RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Abstract

Background

Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC).

Patients and methods

In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases.

Results

RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement.At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not.

Conclusions

Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

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Investigating the role of articulatory organs and perceptual assimilation of native and non-native fricative place contrasts

http://ift.tt/2GbHUpq

Compression in Working Memory and Its Relationship With Fluid Intelligence

Abstract

Working memory has been shown to be strongly related to fluid intelligence; however, our goal is to shed further light on the process of information compression in working memory as a determining factor of fluid intelligence. Our main hypothesis was that compression in working memory is an excellent indicator for studying the relationship between working-memory capacity and fluid intelligence because both depend on the optimization of storage capacity. Compressibility of memoranda was estimated using an algorithmic complexity metric. The results showed that compressibility can be used to predict working-memory performance and that fluid intelligence is well predicted by the ability to compress information. We conclude that the ability to compress information in working memory is the reason why both manipulation and retention of information are linked to intelligence. This result offers a new concept of intelligence based on the idea that compression and intelligence are equivalent problems.

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Age, sex, and type of medication predict the effect of anti-VEGF treatment on central retinal thickness in wet age-related macular degeneration

http://ift.tt/2tuGPqi

Serum calcitonin negative mixed medullary-follicular carcinoma initially diagnosed as medullary thyroid carcinoma by fine-needle aspiration cytology: A case report and review of the literatures

Medullary thyroid carcinoma (MTC) is potentially lethal. A prompt and accurate diagnosis is the prerequisite for the treatment of MTC. Fine-needle aspiration (FNA) is a reliable diagnostic tool in the assessment of thyroid nodules. However, cytologic assessment of MTC based on FNA has several drawbacks due to morphological variants. We present a case of MTC diagnosed through FNA cytology, which was eventually histologically confirmed as a mixed medullary-follicular carcinoma with negative serum calcitonin expression. Hence, diagnosis of MTC based on FNA should be applied with caution. Ultrasound characteristics of suspicious thyroid nodules are recommended to be evaluated by FNA. However, calcitonin levels should be measured in both the FNA washout fluid and serum when features of MTC are presented or cytology result is inconclusive. If adequate FNA sample is available, a supplementary immunocytochemical staining of markers such as calcitonin, chromogranin, carcinoembryonic antigen, and thyroglobulin is helpful for a correct diagnosis of MTC.

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Risk factors associated with malignancy and with triage to surgery in thyroid nodules classified as Bethesda category IV (FN/SFN)

Background

Thyroid nodules diagnosed as Bethesda category IV [follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)] are recommended for surgery. However, only 10%-40% of these nodules turn out to be malignant on histopathological examination. Therefore, selection for surgery of nodules diagnosed as Bethesda category IV is important. We aimed to define predictive factors for malignancy and factors associated with triage to surgery.

Methods

The records of all patients with nodules who underwent fine needle aspiration biopsy (FNAB) and classified by Bethesda reporting system as FN/SFN between January 2011 and July 2017 at our institution were reviewed. Univariate and multivariate analysis were performed to select independent factors associated with thyroid cancer, and with triage to surgery. Using independent risk factors for malignancy predictive index categories were created.

Results

Among 6910 nodules that underwent FNAB, 180 (2.6%) were diagnosed as FN/SFN. Of the 180 patients, 139 (77%) underwent surgery with the associated malignancy rate of 37% (51/139) (upper boundary). Risk of malignancy among all FN/SFN nodules was 28% (lower boundary). Solid structure, size ≥ 4 cm, microcalcification, hypoechogenicity, and increased vascularization were found to be significant and independent risk factors associated for malignancy. None of the clinical and ultrasound factors were associated with triage to surgery.

Conclusions

Our findings showed that using predictive factors for malignancy in the Bethesda IV category as risk indices, 17% of patients who had nodules without any risk factors could be spared surgery. Predictive indices could be considered for the malignancy risk and for selection of patients for surgery.

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CSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behçet from multiple sclerosis

Abstract

In neuro Behçet disease with multiple sclerosis-like features, diagnosis could be challenging. Here, we studied the cerebrospinal fluid and serum inflammatory profile of 11 neuro Behçet and 21 relapsing-remitting multiple sclerosis patients. Between the soluble factors analyzed (MMP9, TNFα, IL6, CXCL13, CXCL10, CXCL8, IFNγ, IL10, IL17, IL23, and others) we found MMP9 increased in neuro Behçet serum compared to multiple sclerosis and decreased in cerebrospinal fluid. Furthermore, neuro Behçet analysis of circulating natural killer CD56_DIM subset suggests their potential involvement in increased MMP9 production. We believe that these findings may have a translational utility in clinical practice.

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Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Abstract

Objective

To determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR).

Background

CMT1B is caused by >200 heterozygous mutations in MPZ, the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment. The prevalence of MPZ mutations that activate the UPR is unknown.

Methods

We developed a dual luciferase reporter assay of Xbp1 splicing using stably transfected RT4 Schwann cells to assay the ability of cDNA constructs bearing 46 distinct MPZ mutations to activate the UPR. Constructs also carried an HA tag to permit detection of ER retention of mutant proteins. UPR activation and ER retention were correlated with clinical phenotypes.

Results

Eighteen mutations demonstrated ER retention and UPR activation to a similar degree as Ser63del and Arg98Cys MPZ. Thirty-five of the mutations activated the UPR > 1.5 fold compared to that of wild-type MPZ. Correlation was high between firefly and Nano-luciferase reporters and between both reporters and ER localization. UPR activity did not correlate with clinical onset or severity.

Conclusion

Many CMT1B causing mutations activate the UPR and may be susceptible to therapeutic efforts to facilitate UPR function.

http://ift.tt/2Fwwtro

Guava leaf extract suppresses osteoarthritis progression in a rat anterior cruciate ligament transection model

Abstract

Guava leaf extract and ellagic acid, one of its polyphenolic components, inhibit the activity of a disintegrin and metalloproteinase with thrombospondin type 5 (ADAMTS-5), which is associated with aggrecan degeneration during the early stage of osteoarthritis (OA). To investigate the efficacy of guava leaf extract for preventing OA, we examined the effect of its dietary intake on cartilage destruction in anterior cruciate ligament-transected (ACLT) rats. Rats were randomly assigned to four groups: ACLT control rats fed with control diet, ACLT rats fed with diet containing 0.2% guava leaf extract, ACLT rats fed with diet containing 0.5% guava leaf extract, and sham-operated rats fed with control diet. Mankin's scores, an index of cartilage damage, were higher in rats that underwent ACLT. Guava leaf extract treatment dose-dependently led to lower Mankin's scores and higher concentrations of ellagic acid in the serum and synovial membrane. Ellagic acid levels in the synovial membrane negatively correlated with cartilage destruction scores. These results suggest that dietary guava leaf extract suppresses OA progression in ACLT rats through ellagic acid-mediated inhibition of early joint destruction.

Dietary guava leaf extract suppressed osteoarthritis progression in animal model. It might be due to inhibition of early knee joint destruction mediated by ellagic acid, one of guava leaf's polyphenols.

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2017 Reviewer Acknowledgment

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Repeat-Specific Functions for the C-Terminal Domain of RNA Polymerase II in Budding Yeast

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.

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Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria

Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n=163) or with a positive family history (n=133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used. In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counselling.

