PIM1 destabilization activates a p53-dependent response to ribosomal stress in cancer cells.

PIM1 destabilization activates a p53-dependent response to ribosomal stress in cancer cells.

Oncotarget. 2016 Mar 14;

Authors: Sagar V, Caldarola S, Aria V, Monteleone V, Fuoco C, Gargioli C, Cannata S, Loreni F

Abstract
Defects in ribosome biogenesis triggers a stress response (ribosomal stress) that can lead to growth arrest and apoptosis. Signaling pathways activated by ribosomal stress are specifically involved in the pathological mechanism of a group of disorders defined as ribosomopathies. However, more generally, the quality control of ribosome synthesis is part of the regulatory circuits that control cell metabolism. A number of studies identified tumor suppressor p53 as a central player in ribosomal stress. We have previously reported that the kinase PIM1 plays a role as a sensor for ribosome deficiency. In this report we address the relationship between PIM1 and p53 in cancer cell lines after depletion of a ribosomal protein. We identified a novel signaling pathway that includes the kinase AKT and the ubiquitin ligase MDM2. In fact, our results indicate that the lower level of PIM1, induced by ribosomal stress, causes inactivation of AKT, inhibition of MDM2 and a consequent p53 stabilization. Therefore, we propose that activation of p53 in response to ribosomal stress, is dependent on the pathway PIM1-AKT-MDM2. In addition, we report evidence that PIM1 level may be relevant to assess the sensitivity of cancer cells to chemotherapeutic drugs that induce ribosomal stress.

PMID: 26993775 [PubMed - as supplied by publisher]

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The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia.

The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia.

Oncotarget. 2016 Mar 14;

Authors: Han K, Wang Q, Cao H, Qiu G, Cao J, Li X, Wang J, Shen B, Zhang J

Abstract
The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme (NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we show that treatment of T-cell acute lymphoblastic leukemia (T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells. However, inhibition of the neddylation of Cullins alone could not explain the effects of MLN4924 in T-ALL cells. Gene expression profiling indicated ribosome function, steroid biosynthesis, and hematopoietic cell lineage pathways were affected by MLN4924 treatment. MLN4924 also induced nucleolar disruption, suggesting nucleolar stress signaling might contribute to the anticancer effects of MLN4924 in T-ALL cells. In addition, MLN4924 treatment reduced 14-3-3ξ\δ protein levels in T-ALL cells. Thus, MLN4924 may inhibit T-ALL cell proliferation via several pathways.

PMID: 26993774 [PubMed - as supplied by publisher]

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Prognostic roles for fibroblast growth factor receptor family members in malignant peripheral nerve sheath tumor.

Prognostic roles for fibroblast growth factor receptor family members in malignant peripheral nerve sheath tumor.

Oncotarget. 2016 Mar 14;

Authors: Zhou W, Du X, Song F, Zheng H, Chen K, Zhang W, Yang J

Abstract
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare, highly malignant, and poorly understood sarcomas. The often poor outcome of MPNST highlights the necessity of identifying prognostic predictors for this aggressive sarcoma. Here, we investigate the role of fibroblast growth factor receptor (FGFR) family members in human MPNSTs.
PATIENTS AND METHODS: We performed microarray-based comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Medical University Cancer Institute and Hospital. Fluorescence in situ hybridization (FISH) was used to validate the gene amplification detected by aCGH analysis. Another cohort of 63 formalin-fixed paraffin-embedded MPNST samples (including 52 samples for FISH assay) was obtained to explore FGFR1, 2, 3, and 4 protein expression by immunohistochemical (IHC) analysis.
RESULTS: aCGH and bioinformatics analysis identified frequent amplification of the FGFR1 gene. FISH analysis revealed that 26.9% MPNST samples had amplification of FGFR1, with both focal and polysomy patterns observed. IHC identified that FGFR1 protein expression was positively correlated with FGFR1 gene amplification. High expression of FGFR1 protein was associated with better overall survival (OS) and was an independent prognostic predictor for OS of MPNST patients. Additionally, combined expression of FGFR1 and FGFR2 protein characterized a subtype of MPNST with better OS. FGFR4 protein was expressed 82.3% of MPNST samples, and was associated with poor disease-free survival.
CONCLUSIONS: Our integrated genomic and molecular studies provide evidence that FGFRs play different prognostic roles in MPNST.

PMID: 26993773 [PubMed - as supplied by publisher]

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Small ubiquitin-related modifier 1 is involved in hepatocellular carcinoma progression via mediating p65 nuclear translocation.

Small ubiquitin-related modifier 1 is involved in hepatocellular carcinoma progression via mediating p65 nuclear translocation.

Oncotarget. 2016 Mar 14;

Authors: Liu J, Tao X, Zhang J, Wang P, Sha M, Ma Y, Geng X, Feng L, Shen Y, Yu Y, Wang S, Fang S, Shen Y

Abstract
Small ubiquitin-related modifier (SUMO) proteins participate in a post-translational modification called SUMOylation and regulate a variety of intracellular processes, such as targeting proteins for nuclear import. The nuclear transport of p65 results in the activation of NF-κB, and p65 contains several SUMO interacting motifs (SIMs). However, the relationship between p65 and SUMO1 in hepatocellular carcinoma (HCC) remains unclear. In this study, we demonstrated the potential roles of SUMO1 in HCC via the regulation of p65 subcellular localization. We found that either SUMO1- or p65-positive immunoreactivity was remarkably increased in the nuclei of tumor tissues in HCC patients compared with non-tumor tissues, and further analysis suggested a correlation between SUMO1- and nuclear p65-positive immunoreactivities (R = 0.851, P = 0.002). We also verified the interaction between p65 and SUMO1 in HCC by co-immunoprecipitation. TNF-α and hypoxia increased SUMO1 protein levels and enhanced SUMO1-modified p65 SUMOylation. Moreover, the knockdown of SUMO1 decreased p65 nuclear translocation and inhibited NF-κB transcriptional activity. Further the results of this study revealed that the knockdown of SUMO1 suppressed the proliferation and migration of hepatoma cells. These results suggest that SUMO1 contributes to HCC progression by promoting p65 nuclear translocation and regulating NF-κB activity.

PMID: 26993772 [PubMed - as supplied by publisher]

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Immortalization capacity of HPV types is inversely related to chromosomal instability.

Immortalization capacity of HPV types is inversely related to chromosomal instability.

Oncotarget. 2016 Mar 14;

Authors: Schütze DM, Krijgsman O, Snijders PJ, Ylstra B, Weischenfeldt J, Mardin BR, Stütz AM, Korbel JO, de Winter JP, Meijer CJ, Quint WG, Bosch L, Wilting SM, Steenbergen RD

Abstract
High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs.Twenty five cell cultures obtained by transduction of ten hrHPV types (i.e. HPV16/18/31/33/35/45/51/59/66/70 E6E7) in two or three HFK donors each were studied.All hrHPV-transduced HFKs showed an increased number of double strand DNA breaks compared to controls, without exhibiting significant differences between types. However, immortal descendants of HPV-transduced HFKs that underwent a prior crisis period (HPV45/51/59/66/70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without crisis (HPV16/18/31/33/35-transduced HFKs). Notably, the hTERT locus at 5p was exclusively gained in cells with a history of crisis and coincided with increased expression. Chromothripsis was detected in one cell line in which multiple rearrangements within chromosome 8 resulted in a gain of MYC.Together we demonstrated that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the viral immortalization capacity. We propose that hrHPV types with reduced immortalization capacity in vitro, reflected by a crisis period, require more genetic host cell aberrations to facilitate immortalization than types that can immortalize without crisis. This may in part explain the observed differences in HPV-type prevalence in cervical cancers and emphasizes that changes in the host cell genome contribute to HPV-induced carcinogenesis.

PMID: 26993771 [PubMed - as supplied by publisher]

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MicroRNA-16 sensitizes breast cancer cells to paclitaxel through suppression of IKBKB expression.

MicroRNA-16 sensitizes breast cancer cells to paclitaxel through suppression of IKBKB expression.

Oncotarget. 2016 Mar 14;

Authors: Tang X, Jin L, Cao P, Cao K, Huang C, Luo Y, Ma J, Shen S, Tan M, Li X, Zhou M

Abstract
Paclitaxel (Taxol) is an effective chemotherapeutic agent for treating breast cancer patients. However, chemoresistance is a major obstacle in cancer treatment. Here, we showed that overexpression of miR-16 promoted Taxol-induced cytotoxicity and apoptosis in breast cancer cells. Furthermore, IκB kinase β (IKBKB) was identified as a direct target of miR-16. Up-regulation of IKBKB suppressed Taxol-induced apoptosis and led to an increased resistance to Taxol, and restoring IKBKB expression in miR-16-overexpressing breast cancer cells recovered Taxol resistance. Moreover, miR-16 was highly expressed in Taxol-sensitive breast cancer tissues compared with Taxol-resistant tissues, and there was an inverse correlation between miR-16 expression and IKBKB expression in breast cancer tissues. The expression levels of miR-16 were negatively associated with T stages, whereas the expression of IKBKB was positively correlated with T stages, lymph node metastasis and clinical stages. Taken together, our data demonstrates that miR-16 sensitizes breast cancer cells to Taxol through the suppression of IKBKB expression, and targeting miR-16/IKBKB axis will be a promising strategy for overcoming Taxol resistance in breast cancer.

