.3 ± 5.6. Procedural success was achieved in 98.7% of patients. All-cause mortality was 2.2% at discharge and 2.7% at 30-day. Stroke rate was 2.2% at discharge and 3.1% at 30-day. Patients requiring a new permanent pacemaker implantation were 30.7% at discharge and 31.8% at 30-day. Paravalvular regurgitation (PVR) was trace/mild in 99.1% of patients at discharge. Only two patients (0.9%) had moderate PVR at discharge and at 30-day, whereas none had severe PVR.

Conclusions

RELEVANT study showed that TAVR using Lotus, in a real-world population of patients with severe aortic stenosis at high surgical risk, was associated with excellent device success implantation and early safety according to VARC-2 definition. The pacemaker implantation rate was about a third of patients. © 2017 Wiley Periodicals, Inc.

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Safety of catheter-directed thrombolysis for massive and submassive pulmonary embolism: Results of a multicenter registry and meta-analysis

Objectives

To evaluate the safety and efficacy of catheter-directed thrombolysis (CDT) in the treatment of acute pulmonary embolism (PE).

Background

The use of CDT for the treatment of acute submassive and massive PE is increasing in frequency. However, its safety and efficacy have not been well elucidated.

Methods

This study is made of two parts: one is a two-center registry of acute PE patients treated with CDT. The safety outcome evaluated was any major complication including fatal, intracranial (ICH), intraocular, or retroperitoneal hemorrhage or any overt bleeding requiring transfusion or surgical repair. The efficacy outcome was acute change in invasive pulmonary artery systolic pressure (PASP). The second part is a meta-analysis of all contemporary studies that used CDT for PE. Reported outcomes are the same as in the registry, with the addition of right ventricular to left ventricular (RV/LV) ratio change.

Results

In the registry, 137 patients were included (age 59 ± 15, 50% male, 88% submassive PE). ICH occurred in two patients and major complications in 13 (9.4%). PASP decreased post procedure by 19 ± 15 mm Hg (95% CI 16–23). In the meta-analysis, 16 studies were included with 860 patients. Rate of ICH was 0.35% and the major complication rate was 4.65%, most requiring transfusion only. In-hospital mortality was 12.9% in the massive and 0.74% in the submassive group. All studies showed improvement in PASP and/or RV/LV ratio post CDT.

Conclusions

CDT is associated with a low major complication rate. Randomized studies are needed to evaluate its efficacy relative to anticoagulation alone. © 2017 Wiley Periodicals, Inc.

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Clinical outcomes after trans-catheter aortic valve replacement in men and women in Ontario, Canada

Objective

Our objective was to evaluate sex-differences in outcomes after trans-catheter aortic valve replacement (TAVR) in a population-based cohort from Ontario, Canada.

Background

Prior studies comparing outcomes in men and women after TAVR have yielded divergent results. Some studies have suggested that women have better survival than men while others have not corroborated this finding.

Methods

A retrospective observational cohort study was conducted using chart abstraction data on all TAVR procedures performed between 2007 and 2013 in Ontario, Canada. Patients who had emergency TAVR procedures were excluded. The primary outcome was all-cause mortality at 30-days and 1-year. Secondary outcomes included mortality at last follow-up, cause-specific, and all-cause hospital readmission. Inverse probability of treatment weighting (IPTW) using propensity score was used to adjust for baseline differences between men and women.

Results

The final study cohort consisted of 453 women and 546 men with a mean follow-up of 3.5 years. Women were generally older and more frail but had less comorbid conditions. Women had lower unadjusted mean EuroScores (7% ± 5% vs 8% ± 7%; P = 0.008), but underwent significantly more trans-apical procedures (26.5% vs 19.2%; P = 0.006) than men. After IPTW, the groups were well balanced. Although mortality was numerically higher for women at 30-days (7.2% vs 5.4%), this was not statistically significant (P = 0.34). At 1-year, there was no difference in mortality (18.2% vs 19.2%; P = 0.85). There were no significant differences in all-cause readmission.

Conclusion

In this population-based cohort including all patients undergoing TAVR, mortality or all-cause readmission were not significantly different between men and women. © 2017 Wiley Periodicals, Inc.

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Atherosclerotic

Atherosclerotic: Pertaining to atherosclerosis, the process of progressive thickening and hardening of the walls of arteries from fat deposits on their inner lining. Atherosclerotic heart disease is the leading cause of death in the US.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Contribution of image-guided adaptive brachytherapy to pelvic nodes treatment in locally advanced cervical cancer

