Background Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers prior to implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). Methods In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cut-off values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n=6) to identify transplantable liver grafts with low BDI. Results Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared to high BDI. The following cut-off values were associated with low BDI: biliary bicarbonate >18 mmol/L (P=0.002), biliary pH >7.48 (P=0.019), biliary glucose
https://ift.tt/2Pa4BCp
Παρασκευή 2 Νοεμβρίου 2018
Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients
Abstract
Background
In the double-blind, phase 3 PALOMA-3 study, palbociclib–fulvestrant significantly prolonged progression-free survival versus placebo–fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3.
Methods
Pre/peri/postmenopausal women with HR+/HER2– MBC were randomized 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/day; 3 weeks on/1 week off; n = 347) or placebo (n = 174). Prespecified exploratory analyses compared the efficacy (data cutoff: October 23, 2015), safety, and pharmacokinetics (data cutoff: December 5, 2014) in Japanese women versus the overall population.
Results
A total of 35 Japanese women were randomized to palbociclib–fulvestrant (n = 27) or placebo–fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5–not estimable) in the Japanese palbociclib–fulvestrant group and 11.2 months (95% CI, 5.6–not estimable) in the placebo–fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively).
Conclusion(s)
The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).
https://ift.tt/2QbdUya
Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function
Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function
Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function, Published online: 02 November 2018; doi:10.1038/s41419-018-1151-3
Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal functionhttps://ift.tt/2P5q4fI
Phosphatidylserine is a marker for axonal debris engulfment but its exposure can be decoupled from degeneration
Phosphatidylserine is a marker for axonal debris engulfment but its exposure can be decoupled from degeneration
Phosphatidylserine is a marker for axonal debris engulfment but its exposure can be decoupled from degeneration, Published online: 02 November 2018; doi:10.1038/s41419-018-1155-z
Phosphatidylserine is a marker for axonal debris engulfment but its exposure can be decoupled from degenerationhttps://ift.tt/2CWexb0
Discrete Choice Experiments in Health Economics: Past, Present and Future
Abstract
Objectives
Discrete choice experiments (DCEs) are increasingly advocated as a way to quantify preferences for health. However, increasing support does not necessarily result in increasing quality. Although specific reviews have been conducted in certain contexts, there exists no recent description of the general state of the science of health-related DCEs. The aim of this paper was to update prior reviews (1990–2012), to identify all health-related DCEs and to provide a description of trends, current practice and future challenges.
Methods
A systematic literature review was conducted to identify health-related empirical DCEs published between 2013 and 2017. The search strategy and data extraction replicated prior reviews to allow the reporting of trends, although additional extraction fields were incorporated.
Results
Of the 7877 abstracts generated, 301 studies met the inclusion criteria and underwent data extraction. In general, the total number of DCEs per year continued to increase, with broader areas of application and increased geographic scope. Studies reported using more sophisticated designs (e.g. D-efficient) with associated software (e.g. Ngene). The trend towards using more sophisticated econometric models also continued. However, many studies presented sophisticated methods with insufficient detail. Qualitative research methods continued to be a popular approach for identifying attributes and levels.
Conclusions
The use of empirical DCEs in health economics continues to grow. However, inadequate reporting of methodological details inhibits quality assessment. This may reduce decision-makers' confidence in results and their ability to act on the findings. How and when to integrate health-related DCE outcomes into decision-making remains an important area for future research.
https://ift.tt/2DkAFNs
Racial disparities in breast cancer persist despite early detection: analysis of treatment of stage 1 breast cancer and effect of insurance status on disparities
Abstract
Purpose
Prior research demonstrates racial disparities in breast cancer treatment. Disparities are commonly attributed to more advanced stage at presentation or aggressive tumor biology. We seek to evaluate if racial disparities persist in the treatment of stage 1 breast cancer patients who by definition are not delayed in presentation.
Methods
We selected stage 1 breast cases in the National Cancer Data Base. Patients were divided into two cohorts based on race and included White and Black patients. We also performed a subgroup analysis of patients with private insurance for comparison to determine if private insurance diminished the racial disparities noted. We analyzed differences in time to treatments by race.
Results
Our analysis included 546,351 patients of which 494,784 (90.6%) were White non-Hispanic and 51,567 (9.4%) were Black non-Hispanic. Black women had significantly longer times to first treatment (35.5 days vs 28.1 days), surgery (36.6 days vs 28.8 days), chemotherapy (88.1 days vs 75.4 days), radiation (131.3 days vs 99.1 days), and endocrine therapy (152.1 days vs 126.5 days) than White women. When patients with private insurance were analyzed the difference in time to surgery decreased by 1.2 days but racial differences remained statistically significant.
Conclusions
Despite selecting for early-stage breast cancer, racial disparities between White and Black women in time to all forms of breast cancer treatment persist. These disparities while likely not oncologically significant do suggest institutional barriers for obtaining care faced by women of color which may not be addressed with improving access to mammography alone.
https://ift.tt/2D0eyek
Fatal subarachnoid hemorrhage caused by rupture of variant anterior communicating artery: a case report and literature review
Abstract
Fatal subarachnoid hemorrhage (SAH) caused by anterior communicating artery (ACoA) rupture is a rare event in medicolegal practice. Anatomical variations of the ACoA tend to make its anatomical structure, and as a result, blood flow through it, more complicated, which may increase hemodynamic stress and cause weak spots in the affected blood vessels. Variant ACoAs are prone to rupture in the event of a blunt-force trauma. Here, we report a fatal case of SAH caused by the rupture of a variant ACoA when the victim's head was struck from behind, causing the head to rotate and the victim to fall forward onto the ground. A medicolegal autopsy revealed diffuse basal SAH and ACoA duplication. The smaller of the two variant ACoA branches had ruptured near its junction with the right anterior cerebral artery. No basal aneurysms or other fatal diseases or injuries were found. This case highlights the significance of anatomical variation in forensic pathology.
https://ift.tt/2CYowg5
Lethal manifestations of angioedema
Abstract
An 86-year-old woman with a history of angioedema was found dead at her home address. She had recently complained of a swollen tongue. At autopsy the tongue was grossly edematous, protruding from the mouth. There was also marked edema of the tonsillar fossae, epiglottis and glottic inlet, causing critical obstruction. Histology of the tongue and upper airway demonstrated marked submucosal edema. Death was attributed to upper airway obstruction due to angioedema of the tongue, oropharynx and glottic inlet. Angioedema is characterized by localized non-pitting edema of the deep dermis and subcutaneous/submucosal tissues. It may be acute or chronic, acquired or inherited. Sudden death may result from critical airway occlusion, although both stroke and ischemic heart disease are known to occur. Post mortem genetic testing for hereditary variants can be conducted for SERPING1 gene and F12 gene/THR328 mutations.