PMID: 26993770 [PubMed - as supplied by publisher]

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Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer.

Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer.

Oncotarget. 2016 Mar 14;

Authors: Jia M, Zhu M, Wang M, Sun M, Qian J, Ding F, Chang J, Wei Q

Abstract
The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.

PMID: 26993769 [PubMed - as supplied by publisher]

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Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes.

Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes.

Oncotarget. 2016 Mar 14;

Authors: Norström MM, Rådestad E, Sundberg B, Mattsson J, Henningsohn L, Levitsky V, Uhlin M

Abstract
Benign prostatic hyperplasia (BPH) is a common chronic non-malignant condition whose prevalence substantially increases with age. Immune cell infiltration and pro-inflammatory mediators have been implicated in the pathogenesis. Here, we characterized 21 extracellular markers on prostate-infiltrating lymphocytes (PILs) and analyzed expression of 26 soluble proteins in prostate tissue obtained from BPH patients (n = 31). These data were correlated with clinical parameters and compared with peripheral blood mononuclear cells (PBMCs) (n = 10). Increased frequencies of T cells expressing co-inhibitory receptors LAG-3, PD-1, TIM-3 or CTLA-4, and co-stimulatory receptors CD28, OX40 or 4-1BB were observed in BPH tissue compared to PBMCs. These findings are consistent with chronic activation and possible functional exhaustion of PILs that may be further augmented by several identified pro-inflammatory factors, such as IL-8 and MCP-1, promoting inflammation and chemotaxis of immune cells to the prostate. Prostate size and plasma prostate-specific antigen levels positively correlated with IL-8 and MCP-1 concentrations, and frequencies of T cells expressing CTLA-4 and TIM-3. It remains to be established whether the link between inflammation and BPH progression supported by our findings reflects a progressive failure of the immune system leading to decreased immune surveillance and development of prostate cancer.

PMID: 26993768 [PubMed - as supplied by publisher]

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MicroRNA-630 suppresses tumor metastasis through the TGF-β- miR-630-Slug signaling pathway and correlates inversely with poor prognosis in hepatocellular carcinoma.

MicroRNA-630 suppresses tumor metastasis through the TGF-β- miR-630-Slug signaling pathway and correlates inversely with poor prognosis in hepatocellular carcinoma.

Oncotarget. 2016 Mar 14;

Authors: Chen WX, Zhang ZG, Ding ZY, Liang HF, Song J, Tan XL, Wu JJ, Li GZ, Zeng Z, Zhang BX, Chen XP

Abstract
The epithelial-mesenchymal transition (EMT) is the key process that drives tumor metastasis. Accumulating evidence suggests that the deregulation of some microRNAs (miRNAs), is implicated in this process. Here, we highlight the function and molecular mechanism of miR-630 and its potential clinical application in hepatocellular carcinoma (HCC). First, we identified the clinical relevance of miR-630 expression in a screen of 97 HCC patient tissues. Patients with low miR-630 expression had higher recurrence rates and shorter overall survival than those with high miR-630 expression. Functional studies demonstrated the overexpression of miR-630 in HCC cells attenuated the EMT phenotype in vitro. Conversely, inhibition of miR-630 promoted EMT in HCC cells. Mechanistically, our data revealed that miR-630 suppressed EMT by targeting Slug. Knockdown of Slug expression reversed miR-630 inhibitor-mediated EMT progression. Furthermore, we found that the TGF-β-Erk/SP1 and JNK/c-Jun signaling pathways repressed miR-630 transcription through occupying transcription factor binding sites. Ectopic expression of miR-630 restored the TGF-β-activated EMT process. Taken together, these findings demonstrate, in HCC cells, miR-630 exerts its tumor-suppressor functions through the TGF-β-miR-630-Slug axis and provides a potential prognostic predictor for HCC patients.

PMID: 26993767 [PubMed - as supplied by publisher]

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Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer.

Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer.

Oncotarget. 2016 Mar 14;

Authors: Destouches D, Sader M, Terry S, Marchand C, Maillé P, Soyeux P, Carpentier G, Semprez F, Céraline J, Allory Y, Courty J, Taille A, Vacherot F

Abstract
Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.

PMID: 26993766 [PubMed - as supplied by publisher]

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BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death.

BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death.

Oncotarget. 2016 Mar 14;

Authors: Relic B, Charlier E, Deroyer C, Malaise O, Neuville S, Desoroux A, Gillet P, Seny D, Malaise MG

Abstract
Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-κB inhibitor BAY 11-7085, through inactivation of PPAR-γ, induces apoptosis in human synovial fibroblasts. In this work we showed that BAY 11-7085 induced autophagy that preceded BAY 11-7085-induced apoptosis. Of interest, BAY 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. BAY 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both BAY 11-7085-induced autophagy and GR activation were down regulated with PPAR-γ agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and BAY 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-γ1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-γ1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-γ inactivation mediated BAY 11-7085-induced autophagy.

PMID: 26993765 [PubMed - as supplied by publisher]

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Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.

Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.

Oncotarget. 2016 Mar 16;

Authors: Bhasin MK, Ndebele K, Bucur O, Yee EU, Otu HH, Plati J, Bullock A, Gu X, Castan E, Zhang P, Najarian R, Muraru MS, Miksad R, Khosravi-Far R, Libermann TA

Abstract
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification.
EXPERIMENTAL DESIGN: Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells.
RESULTS: A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion.
CONCLUSIONS: This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets.

PMID: 26993610 [PubMed - as supplied by publisher]

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Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer.

Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer.

Oncotarget. 2016 Mar 16;

Authors: Tan CL, Lim TH, Lim TK, Tan DS, Chua YW, Ang MK, Pang B, Lim CT, Takano A, Lim AS, Leong MC, Lim WT

Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.

PMID: 26993609 [PubMed - as supplied by publisher]

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Post-translational modification-regulated leukocyte adhesion and migration.

Post-translational modification-regulated leukocyte adhesion and migration.

Oncotarget. 2016 Mar 16;

Authors: Loh JT, Su IH

Abstract
Leukocytes undergo frequent phenotypic changes and rapidly infiltrate peripheral and lymphoid tissues in order to carry out immune responses. The recruitment of circulating leukocytes into inflamed tissues depends on integrin-mediated tethering and rolling of these cells on the vascular endothelium, followed by transmigration into the tissues. This dynamic process of migration requires the coordination of large numbers of cytosolic and transmembrane proteins whose functional activities are typically regulated by post-translational modifications (PTMs). Our recent studies have shown that the lysine methyltransferase, Ezh2, critically regulates integrin signalling and governs the adhesion dynamics of leukocytes via direct methylation of talin, a key molecule that controls these processes by linking integrins to the actin cytoskeleton. In this review, we will discuss the various modes of leukocyte migration and examine how PTMs of cytoskeletal/adhesion associated proteins play fundamental roles in the dynamic regulation of leukocyte migration. Furthermore, we will discuss molecular details of the adhesion dynamics controlled by Ezh2-mediated talin methylation and the potential implications of this novel regulatory mechanism for leukocyte migration, immune responses, and pathogenic processes, such as allergic contact dermatitis and tumorigenesis.

PMID: 26993608 [PubMed - as supplied by publisher]

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The comparison of outcomes from tyrosine kinase inhibitor monotherapy in second- or third-line for advanced non-small-cell lung cancer patients with wild-type or unknown EGFR status.

The comparison of outcomes from tyrosine kinase inhibitor monotherapy in second- or third-line for advanced non-small-cell lung cancer patients with wild-type or unknown EGFR status.

Oncotarget. 2016 Mar 16;

Authors: Bronte G, Franchina T, Alù M, Sortino G, Celesia C, Passiglia F, Savio G, Laudani A, Russo A, Picone A, Rizzo S, De Tursi M, Gambale E, Bazan V, Natoli C, Blasi L, Adamo V, Russo A

Abstract
BACKGROUND: Second-line treatment for advanced non-small-cell lung cancer (NSCLC) patients includes monotherapy with a third-generation cytotoxic drug (CT) or a tyrosine kinase inhibitor (TKI). These options are the actual standard for EGFR wild-type (WT) status, as patients with EGFR mutations achieve greater benefit by the use of TKI in first-line treatment. Some clinical trials and meta-analyses investigated the comparison between CT and TKI in second-line, but data are conflicting.
METHODS: We designed a retrospective trial to gather information about TKI sensitivity in comparison with CT. We selected from clinical records patients treated with at least 1 line of CT and at least 1 line of TKI. We collected data about age, sex, performance status, comorbidity, smoking status, histotype, metastatic sites, EGFR status, treatment schedule, better response and time-to-progression (TTP) for each line of treatment and overall survival (OS).
RESULTS: 93 patients met selection criteria. Mean age 66,7 (range: 46-84). M/F ratio is 3:1. 39 EGFR-WT and 54 EGFR-UK. All patients received erlotinib or gefitinib as second-line treatment or erlotinib as third-line treatment. No TTP differences were observed for both second-line (HR:0,91; p = 0,6333) and third-line (HR:1.1; p = 0,6951) treatment (TKI vs CT). A trend of a benefit in OS in favor of 3rd-line TKI (HR:0,68; p = 0,11).
CONCLUSIONS: This study explores the role of TKIs in EGFR non-mutated NSCLC patients. OS analysis highlights a trend to a benefit in patients who received TKI in third-line, even if this result is statistically non-significant. Further analysis are needed to find an explanation for this observation.