Publication date: Available online 31 January 2017
Source:Brachytherapy
Author(s): Warren Bacorro, Isabelle Dumas, Antonin Levy, Eleonor Rivin Del Campo, Charles-Henri Canova, Tony Felefly, Andres Huertas, Fanny Marsolat, Christine Haie-Meder, Cyrus Chargari, Renaud Mazeron
PurposeWith the increasing use of simultaneous integrated boost in the treatment of cervical cancer, there is a need to anticipate the brachytherapy (BT) contribution at the level of the pathologic pelvic lymph nodes. This study aimed to report the dose delivered at their level during BT.Methods and MaterialsPatients with pelvic nodal involvement and treated with a combination of chemoradiation followed by image-guided adaptive pulsed-dose-rate BT were selected. On per BT three-dimensional images, pelvic lymphadenopathies were delineated, without planning aim. For the purposes of the study, D100, D98, D90, and D50 were reviewed and converted in 2-Gy equivalent doses, using the linear quadratic model with an α/β of 10 Gy.ResultsNinety-one patients were identified, allowing evaluation at the level of 226 lymphadenopathies. The majority of them were external iliac (48%), followed by common iliac (25%), and internal iliac (16%) regions. The 2-Gy equivalent doses D98 were 4.4 ± 1.9 Gy, 5.4 ± 3.1 Gy, and 4.3 ± 2.1 Gy for the obturator, internal iliac, and external iliac, respectively, and 2.8 ± 2.5 Gy for the common iliac. The contribution to the common iliac nodes was significantly lower than the one of external and internal iliac (p < 0.001).ConclusionsBT significantly contributes to the treatment of pelvic nodes at the level of approximately 5 Gy in the internal, external, and obturator areas and 2.5 Gy in the common iliac, allowing the anticipation of nodal boost with the simultaneous integrated boost technique. However, important individual variations have been observed, and evaluation of the genuine BT contribution should be recommended.



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A review of estrogen receptor/androgen receptor genomics in male breast cancer

Male breast cancer is a rare disease, of which little is known. In contrast to female breast cancer, the very vast majority of all cases are positive for estrogen receptor alpha (ERα), implicating the function of this steroid hormone receptor in tumor development and progression. Consequently, adjuvant treatment of male breast cancer revolves around inhibition of ERα. In addition, the androgen receptor (AR) gradually receives more attention as a relevant novel target in breast cancer treatment. Importantly, the rationale of treatment decision making is strongly based on parallels with female breast cancer. Yet, prognostic indicators are not necessarily the same in breast cancer between both genders, complicating translatability of knowledge developed in female breast cancer toward male patients. Even though ERα and AR are expressed both in female and male disease, are the genomic functions of both steroid hormone receptors conserved between genders? Recent studies have reported on mutational and epigenetic similarities and differences between male and female breast cancer, further suggesting that some features are strongly conserved between the two diseases, whereas others are not. This review critically discusses the recent developments in the study of male breast cancer in relation to ERα and AR action and highlights the potential future studies to further elucidate the genomic regulation of this rare disease.

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Validation of a Standalone Smartphone Application for Measuring Heart Rate Using Imaging Photoplethysmography

Telemedicine and e-Health , Vol. 0, No. 0.


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The Epidemiology of Hospital-Referred Head Injury in Ardabil City

Background and Purpose. Trauma is the leading cause of death for youth in developing countries. Given the prevalence of head trauma (HT) in society and its complication and burden, the epidemiologic study of head trauma is necessary and is the main aim of this study. Materials and Methods. This retrospective population-based survey describes the epidemiology of head injury in a defined population in Ardabil city. It includes all 204 patients with head injury referred to the University Hospital of Ardabil, Iran, during 2013-2014. Data were collected by a checklist and analyzed by statistical methods in SPSS.19. Significance level was considered. Results. Of all registered cases, 146 (71.6%) were male and the rest of them were female. Most of HT patients lived in Ardabil city (60.8%). The mean age of patients was 22.6 ± 25.9 and most of victims were young. 24.5% of traumatic patients have injuries in severe to critical level (grade 3-4). The most cause of trauma was accidents (41.7%). Most of injuries occurred in night (55.9%) and in summer season (42.2%). Causes were traffic accident in 41.7%. Conclusion. Results showed that the leading cause of head trauma especially in the warm seasons is accidents and so, designing programs to reduce road accidents can dramatically reduce the rate of trauma in the future in Ardabil province.

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Associations of Adenovirus Genotypes in Korean Acute Gastroenteritis Patients with Respiratory Symptoms and Intussusception

Human adenoviruses (HAdVs) cause a wide range of diseases, including respiratory infections and gastroenteritis, and have more than 65 genotypes. To investigate the current genotypes of circulating HAdV strains, we performed molecular genotyping of HAdVs in the stool from patients with acute gastroenteritis and tried to determine their associations with clinical symptoms. From June 2014 to May 2016, 3,901 fecal samples were tested for an AdV antigen, and 254 samples (6.5%) yielded positive results. Genotyping using PCR and sequencing of the capsid hexon gene was performed for 236 AdV antigen-positive fecal specimens. HAdV-41, of species F, was the most prevalent genotype (60.6%), followed by HAdV-2 of species C (13.8%). Other genotypes, including HAdV-3, HAdV-1, HAdV-5, HAdV-6, HAdV-31, HAdV-40, HAdV-12, and HAdV-55, were also detected. Overall, 119 patients (50.4%) showed concomitant respiratory symptoms, and 32 patients (13.6%) were diagnosed with intussusception. HAdV-1 and HAdV-31 were significantly associated with intussusception (). Our results demonstrate the recent changes in trends of circulating AdV genotypes associated with gastroenteritis in Korea, which should be of value for improving the diagnosis and developing new detection, treatment, and prevention strategies for broad application in clinical laboratories.