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Robust {Phi}C31-Mediated Genome Engineering in Drosophila melanogaster Using Minimal attP/attB Phage Sites

Effective genome engineering should lead to a desired locus change with minimal adverse impact to the genome itself. However, flanking loci with site-directed recombinase recognition sites, such as those of the phage FC31 integrase, allows for creation of platforms for cassette exchange and manipulation of genomic regions in an iterative manner, once specific loci have been targeted. Here we show that a genomic locus engineered with inverted minimal phage FC31 attP/attB sites can undergo efficient recombinase-mediated cassette exchange (RMCE) in the fruit fly Drosophila melanogaster.

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Do checkpoint inhibitors provide new hope for management of metastatic penile carcinoma?

Future Oncology, Ahead of Print.


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CD59: a promising target for tumor immunotherapy

Future Oncology, Ahead of Print.


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Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects

Future Oncology, Ahead of Print.


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Biological imaging for individualized therapy in radiation oncology: part I physical and technical aspects

Future Oncology, Ahead of Print.


http://ift.tt/2FDDWZ4

MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme

Future Oncology, Ahead of Print.


http://ift.tt/2tvf7JP

Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors

Abstract

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the Apc^Min/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc^Min/+/DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis. This article is protected by copyright. All rights reserved.

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Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study

Abstract

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In this study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake. This article is protected by copyright. All rights reserved.

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MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women

ABSTRACT

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of this study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women.

This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N=118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density.

Compared to women with 'minimal' BPE, those who had 'marked' BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, p_trend across all categories=0.001; 150% increase, p_trend=0.001; and 158% increase, p_trend=0.001 respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed.

Serum estrogen concentrations were significantly positively associated with BPE. This study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast. This article is protected by copyright. All rights reserved.

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Caveolin-1, cancer and therapy resistance

Abstract

Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus, a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors. This article is protected by copyright. All rights reserved.

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Clinical Evaluation of Human Papillomavirus 16/18 Oncoprotein Test for Cervical Cancer Screening and HPV Positive Women Triage

Abstract

HPV-16 and -18 account for about 80% of cervical cancers. We evaluated the performance of HPV-16/18 oncoprotein to predict precancer and cancer in corresponding tissue biopsy specimens. 1008 women attending cervical cancer screening program and 638 women referred to colposcopy with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from 4 hospitals were recruited (1646 in total). All women were tested OncoE6 (AVC), Liquid Based Cytology (Hologic) and cobas HPV test (Roche). Colposcopy was performed on women with any abnormal results. The final diagnoses were based on a consensus panel review of the histology. There were 919 normal, 69 CIN1, 53 CIN2, 91 CIN3,474 squamous cell carcinoma(SCC) and 40 adenocarcinoma (ADC) cases, the prevalence of OncoE6 was 1.7%, 10.1%, 13.2%, 44.0%, 80.4% and 65.0%, respectively. The percent positive for cobas was higher than that of OncoE6 in detection of HPV16/18 in entire population (P<0.001). However, the disparity of positive rate between these two tests became tiny among cervical cancer patients (CIN2: 26.4% vs. 13.2%, CIN3: 73.6% vs. 44.0%, SCC: 84.0% vs. 80.4%, ADC: 67.5% vs. 65.0%). OncoE6 was less sensitive than cobas (73.9% versus 93.6%, P<0.001), but more specific (97.1% versus 75.4%, P<0.001) for CIN3+ in entire population; OncoE6 yielded a sensitivity of 77.7% and a specificity of 91.0% for CIN3+ among cobas positive women, which can reduce nearly half of the colposcopy referral numbers. OncoE6 can be considered as a useful tool for cervical cancer screening and a potential powerful biomarker for HPV positive triage. This article is protected by copyright. All rights reserved.

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NCR+ ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice

Abstract

Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 towards the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We observed that NCR+ ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.

This article is protected by copyright. All rights reserved

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SHP2 Inhibition May Resensitize NSCLC Tumors to ALK Inhibitors [Research Watch]

Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.

http://ift.tt/2twHLKG

DNA Damage Response Alterations Predict Responses to Anti-PD-1/PD-L1 [Research Watch]

DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.

http://ift.tt/2tzBI8d

Engineered IL2/IL2R{beta} Pairs May Enhance the Efficacy of T-cell Therapy [Research Watch]

Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.

http://ift.tt/2FCaQJo

Peli1 modulates the subcellular localization and activity of Mdmx

Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation. Consistent with this, knockdown or knockout Peli1 in human cancer cells induced nuclear localization of Mdmx and suppressed p53 activity. Myc-induced tumorigenesis was accelerated in Peli1-null mice and associated with downregulation of p53 function. Clinical samples of human cutaneous melanoma had decreased Peli1 expression which was associated with poor overall survival. Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers.

http://ift.tt/2tsmSA4

Tumor-derived TGF-{beta} alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling

A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDC generally correlates with a poor prognosis, suggesting that pDC may play an important role in the host-tumor relationship. Here we analyze the influence of pDC in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDC showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDC to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGF-β is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that NK cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the crosstalk among pDCs, NK and regulatory T cells in the promotion of tumor growth and their role in the development of anti-tumor immune responses.

http://ift.tt/2oX3w1E

Goldilocks Dosing of TKIs: A Dose that is Just Right Leads to Optimal Outcomes

Higher concentrations of TKIs such as pazopanib are associated with improved outcomes in advanced RCC. A phase 3 trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome.

http://ift.tt/2FrxgOt

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer

On July 17, 2017, the Food and Drug Administration (FDA) approved neratinib (NERLYNX, Puma Biotechnology, Inc) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to neratinib (n=1420) or placebo (n=1420) for one year. The primary endpoint was invasive disease-free survival (iDFS) defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distance recurrence, or death from any cause, with two years and 28 days of follow up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified hazard ratio of 0.66 (95% CI: 0.49, 0.90, p=0.008). Estimated iDFS rate at 2-years was 94.2% (95% CI: 92.6%, 95.4%) in patients treated with neratinib vs. 91.9% (95% CI: 90.2%, 93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE) with a 40% incidence of Grade 3 or 4 diarrhea and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval.

http://ift.tt/2Fy3uUc

Interleukin-31 and interleukin-31 receptor–new therapeutic targets for atopic dermatitis

Abstract

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell–mediated immunity. Interleukin (IL)-31 is a potent pruritogenic cytokine primarily produced by Th2 cells. Both IL-31 transgenic mice and wild-type mice treated with IL-31 exhibit AD-like skin lesions and scratching behaviour. IL-31 receptor α-chain (IL-31RA) are also expressed in peripheral nerves and epidermal keratinocytes, and the roles of IL-31 on pruritus and skin barrier have been investigated. Recently, an anti–IL-31 receptor antibody was shown to significantly improve pruritus in AD patients. This review focuses on IL-31 and IL-31RA in AD.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Fr8Swo

Effect of Vitamin K Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Clinical Trials