https://ift.tt/2P5n4zH
Effects of postmortem positional changes on conjunctival petechiae
Abstract
The present study aimed to determine whether postmortem period, physical constitution, cause of death, and cardiopulmonary resuscitation are associated with positional changes in the postmortem appearance of conjunctival petechiae. We retrospectively investigated serial forensic autopsies from 6 h to 6 days postmortem (n = 442; male, 303; female, 139; median age, 62 years; range, 0–100 years). The causes of death were sharp instrument injury, blunt force trauma, fire, intoxication, asphyxia, drowning, hypothermia, hyperthermia, acute heart failure, and natural causes. Of these, 28 (male, n = 18; female, n = 10) were aged ≤5 years. Palpebral conjunctival petechiae were initially assessed at autopsy in supine bodies, then reassessed in prone bodies after 30 min. Among 414 bodies, 291 (70.2%) and 123 (29.7%) who were aged between 6 and 100 years, and 18 (64.2%) and 10 (35.7%) aged <5 years at the time of death, were discovered in the supine and prone positions, respectively. The amounts of petechiae increased within 1.5 days postmortem, but not in those discovered in the prone position. The rates at which petechiae increased were higher in supine overweight bodies (BMI ≥ 25.0) and in those who were discovered supine and had died of asphyxia or drowning (37.5%). Cardiopulmonary resuscitation for bodies discovered in the supine and prone positions did not statistically affect the occurrence of petechiae. Several postmortem factors can cause hypostatic blood redistribution that manifests as increased amounts of petechiae in the palpebral conjunctivae.
https://ift.tt/2P2sJ9I
Chased by the Past: The Relation Between Childhood Maltreatment and Fear of Childbirth
Abstract
Although childbirth is a normative physiological experience, it may be challenging for some women and especially for those who were exposed to childhood maltreatment. The aim of the study was to examine a model underlying the development of fear of childbirth among pregnant women who were exposed to childhood maltreatment. Given that abusive acts are often directed at and experienced through the victim's mind and body, we proposed a dual-path model, suggesting that these relations are mediated by both self-objectification and a serial mediation of disrupted body boundaries and body shame. A sample of 470 Israeli pregnant women filled out a battery of questionnaires assessing their history of childhood maltreatment, self-objectification, disrupted body boundaries, body shame, and fear of childbirth. Results from Structural Equation Modeling (SEM) indicated that self-objectification and the combination of disruptions in body boundaries and body shame significantly mediated the association between childhood maltreatment and fear of childbirth. These findings stress the integrative experience and consequences of childhood maltreatment among pregnant women. The roles of the two paths in understanding the detrimental long-term effects of childhood maltreatment and in designing effective interventions are discussed.
https://ift.tt/2RyQ9R8
The long and the short of it: insights into the cellular source of autoantibodies as revealed by B cell depletion therapy
Malika Hale | David J Rawlings | Shaun W Jackson
https://ift.tt/2FcMfft
Multiregion sequencing reveals the genetic heterogeneity and evolutionary history of osteosarcoma and matched pulmonary metastases
Osteosarcoma (OS) is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors (PT) and corresponding pulmonary metastatic tumors (MT) by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 OS patients. MT exhibited a significantly higher mutational burden and genomic instability compared to PT, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in MT. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of OS during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant inter-tumoral rather than intra-tumoral heterogeneity between PT and MT. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, MT showed improved immunogenicity including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding PT. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic OS, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.
https://ift.tt/2Dlj1sZ
Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer
Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro co-culture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n=141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap junction intercellular communication and cell-cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients.
https://ift.tt/2JAY5ya
Measurement of plasma cell-free mitochondrial tumor DNA improves detection of glioblastoma in patient-derived orthotopic xenograft models.
The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of glioblastoma (GB) patients are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GB (n=64) and show that tumor size and cell proliferation, but not the integrity of the blood-brain barrier or cell death, affect the release of ctDNA in treatment naïve GB PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (<0.2x coverage) of host (rat) and tumor (human) circulating DNA identified a peak at 145 bp in the human DNA fragments, indicating a difference in the origin or processing of the ctDNA. The concentration of ctDNA correlated with cell death only after treatment with Temozolomide and radiotherapy. Digital PCR detection of plasma tumor mitochondrial DNA (tmtDNA), an alternative to detection of nuclear ctDNA, improved plasma DNA detection rate (82% versus 24%) and allowed detection in cerebrospinal fluid (CSF) and urine. Mitochondrial mutations are prevalent across all cancers and can be detected with high sensitivity, at low cost and without prior knowledge of tumor mutations via capture-panel sequencing. Coupled with the observation that mitochondrial copy number increases in glioma, these data suggest analyzing tmtDNA as a more sensitive method to detect and monitor tumor burden in cancer, specifically in GB where current methods have largely failed.
https://ift.tt/2DjOUSH
Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma
In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In the current study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of PP2A, a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes in vitro and in vivo. This combination treatment resulted in suppression of AKT/mTOR signaling coupled with reduced expression of c-MYC, an oncoprotein implicated in tumor progression and therapeutic resistance. Forced expression of c-MYC or loss of PP2A B56α, the specific PP2A subunit shown to negatively regulate c-MYC, increased resistance to mTOR inhibition. Conversely, decreased c-MYC expression increased the sensitivity of PDA cells to mTOR inhibition. Together these studies demonstrate that combined targeting of PP2A and mTOR suppresses proliferative signaling and induces cell death and implicate this combination as a promising therapeutic strategy for PDA patients.
https://ift.tt/2JCpGPI
T-cell-secreted TNF-alpha induces emergency myelopoiesis and myeloid-derived suppressor cell-differentiation in cancer
Hematopoiesis in cancer patients is characterized by reduced production of red blood cells and an increase in myelopoiesis, which contributes to the immune-suppressive environment in cancer. Some tumors produce growth factors that directly stimulate myelopoiesis such as G-CSF or GM-CSF. However, for a majority of tumors that do not directly secrete hematopoietic growth factors, the mechanisms involved in the activation of myelopoiesis are poorly characterized. In this study, we document in different murine tumor models activated hematopoiesis with increased proliferation of long-term and short-term hematopoietic stem cells and myeloid progenitor cells. As a consequence, the frequency of myeloid-derived suppressor cells (MDSC) and its ratio to CD8+ T cells increased in tumor-bearing mice. Activation of hematopoiesis and myeloid differentiation in tumor-bearing mice was induced by tumor necrosis factor alpha (TNF-alpha), which was mainly secreted by activated CD4+ T cells. Therefore, the activated adaptive immune system in cancer induces emergency myelopoiesis and immunosuppression.
https://ift.tt/2DiNjfJ
Loss of TRIM29 alters keratin distribution to promote cell invasion in squamous cell carcinoma
TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated. Here we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immunoprecipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29-keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics.