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Altered Brain Functional Activity in Infants with Congenital Bilateral Severe Sensorineural Hearing Loss: A Resting-State Functional MRI Study under Sedation

Early hearing deprivation could affect the development of auditory, language, and vision ability. Insufficient or no stimulation of the auditory cortex during the sensitive periods of plasticity could affect the function of hearing, language, and vision development. Twenty-three infants with congenital severe sensorineural hearing loss (CSSHL) and 17 age and sex matched normal hearing subjects were recruited. The amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo) of the auditory, language, and vision related brain areas were compared between deaf infants and normal subjects. Compared with normal hearing subjects, decreased ALFF and ReHo were observed in auditory and language-related cortex. Increased ALFF and ReHo were observed in vision related cortex, which suggest that hearing and language function were impaired and vision function was enhanced due to the loss of hearing. ALFF of left Brodmann area 45 (BA45) was negatively correlated with deaf duration in infants with CSSHL. ALFF of right BA39 was positively correlated with deaf duration in infants with CSSHL. In conclusion, ALFF and ReHo can reflect the abnormal brain function in language, auditory, and visual information processing in infants with CSSHL. This demonstrates that the development of auditory, language, and vision processing function has been affected by congenital severe sensorineural hearing loss before 4 years of age.

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Defected Ground Structure: Fundamentals, Analysis, and Applications in Modern Wireless Trends

Slots or defects integrated on the ground plane of microwave planar circuits are referred to as Defected Ground Structure. DGS is adopted as an emerging technique for improving the various parameters of microwave circuits, that is, narrow bandwidth, cross-polarization, low gain, and so forth. This paper presents an introduction and evolution of DGS and how DGS is different from former technologies: PBG and EBG. A basic concept behind the DGS technology and several theoretical techniques for analysing the Defected Ground Structure are discussed. Several applications of DGS in the field of filters, planar waveguides, amplifiers, and antennas are presented.

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Herpes Simplex Virus Latency: The DNA Repair-Centered Pathway

Like all herpesviruses, herpes simplex virus 1 (HSV1) is able to produce lytic or latent infections depending on the host cell type. Lytic infections occur in a broad range of cells while latency is highly specific for neurons. Although latency suggests itself as an attractive target for novel anti-HSV1 therapies, progress in their development has been slowed due in part to a lack of agreement about the basic biochemical mechanisms involved. Among the possibilities being considered is a pathway in which DNA repair mechanisms play a central role. Repair is suggested to be involved in both HSV1 entry into latency and reactivation from it. Here I describe the basic features of the DNA repair-centered pathway and discuss some of the experimental evidence supporting it. The pathway is particularly attractive because it is able to account for important features of the latent response, including the specificity for neurons, the specificity for neurons of the peripheral compared to the central nervous system, the high rate of genetic recombination in HSV1-infected cells, and the genetic identity of infecting and reactivated virus.

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Ultrasound Utility in the Diagnosis of a Morel-Lavallée Lesion

Morel-Lavallée lesions are uncommon injuries that can be associated with significant comorbidities if not detected early. Rapid diagnosis in the Emergency Department could significantly improve patient outcomes. We describe the diagnosis of such a lesion through the use of ultrasound imaging in the Emergency Department to utilize a fast, cost-effective imaging technique that does not subject the patient to radiation exposure. Our patient received surgical consultation but improved with conservative management. Ultrasound findings associated with this lesion do not require specialized equipment and should be considered when evaluating soft tissue lesions using point of care ultrasound.

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Stability Study of Algerian Nigella sativa Seeds Stored under Different Conditions

In a study to determine the stability of the main volatile constituents of Nigella sativa seeds stored under several conditions, eight storage conditions were established, based on the ecological abiotic effects of air, heat, and light. Six replicates each were prepared and analyzed with Headspace-Gas Chromatography-Mass Spectrometry (HS-GC-MS) for three time points at the initial (1st day (0)), 14th (1), and 28th (2) day of storage. A targeted multivariate analysis of Principal Component Analysis revealed that the stability of the main volatile constituents of the whole seeds was better than that of the ground seeds. Exposed seeds, whole or ground, were observed to experience higher decrement of the volatile composition. These ecofactors of air, heat, and light are suggested to be directly responsible for the loss of volatiles in N. sativa seeds, particularly of the ground seeds.

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The Polarization States of Microglia in TBI: A New Paradigm for Pharmacological Intervention

Traumatic brain injury (TBI) is a serious medical and social problem worldwide. Because of the complex pathophysiological mechanisms of TBI, effective pharmacotherapy is still lacking. The microglial cells are resident tissue macrophages located in the brain and have two major polarization states, M1 phenotype and M2 phenotype, when activated. The M1 phenotype is related to the release of proinflammatory cytokines and secondary brain injury, while the M2 phenotype has been proved to be responsible for the release of anti-inflammation cytokines and for central nervous system (CNS) repair. In animal models, pharmacological strategies inhibiting the M1 phenotype and promoting the M2 phenotype of microglial cells could alleviate cerebral damage and improve neurological function recovery after TBI. In this review, we aimed to summarize the current knowledge about the pathological significance of microglial M1/M2 polarization in the pathophysiology of TBI. In addition, we reviewed several drugs that have provided neuroprotective effects against brain injury following TBI by altering the polarization states of the microglia. We emphasized that future investigation of the regulation mechanisms of microglial M1/M2 polarization in TBI is anticipated, which could contribute to the development of new targets of pharmacological intervention in TBI.