PMID: 26993607 [PubMed - as supplied by publisher]

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Differential roles of estrogen receptors, ESR1 and ESR2, in adult rat spermatogenesis

Publication date: Available online 19 March 2016
Source:Molecular and Cellular Endocrinology
Author(s): Kushaan Dumasia, Anita Kumar, Sharvari Deshpande, Shobha Sonawane, N.H. Balasinor
Estrogens, through their receptors, play an important role in regulation of spermatogenesis. However, the precise role of the estrogen receptors (ESR1 and ESR2) has been difficult to determine as in vivo estradiol treatment would signal through both the ESRs. Hence we had developed in vivo selective ESR agonist administration models in adult male rats to decipher the individual roles of the ESRs. Treatment with both ESR1 and ESR2 agonists decreased sperm counts after 60 days of treatment. The present study aimed to delineate the precise causes of decreased sperm counts following treatment with the two ESR agonists. Treatment with ESR1 agonist causes an arrest in differentiation of round spermatids into elongated spermatids, mainly due to down-regulation of genes involved in spermiogenesis. ESR2 agonist administration reduces sperm counts due to spermiation failure and spermatocyte apoptosis. Spermiation failure observed is due to defects in tubulobulbar complex formation because of decrease in expression of genes involved in actin remodelling. The increase in spermatocyte apoptosis could be due to increase in oxidative stress and decrease in transcripts of anti-apoptotic genes. Our results suggest that the two ESRs regulate distinct aspects of spermatogenesis. ESR1 is mainly involved with regulation of spermiogenesis, while ESR2 regulates spermatocyte apoptosis and spermiation. Activation of estrogen signaling through either of the receptors can affect their respective processes during spermatogenesis and lead to low sperm output. Since many environmental estrogens can bind to the two ESRs with different affinities, these observations can be useful in understanding their potential effects on spermatogenesis.

Graphical abstract

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Optimisation of the round window opening in cochlear implant surgery in wet and dry conditions: impact on intracochlear pressure changes.

Optimisation of the round window opening in cochlear implant surgery in wet and dry conditions: impact on intracochlear pressure changes.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Mittmann P, Ernst A, Mittmann M, Todt I

Abstract
To preserve residual hearing in cochlear implant candidates, the atraumatic insertion of the cochlea electrode has become a focus of cochlea implant research. In a previous study, intracochlear pressure changes during the opening of the round window membrane were investigated. In the current study, intracochlear pressure changes during opening of the round window membrane under dry and transfluid conditions were investigated. Round window openings were performed in an artificial cochlear model. Intracochlear pressure changes were measured using a micro-optical pressure sensor, which was placed in the apex. Openings of the round window membrane were performed under dry and wet conditions using a cannula and a diode laser. Statistically significant differences in the intracochlear pressure changes were seen between the different methods used for opening of the round window membrane. Lower pressure changes were seen by opening the round window membrane with the diode laser than with the cannula. A significant difference was seen between the dry and wet conditions. The atraumatic approach to the cochlea is assumed to be essential for the preservation of residual hearing. Opening of the round window under wet conditions produce a significant advantage on intracochlear pressure changes in comparison to dry conditions by limiting negative outward pressure.

PMID: 26993657 [PubMed - as supplied by publisher]

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Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Kisser U, Kufeldt J, Adderson-Kisser C, Becker S, Baumeister P, Reiter M, Harréus U, Thomas MN, Rittler P

Abstract
Malnutrition is considered as an independent risk factor for morbidity, mortality and a prolonged hospital stay for in-hospital patients. While most available data on the impact of malnutrition on health-related and financial implications refer to gastroenterologic or abdominal surgery patients, little is known about the impact of malnutrition on Ear Nose Throat (ENT)/head and neck surgery patients. The objective of this study was to investigate the impact of malnutrition on morbidity and length of hospital stay in an elective ENT/head and neck surgery patient cohort. The study was performed as a single-center, prospective cohort study at a tertiary referral centre. Nutritional risk at admission was assessed using the NRS-2002 screening tool. Multivariate regression models were used to determine independent risk factors for complications and a prolonged hospitalization. Three hundred fifty one participants were included in the study. A malignant disease was found in 62 participants (17.7 %). 62 patients (17.7 %) were at a moderate to severe risk of malnutrition. A bad general health condition and complications during hospital stay could be identified as independent risk factors for a prolonged hospitalization. Patients with a malignant tumor showed a more than fourfold higher risk of developing at least one complication. Malnutrition, however, was not statistically associated with a higher complication rate or a prolonged hospital stay. Our data suggests that malnutrition does not seem to play such an important role as a risk factor for complications and a prolonged hospital stay in ENT patients as it does in other disciplines like abdominal surgery or gastroenterology.

PMID: 26993656 [PubMed - as supplied by publisher]

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Expansion sphincter pharyngoplasty for obstructive sleep apnea: an update to the recent meta-analysis.

Expansion sphincter pharyngoplasty for obstructive sleep apnea: an update to the recent meta-analysis.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Camacho M, Zaghi S, Piccin O, Certal V

PMID: 26993655 [PubMed - as supplied by publisher]

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Aging and Hearing Health: The Life-course Approach.

Aging and Hearing Health: The Life-course Approach.

Gerontologist. 2016 Apr;56(Suppl 2):S256-S267

Authors: Davis A, McMahon CM, Pichora-Fuller KM, Russ S, Lin F, Olusanya BO, Chadha S, Tremblay KL

Abstract
Sensory abilities decline with age. More than 5% of the world's population, approximately 360 million people, have disabling hearing loss. In adults, disabling hearing loss is defined by thresholds greater than 40 dBHL in the better hearing ear.Hearing disability is an important issue in geriatric medicine because it is associated with numerous health issues, including accelerated cognitive decline, depression, increased risk of dementia, poorer balance, falls, hospitalizations, and early mortality. There are also social implications, such as reduced communication function, social isolation, loss of autonomy, impaired driving ability, and financial decline. Furthermore, the onset of hearing loss is gradual and subtle, first affecting the detection of high-pitched sounds and with difficulty understanding speech in noisy but not in quiet environments. Consequently, delays in recognizing and seeking help for hearing difficulties are common. Age-related hearing loss has no known cure, and technologies (hearing aids, cochlear implants, and assistive devices) improve thresholds but do not restore hearing to normal. Therefore, health care for persons with hearing loss and people within their communication circles requires education and counseling (e.g., increasing knowledge, changing attitudes, and reducing stigma), behavior change (e.g., adapting communication strategies), and environmental modifications (e.g., reducing noise). In this article, we consider the causes, consequences, and magnitude of hearing loss from a life-course perspective. We examine the concept of "hearing health," how to achieve it, and implications for policy and practice.

PMID: 26994265 [PubMed - as supplied by publisher]

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GlideScope video laryngoscope-assisted nasotracheal intubation by cuff-inflation technique in head and neck cancer patients.

GlideScope video laryngoscope-assisted nasotracheal intubation by cuff-inflation technique in head and neck cancer patients.

Br J Anaesth. 2016 Apr;116(4):559-60

Authors: Gupta N, Garg R, Saini S, Kumar V

PMID: 26994237 [PubMed - in process]

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pAKT Expression and Response to Sorafenib in Differentiated Thyroid Cancer.

pAKT Expression and Response to Sorafenib in Differentiated Thyroid Cancer.