https://ift.tt/2JyoGvT
Development and validation of novel signature to predict overall survival in "driver-gene-negative" lung adenocarcinoma (LUAD): results of a multicenter study
Purpose: Examining the role of developmental signaling pathways in "driver-gene-negative" LUAD (LUAD patients negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as "driver-gene-negative") may shed light on the clinical research and treatment for this LUAD subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of "driver-gene-negative" LUAD. Experimental Design: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired LUAD and adjacent normal tissues. In the training phase, tissue microarrays (TMAs) and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature. Results: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in "driver-gene-negative" LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin-pathway-based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3 and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10.42, 6.46-16.79; p<0.001) than patients with low-risk scores. Conclusions: The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for "driver-gene-negative" LUAD.
https://ift.tt/2DkbKth
VCAM-1 targeted magnetic resonance imaging enables detection of brain micrometastases from different primary tumours
Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule-1 (VCAM-1) targeted magnetic resonance imaging (MRI) for early detection of brain micrometastases in mouse models across multiple primary tumour types. Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001) and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n=5-6/group) were injected intravenously with VCAM-1 targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumour-bearing mice injected with non-targeting IgG-MPIO were included. Results: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time-course. T2*-weighted MRI of all tumour-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (p<0.001; two-sided) than control cohorts, despite a lack of blood-brain barrier impairment. Specific MPIO binding to VCAM-1 positive tumour-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumour types. Conclusions: VCAM-1-targeted MRI enables detection of brain micrometastases from the three primary tumour types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.
https://ift.tt/2JE9ayQ
Prognostic models turn the Heat(IT)up on FLT3ITD-mutated AML
The presence of internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase gene have long been known to confer a poor prognosis to acute myeloid leukemia (AML) patients. Now, specific structural features of the ITD are also suggested to alter patient outcome, including sensitivity to targeted therapies, prompting their evaluation in therapeutic algorithms.
https://ift.tt/2Dj9T88
Transmembrane and Juxtamembrane Domain Mutations Activate HER2 [Research Watch]
HER2 transmembrane (TMD) or juxtamembrane domain (JMD) mutations activate HER2 in patients with cancer.
https://ift.tt/2AIP3fN
Obesity Independently Drives NASH and Hepatocellular Carcinoma [Research Watch]
Obesity-induced hepatic STAT3 signaling drives hepatocellular carcinoma (HCC) independent of fibrosis.
https://ift.tt/2AJ9nOo
Nuclear cGAS Blocks DNA Repair to Drive Tumorigenesis [Research Watch]
DNA damage–mediated cGAS nuclear translocation results in the loss of HRR and carcinogenesis.
https://ift.tt/2F3fPnl
A CDK9 Inhibitor May Suppress Tumor Growth and Enhance Immunotherapy [Research Watch]
A drug screen discovers a CDK9 inhibitor that reactivates epigenetically silenced genes.
https://ift.tt/2F0Xo2I
Vemurafenib Has Activity in Patients with BRAFV600-Mutant Glioma [Research Watch]
Vemurafenib achieved objective responses and durable disease control in patients with high-grade glioma.
https://ift.tt/2AHODq6
QTL Mapping on a Background of Variance Heterogeneity
Standard QTL mapping procedures seek to identify genetic loci affecting the phenotypic mean while assuming that all individuals have the same residual variance. But when the residual variance differs systematically between groups, perhaps due to a genetic or environmental factor, such standard procedures can falter: in testing for QTL associations, they attribute too much weight to observations that are noisy and too little to those that are precise, resulting in reduced power and and increased susceptibility to false positives. The negative effects of such "background variance heterogeneity" (BVH) on standard QTL mapping have received little attention until now, although the subject is closely related to work on the detection of variance-controlling genes. Here we use simulation to examine how BVH affects power and false positive rate for detecting QTL affecting the mean (mQTL), the variance (vQTL), or both (mvQTL). We compare linear regression for mQTL and Levene's test for vQTL, with tests more recently developed, including tests based on the double generalized linear model (DGLM), which can model BVH explicitly. We show that, when used in conjunction with a suitable permutation procedure, the DGLM-based tests accurately control false positive rate and are more powerful than the other tests. We also find that some adverse effects of BVH can be mitigated by applying a rank inverse normal transform. We apply our novel approach, which we term "mean-variance QTL mapping", to publicly available data on a mouse backcross and, after accommodating BVH driven by sire, detect a new mQTL for bodyweight.
https://ift.tt/2SM5y1Q
vqtl: An R Package for Mean-Variance QTL Mapping
We present vqtl, an R package for mean-variance QTL mapping. This QTL mapping approach tests for genetic loci that influence the mean of the phenotype, termed mean QTL, the variance of the phenotype, termed variance QTL, or some combination of the two, termed mean-variance QTL. It is unique in its ability to correct for variance heterogeneity arising not only from the QTL itself but also from nuisance factors, such as sex, batch, or housing. This package provides functions to conduct genome scans, run permutations to assess the statistical significance, and make informative plots to communicate results. Because it is inter-operable with the popular qtl package and uses many of the same data structures and input patterns, it will be straightforward for geneticists to analyze future experiments with vqtl as well as re-analyze past experiments, possibly discovering new QTL.
https://ift.tt/2zniqTc
Mean-Variance QTL Mapping Identifies Novel QTL for Circadian Activity and Exploratory Behavior in Mice
We illustrate, through two case studies, that "mean-variance QTL mapping"-QTL mapping that models effects on the mean and the variance simultaneously-can discover QTL that traditional interval mapping cannot. Mean-variance QTL mapping is based on the double generalized linear model, which extends the standard linear model used in interval mapping by incorporating not only a set of genetic and covariate effects for mean but also set of such effects for the residual variance. Its potential for use in QTL mapping has been described previously, but it remains underutilized, with certain key advantages undemonstrated until now. In the first case study, a reduced complexity intercross of C57BL/6J and C57BL/6N mice examining circadian behavior, our reanalysis detected a mean-controlling QTL for circadian wheel running activity that interval mapping did not; mean-variance QTL mapping was more powerful than interval mapping at the QTL because it accounted for the fact that mice homozygous for the C57BL/6N allele had less residual variance than other mice. In the second case study, an intercross between C57BL/6J and C58/J mice examining anxiety-like behaviors, our reanalysis detected a variance-controlling QTL for rearing behavior; interval mapping did not identify this QTL because it does not target variance QTL. We believe that the results of these reanalyses, which in other respects largely replicated the original findings, support the use of mean-variance QTL mapping as standard practice.