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Xeroderma Pigmentosum with Severe Neurological Manifestations/De Sanctis–Cacchione Syndrome and a Novel XPC Mutation

Several genetic disorders caused by defective nucleotide excision repair that affect the skin and the nervous system have been described, including Xeroderma Pigmentosum (XP), De Sanctis–Cacchione syndrome (DSC), Cockayne syndrome, and Trichothiodystrophy. Cutaneous photosensitivity with an increased risk of skin malignancy is a common feature of these disorders, but clinical manifestations commonly overlap these syndromes. Several genes have been found to be altered in these pathologies, but we lack more genotype-phenotype correlations in order to make an accurate diagnosis. Very few cases of DSC syndrome have been reported in the literature. We present a case of a 12-year-old Colombian male, with multiple skin lesions in sun-exposed areas from the age of 3 months and a history of 15 skin cancers. He also displayed severe neurologic abnormalities (intellectual disability, ataxia, altered speech, and hyperreflexia), short stature, and microcephaly, which are features associated with DSC. Genetic testing revealed a novel germline mutation in the XP-C gene (c.547A>T). This is the first case of an XP-C mutation causing De Sanctis–Cacchione syndrome. Multigene panel testing is becoming more widely available and accessible in the clinical setting and will help rapidly unveil the molecular etiology of these rare genetic disorders.

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Dual Roles of IL-27 in Cancer Biology and Immunotherapy

IL-27 is a pleiotropic two-chain cytokine, composed of EBI3 and IL-27p28 subunits, which is structurally related to both IL-12 and IL-6 cytokine families. IL-27 acts through a heterodimer receptor consisting of IL-27Rα (WSX1) and gp130 chains, which mediate signaling predominantly through STAT1 and STAT3. IL-27 was initially reported as an immune-enhancing cytokine that supports CD4+ T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γ production, acting in concert with IL-12. However, subsequent studies demonstrated that IL-27 displays complex immune-regulatory functions, which may result in either proinflammatory or anti-inflammatory effects in relationship to the biological context and experimental models considered. Several pieces of evidence, obtained in preclinical tumor models, indicated that IL-27 has a potent antitumor activity, related not only to the induction of tumor-specific Th1 and cytotoxic T lymphocyte (CTL) responses but also to direct inhibitory effects on tumor cell proliferation, survival, invasiveness, and angiogenic potential. Nonetheless, given its immune-regulatory functions, the effects of IL-27 on cancer may be dual and protumor effects may also occur. Here, we will summarize IL-27 biological activities and its functional overlaps with the IFNs and discuss its dual role in tumors in the light of potential applications to cancer immunotherapy.

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The Autophagy Level Is Increased in the Synovial Tissues of Patients with Active Rheumatoid Arthritis and Is Correlated with Disease Severity

Rheumatoid arthritis (RA) is a complex and not fully understood autoimmune disease associated with multijoint damage. The main effector cells, the synovial fibroblasts, are apoptosis resistant and hyperplastic which indicate that autophagy level is high in synovial tissue. Real-time PCR, immunocytochemistry, and western blotting were used in this paper to study the autophagy status of the synovial tissues obtained from RA and OA patients at the time of joint replacement surgery. We further evaluated the correlation between autophagy levels with RA activity-associated serum markers with SPSS. The results showed that the expression levels (both in mRNA and in protein level) of autophagy-related proteins (belcin1, Atg5, and LC3) in the synovial tissue of patients with active rheumatoid arthritis () were significantly higher than those in OA patients (). We further showed that the LC3-II/β-actin relative gray value was strongly correlated with the serum levels of several RA activity-related markers: CRP, ESR, CCP, and RF. Our results indicate that evaluating the autophagy level of synovial biopsies might be a useful way to diagnose RA and to estimate the disease activity. Reducing the expression level of autophagy-related genes might become a new therapeutic target for active rheumatoid arthritis.

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Research and Modeling of the Bidirectional Half-Bridge Current-Doubler DC/DC Converter

Due to its high step-up voltage ratio, high utilization rate, and good stability, the bidirectional half-bridge current-doubler topology is widely used in lithium battery system. This paper will further analyze the bidirectional half-bridge current-doubler topology. Taking into account the fact that the current is not equal to the two times current inductance may lead to a greater transformer magnetizing current leaving the transformer core saturation occurring. This paper will focus on the circuit modeling of steady-state analysis and small signal analysis, analyzing the influence parameters for the inductor current by steady-state model and analyzing the stability of the system by the small signal model. The PID controllers and soft start algorithm are designed. Then the influence of circuit parameters on the steady state and the effect of soft start algorithm is verified, and finally the function of the soft start algorithm is achieved by the experimental prototype.

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Image Retrieval Method for Multiscale Objects from Optical Colonoscopy Images

Optical colonoscopy is the most common approach to diagnosing bowel diseases through direct colon and rectum inspections. Periodic optical colonoscopy examinations are particularly important for detecting cancers at early stages while still treatable. However, diagnostic accuracy is highly dependent on both the experience and knowledge of the medical doctor. Moreover, it is extremely difficult, even for specialist doctors, to detect the early stages of cancer when obscured by inflammations of the colonic mucosa due to intractable inflammatory bowel diseases, such as ulcerative colitis. Thus, to assist the UC diagnosis, it is necessary to develop a new technology that can retrieve similar cases of diagnostic target image from cases in the past that stored the diagnosed images with various symptoms of colonic mucosa. In order to assist diagnoses with optical colonoscopy, this paper proposes a retrieval method for colonoscopy images that can cope with multiscale objects. The proposed method can retrieve similar colonoscopy images despite varying visible sizes of the target objects. Through three experiments conducted with real clinical colonoscopy images, we demonstrate that the method is able to retrieve objects of any visible size and any location at a high level of accuracy.