Horm Cancer. 2016 Mar 18;

Authors: Yarchoan M, Ma C, Troxel AB, Stopenski SJ, Tang W, Cohen AB, Pappas-Paxinos M, Johnson BA, Chen EY, Feldman MD, Brose MS

Abstract
Sorafenib has an antitumor activity in patients with radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC). Prior research has implicated signaling through the MAPK and AKT/PI3K pathways in the progression of DTC. To assess whether the activity of these pathways is predictive of response to sorafenib, we retrospectively studied molecular tumor markers from these two pathways from a phase 2 study of sorafenib in RAIR-DTC. Tumor samples from 40 of 53 DTC subjects obtained prior to initiation of sorafenib were immunostained with DAB-labeled antibodies to phospho-AKT (pAKT), phospho-ERK (pERK), and phospho-S6 (pS6). BRAFV600E genetic mutation analysis was performed on all samples. Expression levels and mutational status were compared to response and progression-free survival (PFS) for each patient. Low tumor expression of nuclear pAKT was associated with partial response to sorafenib (p < 0.01). Patients with nuclear pAKT expression that was below the median for our sample were more than three times as likely to have a partial response as patients with equal to or above median expression. There was no correlation between tumor expression of nuclear pERK or pS6 and response. Endothelial cell and pericyte expression of pERK, pAKT, and pS6 were not predictive of response. There was no correlation between BRAFV600E mutation status and partial response. No correlation was observed between either the expression of pAKT, pERK, or pS6, or the presence of the BRAFV600E mutation, and PFS. In conclusion, lower tumor expression of nuclear pAKT was associated with higher rate of response to sorafenib. This observation justifies evaluation of combination therapy with sorafenib and an inhibitor of the PI3K/AKT signaling pathway in RAIR-DTC.

PMID: 26994002 [PubMed - as supplied by publisher]

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Significance of endothelial progenitor cells (EPC) for tumorigenesis of head and neck squamous cell carcinoma (HNSCC): possible marker of tumor progression and neovascularization?

Significance of endothelial progenitor cells (EPC) for tumorigenesis of head and neck squamous cell carcinoma (HNSCC): possible marker of tumor progression and neovascularization?

Clin Oral Investig. 2016 Mar 19;

Authors: Ziebart T, Blatt S, Günther C, Völxen N, Pabst A, Sagheb K, Kühl S, Lambrecht T

Abstract
OBJECTIVES: Angiogenesis and neovascularisation plays a crucial role for tumorigenesis and tumor progression in head and neck squamous cell carcinoma (HNSCC). The aim of our study was to investigate the neovascularization capacity by endothelial progenitor cells (EPC) in tumor patient as a possible predictor for tumor progression and tumor stage.
MATERIALS AND METHODS: Therefore, we investigated the cell number and biologic activity by cell migration and colony-forming ability of EPC. Cells were isolated from the peripheral venous blood of 79 patients who suffer HNSCC in different stages of disease. Thirty-three healthy individuals served as the control group.
RESULTS: Significantly increased biological activities were reflected by expression of the migration rate (1027 ± 1510) in comparison to the control group (632 ± 269) and the clonal potency measured by colony-forming unit (CFU) (tumor patients (19.7 ± 12.3) vs. control group (10.84 ± 4.8)). To determine whether or not EPC number can be used as a valid prognostic marker for clinical outcome of tumor patients, we furthermore compared a "high EPC-number-subgroup" (HI) with a "low EPC-number-subgroup" (LO) in a Kaplan-Meier survival curve. The HI-subgroup shows herein clearly a worse outcome.
CONCLUSIONS: Our findings indicate a possible pathway for EPC to play a critical role in the vasculogenesis and consequently in the progression of HNSCC.
CLINICAL RELEVANCE: Our findings could serve as possible predictors for the neovascularisation potential in HNSCC tumor patients.

PMID: 26993659 [PubMed - as supplied by publisher]

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Optimisation of the round window opening in cochlear implant surgery in wet and dry conditions: impact on intracochlear pressure changes.

Optimisation of the round window opening in cochlear implant surgery in wet and dry conditions: impact on intracochlear pressure changes.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Mittmann P, Ernst A, Mittmann M, Todt I

Abstract
To preserve residual hearing in cochlear implant candidates, the atraumatic insertion of the cochlea electrode has become a focus of cochlea implant research. In a previous study, intracochlear pressure changes during the opening of the round window membrane were investigated. In the current study, intracochlear pressure changes during opening of the round window membrane under dry and transfluid conditions were investigated. Round window openings were performed in an artificial cochlear model. Intracochlear pressure changes were measured using a micro-optical pressure sensor, which was placed in the apex. Openings of the round window membrane were performed under dry and wet conditions using a cannula and a diode laser. Statistically significant differences in the intracochlear pressure changes were seen between the different methods used for opening of the round window membrane. Lower pressure changes were seen by opening the round window membrane with the diode laser than with the cannula. A significant difference was seen between the dry and wet conditions. The atraumatic approach to the cochlea is assumed to be essential for the preservation of residual hearing. Opening of the round window under wet conditions produce a significant advantage on intracochlear pressure changes in comparison to dry conditions by limiting negative outward pressure.

PMID: 26993657 [PubMed - as supplied by publisher]

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Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Kisser U, Kufeldt J, Adderson-Kisser C, Becker S, Baumeister P, Reiter M, Harréus U, Thomas MN, Rittler P

Abstract
Malnutrition is considered as an independent risk factor for morbidity, mortality and a prolonged hospital stay for in-hospital patients. While most available data on the impact of malnutrition on health-related and financial implications refer to gastroenterologic or abdominal surgery patients, little is known about the impact of malnutrition on Ear Nose Throat (ENT)/head and neck surgery patients. The objective of this study was to investigate the impact of malnutrition on morbidity and length of hospital stay in an elective ENT/head and neck surgery patient cohort. The study was performed as a single-center, prospective cohort study at a tertiary referral centre. Nutritional risk at admission was assessed using the NRS-2002 screening tool. Multivariate regression models were used to determine independent risk factors for complications and a prolonged hospitalization. Three hundred fifty one participants were included in the study. A malignant disease was found in 62 participants (17.7 %). 62 patients (17.7 %) were at a moderate to severe risk of malnutrition. A bad general health condition and complications during hospital stay could be identified as independent risk factors for a prolonged hospitalization. Patients with a malignant tumor showed a more than fourfold higher risk of developing at least one complication. Malnutrition, however, was not statistically associated with a higher complication rate or a prolonged hospital stay. Our data suggests that malnutrition does not seem to play such an important role as a risk factor for complications and a prolonged hospital stay in ENT patients as it does in other disciplines like abdominal surgery or gastroenterology.

PMID: 26993656 [PubMed - as supplied by publisher]

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Expansion sphincter pharyngoplasty for obstructive sleep apnea: an update to the recent meta-analysis.

Expansion sphincter pharyngoplasty for obstructive sleep apnea: an update to the recent meta-analysis.

Eur Arch Otorhinolaryngol. 2016 Mar 18;

Authors: Camacho M, Zaghi S, Piccin O, Certal V

PMID: 26993655 [PubMed - as supplied by publisher]

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Modulatory Effects of Mild Carbon Monoxide Exposure in the Developing Mouse Cochlea.

Modulatory Effects of Mild Carbon Monoxide Exposure in the Developing Mouse Cochlea.

Neurochem Res. 2016 Mar 19;

Authors: Lopez IA, Acuna D, Edmond J

Abstract
Carbon monoxide (CO) is well known as a highly toxic poison at high concentrations, yet in physiologic amounts it is an endogenous biological messenger in organs such as the internal ear and brain. In this study we tested the hypothesis that chronic very mild CO exposure at concentrations 25-ppm increases the expression of oxidative stress protecting enzymes within the cellular milieu of the developing inner ear (cochlea) of the normal CD-1 mouse. In addition we tested also the hypothesis that CO can decrease the pre-existing condition of oxidative stress in the mouse model for the human medical condition systemic lupus erythematosus by increasing two protective enzymes heme-oxygenase-1 (HO-1), and superoxide dismutase-2 (SOD-2). CD-1 and MRL/lpr mice were exposed to mild CO concentrations (25 ppm in air) from prenatal only and prenatal followed by early postnatal day 5 to postnatal day 20. The expression of cell markers specific for oxidative stress, and related neural/endothelial markers were investigated at the level of the gene products by immunohistochemistry, proteomics and mRNA expression (quantitative real time-PCR). We found that in the CD-1 and MRL/lpr mouse cochlea SOD-2 and HO-1 were upregulated. In this mouse model of autoimmune disease defense mechanism are attenuated, thus mild CO exposure is beneficial. Several genes (mRNA) and proteins detected by proteomics involved in cellular protection were upregulated in the CO exposed CD-1 mouse and the MRL/lpr mouse.

PMID: 26993631 [PubMed - as supplied by publisher]

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Cell fate determination in cisplatin resistance and chemosensitization.

Cell fate determination in cisplatin resistance and chemosensitization.

Oncotarget. 2016 Mar 16;

Authors: Luong KV, Wang L, Roberts BJ, Wahl Iii JK, Peng A

Abstract
Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage. Interestingly, checkpoint slippage occurred predominantly in cells treated in late S and G2 phases, and cells in M-phase were hypersensitive to cisplatin. Moreover, although the cisplatin-resistant progression of mitosis exhibited no delay in general, prolonged mitosis was correlated with the induction of cell death in mitosis. The finding thus suggested a combinatorial treatment using cisplatin and an agent that blocks mitotic exit. Consistently, we showed a strong synergy between cisplatin and the proteasome inhibitor Mg132. Finally, targeting the DNA damage checkpoint using inhibitors of ATR, but not ATM, effectively sensitized UM-SCC-38 to cisplatin treatment. Surprisingly, checkpoint targeting eliminated both checkpoint arrest and checkpoint slippage, and augmented the induction of cell death in interphase without mitotic entry. Taken together, our study, by profiling cell fate determination after cisplatin treatment, reveals new insights into chemoresistance and suggests combinatorial strategies that potentially overcome cancer resistance.