https://ift.tt/2SHu18g
Fitness and Genomic Consequences of Chronic Exposure to Low Levels of Copper and Nickel in Daphnia pulex Mutation Accumulation Lines
In at least some unicellular organisms, mutation rates are temporarily raised upon exposure to environmental stress, potentially contributing to the evolutionary response to stress. Whether this is true for multicellular organisms, however, has received little attention. This study investigated the effects of chronic mild stress, in the form of low-level copper and nickel exposure, on mutational processes in Daphnia pulex using a combination of mutation accumulation, whole genome sequencing and life-history assays. After over 100 generations of mutation accumulation, we found no effects of metal exposure on the rates of single nucleotide mutations and of loss of heterozygosity events, the two mutation classes that occurred in sufficient numbers to allow statistical analysis. Similarly, rates of decline in fitness, as measured by intrinsic rate of population increase and of body size at first reproduction, were negligibly affected by metal exposure. We can reject the possibility that Daphnia were insufficiently stressed to invoke genetic responses as we have previously shown rates of large-scale deletions and duplications are elevated under metal exposure in this experiment. Overall, the mutation accumulation lines did not significantly depart from initial values for phenotypic traits measured, indicating the lineage used was broadly mutationally robust. Taken together, these results indicate that the mutagenic effects of chronic low-level exposure to these metals are restricted to certain mutation classes and that fitness consequences are likely minor and therefore unlikely to be relevant in determining the evolutionary responses of populations exposed to these stressors.
https://ift.tt/2zoyi7X
FDA Approves Powerful New Opioid Despite Criticisms
FRIDAY, Nov. 2, 2018 -- Ruling against the recommendation of one of its chief experts, the U.S. Food and Drug Administration today approved an extremely potent new opioid painkiller, Dsuvia. The drug is a 30-mcg pill that packs the same punch as 5...
https://ift.tt/2CYKXSs
U.S. Opioid Overdose Deaths Reach Record Number
FRIDAY, Nov. 2, 2018 -- The number of opioid overdose deaths in the United States reached a new record last year with 72,000 deaths, which works out to about 200 a day, according to a Drug Enforcement Administration report released today. The report...
https://ift.tt/2P7UJsA
Age to Stop Cervical Cancer Screening Depends on Test Used
FRIDAY, Nov. 2, 2018 -- Continuing regular cytology screening up to age 75 years or performing an exit human papillomavirus (HPV) test to confirm the absence of oncogenic HPV strains past the age of 55 years offers preventive benefit for older women...
https://ift.tt/2CXDmn4
Sign-Up Season Begins on HealthCare.gov
FRIDAY, Nov. 2, 2018 -- The federal government website where Americans can sign up for health insurance under the Affordable Care Act is up and running, officials said yesterday. Before HealthCare.gov went live for the sixth sign-up season, it had...
https://ift.tt/2P3nXZL
American Academy of Ophthalmology, Oct. 27-30
The 122nd Annual Meeting of the American Academy of Ophthalmology The annual meeting of the American Academy of Ophthalmology was held from Oct. 27 to 30 in Chicago and attracted approximately 6,000 participants from around the world, including...
https://ift.tt/2CY8UJv
Quality of Life for Patients with Favorable Risk HPV-Associated Oropharyngeal Cancer After De-Intensified Chemoradiotherapy
We examined quality of life data from two prospective phase 2 studies of de-intensified chemoradiotherapy in patients with HPV-associated oropharyngeal cancer. Overall results were favorable, and most quality of life domains and symptoms returned to baseline by 3 to 6 months. Xerostomia and dysphagia continued to improve beyond 1 year post-treatment.
https://ift.tt/2P3ok6B
Introducing proton track-end objectives in intensity modulated proton therapy optimization to reduce linear energy transfer and relative biological effectiveness in critical structures
Proton track-end objectives have been introduced in the optimization of intensity modulated proton therapy plans to reduce linear energy transfer (LET) and relative biological effectiveness (RBE) in critical structures. The method was evaluated for six patients, plans optimized with dose objectives were compared with plans optimized with dose and track-end objectives. Track-end objectives allow for LET and RBE reductions in critical structures, which potentially could reduce normal tissue toxicity, without compromising the physical target dose.
https://ift.tt/2CVNc93
Validity of a Recently-Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Brain Metastasis Patients Undergoing Multiple Radiosurgical Procedures
To our knowledge, this is the first analysis to validate the clinical significance of the Brain Metastasis Velocity score based on a large patient series, i.e., more than 1000 patients in whom multiple gamma knife stereotactic radiosurgery (SRS) procedures were performed. Furthermore, we assessed the feasibility of applying this grading index not only after the second SRS but also after the third or fourth SRS to predict the survival periods of our patients.
https://ift.tt/2P5avV3
Daily Lisinopril vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial
Previous biologic and clinical evidence has suggested that lisinopril, an angiotensin-converting enzyme inhibitor, may mitigate chemoradiation (CRT)-induced pneumonitis. We conducted a pilot, double-blind, placebo-controlled randomized trial of 23 patients with advanced non–small cell lung cancer who had concurrent fractionated CRT. They received 20 mg lisinopril or placebo daily during and 3 months after RT. Few patient-reported outcome indices showed that lisinopril was safe, and possibly beneficial, in mitigating RT-induced pulmonary distress, pending further studies.
https://ift.tt/2CYLpQE
Single versus multifraction stereotactic radiosurgery for large brain metastases: An international meta-analysis of 24 trials
Fractionated stereotactic radiosurgery is believed to carry a decreased risk of radionecrosis and similar rates of 1-year local control compared to SRS in patients with large brain metastases. A meta-analysis was performed to compare these outcomes in patients who received fractionated SRS or SRS as definitive or post-operative treatment. Fractionated SRS offers enhanced safety and is as efficacious as SRS in the treatment of large brain metastases.
https://ift.tt/2CYYcCD
Drowsy Driving, Sleep Duration, and Chronotype in Adolescents
To determine whether self-reported drowsy driving was associated with an evening chronotype, a biologically-based difference in circadian sleep-wake timing, and shorter school-night sleep duration in a sample of high school drivers.
https://ift.tt/2CYKVtz
Randomized Clinical Trial Comparing Breath-Enhanced to Conventional Nebulizers in the Treatment of Children with Acute Asthma
To compare the efficacy of a breath-enhanced and a conventional jet nebulizer in the treatment of children with moderate to severe acute asthma.
https://ift.tt/2P3qAuu
Urban-Rural Residence and Child Physical Abuse Hospitalizations: A National Incidence Study
To determine if child physical abuse hospitalization rates vary across urban-rural regions overall and after accounting for race/ethnicity and poverty demographics.
https://ift.tt/2P4Q9vb
Sildenafil Use in Children with Pulmonary Hypertension
To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil.
https://ift.tt/2CYT7dx
Antifungal activity of recombinant thanatin in comparison with two plant extracts and a chemical mixture to control fungal plant pathogens
The most common method for controlling plant diseases is the application of chemical pesticides and sometimes use of resistant cultivars. Due to the effects of chemical pesticides on human and environmental he...
https://ift.tt/2F0ye4g
Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin
Suleiman Furmli<br />Oct 9, 2018; 2018:bcr-2017-221854-bcr-2017-221854<br />Myth exploded
https://ift.tt/2yNLDXJ
Measurement of Force-Sensitive Protein Dynamics in Living Cells Using a Combination of Fluorescent Techniques
Here, we present a protocol for the simultaneous use of Förster resonance energy transfer-based tension sensors to measure protein load and fluorescence recovery after photobleaching to measure protein dynamics enabling the measurement of force-sensitive protein dynamics within living cells.