Horm Metab Res 2018; 50: 227-235
DOI: 10.1055/s-0044-100616

Type 2 diabetes mellitus (T2DM) is one of the most important public health issues. Vitamin K supplementation might have favorable effect on risk factors of T2DM. The aim of this study was to perform a systematic review and meta-analysis of interventional studies to examine the effect of vitamin K supplementation on glycemic indices. A systematic search was performed in electronic databases including PubMed, Science Direct, ProQuest, Institute of Scientific Information Web of Science, and Google scholar up to July 2017. We used a random effects model to estimate pooled effect size of fasting blood sugar (FBS), 2-h oral glucose tolerance test (2-h OGTT), fasting insulin (FINS), and homeostasis model assessment-estimated insulin resistance (HOMA-IR). Five clinical trials (533 participants) fulfilled the eligibility criteria of the present meta-analysis. Overall, meta-analysis could not show any beneficial effect of vitamin K supplementation on FBS (–0.91 mg/dl, 95% CI: –2.57, 0.76, p=0.28), FINS (–0.35 μIU/ml, 95% CI: –1.70, 1.00, p=0.61), HOMA-IR (–0.06, 95% CI: –0.32, –0.19, p=0.63), and 2-h OGTT (–4.00 mg/dl, 95% CI: –20.00, 11.99, p=0.62). Sensitivity analysis showed that overall estimates were not affected by elimination of any study. We did not observe any evidence regarding publication bias. In conclusion, vitamin K supplementation had no significant effect on glycemic control in healthy subjects. However, further studies should be performed on diabetic and pre-diabetic patients to determine the effect of vitamin K supplementation on impaired glycemic control.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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The Effects of Supplementation with Chromium on Insulin Resistance Indices in Women with Polycystic Ovarian Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Horm Metab Res 2018; 50: 193-200
DOI: 10.1055/s-0044-101835

Recently, the effects of nutritional supplementation on improvement or prevention of polycystic ovary syndrome (PCOS) have been considered. Several studies have been carried out on the effect of chromium supplementation in improving PCOS patients. This study aimed to summarize the available findings regarding the effect of chromium on improving the polycystic ovary syndrome. The review includes randomized controlled trials (RCTs) comparing chromium treatment with placebo or other treatments in women with PCOS. Women with PCOS diagnosed according to the ESHRE/ASRM or NIH criteria in reproductive age were eligible. Electronic searches using the MeSH terms were conducted in the following databases: Medline, Embase, Scopus, Web of Science, and The Cochrane Library. Effects were measured as weighted mean difference (WMD) and 95% confidence intervals (CI) for studies of PCOS and control subjects were calculated by using random-effects model. The initial search yielded potentially 100 relevant articles of randomized clinical trials on dietary chromium supplements: 16 from Pubmed, 36 from Embase, 29 from Scopus, and 19 from Web of Science. After studying these publications, 5 were potentially eligible and retrieved in full text. The five studies included in the meta-analysis reported data on 137 women with PCOS and 131 controls. A meta-analysis of 5 studies showed a non-significant difference in fasting insulin between chromium, and placebo or other treatment (mean difference (MD): –1.14; (95% CI: –4.11 to 1.83, p=0.45). We retrieved two randomized controlled trials, in which Quantitative Insulin Sensitivity Check Index (QUICKI) was compared between chromium, and placebo or other treatment in 156 women with PCOS. Meta-analysis of two RCTs showed no significant difference in QUICKI score between chromium and placebo (MD: 0.01; 95% CI: –0.01 to 0.04, p=0.34). Two randomized controlled trials compared Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) between chromium, and placebo or other treatment in 81 women with PCOS. After combining the data, there was a significantly lower HOMA-IR in the chromium group (MD: –1.68; 95% CI: –2.42 to –0.94, p<0.001). One RCT reported a significant difference in Homeostatic Model Assessment-beta-cell function (HOMA-B) between chromium and placebo groups (–15.5±32.3 vs. +13.6±23.1, p<0.001). No significant effect of chromium on fasting insulin and QUICKI score was found in women with PCOS. Chromium supplementation significantly improved HOMA-IR and HOMA-B among patients with diabetes. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials in well characterized studies that address the limitations in the current evidence are needed before definitive claims can be made about the effect of chromium supplementation.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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Correction: Incidence of Diabetic Ketoacidosis of New-Onset Type 1 Diabetes in Children and Adolescents in Different Countries Correlates with Human Development Index (HDI): An Updated Systematic Review, Meta-Analysis, and Meta-Regression

Horm Metab Res 2018; 50: e2-e2
DOI: 10.1055/a-0584-6211

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Associations Between Thyroid and Blood Pressure in Euthyroid Adults: A 9-Year Longitudinal Study

Horm Metab Res 2018; 50: 236-241
DOI: 10.1055/s-0044-101756

Longitudinal studies considering associations between thyroid function in the reference range (RR) with blood pressure (BP) are scarce and contradictory. We aimed to investigate the associations of serum thyrotropin (TSH) and free T4 (FT4) with different components of BP also incident prehyperetension (preHTN) and HTN during a 9-year follow-up. A sum of 2282 euthyroid individuals from an ongoing population-based cohort study were selected. A sex-stratified multivariate generalized estimating equation (GEE) method was employed. Moreover, a multivariate transitional model was used considering preceding BP status as a predictor of dichotomous outcomes of preHTN and HTN. Multivariate-adjusted GEE analysis revealed a decreasing trend for systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP) throughout the study period in both men and women, either adjusted for serum TSH or FT4 levels. Serum FT4 within the RR was positively associated with all BP parameters in total population and in men, but serum TSH had a statistically significant mild increasing effect only on SBP, DBP and MAP of men. Multivariate transitional model found no association between serum TSH levels within the reference range (RR) and BP status; regarding serum FT4, a 1 ng/dl higher FT4 was associated with 40% increased risk of preHTN [OR (95% CI), 1.40 (1.02–1.90)], but not with HTN [OR (95% CI), 0.93 (0.80–1.09)]. It is concluded that serum FT4 within the RR is more strongly associated with BP parameters compared to TSH. This association is not consistent between men and women. Moreover, higher FT4 is associated with increased risk of preHTN.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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MicroRNAs and Target Genes in Pituitary Adenomas

Horm Metab Res 2018; 50: e3-e3
DOI: 10.1055/a-0585-7410

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Similar Aquaporin9 and MAPK Expression Profiles in the Liver of Types 1 and 2 Diabetes Mellitus

Horm Metab Res
DOI: 10.1055/s-0043-123470

Aquaporin-9 (AQP9) is an aquaglyceroporin that biophysically conducts water, glycerol, and other small solutes. AQP9 is expressed in hepatocytes on the sinusoidal surfaces of hepatocyte plates in the liver, where it is considered responsible for the glycerol uptake in gluconeogenesis. However, limited information is available on the expression and regulating mechanism of AQP9 in different hyperglycemia models. Thus, this study examined the expression patterns of AQP9 and mitogen-activated protein kinase (MAPK) in Types 1 and 2 diabetes mellitus (DM) to clarify the roles and regulating mechanism of AQP9 in gluconeogenesis. Compared with the control group, the AQP9 expression significantly increased in both Types 1 and 2 DM, and the increased expression was associated with the activation of phosphorylated JNK (p-JNK) and the inhibition of phosphorylated p38 (p-p38). By contrast, phosphorylated ERK remained stable in the liver with Type 1 or 2 DM. These effects could be reversed by insulin treatment. That is, insulin downregulated AQP9 by inhibiting p-JNK and activating p-p38. The upregulation of AQP9 could be involved in gluconeogenesis and co-regulated by the JNK and p38 MAPK pathway in both Types 1 and 2 DM.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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High-definition colonoscopy versus Endocuff versus EndoRings versus Full-Spectrum Endoscopy for adenoma detection at colonoscopy: a multicenter randomized trial

Devices used to improve polyp detection during colonoscopy have seldom been compared with each other.