PMID: 26993599 [PubMed - as supplied by publisher]

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Endoscope-assisted medial sural artery perforator flap for head and neck reconstruction.

Endoscope-assisted medial sural artery perforator flap for head and neck reconstruction.

J Plast Reconstr Aesthet Surg. 2016 Feb 12;

Authors: Shen XQ, Shen H, Lv Y, Lu H, Wu SC, Lin XJ

Abstract
BACKGROUND: Head and neck defect reconstructions with various free perforator flaps have been widely reported. We recommend a technique of using endoscopy to confirm the location of the medial sural artery perforator (MSAP). Further, we use a free MSAP flap for the reconstruction of head and neck defects.
PATIENTS AND METHODS: Since 2010, we have carried out 18 transfers of the free MSAP flap in various anatomical locations of the head and neck. The free flap was designed based on endoscopy confirmation and contained perforator vessels. The donor site was directly sutured or skin grafted.
RESULTS: Twenty perforators (35.7%) detected by Doppler were confirmed by endoscopy. The number of sizable perforators ranged from one to three (mean, 1.4). The size of the flaps ranged from 22 to 88 cm(2) (mean, 41 cm(2)). The length of vascular pedicle ranged from 5 to 14 cm (mean, 8.3 cm). All 18 flaps survived with good quality and aesthetic contours.
CONCLUSIONS: The MSAP flap is an ideal flap for head and neck reconstruction. It has generally thin and pliable skin, a long and reliable vascular pedicle, straightforward intramuscular dissection, the possibility of chimeric flap design, and minimal donor-site morbidity. The reliability and safety of harvesting an MSAP flap may be increased by endoscopic confirmation of the perforators.

PMID: 26993589 [PubMed - as supplied by publisher]

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Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors.

Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors.

Cancer Immunol Immunother. 2016 Mar 18;

Authors: van Kempen PM, Noorlag R, Swartz JE, Bovenschen N, Braunius WW, Vermeulen JF, Van Cann EM, Grolman W, Willems SM

Abstract
OBJECTIVES: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs) have an improved prognosis compared to HPV-negative OPSCCs. Several theories have been proposed to explain this relatively good prognosis. One hypothesis is a difference in immune response. In this study, we compared tumor-infiltrating CD3+, CD4+, CD8+ T-cells, and granzyme inhibitors (SERPINB1, SERPINB4, and SERPINB9) between HPV-positive and HPV-negative tumors and the relation with survival.
METHODS: Protein expression of tumor-infiltrating lymphocytes (TILs) (CD3, CD4, and CD8) and granzyme inhibitors was analyzed in 262 OPSCCs by immunohistochemistry (IHC). Most patients (67 %) received primary radiotherapy with or without chemotherapy. Cox regression analysis was carried out to compare overall survival (OS) of patients with low and high TIL infiltration and expression of granzyme inhibitors.
RESULTS: HPV-positive OPSCCs were significantly more heavily infiltrated by TILs (p < 0.001) compared to HPV-negative OPSCCs. A high level of CD3+ TILs was correlated with a favorable outcome in the total cohort and in HPV-positive OPSCCs, while it reached no significance in HPV-negative OPSCCs. There was expression of all three granzyme inhibitors in OPSCCs. No differences in expression were found between HPV-positive and HPV-negative OPSCCs. Within the group of HPV-positive tumors, a high expression of SERPINB1 was associated with a significantly worse overall survival.
CONCLUSION: HPV-positive OPSCCs with a low count of CD3+ TILs or high expression of SERPINB1 have a worse OS, comparable with HPV-negative OPSCCs. This suggests that the immune system plays an important role in the carcinogenesis of the virally induced oropharynx tumors.

PMID: 26993499 [PubMed - as supplied by publisher]

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Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

Radiother Oncol. 2016 Mar 15;

Authors: Rasmussen JH, Håkansson K, Vogelius IR, Aznar MC, Fischer BM, Friborg J, Loft A, Kristensen CA, Bentzen SM, Specht L

Abstract
PURPOSE: The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC).
METHODS AND MATERIALS: CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTVPET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTVPET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTVPET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTVPET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist.
RESULTS: Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects.
CONCLUSIONS: With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial.

PMID: 26993418 [PubMed - as supplied by publisher]

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Oropharyngeal exercises in the treatment of obstructive sleep apnoea: our experience.

Oropharyngeal exercises in the treatment of obstructive sleep apnoea: our experience.

Sleep Breath. 2016 Mar 18;

Authors: Verma RK, Johnson J JR, Goyal M, Banumathy N, Goswami U, Panda NK

Abstract
INTRODUCTION: Oropharyngeal exercises are new, non-invasive, cost effective treatment modality for the treatment of mild to moderate obstructive sleep apnoea. It acts by increasing the tone of pharyngeal muscles, is more physiological, and effects are long lasting.
AIM OF THE STUDY: The aim of our present study was to evaluate the effect of oropharyngeal exercises in the treatment of mild to moderate obstructive sleep apnoea.
METHOD: Twenty patients of mild to moderate obstructive sleep apnoea syndrome (OSAS) were given oropharyngeal exercise therapy for 3 months divided into three phases in graded level of difficulty. Each exercise had to be repeated 10 times, 5 sets per day at their home. Oropharyngeal exercises were derived from speech-language pathology and included soft palate, tongue, and facial muscle exercises. Anthropometric measurements, snoring frequency, intensity, Epworth daytime sleepiness and Berlin sleep questionnaire, and full polysomnography were performed at baseline and at study conclusion.
RESULTS: Body mass index (25.6 ± 3.1) did not change significantly at the end of the study period. There was significant reduction in the neck circumference (38.4 ± 1.3 to 37.8 ± 1.6) at the end of the study. Significant improvement was seen in symptoms of daytime sleepiness, witnessed apnoea, and snoring intensity. Significant improvement was also seen in sleep indices like minimum oxygen saturation, time duration of Sao2 < 90 %, sleep efficiency, arousal index, and total sleep time N3 stage of sleep at the end of study.
CONCLUSION: Graded oropharyngeal exercise therapy increases the compliance and also reduces the severity of mild to moderate OSAS.

PMID: 26993338 [PubMed - as supplied by publisher]

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Streptococcus agalactiae infection in cancer patients: a five-year study.

Streptococcus agalactiae infection in cancer patients: a five-year study.

Eur J Clin Microbiol Infect Dis. 2016 Mar 18;

Authors: Pimentel BA, Martins CA, Mendonça JC, Miranda PS, Sanches GF, Mattos-Guaraldi AL, Nagao PE

Abstract
Although the highest burden of Streptococcus agalactiae infections has been reported in industrialized countries, studies on the characterization and epidemiology are still limited in developing countries and implementation of control strategies remains undefined. The aim of this retrospective study was to assess the epidemiological, clinical, and microbiological aspects of S. agalactiae infections in cancer patients treated at a Reference Brazilian National Cancer Institute - INCA, Rio de Janeiro, Brazil. We reviewed the clinical and laboratory records of all cancer patients identified as having invasive S. agalactiae disease during 2010-2014. The isolates were identified by biochemical analysis and tested for antimicrobial susceptibility. A total of 263 strains of S. agalactiae were isolated from cancer patients who had been clinically and microbiologically classified as infected. S. agalactiae infections were mostly detected among adults with solid tumors (94 %) and/or patients who have used indwelling medical devices (77.2 %) or submitted to surgical procedures (71.5 %). Mortality rates (in-hospital mortality during 30 days after the identification of S. agalactiae) related to invasive S. agalactiae infections (n = 28; 31.1 %) for the specific category of neoplasic diseases were: gastrointestinal (46 %), head and neck (25 %), lung (11 %), hematologic (11 %), gynecologic (4 %), and genitourinary (3 %). We also found an increase in S. agalactiae resistance to erythromycin and clindamycin and the emergence of penicillin-less susceptible isolates. A remarkable number of cases of invasive infections due to S. agalactiae strains was identified, mostly in adult patients. Our findings reinforce the need for S. agalactiae control measures in Brazil, including cancer patients.

PMID: 26993288 [PubMed - as supplied by publisher]

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Relative plan robustness of step-and-shoot vs rotational intensity-modulated radiotherapy on repeat computed tomographic simulation for weight loss in head and neck cancer.

Relative plan robustness of step-and-shoot vs rotational intensity-modulated radiotherapy on repeat computed tomographic simulation for weight loss in head and neck cancer.