https://ift.tt/2CYuu0z
4 alerts you should set up on your ePCR
ePCR alerts, milestones and triggers can prompt meaningful analysis, immediate action or additional training
https://ift.tt/2yP0zVF
4 alerts you should set up on your ePCR
ePCR alerts, milestones and triggers can prompt meaningful analysis, immediate action or additional training
https://ift.tt/2P1BC3k
Measuring Interactions of Globular and Filamentous Proteins by Nuclear Magnetic Resonance Spectroscopy (NMR) and Microscale Thermophoresis (MST)
Here, we present a protocol for the production and purification of proteins that are labeled with stable isotopes, and subsequent characterization of protein-protein interactions using Nuclear Magnetic Resonance (NMR) spectroscopy and MicroScale Thermophoresis (MST) experiments.
https://ift.tt/2Ql0gJ6
Use of Pre-Assembled Plastic Microfluidic Chips for Compartmentalizing Primary Murine Neurons
https://ift.tt/2qqw43W
Probing Cell Mechanics with Bead-Free Optical Tweezers in the Drosophila Embryo
We present a setup of optical tweezers coupled to a light sheet microscope, and its implementation to probe cell mechanics without beads in the Drosophila embryo.
https://ift.tt/2QdPILx
Angiographic Characteristics of Hemorrhagic and Ischemic Phases of Reversible Cerebral Vasoconstriction Syndrome
Abstract
Purpose
This study aimed to assess the evolution of imaging patterns over time in patients with neurological complications caused by reversible cerebral vasoconstriction syndrome.
Methods
A total of 24 consecutive patients with reversible cerebral vasoconstriction syndrome presenting between 2009 and 2016 were included, whose disease course was complicated by intracranial hemorrhage and/or ischemic events. In total 55 angiographic studies were carried out. The nature of the intracranial complication and location of vasoconstriction on the angiograms in relation to the time interval since symptom-onset were assessed.
Results
Complications included subarachnoid hemorrhage (n = 19, 79%), intracerebral hemorrhage (n = 7, 29%), ischemic stroke (n = 6, 25%), and transient ischemic attack (n = 4, 17%). Hemorrhagic complications mainly occurred within 7 days after symptom onset (18/19 patients, 95%), whereas ischemic events only occurred after the first week (10/10 patients, 100%, p < 0.00001). Distal vasospasm was predominantly observed within 7 days (26/28 angiograms, 93%) and proximal vasospasm ≥7 days (23/27 angiograms, 85%, p < 0.00001).
Conclusion
In reversible cerebral vasoconstriction syndrome causing neurological complications, an early hemorrhagic phase with distal vasospasm and a delayed ischemic phase with proximal vasospasm can be discriminated.
https://ift.tt/2SGKwkT
AAP: Parents Frequently Save Leftover Antibiotics
FRIDAY, Nov. 2, 2018 -- Almost half of parents report saving leftover antibiotics, and almost three-quarters of these parents subsequently divert the antibiotics, according to a study presented at the annual meeting of the American Academy of...
https://ift.tt/2Diu9GY
Age, Racial Disparities Seen in Hospitalization for Heart Failure
FRIDAY, Nov. 2, 2018 -- For emergency department patients with heart failure, data reveal age and racial disparities in hospitalization rates, according to a study published in the November issue of the American Journal of Preventive...
https://ift.tt/2JyCKpj
CDC: Prevalence of Gestational Diabetes 6.0 Percent in 2016
FRIDAY, Nov. 2, 2018 -- The prevalence of gestational diabetes was 6.0 percent in 2016, with a slight increase seen from 2012 to 2016, according to research published in the Nov. 2 issue of the U.S. Centers for Disease Control and Prevention's...
https://ift.tt/2Dhq4Tx
Social Stigma Worsens Mental Health With Autism
FRIDAY, Nov. 2, 2018 -- Stress related to social stigma may contribute to why people with autism experience more mental health problems than the general population, according to a study published online Oct. 12 in Society and Mental Health. Monique...
https://ift.tt/2JxGNC6
HPV Vaccination Uptake Increasing, but Still Too Low
FRIDAY, Nov. 2, 2018 -- Although progress has been made in increasing human papillomavirus (HPV) vaccination, coverage is still too low to achieve full cancer prevention potential, according to a report from the President's Cancer Panel published...
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National Youth Obesity Rate at 15.8 Percent for 2016 to 2017
FRIDAY, Nov. 2, 2018 -- In 2016 to 2017, the national obesity rate for youth ages 10 to 17 years was 15.8 percent, which was not statistically different from the 16.1 percent rate in 2016 alone, according to a report published by the Robert Wood...
https://ift.tt/2JFDpW9
Head and Neck Cancer Survivors Have Increased Suicide Risk
FRIDAY, Nov. 2, 2018 -- Head and neck cancer (HNC) survivors have an increased risk for suicide compared with other cancer survivors, according to a study published online Oct. 18 in Cancer. Nosayaba Osazuwa-Peters, Ph.D., M.P.H., from the St. Louis...
https://ift.tt/2Diu9qs
Higher Serum Cortisol Level Linked to Lower Brain Volumes
FRIDAY, Nov. 2, 2018 -- Higher serum cortisol level is associated with lower brain volumes and impaired memory in asymptomatic younger to middle-aged adults, according to a study published online Oct. 24 in Neurology. Justin B. Echouffo-Tcheugui,...
https://ift.tt/2JxIX4J
Earlier Vascular Access Seen in Insured Dialysis Patients
FRIDAY, Nov. 2, 2018 -- Patients with Medicare or Medicaid are more likely than uninsured patients to use an arteriovenous fistula or graft by their fourth dialysis month, according to a study published online Nov. 1 in the Clinical Journal of the...
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AAP: More Children Visiting Pediatric EDs for Mental Health
FRIDAY, Nov. 2, 2018 -- From 2012 to 2016 there was an increase in the number of children visiting pediatric emergency departments (PEDs) with mental health-related diagnoses, according to a study presented at the annual meeting of the American...
https://ift.tt/2JzYi4L
Detection and Quantification of Plasmodium falciparum in Aqueous Red Blood Cells by Attenuated Total Reflection Infrared Spectroscopy and Multivariate Data Analysis
Here, we present a protocol for the detection and quantification of Plasmodium falciparum in infected aqueous red blood cells using an attenuated total reflection infrared spectrometer and multivariate data analysis.
https://ift.tt/2P3hIFg
A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
IκB Kinase 1/α (IKK1/α CHUK) is a Ser/Thr protein kinase that is involved in a myriad of cellular activities primarily through activation of NF-κB transcription factors. Here, we describe the main steps necessary for the production and crystal structure determination of this protein.