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Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn’s disease

Crohn's disease (CD) is a chronic inflammatory bowel disease traditionally requiring treatments with important side effects, such as anti-TNF (tumor necrosis factor) therapy, which is efficient only for 30 to 40% patients who, moreover, can become non-responders later (up to 50% of them) (Olesen et al., 2016). This therapy can further generate adverse effects like infections and up to half of the CD patients will not continue therapy (non-compliance). Therefore, because vagus nerve stimulation (VNS) is thought to activate the cholinergic anti-inflammatory pathway, an anti-tumor necrosis factor (TNF) pathway partly through the action of acetylcholine on immune cells releasing TNF (Bonaz et al., 2013), VNS is being evaluated in CD patients as an alternative (or a complement) to pharmaceutical treatments (Bonaz et al., 2016;2017a).

http://ift.tt/2tAYI6S

Systemic effects of deep brain stimulation on synergic control in Parkinson’s disease

Deep brain stimulation (DBS) of nuclei within the basal ganglia, typically the subthalamic nucleus and globus pallidus, has been used as an effective treatment of Parkinson's disease (PD), commonly in combination with dopamine-replacement medications (reviewed in Kalia et al., 2013; DeLong and Wichmann, 2015). Many studies have reported significant positive effects of DBS on clinical indices such as Unified Parkinson's Disease Rating Scale (UPDRS) scores and general characteristics of movements such as maximal force, peak velocity, and movement time (Brown et al., 1999; Alberts et al., 2008; Daneault et al., 2016).

http://ift.tt/2FJd9dA

Emotion identification and aging: Behavioral and neural age-related changes

Emotion identification is a key element of nonverbal communication, with emotions often expressed through changes in facial expression, eye contact, body posture and movement. Across the life span, accurate identification of emotional expressions is essential for successful interpersonal functioning (Carstensen et al., 1997). Inferring the emotions that others are experiencing is an important feature in avoiding conflict and providing social support. Furthermore, intact emotion identification skills are essential to regulate behavior.

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Absence of key protein, TTP, rapidly turns young bones old

The absence of TTP, a protein critical to the control of inflammation, may lead to rapid and severe bone loss, according to a new study.

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Autopsy-detected diagnostic errors over time in the intensive care unit

We evaluate the evolution over time of discrepancies between clinical diagnoses and post-mortem findings in critically ill patients, and to assess the factors associated with these discrepancies. We conducted a prospective study of all consecutive patients who underwent autopsy autopsies in a medical-surgical ICU between January 2008 and December 2015. Among 7.655 patients admitted to our ICU, 671 (8.8%) died. Clinical autopsy was performed in 215 (32%) patients. Major missed diagnoses were noted in 38 patients (17.7%).

http://ift.tt/2HlP7CC

A unique evolution of the kidney phenotype in a patient with autosomal recessive Alport syndrome

Alport syndrome is due to mutations in one of the genes encoding (α3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin, and with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who was biopsied for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Due to a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation and a mutation of α3 type IV collagen (COL4A3) was detected.

http://ift.tt/2oWscHc

Tetracaine Challenges Old Dogma for Emergency Department Management of Corneal Abrasion Pain and Beckons a Definitive Study

SEE RELATED ARTICLE, P. ■■■

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Systemic Antibiotics for the Treatment of Skin and Soft Tissue Abscesses: A Systematic Review and Meta-Analysis

The addition of antibiotics to standard incision and drainage is controversial, with earlier studies demonstrating no significant benefit. However, 2 large, multicenter trials have recently been published that have challenged the previous literature. The goal of this review was to determine whether systemic antibiotics for abscesses after incision and drainage improve cure rates.

http://ift.tt/2FBOYhn

Triage, Machine Learning, Algorithms, and Becoming the Borg

SEE RELATED ARTICLE, P. ■■■.

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Informing Medicare’s Two-Midnight Rule Policy With an Analysis of Hospital-Based Long Observation Stays

Outpatient observation stays are increasingly substituting for standard inpatient hospitalizations. In 2013, the Centers for Medicare & Medicaid Services adopted the controversial Two-Midnight Rule policy to curb long observation stays and better define the use of hospital-based observation services versus inpatient hospitalizations. We seek to determine the extent to which Medicare beneficiaries exposed to long observation stays (>48 hours) are clinically similar to those with short observation stays (≤48 hours) because this has relevance to the Two-Midnight Rule.

http://ift.tt/2FAVEfN

Is Loop Drainage Technique More Effective for Treatment of Soft Tissue Abscess Compared With Conventional Incision and Drainage?

Authors identified 11,047 studies after removal of duplicates, of which they included 4 studies for the meta-analysis comprising 460 patients (Table). Three studies were retrospective, and the fourth study was a randomized controlled trial. Two studies included pediatric patients only (<18 years),2,3 and 2 studies included adult patients (Table).4,5 The conventional incision and drainage technique failed in 9.43% of cases (25/265), whereas the loop drainage technique resulted in failure in 4.10% of patients (8/195).

http://ift.tt/2HkDQ5x

Implementation of a Clinical Bundle to Reduce Out-of-Hospital Peri-intubation Hypoxia

Peri-intubation hypoxia is an important adverse event of out-of-hospital rapid sequence intubation. The aim of this project is to determine whether a clinical bundle encompassing positioning, apneic oxygenation, delayed sequence intubation, and goal-directed preoxygenation is associated with decreased peri-intubation hypoxia compared with standard out-of-hospital rapid sequence intubation.

http://ift.tt/2FGNjak

Safety of a Brief Emergency Department Observation Protocol for Patients With Presumed Fentanyl Overdose

Fentanyl overdoses are increasing and few data guide emergency department (ED) management. We evaluate the safety of an ED protocol for patients with presumed fentanyl overdose.

http://ift.tt/2HnGZSq

Associations of Childhood Maltreatment with Single and Multiple Suicide Attempts among Older Chinese Adolescents

To test, among older Chinese adolescents, the associations of childhood maltreatment with single and multiple suicide attempts and whether these associations vary in relation to the presence of sleep disturbance.

http://ift.tt/2txBT3F

Refining the Use of Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants

To identify clinical and demographic variables that predict nasal high-flow (nHF) treatment failure when used as a primary respiratory support for preterm infants.

http://ift.tt/2FohkfG

Menopause in CKD

Most women with dialysis-dependent chronic kidney disease (CKD) stage 5 (CKD stage 5D) are in the postmenopausal age group. Early menopause is reported for all CKD stages (stages 3-5D). The traditional definition of menopause is not applicable in CKD stage 5(D) because menses can resume with hormone replacement therapy or kidney transplantation. Treatment of vasomotor symptoms continues to be the primary indication for hormone replacement therapy, with no dosing studies done specifically for CKD or kidney transplantation populations.

http://ift.tt/2FBSHLM

The Effects of the Selective Muscarinic M3 Receptor Antagonist Darifenacin, and of Hyoscine (scopolamine), on Motion Sickness, Skin Conductance & Cognitive Function

Abstract

Aims

The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist Darifenacin, oral Hyoscine hydrobromide and Placebo on motion sickness induced by cross-coupled stimulation.

Methods

The effects of Darifenacin 10 mg or 20 mg, Hyoscine hydrobromide 0.6 mg and Placebo were assessed in a randomised, double-blind, 4-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated.