Med Dosim. 2016 Mar 15;

Authors: Thomson DJ, Beasley WJ, Garcez K, Lee LW, Sykes AJ, Rowbottom CG, Slevin NJ

Abstract
INTRODUCTION: Interfractional anatomical alterations may have a differential effect on the dose delivered by step-and-shoot intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). The increased degrees of freedom afforded by rotational delivery may increase plan robustness (measured by change in target volume coverage and doses to organs at risk [OARs]). However, this has not been evaluated for head and neck cancer.
MATERIALS AND METHODS: A total of 10 patients who required repeat computed tomography (CT) simulation and replanning during head and neck IMRT were included. Step-and-shoot IMRT and VMAT plans were generated from the original planning scan. The initial and second CT simulation scans were fused and targets/OAR contours transferred, reviewed, and modified. The plans were applied to the second CT scan and doses recalculated without repeat optimization. Differences between step-and-shoot IMRT and VMAT for change in target volume coverage and doses to OARs between first and second CT scans were compared by Wilcoxon signed rank test.
RESULTS: There were clinically relevant dosimetric changes between the first and the second CT scans for both the techniques (reduction in mean D95% for PTV2 and PTV3, Dmin for CTV2 and CTV3, and increased mean doses to the parotid glands). However, there were no significant differences between step-and-shoot IMRT and VMAT for change in any target coverage parameter (including D95% for PTV2 and PTV3 and Dmin for CTV2 and CTV3) or dose to any OARs (including parotid glands) between the first and the second CT scans.
CONCLUSIONS: For patients with head and neck cancer who required replanning mainly due to weight loss, there were no significant differences in plan robustness between step-and-shoot IMRT and VMAT. This information is useful with increased clinical adoption of VMAT.

PMID: 26993081 [PubMed - as supplied by publisher]

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Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis.

Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis.

Mol Cell Biochem. 2016 Mar 18;

Authors: Rastogi B, Raut SK, Panda NK, Rattan V, Radotra BD, Khullar M

Abstract
Histone deacetylases (HDACs) are a family of deacetylase enzymes that regulate the acetylation state of histones and a variety of other non-histone proteins including key oncogenic and tumor suppressor proteins, which modulates chromatin conformation, leading to regulation of gene expression. HDACs has been grouped into classes I-IV and histone deacetylase 9 (HDAC9) belongs to class IIa which exhibits tissue-specific expression. Recent reports have demonstrated both pro-oncogenic and tumor suppressive role for HDAC9 in different cancers; however, its role in OSCC remains elusive. Here, we investigated the role of HDAC9 in pathogenesis of oral squamous cell carcinoma (OSCC). Our data showed significantly increased mRNA and protein expression of HDAC9 in clinical OSCC samples and UPCI-SCC-116 cells as compared to normal counterpart. Kaplan-Meier analysis showed that the patients with high-level of HDAC9 expression had significantly reduced overall survival than those with low-level of HDAC9 expression (p = 0.034). Knockdown of HDAC9 using siRNA interference suppressed cell proliferation, increased apoptosis, and induced G0/G1 cell cycle arrest in UPCI-SCC-116 cells. Immunofluorescence analysis showed increased nuclear localization of HDAC9 in frozen OSCC sections, and indicative of active HDAC9 that may transcriptionally repress its downstream target genes. Subsequent investigation revealed that overexpression of HDAC9 contributes to OSCC carcinogenesis via targeting a transcription factor, MEF2D, and NR4A1/Nur77, a pro-apoptotic MEF2 target.

PMID: 26992905 [PubMed - as supplied by publisher]

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High-resolution MEG source imaging approach to accurately localize Broca’s area in patients with brain tumor or epilepsy

Publication date: May 2016
Source:Clinical Neurophysiology, Volume 127, Issue 5
Author(s): Charles W. Huang, Ming-Xiong Huang, Zhengwei Ji, Ashley Robb Swan, Anne Marie Angeles, Tao Song, Jeffrey W. Huang, Roland R. Lee
ObjectiveLocalizing expressive language function has been challenging using the conventional magnetoencephalography (MEG) source modeling methods. The present MEG study presents a new accurate and precise approach in localizing the language areas using a high-resolution MEG source imaging method.MethodsIn 32 patients with brain tumors and/or epilepsies, an object-naming task was used to evoke MEG responses. Our Fast-VESTAL source imaging method was then applied to the MEG data in order to localize the brain areas evoked by the object-naming task.ResultsThe Fast-VESTAL results showed that Broca's area was accurately localized to the pars opercularis (BA 44) and/or the pars triangularis (BA 45) in all patients. Fast-VESTAL also accurately localized Wernicke's area to the posterior aspect of the superior temporal gyri in BA 22, as well as several additional brain areas. Furthermore, we found that the latency of the main peak of the response in Wernicke's area was significantly earlier than that of Broca's area.ConclusionIn all patients, Fast-VESTAL analysis established accurate and precise localizations of Broca's area, as well as other language areas. The responses in Wernicke's area were also shown to significantly precede those of Broca's area.SignificanceThe present study demonstrates that using Fast-VESTAL, MEG can serve as an accurate and reliable functional imaging tool for presurgical mapping of language functions in patients with brain tumors and/or epilepsies.



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Rapid diagnostic method for the identification of Mycoplasma pneumoniae respiratory tract infection.

Rapid diagnostic method for the identification of Mycoplasma pneumoniae respiratory tract infection.

J Infect Chemother. 2016 Mar 15;

Authors: Miyashita N, Kawai Y, Kato T, Tanaka T, Akaike H, Teranishi H, Nakano T, Ouchi K, Okimoto N

Abstract
Rapid diagnostic tests are useful tools in the early diagnosis of respiratory tract infections (RTIs) caused by a specific pathogens. We investigated the sensitivity and specificity of a rapid and simple antigen test for the detection of Mycoplasma pneumoniae, Ribotest Mycoplasma(®) in adolescent and adult patients with RTIs. In addition, we evaluated the accuracy of clinical and laboratory findings for the early presumptive diagnosis of M. pneumoniae RTI. We compared 55 cases with laboratory-confirmed M. pneumoniae infection using serology, culture, and polymerase chain reaction (PCR) and 346 cases without laboratory-confirmed M. pneumoniae infection. Pneumonia cases were excluded in this study. Among patients with M. pneumoniae infection, the incidences of cough, sore throat, and sputum production were high, with rates of 98%, 61%, and 67%, respectively, but the specificity was low. The prevalence of nasal symptoms was significantly lower in patients with M. pneumoniae infection (9%) than in non-M. pneumoniae infection (70%; p < 0.0001). When PCR was used as the control test, the sensitivity, specificity, and overall agreement rates with Ribotest(®) were 71%, 89%, and 87%, respectively. Clinical symptoms and laboratory data were of limited value in making the diagnosis of M. pneumoniae RTI in adolescent and adult patients. Our results suggested that Ribotest(®) may be helpful in distinguishing M. pneumoniae RTI patients from those without the disease. Physicians should consider the use of Ribotest(®) when patients have a persistent cough without nasal symptoms.

PMID: 26993174 [PubMed - as supplied by publisher]

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Adult Common Variable Immunodeficiency.

Adult Common Variable Immunodeficiency.

Am J Med Sci. 2016 Mar;351(3):239-43

Authors: Dong J, Liang H, Wen D, Wang J

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, defective antibody production and recurrent upper and lower respiratory tract infections. The diagnosis in adult patients is often thought to be rare, and thus misdiagnosis often occurs. A limited number of cases of adult-onset CVID have been reported in China, and the features of the syndrome remain unclear. The objective of this study was to describe the main characteristics of CVID, and evaluate the treatment of adult patients who present with CVID.
MATERIALS AND METHODS: This was a retrospective analysis of 8 patients with CVID from different departments in 1 center in China. Patients were diagnosed according to the diagnostic criteria of the European Society for Immunodeficiency Diseases. Demographics, clinical and immunological data from each patient were collected and a statistical analysis was undertaken.
RESULTS: The mean age at diagnosis was 43 ± 13.7 years, whereas the mean duration of diagnostic delay was 10.5 years. The median total serum levels of immunoglobulin (Ig) G, IgA and IgM at diagnosis were 2.5 ± 0.59, 0.23 ± 0.05 and 0.17 ± 0.05g/L, respectively. A total of 7 patients also had a low CD4(+)/CD8(+) ratio. All patients presented with recurrent respiratory infections. Regular infusions of intravenous immunoglobulin every 3 weeks substantially reduced pneumonic episodes.
CONCLUSIONS: Diagnosis is often delayed in adult CVID. Pulmonary infections and diseases were the most frequent presentations at onset of the disease. Regular intravenous immunoglobulin infusions were beneficial in controlling recurrent infections.

PMID: 26992251 [PubMed - in process]

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Virtual reality training in laparoscopic surgery: a systematic review & meta-analysis.

Virtual reality training in laparoscopic surgery: a systematic review & meta-analysis.