https://ift.tt/2CVB9IQ
Cancers, Vol. 10, Pages 420: Automated Knowledge-Based Intensity-Modulated Proton Planning: An International Multicenter Benchmarking Study
Cancers, Vol. 10, Pages 420: Automated Knowledge-Based Intensity-Modulated Proton Planning: An International Multicenter Benchmarking Study
Cancers doi: 10.3390/cancers10110420
Authors: Alexander R. Delaney Lei Dong Anthony Mascia Wei Zou Yongbin Zhang Lingshu Yin Sara Rosas Jan Hrbacek Antony J. Lomax Ben J. Slotman Max Dahele Wilko F. A. R. Verbakel
Background: Radiotherapy treatment planning as an increasingly automated and knowledge-based planning has been shown to match and sometimes improve upon manual clinical plans, with increased consistency and efficiency. In this study, we benchmarked a novel prototype knowledge-based intensity-modulated proton therapy (IMPT) planning solution, against three international proton centers. Methods: A model library was constructed, comprising 50 head and neck cancer (HNC) manual IMPT plans from a single center. Three external-centers each provided seven manual benchmark IMPT plans. A knowledge-based plan (KBP) using a standard beam arrangement for each patient was compared with the benchmark plan on the basis of planning target volume (PTV) coverage and homogeneity and mean organ-at-risk (OAR) dose. Results: PTV coverage and homogeneity of KBPs and benchmark plans were comparable. KBP mean OAR dose was lower in 32/54, 45/48 and 38/53 OARs from center-A, -B and -C, with 23/32, 38/45 and 23/38 being >2 Gy improvements, respectively. In isolated cases the standard beam arrangement or an OAR not being included in the model or being contoured differently, led to higher individual KBP OAR doses. Generating a KBP typically required <10 min. Conclusions: A knowledge-based IMPT planning solution using a single-center model could efficiently generate plans of comparable quality to manual HNC IMPT plans from centers with differing planning aims. Occasional higher KBP OAR doses highlight need for beam angle optimization and manual review of KBPs. The solution furthermore demonstrated the potential for robust optimization.
https://ift.tt/2QdPZhF
Non-superiority of lumen-apposing metal stents: Is the evidence conclusive?
With great interest we have read the work of Bang et al, comparing the efficacy of lumen-apposing metal stents (LAMS) and double-pigtail plastic stents (DPS) for endoscopic drainage of walled-off necrosis (WON).1 We congratulate the authors on completing the first randomised controlled trial comparing these two drainage strategies. They found no difference in the total number of procedures needed to achieve treatment success at 6-month follow-up. However, we feel that three important limitations have not been mentioned in the discussion.
First, we question whether the potential benefits of LAMS could have been proven in the included study population. The larger calibre lumen of the LAMS allows spontaneous drainage of necrotic tissue, hypothetically reducing the need for endoscopic necrosectomy. Bang et al indeed demonstrated a very low number of endoscopic necrosectomies in patients treated with LAMS (13%), but also an unusual low number of endoscopic necrosectomies in patients drained with...
https://ift.tt/2Rv9aDN
Tree of Life synagogue shooting shows need for TEMS teams
Tactical emergency medical support medics were able to get to victims of the Pittsburgh shooting quickly and render aid
https://ift.tt/2DjpiFk
A Systematic Review and Meta-Analysis Comparing the Short- and Long-Term Outcomes for Laparoscopic and Open Liver Resections for Hepatocellular Carcinoma: Updated Results from the European Guidelines Meeting on Laparoscopic Liver Surgery, Southampton, UK, 2017
Abstract
Background
The laparoscopic approach to liver resection has experienced exponential growth in recent years; however, its application is still under debate and objective, evidence-based guidelines for its safe future progression are needed.
Objective
The aim of this study was to perform a systematic review and meta-analysis comparing the short- and long-term outcomes of laparoscopic and open liver resections for hepatocellular carcinoma (HCC).
Methods
To identify all the comparative manuscripts reporting on laparoscopic and open liver resection for HCC, all published English-language studies with more than 10 cases were screened. In addition to the primary meta-analysis, four specific subgroup analyses were performed on patients with Child–Pugh A cirrhosis, resections for solitary tumors, and those undergoing minor and major resections. The quality of the studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology and the Newcastle–Ottawa Scale.
Results
From the initial 361 manuscripts, 28 were included in the meta-analysis. Five of these 28 manuscripts were specific to patients with Child–Pugh A cirrhosis (321 cases), 11 focused on solitary tumors (1003 cases), 16 focused on minor resections (1286 cases), and 3 focused on major resections (164 cases). Three manuscripts compared 1079 cases but could not be assigned to any of the above subanalyses. In general terms, short-term outcomes were favorable when using a laparoscopic approach, especially in minor resections. The only advantage seen with an open approach was reduced operative time during major liver resections. No differences in long-term outcomes were observed between the approaches.
Conclusions
Laparoscopic liver resection for HCC is feasible and offers improved short-term outcomes, with comparable long-term outcomes as the open approach.
https://ift.tt/2Ollgxa
Ultrahigh Resolution Mouse Optical Coherence Tomography to Aid Intraocular Injection in Retinal Gene Therapy Research
https://ift.tt/2qneLAA
Quantitative comparison of drug efficacy in treating hot flashes in patients with breast cancer
Abstract
Objective
This study aimed to quantitatively evaluate drug efficacy and identify relevant factors that affect the relief of hot flashes in patients with breast cancer.
Methods
A comprehensive literature search was performed using public databases. Randomized clinical studies on drug therapy for the treatment of hot flashes in patients with breast cancer were identified. A time-effect model was established, and crucial pharmacodynamic parameters, such as maximal efficacy (Emax) and onset time (ET50), were used to reflect the differences in efficacy among the drugs.
Results
Eighteen studies involving 5178 subjects were included. It was found that the baseline of hot flashes was an important factor for the Emax value of drugs. After correcting the baseline to the level of eight times per day, the Emax values of progesterone, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), neuroleptic agents, tibolone, phytoestrogen, other types of drugs, and placebo were 8.3(95%CI 6.8, 9.9),5.1(95%CI 4.4, 5.7), 4.4(95%CI 3.6, 5.3), 4.0(95%CI 3.6, 4.3), 3.4(95%CI 2.4, 4.3), 2.5(95%CI 0.8, 4.2), and 2.7(95%CI 2.1, 3.3), respectively. The ET50 of all the drugs were approximately 2–2.5 weeks, which was obviously longer than that of the placebo (1.2 weeks). When compared with the previously reported efficacy characteristics in natural menopausal women, no significant difference was found between the two populations.