Results

Hyoscine hydrobromide produced significantly increased tolerance to motion versus Placebo (P<0.05 to P<0.01). The motion protection effect of Darifenacin (10 or 20 mg) was approximately one third of that of Hyoscine hydrobromide, but was not significant versus Placebo. Darifenacin and Hyoscine hydrobromide both significantly reduced skin conductance versus Placebo. Darifenacin produced either no effect or an enhanced effect on cognitive function in contrast to Hyoscine hydrobromide where there was significant impairment of psychomotor performance.

Conclusion

The results suggest that selective antagonism of the M3 receptor may not be important in the prevention of motion sickness. However selective M3 antagonism does not impair cognitive function. These observations may be important given that long term treatment with non-selective anti-muscarinic agents such as Oxybutynin may lead to an increased incidence of dementia.

http://ift.tt/2Fo79Ia

Full Covariate Modeling Approach in Population Pharmacokinetics: Understanding the Underlying Hypothesis Tests and Implications of Multiplicity

Abstract

Objective

To clarify the hypothesis tests associated with the full covariate modeling (FCM) approach in population pharmacokinetic (PPK) analysis, investigate the potential impact of multiplicity in PPK analysis, and evaluate simultaneous confidence intervals (SCI) as an approach to control multiplicity.

Methods

Clinical trial simulations were performed using a simple one-compartment PK model. Different numbers of covariates, sample sizes, effect sizes of covariates, and correlations among covariates were explored. The false positive rate (FPR) and power were evaluated.

Results

The FPR for the FCM approach dramatically increases with number of covariates. The chance of incorrectly selecting ≥1 seemingly "clinically relevant" covariates can be increased from 5% to a 40% - 70% range for 10 - 20 covariates. The SCI approach may provide appropriate control of the family-wise FPR, allowing more appropriate decision making. As a result, the power detecting real effects without incorrectly identifying non-existing effects can be greatly improved by the SCI approach compared to the approach in current practice. The performance of the SCI approach is driven by the ratio of sample size to number of covariates. The FPR can be controlled at 5% and 10% using the SCI approach when the ratio was ≥ 20 and 10, respectively.

Conclusion

The FCM approach still lies within the framework of statistical testing, and therefore multiplicity is an issue for this approach. It is imperative to consider multiplicity reporting and adjustments in FCM modeling practice to ensure more appropriate decision making.

http://ift.tt/2FxEdti

Examining the Relationship Between Nursing Informatics Competency and the Quality of Information Processing

The purpose of this study was to examine nursing informatics competency and the quality of information processing among nurses in Jordan. The study was conducted in a large hospital with 380 registered nurses. The hospital introduced the electronic health record in 2010. The measures used in this study were personal and job characteristics, self-efficacy, Self-Assessment Nursing Informatics Competencies, and Health Information System Monitoring Questionnaire. The convenience sample consisted of 99 nurses who used the electronic health record for at least 3 months. The analysis showed that nine predictors explained 22% of the variance in the quality of information processing, whereas the statistically significant predictors were nursing informatics competency, clinical specialty, and years of nursing experience. There is a need for policies that advocate for every nurse to be educated in nursing informatics and the quality of information processing.

http://ift.tt/2p4BUqn

HIMSS-ANI Recognizes Leadership in Nursing Informatics With Joint Award

No abstract available

http://ift.tt/2Ih9CBK

Learning With E-books and Project-based Strategy in a Community Health Nursing Course

With advances in information technology, "information-assisted instruction" has been gradually introduced to nursing education curricula. Specifically, the integration of an e-book system can effectively enhance nursing students' attention and interest. Most studies on nursing education that incorporated e-books have focused on the advantages of convenience and assistance provided by e-books. Few studies have addressed community health nursing and off-campus practice activities in relation to suitable teaching strategies for learning activities. This study involved designing and planning a multimedia e-book learning system with a project-based learning activity that conforms to the curriculum and practical requirements of a community health nursing course. The purpose was to reduce the gap between theory and practice and realize an effective learning process. For learning evaluations, a final examination analysis with an independent sample t test; a scoring scheme with intrateam, interteam, and expert ratings; and Bloom's taxonomy-based analysis were conducted. The evaluation results indicated that the comprehension and learning abilities of the experimental group using the e-book system with a mobile device were effectively improved. In addition, the exploratory process involved in project-based learning can develop multiple cognitive skills and problem-solving ability, thereby realizing effective learning.

http://ift.tt/2p0R8fW

Smartphone Use by Nurses in Acute Care Settings

The use of smartphones in acute care settings remains controversial due to security concerns and personal use. The purposes of this study were to determine (1) the current rates of personal smartphone use by nurses in acute care settings, (2) nurses' preferences regarding the use of smartphone functionality at work, and (3) nurse perceptions of the benefits and drawbacks of smartphone use at work. An online survey of nurses from six acute care facilities within one healthcare system assessed the use of personal smartphones in acute care settings and perceptions of the benefits and drawbacks of smartphone use at work. Participants (N = 735) were primarily point-of-care nurses older than 31 years. Most participants (98%) used a smartphone in the acute care setting. Respondents perceived the most common useful and beneficial smartphone functions in acute care settings as allowing them to access information on medications, procedures, and diseases. Participants older than 50 years were less likely to use a smartphone in acute care settings and to agree with the benefits of smartphones. There is a critical need for recognition that smartphones are used by point-of-care nurses for a variety of functions and that realistic policies for smartphone use are needed to enhance patient care and minimize distractions.

http://ift.tt/2Ih9B0E

To Tell or Not to Tell: Nursing Students’ Attitudes Toward Disclosing Patients’ Protected Health Information

No abstract available

http://ift.tt/2De02vO

Quality of Electronic Nursing Records: The Impact of Educational Interventions During a Hospital Accreditation Process

Hospital accreditation is a strategy for the pursuit of quality of care and safety for patients and professionals. Targeted educational interventions could help support this process. This study aimed to evaluate the quality of electronic nursing records during the hospital accreditation process. A retrospective study comparing 112 nursing records during the hospital accreditation process was conducted. Educational interventions were implemented, and records were evaluated preintervention and postintervention. Mann-Whitney and χ2 tests were used for data analysis. Results showed that there was a significant improvement in the nursing documentation quality postintervention. When comparing records preintervention and postintervention, results showed a statistically significant difference (P

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Effects of a System Thinking-Based Simulation Program for Congestive Heart Failure

This study evaluated a system thinking–based simulation program for the care of patients with congestive heart failure. Participants were 67 undergraduate nursing students from a nursing college in Seoul, South Korea. The experimental group was given a 4-hour system-thinking program and a 2-hour simulation program, whereas the control group had a 4-hour case study and a 2-hour simulation program. There were significant improvements in critical thinking in both groups, but no significant group differences between educational methods (F = 3.26, P = .076). Problem-solving ability in the experimental group was significantly higher than in the control group (F = 5.04, P = .028). Clinical competency skills in the experimental group were higher than in the control group (t = 2.12, P = .038). A system thinking–based simulation program is a more effective learning method in terms of problem-solving ability and clinical competency skills compared to the existing simulation program. Further research using a longitudinal study is needed to test the long-term effect of the intervention and apply it to the nursing curriculum.

http://ift.tt/2DfcR92

Effectiveness of Specimen Collection Technology in the Reduction of Collection Turnaround Time and Mislabeled Specimens in Emergency, Medical-Surgical, Critical Care, and Maternal Child Health Departments