Int J Surg. 2016 Mar 15;

Authors: Alaker M, Wynn GR, Arulampalam T

Abstract
INTRODUCTION: Laparoscopic surgery requires a different and sometimes more complex skill set than does open surgery. Shortened working hours, less training times, and patient safety issues necessitates that these skills need to be acquired outside the operating room. Virtual reality simulation in laparoscopic surgery is a growing field, and many studies have been published to determine its effectiveness.
AIMS: This systematic review and meta-analysis aims to evaluate virtual reality simulation in laparoscopic abdominal surgery in comparison to other simulation models and to no training.
METHODS: A systematic literature search was carried out until January 2014 in full adherence to PRISMA guidelines. All randomised controlled studies comparing virtual reality training to other models of training or to no training were included. Only studies utilizing objective and validated assessment tools were included.
RESULTS: Thirty one randomised controlled trials that compare virtual reality training to other models of training or to no training were included. The results of the meta-analysis showed that virtual reality simulation is significantly more effective than video trainers, and at least as good as box trainers.
CONCLUSION: The use of Proficiency-based VR training, under supervision with prompt instructions and feedback, and the use of haptic feedback, has proven to be the most effective way of delivering the virtual reality training. The incorporation of virtual reality training into surgical training curricula is now necessary. A unified platform of training needs to be established. Further studies to assess the impact on patient outcomes and on hospital costs are necessary. (PROSPERO Registration number: CRD42014010030).

PMID: 26992652 [PubMed - as supplied by publisher]

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Prevalence of Intracranial Aneurysms in Patients with Connective Tissue Diseases: A Retrospective Study.

Prevalence of Intracranial Aneurysms in Patients with Connective Tissue Diseases: A Retrospective Study.

AJNR Am J Neuroradiol. 2016 Mar 18;

Authors: Kim ST, Brinjikji W, Kallmes DF

Abstract
BACKGROUND AND PURPOSE: Few studies have examined the prevalence of intracranial aneurysms in connective tissue diseases such as Marfan syndrome, Ehlers-Danlos syndrome, neurofibromatosis type 1, and Loeys-Dietz syndrome. We studied the prevalence of intracranial aneurysms and other intracranial neurovascular pathologies such as arteriovenous malformations and intracranial dissections, in these 4 patient populations.
MATERIALS AND METHODS: We retrospectively reviewed all patients who had a clinical diagnosis of Marfan syndrome, Ehlers-Danlos syndrome, neurofibromatosis type 1, or Loeys-Dietz syndrome who underwent MRA, CTA, and/or DSA imaging of the intracranial circulation between January 1, 2005, and January 31, 2015. The presence, location, and maximum dimensions of intracranial aneurysms were catalogued. Other neurovascular findings studied included intracranial dissections and arteriovenous fistulas and shunts. Baseline data collected included demographic characteristics (sex, age, smoking history), imaging modality, and cardiovascular comorbidities.
RESULTS: The prevalence of intracranial saccular and fusiform aneurysms was as follows: 14% (8/59) among patients with Marfan syndrome, 12% (12/99) among patients with Ehlers-Danlos syndrome, 11% (5/47) among patients with neurofibromatosis type 1, and 28% (7/25) among patients with Loeys-Dietz syndrome. Intracranial dissections were found in 2 patients (3%) with Marfan syndrome and 1 patient (1%) with Ehlers-Danlos syndrome. No intracranial dissections were found in patients with neurofibromatosis type 1 or Loeys-Dietz syndrome.
CONCLUSIONS: Patients with connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome, neurofibromatosis type 1, and Loeys-Dietz syndrome, have a high prevalence of intracranial aneurysms.

PMID: 26992822 [PubMed - as supplied by publisher]

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MiR 20a,-20b and -200c are involved in hydrogen sulfide stimulation of VEGF production in human placental trophoblasts.

MiR 20a,-20b and -200c are involved in hydrogen sulfide stimulation of VEGF production in human placental trophoblasts.

Placenta. 2016 Mar;39:101-10

Authors: Hu TX, Wang G, Guo XJ, Sun QQ, He P, Gu H, Huang Y, Gao L, Ni X

Abstract
UNLABELLED: Hydrogen sulfide (H2S) has been implicated to angiogenesis in various tissues. We sought to investigate the role of hydrogen sulfide (H2S) in regulating production of vascular endothelial growth factor (VEGF) proteins, the key factors of angiogenesis and vasculogenesis, in placenta.
METHODS: Placental tissues were obtained from pregnant women with preeclampsia and healthy pregnant women who underwent elective cesarean section. Explants and trophoblasts were isolated from healthy placentas and treated with H2S donor and precursor. Western blotting was used to determine the levels of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). The levels of VEGF mRNA, miR miR-200c,-20a and -20b were determined by quantitative real time PCR.
RESULTS: NaHS and l-cysteine increased VEGF but not placenta growth factor (PlGF) production in cultured explants and trophoblasts. Transfection of CBS and CSE siRNA reversed the stimulatory effect of l-cysteine on VEGF production in placental cells. H2S prolonged the half-life of VEGF mRNA and decreased the expression of miR-200c,-20a and -20b in placental cells. MiR-200c mimic and inhibitor affected VEGF mRNA and protein level, whereas miR-20a or -20b mimic and inhibitor affect VEGF protein release but not mRNA expression. The expression level of miR-200c,-20a and -20b as well as the level of CBS, CSE and VEGF were downregulated in preeclamptic placentas.
CONCLUSION: H2S produced via CSE and CBS plays a critical role in VEGF production in human placenta. Reduced expression of CSE and CBS may contribute to the abnormal production of angiogenic factors in preeclamptic placenta.

PMID: 26992682 [PubMed - in process]

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EFFECT OF TIME EXPOSURE ON THERMOLUMINESCENCE GLOW CURVE FOR UV-INDUCED ZRO2:MG PHOSPHOR.

EFFECT OF TIME EXPOSURE ON THERMOLUMINESCENCE GLOW CURVE FOR UV-INDUCED ZRO2:MG PHOSPHOR.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Sadati SM, Feghhi SA, Mohammadi K

Abstract
In this research, the effect of magnesium (Mg) impurity on thermoluminescence (TL) response of ZrO2 phosphors is studied experimentally. In the experimental procedure, ZrO2:Mg phosphors in the powder form were synthesised by the sol-gel method. The obtained hydrogel was dried in air and then calcinated in air at 1200°C for 5 h and next was annealed at 250°C for 2 h. Sample characterisations were done by X-ray diffraction and scanning electron microscopy. Obtained materials had monoclinic phase and porous microstructure. Then, known amounts of ZrO2:Mg powder were exposed to ultraviolet lamp from 0.5 to 120 min. The TL peaks were obtained at the same temperature as 75, 137 and 260°C, respectively. Adding Mg to pure zirconia caused to increase TL intensity and shift peaks related to pure zirconia. The TL peaks of the pure zirconia were seen at the 83, 132 and 235°C. Finally, ZrO2:Mg TL experimental results show the linear dose response, high stability and less fading.

PMID: 26994097 [PubMed - as supplied by publisher]

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BEAM QUALITY CORRECTION FACTORS FOR KAP METERS FOR LIGHTLY AND HEAVILY FILTERED X-RAY BEAMS.

BEAM QUALITY CORRECTION FACTORS FOR KAP METERS FOR LIGHTLY AND HEAVILY FILTERED X-RAY BEAMS.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Herrnsdorf L, Petersson H

Abstract
Kerma-area product (KAP) meters have a pronounced energy dependence when measuring air KAP for lightly filtered X-ray beams (RQR). Today, it is also common with more heavily filtered beams. In this work, the energy dependence for lightly as well as heavily filtered beams (RQC) was investigated for several KAP meter models. The relative energy dependence of the readings of an external and an internal KAP meter was determined relative to an ionisation chamber, which had been calibrated at the primary standards laboratory. As a complement to the measurements, the sensitivity of a KAP meter for various X-ray beam qualities was modelled using Monte Carlo simulations of photon transport and absorption. The result showed a variation in relative energy dependence of up to 30 % for KAP meters for RQC beam qualities compared with RQR qualities. A reduced sensitivity of KAP meters for heavily filtered beams in comparison with lightly filtered ones was found, and it is important that the beam-specific radiation quality correction factors are applied to correct the registered KAP values.

PMID: 26994096 [PubMed - as supplied by publisher]

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RETROSPECTIVE DOSIMETRY USING SALTED SNACKS AND NUTS: A FEASIBILITY STUDY.

RETROSPECTIVE DOSIMETRY USING SALTED SNACKS AND NUTS: A FEASIBILITY STUDY.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Christiansson M, Geber-Bergstrand T, Bernhardsson C, Mattsson S, Rääf CL

Abstract
The possibility of using ordinary household table salt for dosimetry is suggested by its high sensitivity to ionising radiation, which generates a readout of optically stimulated luminescence (OSL). However, to exploit this finding for retrospective human dosimetry, it would be needed to find salt in close proximity to the exposed individual. Finding salty snacks frequently tucked into handbags, backpacks or pockets seemed to be a possibility; these items therefore became the test materials of the present study. The aluminium or cardboard packages used to exclude the moisture that makes crisps and nuts go soft and stale also helps to retain the induced OSL signal. Therefore, different snacks, either their salt component alone or mixed with the snack, are exposed to ionising radiation and then were assessed for their dosimetric properties. The results indicate the feasibility of using some salty snacks for dosimetry, with a minimum detectable dose as low as 0.2 mGy.