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Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for  h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey’s test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis () and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all ). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.

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Buparvaquone Nanostructured Lipid Carrier: Development of an Affordable Delivery System for the Treatment of Leishmaniases

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming for -average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed low -averages (

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Development of a Patient-Specific Finite Element Model for Predicting Implant Failure in Pelvic Ring Fracture Fixation

Introduction. The main purpose of this study is to develop an efficient technique for generating FE models of pelvic ring fractures that is capable of predicting possible failure regions of osteosynthesis with acceptable accuracy. Methods. Patient-specific FE models of two patients with osteoporotic pelvic fractures were generated. A validated FE model of an uninjured pelvis from our previous study was used as a master model. Then, fracture morphologies and implant positions defined by a trauma surgeon in the preoperative CT were manually introduced as 3D splines to the master model. Four loading cases were used as boundary conditions. Regions of high stresses in the models were compared with actual locations of implant breakages and loosening identified from follow-up X-rays. Results. Model predictions and the actual clinical outcomes matched well. For Patient A, zones of increased tension and maximum stress coincided well with the actual locations of implant loosening. For Patient B, the model predicted accurately the loosening of the implant in the anterior region. Conclusion. Since a significant reduction in time and labour was achieved in our mesh generation technique, it can be considered as a viable option to be implemented as a part of the clinical routine to aid presurgical planning and postsurgical management of pelvic ring fracture patients.

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Many people are unaware of thyroid conditions - News-Press Now

News-Press Now

Many people are unaware of thyroid conditions News-Press Now Other thyroid disorders include nodules, typically benign growths on the thyroid, and thyroid cancer. Many nodules do not cause symptoms but can cause difficulty swallowing, pain and goiter if they become large enough. Benign nodules aren't life ...

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The “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) project: advancing the care of physically frail and sarcopenic older people

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The “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) randomized controlled trial: design and methods

Abstract

The sustainability of health and social care systems is threatened by a growing population of older persons with heterogeneous needs related to multimorbidity, frailty, and increased risk of functional impairment. Since disability is difficult to reverse in old age and is extremely burdensome for individuals and society, novel strategies should be devised to preserve adequate levels of function and independence in late life. The development of mobility disability, an early event in the disablement process, precedes and predicts more severe forms of inability. Its prevention is, therefore, critical to impede the transition to overt disability. For this reason, the Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT) project is conducting a randomized controlled trial (RCT) to test a multicomponent intervention (MCI) specifically designed to prevent mobility disability in high-risk older persons. SPRINTT is a phase III, multicenter RCT aimed at comparing the efficacy of a MCI, based on long-term structured physical activity, nutritional counseling/dietary intervention, and an information and communication technology intervention, versus a healthy aging lifestyle education program designed to prevent mobility disability in 1500 older persons with physical frailty and sarcopenia who will be followed for up to 36 months. The primary outcome of the SPRINTT trial is mobility disability, operationalized as the inability to walk for 400 m within 15 min, without sitting, help of another person, or the use of a walker. Secondary outcomes include changes in muscle mass and strength, persistent mobility disability, falls and injurious falls, disability in activities of daily living, nutritional status, cognition, mood, the use of healthcare resources, cost-effectiveness analysis, quality of life, and mortality rate. SPRINTT results are expected to promote significant advancements in the management of frail older persons at high risk of disability from both clinical and regulatory perspectives. The findings are also projected to pave the way for major investments in the field of disability prevention in old age.

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SPRINTT and the involvement of stakeholders: strategy and structure

Abstract

The current healthcare systems are built around the traditional paradigm of patients suffering from a single acute illness. They are, therefore, largely unprepared to face the increasing demands for health services arising from the expansion of an older population with specific medical needs related to multiple chronic disorders. As a consequence, the medical conditions of a large and growing segment of the older European population are not efficiently managed by the available healthcare services. In the context of an aging population, policy makers such as the European Commission and European Institutions, such as the European Medicines Agency (EMA), devote time and resources to study and accompany the need of the aging population. The EMA recognizes the importance of making sure that the needs of the Elderly are considered during development, approval, and use of new medicines, and, therefore, engages with healthcare professional organisations. The Sarcopenia and Physical Frailty in Older People: Multicomponent Intervention Strategies (SPRINTT) is the obvious result of these strategies. The present article describes the SPRINTT workpackage activities aimed at engaging the scientific discussion on the physical frailty and sarcopenia with the EMA as one of its interlocutor, acknowledging the need to collaborate on this topic to foster a productive dialogue.

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Watch that mouth, literally - Chandigarh Tribune

Chandigarh Tribune

Watch that mouth, literally Chandigarh Tribune Tobacco smoking increases risk by six times; when chewed, it increases by an astounding 50 times! Excessive consumption of alcohol increases the risk proportionately. Certain strains of human papilloma virus (HPV) are associated with cancer of tonsil area.