The objective of this study was to evaluate the impact of specimen collection technology implementation featuring computerized provider order entry, positive patient identification, bedside specimen label printing, and barcode scanning on the reduction of mislabeled specimens and collection turnaround times in the emergency, medical-surgical, critical care, and maternal child health departments at a community teaching hospital. A quantitative analysis of a nonrandomized, pre-post intervention study design evaluated the statistical significance of reduction of mislabeled specimen percentages and collection turnaround times affected by the implementation of specimen collection technology. Mislabeled specimen percentages in all areas decreased from an average of 0.020% preimplementation to an average of 0.003% postimplementation, with a P

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Quality of Electronic Nursing Records: The Impact of Educational Interventions During a Hospital Accreditation Process

No abstract available

http://ift.tt/2DezHxT

Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis

Here we describe a protocol to determine pulmonary fungal burden in mice with invasive aspergillosis by quantification of Gomori's modified methanamine silver staining in histological sections. Use of this method resulted in comparable results with less animals compared to assessment of fungal burden by quantitative PCR of lung fungal DNA.

http://ift.tt/2tsOyoy

Midwifery students’ experiences of problem solving based interprofessional learning: A qualitative study

Publication date: Available online 9 March 2018
Source:Women and Birth
Author(s): Fereshteh Aein
BackgroundInterprofessional learning is identified as one of the most innovative ways to encourage students of different disciplines to communicate with each other in interprofessional teams. A review of existing studies identified that inter-professional learning with nursing and midwifery students learning together had not previously been reported.AimThis qualitative study sought to explore perceptions and experiences of midwifery students from interprofessional learning with nursing students.MethodsThis study was an exploratory qualitative study employing focus groups. Participants were 30 female students in the fourth year Bachelor of Midwifery at one university in Iran who undertook the surgical training course in midwifery in their seventh semester by inter-professional learning based on problem solving. Data were analysed according to the six steps of the concurrent thematic analysis method.FindingsOne main theme of challenging approach in learning emerged and two sub-themes 1) being challenged in a simulated clinical situation and 2) demonstrating professional knowledge.ConclusionInterprofessional learning by challenging students of various professions during shared interprofessional learning can be followed by positive outcomes such as improved critical thinking, interprofessional communication, teaching–learning motivation and independent learning.



http://ift.tt/2FEQbnS

Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study

Summary

Aims

To determine the preventability of serious adverse drug reactions (ADR) related to the use of direct oral anticoagulants (DOAC), and to explore contributing factors to preventable ADRs. Results were compared with vitamin K antagonists (VKA).

Methods

We conducted a prospective observational study in the emergency departments of two teaching hospitals from July 2015 to January 2016. Patients admitted with a thrombotic or bleeding event while under DOAC or VKA were included. Four independent reviewers assessed causality, seriousness and preventability of ADRs, using pilot-tested scales. For cases of serious and potentially preventable ADRs, we performed semi-structured interviews with general practitioners to identify contributing factors to ADRs. The primary outcome was the proportion of serious ADRs that were potentially preventable.

Results

The analysis included 46 DOAC and 43 VKA patients (median age 79 years). Gastro-intestinal (n=44) and intracranial (n=16) bleedings were the most frequent ADRs. 53% of DOAC- and 61% of VKA-related serious ADRs were deemed potentially preventable. Prescribing issues and inadequate monitoring were frequent for DOAC and VKA respectively. We identified many causes of preventable ADRs that applied to all oral anticoagulants, such as pharmacodynamics drug interactions and lack of communication.

Conclusions

More than half of serious ADRs were potentially preventable for both DOACs and VKAs. Interventions focusing on prescribing, patient education and continuity of care should help improve the use of DOACs in practice.

http://ift.tt/2HloBt4

Measuring Endoreduplication by Flow Cytometry of Isolated Tuber Protoplasts

The protocol described herein is a method for measuring endoreduplication within tubers of potato (Solanum tuberosum). It includes plasmolysis and protoplast extraction steps to decrease the noise and debris in downstream flow cytometric analysis.

http://ift.tt/2p5xfV0

Isolation and Culture of Rodent Microglia to Promote a Dynamic Ramified Morphology in Serum-free Medium

Efforts to understand microglial function in detail have been hindered by the lack of microglial culture models that recapitulate the properties of mature in vivo microglia. This protocol describes an isolation and culture approach designed to maintain robust survival of highly ramified mature rat microglia under defined-medium conditions.

http://ift.tt/2If1MZv

ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma, Published online: 09 March 2018; doi:10.1038/s41419-018-0399-y

ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

http://ift.tt/2p2cMAF

Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines

Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines

Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines, Published online: 09 March 2018; doi:10.1038/s41419-018-0380-9

Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines

http://ift.tt/2IhrCMe

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling, Published online: 09 March 2018; doi:10.1038/s41419-018-0429-9

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling

http://ift.tt/2DeVsxe

The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update

The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update

The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update, Published online: 09 March 2018; doi:10.1038/s41419-018-0416-1

The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update

http://ift.tt/2IbKpIV

SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway

SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway

SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway, Published online: 09 March 2018; doi:10.1038/s41419-018-0419-y

SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway

http://ift.tt/2p0D5XK

Adult Mouse DRG Explant and Dissociated Cell Models to Investigate Neuroplasticity and Responses to Environmental Insults Including Viral Infection

In this report, the advantages of organotypic cultures and dissociated primary cultures of mouse-derived dorsal root ganglia are highlighted to investigate a wide range of mechanisms associated with neuron-glial interaction, neuroplasticity, neuroinflammation, and response to viral infection.

http://ift.tt/2p11sVx

Preparation of DMMTAV and DMDTAV Using DMAV for Environmental Applications: Synthesis, Purification, and Confirmation

This article presents modified experimental protocols for dimethylmonothioarsinic acid (DMMTAV) and dimethyldithioarsinic acid (DMDTAV) synthesis, inducing dimethylarsinic acid (DMAV) thiolation through mixing of DMAV, Na2S, and H2SO4. The modified protocol provides an experimental guideline, thereby overcoming limitations of the synthesis steps that could have caused experimental failures in quantitative analysis.

http://ift.tt/2IhpHau

Loss and Rebirth of the Animal Microtubule Organizing Center: How Maternal Expression of Centrosomal Proteins Cooperates with the Sperm Centriole in Zygotic Centrosome Reformation

Centrosomes are the main microtubule organizing centers in animal cells. In particular during embryogenesis, they ensure faithful spindle formation and proper cell divisions. As metazoan centrosomes are eliminated during oogenesis, they have to be reassembled upon fertilization. Most metazoans use the sperm centrioles as templates for new centrosome biogenesis while the egg's cytoplasm re-prepares all components for on-going centrosome duplication in rapidly dividing embryonic cells. We discuss our knowledge and the experimental challenges to analyze zygotic centrosome reformation, which requires genetic experiments to enable scrutinizing respective male and female contributions. Male and female knockout animals and mRNA injection to mimic maternal expression of centrosomal proteins could point a way to the systematic molecular dissection of the process. The most recent data suggest that timely expression of centrosome components in oocytes is the key to zygotic centrosome reformation that uses male sperm as coordinators for de novo centrosome production.