PMID: 26994095 [PubMed - as supplied by publisher]

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DOSE-RESPONSE STUDY USING MICRONUCLEUS CYTOME ASSAY: A TOOL FOR BIODOSIMETRY APPLICATION.

DOSE-RESPONSE STUDY USING MICRONUCLEUS CYTOME ASSAY: A TOOL FOR BIODOSIMETRY APPLICATION.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Nairy RK, Bhat NN, Sanjeev G, Yerol N

Abstract
The present study is aimed at obtaining in vitro dose-response data for the induction of micronucleus (MN) and nucleoplasmic bridges (NPBs) in human lymphocytes using (60)Co-gamma rays and 8 MeV pulsed electron beam. An attempt was made to validate the possibility of applying NPBs as new biodosimetry endpoint in the dose range of 0-6 Gy. A total of 1000 binucleated cells (BNCs) per dose point were evaluated for the frequency of MN and NPBs. From the study, it is clear that the dose-response increase of MN and NPBs is linear quadratic in nature. The study provides linear and quadratic parameter for biodosimetry application. The relative biological effectiveness value of the 8 MeV electron beam was estimated using slope values and is found to be 1.18 ± 0.01 for MN/BNCs, 1.27 ± 0.02 for the fraction of BNCs with MN, 1.16 ± 0.13 for MN/(BNCs with MN) and 1.09±0.01 for NPBs.

PMID: 26994094 [PubMed - as supplied by publisher]

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EFFECT OF RADIATION DOSE LEVEL ON ACCURACY AND PRECISION OF MANUAL SIZE MEASUREMENTS IN CHEST TOMOSYNTHESIS EVALUATED USING SIMULATED PULMONARY NODULES.

EFFECT OF RADIATION DOSE LEVEL ON ACCURACY AND PRECISION OF MANUAL SIZE MEASUREMENTS IN CHEST TOMOSYNTHESIS EVALUATED USING SIMULATED PULMONARY NODULES.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Söderman C, Johnsson ÅA, Vikgren J, Norrlund RR, Molnar D, Svalkvist A, Månsson LG, Båth M

Abstract
The aim of the present study was to investigate the dependency of the accuracy and precision of nodule diameter measurements on the radiation dose level in chest tomosynthesis. Artificial ellipsoid-shaped nodules with known dimensions were inserted in clinical chest tomosynthesis images. Noise was added to the images in order to simulate radiation dose levels corresponding to effective doses for a standard-sized patient of 0.06 and 0.04 mSv. These levels were compared with the original dose level, corresponding to an effective dose of 0.12 mSv for a standard-sized patient. Four thoracic radiologists measured the longest diameter of the nodules. The study was restricted to nodules located in high-dose areas of the tomosynthesis projection radiographs. A significant decrease of the measurement accuracy and intraobserver variability was seen for the lowest dose level for a subset of the observers. No significant effect of dose level on the interobserver variability was found. The number of non-measurable small nodules (≤5 mm) was higher for the two lowest dose levels compared with the original dose level. In conclusion, for pulmonary nodules at positions in the lung corresponding to locations in high-dose areas of the projection radiographs, using a radiation dose level resulting in an effective dose of 0.06 mSv to a standard-sized patient may be possible in chest tomosynthesis without affecting the accuracy and precision of nodule diameter measurements to any large extent. However, an increasing number of non-measurable small nodules (≤5 mm) with decreasing radiation dose may raise some concerns regarding an applied general dose reduction for chest tomosynthesis examinations in the clinical praxis.

PMID: 26994093 [PubMed - as supplied by publisher]

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NEED FOR INDIVIDUAL CANCER RISK ESTIMATES IN X-RAY AND NUCLEAR MEDICINE IMAGING.

NEED FOR INDIVIDUAL CANCER RISK ESTIMATES IN X-RAY AND NUCLEAR MEDICINE IMAGING.

Radiat Prot Dosimetry. 2016 Mar 17;

Authors: Mattsson S

Abstract
To facilitate the justification of an X-ray or nuclear medicine investigation and for informing patients, it is desirable that the individual patient's radiation dose and potential cancer risk can be prospectively assessed and documented. The current dose-reporting is based on effective dose, which ignores body size and does not reflect the strong dependence of risk on the age at exposure. Risk estimations should better be done through individual organ dose assessments, which need careful exposure characterisation as well as anatomical description of the individual patient. In nuclear medicine, reference biokinetic models should also be replaced with models describing individual physiological states and biokinetics. There is a need to adjust population-based cancer risk estimates to the possible risk of leukaemia and solid tumours for the individual depending on age and gender. The article summarises reasons for individual cancer risk estimates and gives examples of methods and results of such estimates.

PMID: 26994092 [PubMed - as supplied by publisher]

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Endoscopic Endonasal Management of Olfactory Neuroblastoma: A Retrospective Analysis of 10 Patients with Quality-of-Life Measures

Publication date: June 2016
Source:World Neurosurgery, Volume 90
Author(s): Christine Manthuruthil, Jeremy Lewis, Caitlin McLean, Pete S. Batra, Samuel L. Barnett
ObjectiveAnterior craniofacial resection has served as the traditional surgical treatment of olfactory neuroblastoma (ON). With the development of extended endonasal approaches, the opportunity exists for using minimal access techniques for management of select tumors. This study assesses the impact of endoscopic resection on ON and patient outcomes and quality of life.MethodsA retrospective review identified 10 patients with ON (3 women, 7 men; mean age 49.1 years) who underwent endoscopic resection during the period 2010–2013. Modified Kadish staging divided the cohort into 3 stage B patients (30%), 5 stage C patients (50%), and 2 stage D patients (20%). Outcome measures included extent of resection, complications, recurrence, and preoperative and postoperative Sino-Nasal Outcome Test-20 scores.ResultsGross total resection was achieved in all patients, with negative margins in 9 patients. One patient had negative frozen section pathology but was noted to have a positive posterior dural margin on final pathology. There was a 20% complication rate (pneumocephalus, ethmoid meningoencephalocele). Neoadjuvant chemotherapy and radiation were performed in 2 patients (Kadish stage C and D). Adjuvant chemotherapy and radiation were performed in 5 patients (4 Kadish stage C and 1 stage D). Postoperative radiation alone was administered in 3 patients (Kadish stage B). Analysis of postoperative Sino-Nasal Outcome Test-20 scores demonstrated no significant change relative to preoperative Sino-Nasal Outcome Test-20 scores. At the most recent follow-up examination, there was no evidence of recurrent disease in patients who underwent endoscopic resection. One patient (Kadish stage D) died during the follow-up period. Mean follow-up duration was 21.1 months.ConclusionsThis series adds to the growing body of literature that suggests equivalent or improved outcomes of purely endonasal resection for select patients. Given the advanced Kadish stage of most of our patients, longer follow-up is required to determine the full applicability of purely endoscopic approaches to the treatment of ON.



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Response to Wheatley et al., "Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation", Cancer Treatment Reviews.

Response to Wheatley et al., "Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation", Cancer Treatment Reviews.

Cancer Treat Rev. 2016 Mar 14;45:76

Authors: Madu M, van Akkooi AC

PMID: 26994326 [PubMed - as supplied by publisher]

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New perspectives on complement mediated immunotherapy.

New perspectives on complement mediated immunotherapy.

Cancer Treat Rev. 2016 Mar 8;45:68-75

Authors: Stasiłojć G, Österborg A, Blom AM, Okrój M

Abstract
Tumor-specific monoclonal antibodies (mAbs) offer several modes of tumor cell killing, from direct cytotoxic activity to indirect mechanisms employing the host immune system, particularly its innate branch. The latter effector functions seem to dominate among clinically approved anti-cancer mAbs and major efforts are being undertaken by both academia and the pharmaceutical industry with the aim to improve complement activation, antibody-dependent cellular cytotoxicity (ADCC) and Fc/opsonin-mediated phagocytosis. On one hand, there are a variety of available effector mechanisms to allow multistep elimination of tumor cells. On the other hand, tumor cells adopt a number of strategies to evade immune attack, such as overexpression of complement inhibitors, trogocytosis, shedding or internalization of mAb-targeted epitopes, which all contribute to their resistance against host defense mechanisms. Another problem recognized only recently is the depletion of immune effectors during the first round of treatment, which in concordance with delayed turnover of immune components renders subsequent rounds of therapy ineffective. Herein, we discuss newly identified limiting factors but also novel mechanistic data on complement activation by antitumor antibodies as issues important for guidance towards the next generations of immunotherapeutics.

PMID: 26994325 [PubMed - as supplied by publisher]

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