Conclusions
Progesterone showed the highest efficacy, followed by SSRIs/SNRIs, neuroleptic agents, and tibolone, while phytoestrogen and other types of drugs showed no efficacy advantages. There is a significant association between the baseline of hot flashes and drug efficacy, while there was no significant difference between breast cancer patients and natural menopausal women.
https://ift.tt/2EYqyPQ
Notch Signaling Promotes Development of Allergic Rhinitis by Suppressing Foxp3 Expression and Treg Cell Differentiation
Background: The Notch signaling pathway plays an important role in regulating human immune function, but the relationship between allergic rhinitis (AR) and Notch signaling remains unclear. Objective: To investigate the role of Notch signaling in the pathogenesis of AR and its regulation on Foxp3-Treg cells. Method: The sera of 100 patients with AR and 50 controls were collected to assess the differences in Notch1, Jagged1, and DLL1 (Delta-like 1) expression. Experimental mice were divided into normal control, AR, Notch inhibitor, and dexamethasone groups. Allergic symptoms, total IgE levels, and the proportion of Treg cells in the peripheral blood were detected. Notch1, Jagged1, NICD (Notch intracellular domain, also known as ICN), and Foxp3 expression and Th1/Th2/Th17-related cytokines in the spleen were detected and compared between each group of mice. Results: Compared with the control group, the expression of Notch1 and Jagged1 in patients with AR was significantly elevated (p #x3c; 0.05). The expression of Notch1 and Jagged1 in patients with severe AR was higher than that observed in the mild to moderate AR patients and positively correlated with the levels of allergen sIgE (p #x3c; 0.05). The animal experiments revealed that compared with the normal control group, the expression of Notch1, Jagged1, and NICD in the AR group was increased, Foxp3 expression was decreased, and the proportion of Treg cells was decreased (p #x3c; 0.05). Compared with the AR group, allergic symptoms and total serum IgE levels and the expression of Notch1, Jagged1, and NICD were significantly decreased in the Notch inhibited group, whereas the expression of Foxp3 and the proportion of Treg cells were increased significantly (p #x3c; 0.05). The Th2-type immune responses were also enhanced and Th1-type immune responses decreased in the AR group, but the Th1/Th2 imbalance was reversed in the Notch inhibited group. Conclusion: Notch signaling downregulates Foxp3 expression and inhibits the differentiation of Treg cells to promote the development of AR. Blocking Notch signaling may be a potential treatment for AR.
Int Arch Allergy Immunol
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Int Arch Allergy Immunol
https://ift.tt/2QeR5JQ
Intralymphatic Immunotherapy: Update and Unmet Needs
Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes – intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations.
Int Arch Allergy Immunol
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When should EMS professionals report abuse?
Our cohosts discuss a recent event involving a paramedic allegedly choking a patient, and how and when to speak up in that situation
https://ift.tt/2QaSQIg
Cost-Effectiveness of Primary Prevention with Statin Treatment for Chinese Patients with Type 2 Diabetes
Abstract
Introduction
Statins can reduce the risk of cardiovascular events in patients with diabetes. The objective of this analysis was to evaluate whether primary prevention with statin treatment is cost-effective for newly diagnosed type 2 diabetes mellitus (T2DM) patients in the Chinese context.
Methods
An economic analysis of primary prevention with statin treatment was conducted using the Chinese Outcomes Model for T2DM with a time horizon of a lifetime, which was developed and validated based on the Chinese population. Clinical costs and utility inputs were gathered from published sources. Lifetime discounted quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER) were measured. The uncertainty was evaluated by one-way and probabilistic sensitivity analyses.
Results
Statin treatment with atorvastatin 10 mg could add 0.08 QALYs with an additional $1676 compared with that of no statin management (control strategy) over a lifetime horizon, which led to an ICER of $21,924 per QALY gained. At a willingness-to-pay threshold of $27,351 per QALY gained, there was an approximately 80% probability of statin treatment being cost-effective compared with the control strategy. The model outcomes were most sensitive to the length of the expected life and age at the T2DM diagnosis.
Conclusions
Statin treatment with atorvastatin is most likely cost-effective for primary prevention in Chinese patients newly diagnosed with type 2 diabetes.
Funding
Partially funded by Pfizer Inc.
https://ift.tt/2Qf3EF4
Inner ear pathologies impair sodium-regulated ion transport in Meniere’s disease
Abstract
Meniere's disease (MD), a syndromal inner ear disease, is commonly associated with a pathological accumulation of endolymphatic fluid in the inner ear, termed "idiopathic" endolymphatic hydrops (iEH). Although numerous precipitating/exacerbating factors have been proposed for MD, its etiology remains elusive. Here, using immunohistochemistry and in situ protein–protein interaction detection assays, we demonstrate mineralocorticoid-controlled sodium transport mechanisms in the epithelium of the extraosseous portion of the endolymphatic sac (eES) in the murine and human inner ears. Histological analysis of the eES in an extensive series of human temporal bones consistently revealed pathological changes in the eES in cases with iEH and a clinical history of MD, but no such changes were found in cases with "secondary" EH due to other otological diseases or in healthy controls. Notably, two etiologically different pathologies—degeneration and developmental hypoplasia—that selectively affect the eES in MD were distinguished. Clinical records from MD cases with degenerative and hypoplastic eES pathology revealed distinct intergroup differences in clinical disease presentation. Overall, we have identified for the first time two inner ear pathologies that are consistently present in MD and can be directly linked to the pathogenesis of EH, and which potentially affect the phenotypical presentation of MD.
https://ift.tt/2P9LEje
Correction to: Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours
In the publication of this article (1), there is an error in Fig. 5b. This has now been updated in the original article (1).
https://ift.tt/2SG6NiL
Early cross-sectional imaging following open and laparoscopic cholecystectomy: a primer for radiologists
Abstract
Performed on either an elective or urgent basis, cholecystectomy currently represents the most common abdominal operation due to the widespread use of laparoscopy and the progressively expanded indications. Compared to traditional open surgery, laparoscopic cholecystectomy minimised the duration of hospitalisation and perioperative mortality. Albeit generally considered safe, cholecystectomy may result in adverse outcomes with non-negligible morbidity. Furthermore, the incidence of worrisome haemorrhages and biliary complications has not been influenced by the technique shift. Due to the growing medico-legal concerns and the vast number of cholecystectomies, radiologists are increasingly requested to investigate recently operated patients. Aiming to increase familiarity with post-cholecystectomy cross-sectional imaging, this paper provides a brief overview of indications and surgical techniques and illustrates the expected early postoperative imaging findings. Afterwards, most iatrogenic complications following open, converted, laparoscopic and laparo-endoscopic rendezvous cholecystectomy are reviewed with examples, including infections, haematoma and active bleeding, residual choledocholithiasis, pancreatitis, biliary obstruction and leakage. Multidetector computed tomography (CT) represents the "workhorse" modality to rapidly investigate the postoperative abdomen in order to provide a reliable basis for an appropriate choice between conservative, interventional or surgical treatment. Emphasis is placed on the role of early magnetic resonance cholangiopancreatography (MRCP) and additional gadoxetic acid-enhanced MRCP to provide a non-invasive anatomic and functional assessment of the operated biliary tract.
Teaching Points
• Having minimised perioperative mortality and hospital stay, laparoscopy has now become the first-line approach to performing cholecystectomy, even in patients with acute cholecystitis.