Centrosome reformation at fertilization is essential for metazoan development. It requires a complicated interplay of sperm centrioles and the cytoplasm of the oocyte, which has eliminated its centrioles during oogenesis. The male centrioles launch centrosome duplication using female centrosome proteins for the first metazoan cell divisions.

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Integrity of IKK/NF-κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α (IKKα) is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases.

IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms.

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How Polycomb-Mediated Cell Memory Deals With a Changing Environment

Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment.

Cellular microenvironment can regularly change, hence the need for a dynamic modulation of transcriptional programs by the epigenome. In the current review, we highlight novel emerging aspects of epigenetic memory controlled by PcG proteins and the evolution of specialized functions to convey plasticity and adaptability to environmental changes.

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Does Patient Reporting lead to Earlier Detection of Drug Safety Signals? A Retrospective Comparison of Time to Reporting Between Patients and Healthcare Professionals in a Global Database

Abstract

Objective

To explore if there is a difference between patients and healthcare professionals (HCPs) in time to reporting drug-adverse drug reaction (ADR) associations which led to drug safety signals.

Design

This was a retrospective comparison of time to reporting selected drug-ADR associations which led to drug safety signals between patients and healthcare professionals.

Setting

ADR reports were selected from the World Health Organization Global database of individual case safety reports, VigiBase. Reports were selected based on drug-ADR associations of actual drug safety signals.

Main outcome measures

Primary outcome was the difference in time to reporting between patients and HCPs. The date of the first report for each individual signal was used as time zero. The difference in time between the date of the reports and time zero was calculated. Statistical differences in timing were analysed on the corresponding survival curves using a Mann-Whitney U test.

Results

In total 2822 reports were included, of which 52.7% were patient reports, with a median of 25% for all included signals. For all signals, median time to signal detection was 10.4 years. Overall, HCPs reported earlier than patients: median 7.0 vs 8.3 years (p <0.001).

Conclusions

Patients contributed a large proportion of reports on drug-ADR pairs that eventually became signals. HCPs reported 1.3 year earlier than patients. These findings strengthen the evidence on the value of patient reporting in signal detection, and highlight an opportunity to encourage patients to report suspected ADRs even earlier in the future.

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Providing safe, efficient and affordable sedation in endoscopy

We compliment the authors of the ProSed 2 Study1 for their large-scale analysis on the safety of sedation in endoscopic procedures. The vast majority of the over 300 000 endoscopies in this study have been performed under propofol sedation administered by the endoscopic team and only 0.2% were supported by an anaesthetist.

In Germany and many other European countries, propofol is routinely administered by the endoscopist or trained endoscopy nurse according to clearly defined standards as set out in the European or German guidelines.2 3 Propofol sedation administered by non-anaesthetists is even practised widely in doctors' surgeries with endoscopy facilities.

Currently, according to recommendations of a working party of the Royal College of Anaesthetists and the British Society of Gastroenterology (BSG),4 intravenous propofol administration for endoscopic procedures in the UK requires an additional anaesthetic team including an anaesthetist and usually also operating department personnel. The...

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Real-time Breath Analysis by Using Secondary Nanoelectrospray Ionization Coupled to High Resolution Mass Spectrometry

A protocol for characterizing chemical composition of exhaled breath in real time by using secondary nanoelectrospray ionization coupled to high resolution mass spectrometry is demonstrated.

http://ift.tt/2p2NlPg

Noninvasive quantitation of rat cerebral blood flow using 99m Tc-HMPAO—assessment of input function with dynamic chest planar imaging

Abstract

Background

Cerebral blood flow (CBF) quantitation using technetium-99m hexamethylpropyleneamine oxime (^99mTc-HMPAO) generally requires assessment of input function by arterial blood sampling, which would be invasive for small animals. We therefore performed chest dynamic planar imaging, instead of arterial blood sampling, to estimate the input function and establish noninvasive quantitation method of rat CBF using the image-derived input function.

Results

Integrated radioactivity concentration in the heart-blood pool on planar images (AUC_Blood-planar) was identical to that in arterial blood samples (AUC_Blood-sampling). Radioactivity concentration in the brain determined by SPECT imaging (C_Brain-SPECT) was identical to that using brain sampling (C_Brain-sampling). Noninvasively calculated CBF obtained by dividing C_Brain-SPECT by AUC_Blood-planar was well correlated with conventionally estimated CBF obtained by dividing C_Brain-sampling by AUC_Blood-sampling.

Conclusion

Rat CBF could be noninvasively quantitated using ^99mTc-HMPAO chest dynamic planar imaging and head SPECT imaging without arterial blood sampling.

http://ift.tt/2p0fYMY

Inhibition of PC4 radiosensitizes non-small cell lung cancer by transcriptionally suppressing XLF

Abstract

Positive cofactor 4 (PC4) participates in DNA damage repair and involved in nonhomologous end joining (NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4-like factor (XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non-small cell lung cancer (NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4-knockdown NSCLC cells. In addition, PC4 knockdown inhibited XLF expression by transcriptionally suppressing of XLF. Moreover, PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression-free survival (PFS) in patients with NSCLC. These findings suggest that PC4 could be used as a promising therapeutic target for NSCLC.

Knockdown of PC4 increased radiosensitivity in NSCLC. PC4 regulated XLF expression by transcriptionally suppressing XLF. PC4 was an independent predictor for progression-free survival of patients with NSCLC

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Integrative analysis of competing endogenous RNA network focusing on long noncoding RNA associated with progression of cutaneous melanoma

Abstract

Cutaneous melanoma (CM) is the most malignant tumor of skin cancers because of its rapid development and high mortality rate. Long noncoding RNAs (lncRNAs), which play essential roles in the tumorigenesis and metastasis of CM and interplay with microRNAs (miRNAs) and mRNAs, are hopefully considered to be efficient biomarkers to detect deterioration during the progression of CM to improve the prognosis. Bioinformatics analysis was fully applied to predict the vital lncRNAs and the associated miRNAs and mRNAs, which eventually constructed the competing endogenous RNA (ceRNA) network to explain the RNA expression patterns in the progression of CM. Further statistical analysis emphasized the importance of these key genes, which were statistically significantly related to one or few clinical features from the ceRNA network. The results showed the lncRNAs MGC12926 and LINC00937 were verified to be strongly connected with the prognosis of CM patients.

Twenty lncRNAs, 10 miRNAs, and 54 mRNAs, which are associated with the prognosis of CM, were conducted the competing endogenous network based on their regulation relationship. Squares represent miRNAs, balls represent mRNAs, and balls with a green circle around represent lncRNAs. Red means upregulated genes, while blue means downregulated genes.

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Antitumor effects of duvelisib on Epstein–Barr virus-associated lymphoma cells

Abstract

Epstein–Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in EBV-associated lymphomas and can be a novel therapeutic target. An oral dual inhibitor of PI3Kγ and PI3Kδ, duvelisib, is in clinical trials for the treatment of lymphoid malignancies. In this study, we evaluated how duvelisib affects the activity of the PI3K/Akt signaling pathway and if it has antitumor effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt signaling pathway was activated in most of the B and T cell lymphoma cell lines tested. Additionally, duvelisib treatment inhibited cellular growth in the tested cell lines. Overall, B cell lines were more susceptible to duvelisib than T and NK cell lines in vitro regardless of EBV infection. However, the additional influence of duvelisib on the tumor microenvironment was not assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore, duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and gp350/220) in EBV-positive B cell lines, suggesting that duvelisib suppresses the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib did not induce a remarkable change in the expression of EBV latent genes. These results may indicate that there is therapeutic potential for duvelisib administration in the treatment of EBV-associated B cell lymphomas and other B cell malignancies.