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Oncolytic adenoviral delivery of an EGFR-targeting T cell engager improves antitumor efficacy

Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses which were armed with bispecific T cell-engager antibodies (BiTE antibodies). The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE which retained its oncolytic properties in vitro. cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE-infected cells, and the secreted BiTEs bound specifically to both CD3+ and EGFR+ cells. In cell co-culture assays, ICOVIR-15K-cBiTE-mediated oncolysis resulted in robust T cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cells in vivo, compared to the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy.

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Pre-steady-state Kinetics Reveal the Substrate Specificity and Mechanism of Halide Oxidation of Truncated Human Peroxidasin 1 [Protein Structure and Folding]

Human peroxidasin 1 is a homotrimeric multidomain peroxidase that is secreted to the extracellular matrix. The heme enzyme was shown to release hypobromous acid which mediates the formation of specific covalent sulfilimine bonds to reinforce collagen IV in basement membranes. Maturation by proteolytic cleavage is known to activate the enzyme. Here we present the first multi-mixing stopped-flow study on a fully functional truncated variant of human peroxidasin 1 comprising four immune-globulin-like domains and the catalytically active peroxidase domain. The kinetic data unravel the so far unknown substrate specificity and mechanism of halide oxidation of human peroxidasin 1. The heme enzyme is shown to follow the halogenation cycle which is induced by the rapid H2O2-mediated oxidation of the ferric enzyme to the redox intermediate Compound I. We demonstrate that chloride cannot act as two-electron donor of Compound I, whereas thiocyanate, iodide and bromide efficiently restore the ferric resting state. We present all relevant apparent bimolecular rate constants, the spectral signatures of the redox intermediates and the standard reduction potential of the Fe(III)/Fe(II) couple and we demonstrate that the prosthetic heme group is posttranslationally modified and cross-linked with the protein. These structural features provide the basis of human peroxidasin 1 to act as an effective generator of hypobromous acid which mediates the formation of covalent crosslinks in collagen IV.

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Autocrine and paracrine interactions between multiple myeloma cells and bone marrow stromal cells by growth arrest-specific gene 6 crosstalk with interleukin-6 [Signal Transduction]

The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant upregulation of growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein with a structural homology with protein S, in bone marrow (BM) cells of MM patients. ELISA showed that the serum levels of soluble Gas6 were significantly increased in the MM patients when compared with healthy controls. Gas6 was overexpressed in the human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 suppressed apoptosis induced by serum deprivation, and enhanced cell proliferation of the MM cells. The conditional media from the human BM stromal cell line HS-5 induced cell proliferation and anti-apoptosis of the MM cells with extracellular signal-regulated kinase, Akt, and nuclear factor-κB phosphorylation, which were reversed by the neutralizing antibody to Gas6 or interleukin-6 (IL-6). The expression of the TAM-family receptor Mer, which has been identified as a Gas6 receptor, was overexpressed in BM cells of MM patients. The knockdown of Mer by siRNA inhibited cell proliferation, anti-apoptosis and upregulation of intercellular cell adhesion molecule-1 (ICAM-1) in MM cells stimulated by a HS-5 cell-conditioned media. Furthermore, the Gas6 neutralizing antibody reduced the upregulation of IL-6 and ICAM-1 induced by a HS-5 cell-conditioned media in MM cells. The present study provides new evidence that autocrine and paracrine stimulation of Gas6 in concert with IL-6 contributes to the pathogenesis of MM, suggesting that Gas6-Mer related signaling pathways may be a promising novel target for treating MM.

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Functional characterization of CsBGlu12, a {beta}-glucosidase from Crocus sativus provides insights into its role in abiotic stress through accumulation of antioxidant flavonols [Metabolism]

Glycosylation and deglycosylation is an impressive mechanism that allows plants to regulate biological activity of an array of secondary metabolites. While glycosylation improves solubility and renders the metabolites suitable for transport and sequestration, deglycosylation activates them to carry out biological functions. Herein, we report functional characterization of CsBGlu12, a β-glucosidase from Crocus sativus. CsBGlu12 has a characteristic glucoside hydrolase 1 family (α/β)8 TIM barrel structure with highly conserved active site. In vitro enzyme activity revealed that CsBGlu12 catalyzes the hydrolysis of flavonol β-glucosides and cello-oligosaccharides. Site directed mutagenesis of any of the two conserved catalytic glutamic acid residues (Glu200 and Glu414) of the active site completely abolishes the β-glucosidase activity. Transcript analysis revealed that CsBGlu12 is highly induced in response to UV-B, dehydration, NaCl, methyl jasmonate and abscisic acid treatments indicating its possible role in plant stress response. Transient overexpression of CsBGlu12 leads to the accumulation of antioxidant flavonols in Nicotiana benthamiana and confers tolerance to abiotic stresses. Antioxidant assays indicated that accumulation of flavonols alleviate the accretion of reactive oxygen species during abiotic stress conditions. β-glucosidases are known to play role in abiotic stresses particularly dehydration through abscisic acid, however, their role through accumulation of ROS scavenging flavonols has not been established. Further, only one β-glucosidase 12 homolog has been characterized so far. Therefore, this work presents an important report on characterization of CsBGlu12 and its role in abiotic stress through ROS scavenging.

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TGF-{beta} directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with SMAD pathway [Cell Biology]

Transforming growth factor-β (TGF-β) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-β functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGFβRI binding protein and is absolutely required for phosphorylation of STATs in a SMADs-independent manner within minutes of TGF-β stimulation. Following the activation of SMADs, TGF-β also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicate that the non-SMAD JAK1/STATs pathway is essential for the expression of a subset of TGF-β target genes in hepatic stellate cells, and the cooperation between JAK1-STAT3 and SMADs pathways is critical to the roles of TGF-β in liver fibrosis.

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CD44 and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation [Cell Biology]

Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage or retrieval. Here, we find that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown in vitro, suggesting that CD44 functions to regulate NSC proliferation in a cell autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.

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Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks

Abstract

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [¹⁸F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression.

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Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

Abstract

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future.

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Influence of blood-brain barrier permeability on O-(2- 18 F-fluoroethyl)-L-tyrosine uptake in rat gliomas

Abstract

Purpose

O-(2-¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on ¹⁸F-FET uptake in two rat glioma models and one human xenograft model.

Methods

F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent ¹⁸F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of ¹⁸F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs.

Results

In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of ¹⁸F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010).

Conclusion

Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of ¹⁸F-FET uptake were noted in this experimental study. Thus, ¹⁸F-FET uptake in gliomas appears to be widely independent of the permeability of the BBB.

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Direct Cytosolic Delivery of CRISPR/Cas9-Ribonucleoprotein for Efficient Gene Editing

ACS Nano

DOI: 10.1021/acsnano.6b07600

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Response to Letter: The Use of Integra Dermal Regeneration Template versus Flaps for Reconstruction of Full-Thickness Scalp Defects Involving the Calvaria: A Cost-Benefit Analysis

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Contact Cooling of Random-Pattern Cutaneous Flaps: Does it Increase Necrosis?

Abstract

Background

Cooling after surgery reduces pain, swelling and ecchymosis. However, the fear of adverse effects of vasoconstriction caused by cooling may prevent its use when the skin is undermined extensively, for example, after rhytidectomy. The purpose of this study is to determine whether the contact cooling of random-pattern skin flaps increases the area of necrosis observed.

Methods

Twenty-eight random-pattern skin flaps (4 × 10 cm) were raised on four pigs. Flaps were divided into three groups: control, intermittently cooled and continuously cooled. Pads connected to a ThermaZone cooling device delivered local hypothermia in the range of 4–6 °C for 24 h postoperatively. ImageJ software was used to calculate the area of necrosis on each flap on postoperative day 7, confirmed with histological analysis.

Results

The average areas of necrosis observed were as follows: control (17.61 cm²; SD 5.23), intermittent cooling (15.65 cm²; SD 3.76) and continuous cooling (14.16 cm²; SD 3.91). An ANOVA revealed no statistically significant differences between the three interventions (p = 0.35).

Conclusions

Postoperative continuous or intermittent cooling does not increase the area of necrosis in random-pattern flaps. In fact, a trend was observed, demonstrating decreasing area of necrosis with increased periods of hypothermia.

No Level Assigned

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. http://ift.tt/18t7xNj.

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The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder

Abstract

Introduction

Ample evidence suggested a role of sigma-1 receptor in affective disorders since the interaction of numerous antidepressants with sigma receptors was discovered. A recent study on Japanese subjects found a genetic variant within the encoding gene SIGMAR1 (rs1800866A>C) associated with major depressive disorder (MDD). We aimed to evaluate the same polymorphism in both MDD and bipolar disorder (BD) as well as its relationship to response to treatment with antidepressants and mood stabilizers.

Methods

A total of 238 MDD patients treated for an acute episode of depression, 132 BD patients in treatment with mood stabilizers for a manic or mixed episode, and 324 controls were genotyped for rs1800866. At discharge, response to treatments was evaluated in MDD and BD patients by the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Score (YMRS), respectively.

Results

In our Korean sample, allele frequencies were different from those reported in other Asian and non-Asian populations. The CC genotype was associated with BD and, as a trend, with MDD. No significant effect was observed on response to antidepressants in MDD or mood stabilizers in BD, although the CC genotype was more frequent among BD patients experiencing a mixed episode.

Conclusion

The present findings are the first to propose the putative role of genetic variants within SIGMAR1 and sigma-1 receptor in BD. Sigma-1 receptor can modulate a number of central neurotransmitter systems as well as some other signaling pathways (e.g., neurotrophin and growth factor signaling) which are seemingly involved in BD and other mood disorders.

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Erratum to: Chronic Obstructive Pulmonary Disease Individualized Therapy: Tailored Approach to Symptom Management

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Impact of Adalimumab on Work Productivity and Activity Impairment in Japanese Patients with Rheumatoid Arthritis: Large-Scale, Prospective, Single-Cohort ANOUVEAU Study

Abstract

Introduction

The Adalimumab Non-interventional Trial for Up-verified Effects and Utility (ANOUVEAU) was a large-scale, multicenter, prospective, observational, single-cohort study that evaluated the effects of adalimumab (ADA) on rheumatoid arthritis (RA)-related work productivity and activity impairment (RA-related WPAI) and disease activity in routine rheumatology care in Japan.

Methods

Patients with RA were categorized as paid workers (PWs, ≥35 h/week), part-time workers (PTWs, <35 h/week), or homemakers (HMs, unemployed) and were administered the WPAI for RA (WPAI/RA) questionnaire. All patients who received ADA were followed for 48 weeks to evaluate safety and effectiveness.