PI3K/Akt signaling pathway was activated in EBV-associated lymphoma cell lines. Treatment with duvelisib, inhibitor of PI3Kγ and PI3Kδ, induced both apoptosis and cell-cycle arrest in EBV-associated B cell lymphoma cell lines, suggesting that duvelisib has therapeutic potential.

http://ift.tt/2De923S

Differentially expressed and survival-related proteins of lung adenocarcinoma with bone metastasis

Abstract

Despite recent advances in targeted and immune-based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. First, two-dimensional gel electrophoresis (2-DE) was used to identify proteins that were differentially expressed in LUAD with BM, and then matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) was used to identify these proteins. Second, the Cancer Genome Atlas (TCGA) was used to identify mutations in these differentially expressed proteins and Kaplan–Meier plotter (KM Plotter) was used to generate survival curves for the analyzed cases. Immunohistochemistry (IHC) was used to check the expression of proteins in 28 patients with BM and nine patients with LUAD. Lastly, the results were analyzed with respect to clinical features and patient's follow-up. We identified a number of matched proteins from 2-DE. High expression of enolase 1 (ENO1) (HR = 1.67, logrank P = 1.9E-05), ribosomal protein lateral stalk subunit P2 (RPLP2) (HR = 1.77, logrank P = 2.9e-06), and NME/NM23 nucleoside diphosphate kinase 2 (NME1-NME2) (HR = 2.65, logrank P = 3.9E-15) was all significantly associated with poor survival (P < 0.05). Further, ENO1 was upregulated (P = 0.0004) and calcyphosine (CAPS1) was downregulated (P = 5.34E-07) in TCGA LUAD RNA-seq expression data. IHC revealed that prominent ENO1 staining (OR = 7.5, P = 0.034) and low levels of CAPS1 (OR = 0.01, P < 0.0001) staining were associated with BM incidence. Finally, we found that LUAD patients with high expression of ENO1 and RPLP2 had worse overall survival. This is the first instance where the genes ENO1, RPLP2, NME1-NME2 and CAPS1 were associated with disease severity and progression in LUAD patients with BM. Thus, with this study, we have identified potential biomarkers and therapeutic targets for this disease.

Proteomics identified proteins significantly associated with bone metastasis (BM). Online databases and clinical data verified potential predictive and diagnosis biomarkers. The values for drug development and treatment of lung adenocarcinoma with BM.

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Apoptin-derived peptide reverses cisplatin resistance in gastric cancer through the PI3K–AKT signaling pathway

Abstract

The prognosis of gastric cancer (GC) remains poor due to clinical drug resistance, and novel drugs are urgently needed. Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. MTT and colony-formation assays and Hoechst 33342 staining were used to measure the cytotoxicity of CDDP and AdP in GC cells. Cell apoptosis was measured using an Annexin-V-FITC/PI dual staining assay. Western blot analysis was conducted to detect the expression of proteins in the PI3K/AKT signaling pathway and resistance-related markers. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells in a concentration- and time-dependent manner. AdP also suppressed cell invasion and migration. Additionally, AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) in the PI3K/AKT/ARNT signaling pathway, which promoted apoptosis and necrosis in GC cells. AdP promoted apoptosis in CDDP-resistant GC cells by suppressing the PI3K/AKT/ARNT signaling pathway and might be considered a candidate agent for the clinical treatment of cisplatin-resistant GC.

Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells, and suppressed invasion and migration. AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) within the PI3K/AKT/ARNT signaling pathway.

http://ift.tt/2Fu8TLX

Development and validation of an individualized diagnostic signature in thyroid cancer

Abstract

New molecular signatures are needed to improve the diagnosis of thyroid cancer (TC) and avoid unnecessary surgeries. In this study, we aimed to develop a robust and individualized diagnostic signature in TC. Gene expression profiles of tumor and nontumor samples were from 13 microarray datasets of Gene Expression Omnibus (GEO) database and one RNA-sequencing dataset of The Cancer Genome Atlas (TCGA). A total of 1246 samples were divided into a training set (N = 435), a test set (N = 247), and one independent validation set (N = 564). In the training set, 115 most frequent differentially expressed genes (DEGs) among the included datasets were used to construct 6555 gene pairs, and 19 significant pairs were detected to further construct the diagnostic signature by a penalized generalized linear model. The signature showed a good diagnostic ability for TC in the training set (area under receiver operating characteristic curve (AUC) = 0.976), test set (AUC = 0.960), and TCGA dataset (AUC = 0.979). Subgroup analyses showed consistent results when considering the type of nontumor samples and microarray platforms. When compared with two existing molecular signatures in the diagnosis of thyroid nodules, the signature (AUC = 0.933) also showed a higher diagnostic ability (AUC = 0.886 for a 7-gene signature and AUC = 0.892 for a 10-gene signature). In conclusion, our study developed and validated an individualized diagnostic signature in TC. Large-scale prospective studies were needed to further validate its diagnostic ability.

We develop and validate an individualized diagnostic signature in thyroid cancer.

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Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Abstract

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.

In this case-control study of well-characterized breast cancer patients, we confirm ATM, CHEK2, PALB2, CDH1, and TP53 as BC risk genes, no association was observed for NBN. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC and both, ATM and CHEK2, were negatively associated with TNBC and (ER)-negative tumor phenotypes. Our study confirmed the benefit of multi-gene testing for risk assessment in BC families while clinical phenotypes associated with non-BRCA1/2 gene mutations remain to be determined.

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Targeted Therapy Larotrectinib Shows Promise in Early Trials, Regardless of Cancer Type

Initial results from a series of three small clinical trials of a targeted cancer therapy called larotrectinib suggest that it may be effective in patients—children and adults—with a wide variety of cancer types.

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Impact of Serotonin Reuptake Inhibitor Use on Breast Milk Supply in Mothers of Preterm Infants: A Retrospective Cohort Study

Abstract

Aims

To examine the association between late pregnancy exposure to serotonin reuptake inhibitor (SRI) antidepressants and difficulties in achieving an adequate breast milk supply in women who gave birth to preterm infants, while accounting for the potential impacts of underlying maternal psychiatric illness.

Methods

Retrospective cohort study of 3,024 women delivering liveborn preterm infants (<37 weeks' gestation) between January 2004 and December 2008. The primary outcome was postnatal domperidone use, considered a valid proxy for presence and pharmacological management of low milk supply. Relative risks adjusted for maternal soiodemographics and comorbidities (aRRs) were calculated for low milk supply, comparing women with late pregnancy exposure to SRI antidepressants (n = 86), women with a psychiatric illness but no antidepressant use (n = 126), and women with neither antenatal exposures (n = 2 812).

Results

Compared to non-exposed women, non-medicated psychiatric illness (aRR 1.64; 95%CI 1.16-2.30) but not late pregnancy SRI use (aRR 1.00; 95%CI 0.59-1.70) was associated with an increased risk of domperidone use, indicative of low milk supply.

Conclusions

These findings do not support the previously observed negative impacts of antidepressant use on breastfeeding, instead suggesting that women with an underlying psychiatric illness appear at greatest risk of experiencing low milk supply and could benefit from additional breastfeeding education and support.

http://ift.tt/2oVdnVw