Results

Of the 1808 patients analyzed, 825, 243, and 740 patients were PWs, PTWs, and HMs, respectively. WPAI/RA domain scores significantly improved at weeks 12, 24, and 48 in all groups, with maximum improvement observed for PWs (p < 0.05). Additionally, remission rates (according to Disease Activity Score 28, erythrocyte sedimentation rate, Simplified Disease Activity Index, or Health Assessment Questionnaire-Disability Index scores) and EuroQol 5-Dimension 3-Level scores significantly increased from baseline to 48 weeks in all groups (p < 0.0001). Analysis of patient subgroups revealed better WPAI/RA outcomes for patients who were biologic-naïve, treated with concomitant methotrexate, or with RA duration of ≤2 years (p < 0.05). The rate of serious adverse events over 48 weeks of ADA treatment was 5.23%.

Conclusions

Treatment with ADA provided sustained improvement in WPAI and had an acceptable safety profile in patients with RA.

Funding

AbbVie GK and Eisai Co., Ltd.

Trial Registration

ClinicalTrials.gov identifier, NCT01346488.

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A Retrospective Study of Ranibizumab Treatment Regimens for Neovascular Age-Related Macular Degeneration (nAMD) in Australia and the United Kingdom

Abstract

Introduction

Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss among persons aged 65 years and older. Anti-vascular endothelial growth factor (anti-VEGF) treatment is the recommended standard of care. The current study compares the effectiveness of ranibizumab in routine clinical practice in two countries that generally apply two different treatment regimens, treat-and-extend (T&E) in Australia or pro re nata (PRN) in the UK.

Methods

This retrospective, comparative, non-randomised cohort study is based on patients’ data from electronic medical record (EMR) databases in Australia and the UK. Treatment regimens were defined based on location, with Australia as a proxy for analysing T&E and UK as a proxy for analysing PRN. The study included patients with a diagnosis of nAMD who started treatment with ranibizumab between January 2009 and July 2014. A total of 647 eyes of 570 patients in Australia and 3187 eyes of 2755 patients in the UK with complete 12-months follow-up were analysed.

Results

Baseline patient characteristics were comparable between the two cohorts. After 1 year of treatment, T&E-treated eyes achieved higher mean (±SE) visual acuity (VA) gains (5.00 ± 0.54 letters [95% confidence interval (CI) 3.93–6.06]) than PRN-treated eyes [3.04 ± 0.24 letters (95% CI 2.57–3.51); difference in means 2.07 ± 0.69 (95% CI 0.73–3.41), p < 0.001]. Non-inferiority of T&E compared to PRN was concluded based on the change in mean visual acuity gains at 12 months. Over the 12-month follow-up, T&E-treated eyes received a higher mean [±standard deviation (SD)] number of injections (9.29 ± 2.43) than PRN-treated eyes (6.04 ± 2.19) (p < 0.0001). Australian patients had a lower mean (±SD) number of total clinic visits (10.29 ± 2.90) than UK patients (11.47 ± 2.93) (p < 0.0001).

Conclusion

The higher injection frequency in the T&E cohort may account for the trend toward improved vision.

Funding

Novartis Pharma AG, Basel, Switzerland

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Atorvastatin from target screening attenuates endothelial cell tube formation and migration by regulating urokinase receptor-related signaling pathway and F/G actin

Angiogenesis and cytoskeletal transformation are common denominators of many pathological developments. The relationship between angiogenesis, urokinase plasminogen activator receptor (uPAR) signaling pathway, and cytoskeletal transformation is still unknown. In this study, a pGL3-uPAR promoter reporter system combined with Bio-Plex mRNA analysis was established for discovering uPAR modulators to analyze this interconnection.

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Frequency of TV viewing and prevalence of overweight and obesity among adult women in Bangladesh: a cross-sectional study

Background

Research in developed countries has demonstrated an association of varying degrees between watching TV and the risk of being overweight and obese. However, there is no evidence of such an association in the context of the South Asian population.

Objective

To investigate whether watching TV increases the risk of being overweight and obese among women in Bangladesh.

Setting

Rural and urban areas in Bangladesh.

Participants

Participants were 16 624 non-pregnant women aged between 15 and 49 years.

Methods

The study was based on cross-sectional data from the Bangladesh Demographic and Health Survey (BDHS) conducted in 2014. The main outcome variables were overweight and obesity measured by body mass index. Data were analysed by using descriptive statistics, cross-tabulation and multivariable logistic regression models.

Results

The prevalence of overweight and obesity in the sample population were, respectively, 4.5% (4.18% to 4.82%) and 20% (95% CI 19.39% to 20.61%). In the multivariable analysis, no statistically significant association was found between watching TV and being overweight. However, the odds of being obese among rural women were 63% higher (adjusted OR (AOR) 1.625, 95% CI 1.179 to 2.241) among those who watched less than once a week, and 68% (AOR 1.683, 95% CI 1.029 to 2.751) higher among women who watched TV at least once a week compared to those who did not watch TV at all. Urban women who watched TV at least once a week were 67% more likely to be obese (AOR 1.665, 95% CI 1.079 to 2.568) compared to those who did not watch at all.

Conclusions

Prevalence of overweight and obesity has risen considerably among women aged between 15 and 49 years since the previous estimates based on BDHS data. Frequent TV watching was associated with a higher risk of being obese among adult women in rural areas.

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