• Laparoscopic, laparo-endoscopic rendezvous, converted and open cholecystectomy remain associated with non-negligible morbidity, including surgical site infections, haemorrhage, residual lithiasis, pancreatitis, biliary obstruction and leakage.
• Contrast-enhanced multidetector computed tomography (CT) is increasingly requested early after cholecystectomy and represents the "workhorse" modality that rapidly provides a comprehensive assessment of the operated biliary tract and abdomen.
• Magnetic resonance cholangiopancreatography (MRCP) is the best modality to provide anatomic visualisation of the operated biliary tract and is indicated when biliary complications are suspected.
• Additional gadoxetic acid (Gd-EOB-DTPA)-enhanced MRCP non-invasively provides functional biliary assessment, in order to confirm and visualise bile leakage.
https://ift.tt/2qsaknX
Neuroimaging in Fabry disease: current knowledge and future directions
Abstract
Fabry disease (FD) is a rare X-linked disorder characterised by abnormal progressive lysosomal deposition of globotriaosylceramide in a large variety of cell types. The central nervous system (CNS) is often involved in FD, with a wide spectrum of manifestations ranging from mild symptoms to more severe courses related to acute cerebrovascular events. In this review we present the current knowledge on brain imaging for this condition, with a comprehensive and critical description of its most common neuroradiological imaging findings. Moreover, we report results from studies that investigated brain physiopathology underlying this disorder by using advanced imaging techniques, suggesting possible future directions to further explore CNS involvement in FD patients.
Teaching Points
• Conventional neuroradiological findings in FD are aspecific.
• White matter hyperintensities represent the more consistent brain imaging feature of FD
• Abnormalities of the vasculature wall of posterior circulation are also consistent features.
• The pulvinar sign is not reliable as a finding pathognomonic for FD.
• Advanced imaging techniques have increased our knowledge about brain involvement in FD.
https://ift.tt/2QftGs3
Voters’ Preexisting Opinions Shift to Align with Political Party Positions
The views expressed by political party leaders can change how individual voters feel about an issue, according to findings from a longitudinal study of voters in New Zealand. The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"Partisanship is indeed a powerful force in shaping our own attitudes and preferences," says lead researcher Nicole Satherley of the University of Auckland. "Our research shows that the positions taken by political leaders and political parties can have an important impact on peoples' preferences, even on issues that are supposed to reflect personal preferences."
Laboratory-based research has shown the effects that partisan cues can have on political issues, but Satherley and colleagues wanted to investigate the phenomenon in a real-world setting by measuring actual voters' attitudes on real-life issues.
In 2015, New Zealand held a referendum on changing the national flag, an issue that quickly became polarized along party lines. John Key, then-New Zealand Prime Minister and leader of the centre-right National Party, advocated for changing the flag design, while, Andrew Little, then-leader of the centre-left Labour Party, opposed the change.
The New Zealand Attitudes and Values Study (NZAVS) happened to include questions measuring voters' attitudes about changing the flag in 2013, before the referendum was introduced, and again in 2016, after it had been introduced. Satherley and colleagues capitalized on these data, examining participants' support for changing the flag ("yes," "no," or "unsure") and the degree to which participants in the study also supported or opposed the National and Labour parties.
As the researchers hypothesized, the data showed that participants tended to shift their opinions to align with those of their preferred political party. Overall, 30.5% of National Party voters and 27.5% of Labour Party voters moved away from the position they originally reported in 2013 to become closer to, or consistent with, the position endorsed by their party leader.
In other words, the researchers found that support for either the National Party or Labour Party predicted whether individual voters remained stable in their views or changed over time. Relative to remaining opposed to changing the existing flag design, strong supporters of the National Party were over three times as likely to shift their opinion in favor of a flag change compared with those who expressed low support for the National Party. At the same time, strong supporters of the Labour Party who originally backed the change were more likely to shift toward opposing the change compared with participants who expressed low support for the Labour Party.
And strong party supporters whose opinions were already in line with the party position were less likely to shift their attitudes over time compared with participants who expressed low levels of party support.
"Taken together, these findings suggest that heated debate over important, albeit seemingly non-partisan, issues can quickly become polarized along partisan lines and sway public opinion," explains Satherley. "When considering political issues, members of the public should therefore be aware of this potential influence, and carefully consider whether politicians' views and arguments truly align with their own opinions."
The researchers note that the findings generate some important questions for future research. For example, what motivates party supporters to change their vote? Do they shift their opinions to align with their party leaders or is it possible they shift in order to combat the opinions of the opposing party? Future research should also explore other factors that are likely to make a difference in the strength of partisan effects, such as political awareness, the perceived importance of an issue, and the degree of polarization on an issue.
"In the future, we would like to continue examining other outcomes that partisan cues impact and then identify the factors that reduce such partisan effects in real-world settings," says Satherley.
Coauthors on the research include Kumar Yogeeswaran of the University of Canterbury and Danny Osborne and Chris G. Sibley of the University of Auckland.
Collection of the New Zealand Attitudes and Values Study data analyzed in this article was supported by a grant from the Templeton Religion Trust (No. TRT0196) awarded to C. G. Sibley and a University of Auckland faculty research grant (No. 3709123) awarded to D. Osborne. N. Satherley was supported by a University of Auckland doctoral scholarship.
All materials have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Materials.
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Pulsara unveils 3 new patient-type modules for communication platform
The additional modules include Trauma, Sepsis and Cardiac Arrest, allowing care team members to communicate about patients more efficiently
https://ift.tt/2P6qfHA
Cancers, Vol. 10, Pages 419: A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico
Cancers, Vol. 10, Pages 419: A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico
Cancers doi: 10.3390/cancers10110419
Authors: Hector J. Diaz-Zabala Ana P. Ortiz Lisa Garland Kristine Jones Cynthia M. Perez Edna Mora Nelly Arroyo Taras K. Oleksyk Miguel Echenique Jaime L. Matta Michael Dean Julie Dutil
Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.
https://ift.tt/2SFPMFG
Local dynamic stability in temporal pattern of intersegmental coordination during various stride time and stride length combinations
Abstract
For the regulation of walking speed, the central nervous system must select appropriate combinations of stride time and stride length (stride time–length combinations) and coordinate many joints or segments in the whole body. However, humans achieve both appropriate selection of stride time–length combinations and effortless coordination of joints or segments. Although this selection of stride time–length combination has been explained by minimized energy cost, it may also be explained by the stability of kinematic coordination. Therefore, we investigated the stability of kinematic coordination during walking across various stride time–length combinations. Whole body kinematic coordination was quantified as the kinematic synergies that represents the groups of simultaneously move segments (intersegmental coordination) and their activation patterns (temporal coordination). In addition, the maximum Lyapunov exponents were utilized to evaluate local dynamic stability. We calculated the maximum Lyapunov exponents in temporal coordination of kinematic synergies across various stride time–length combinations. The results showed that the maximum Lyapunov exponents of temporal coordination depended on stride time–length combinations. Moreover, the maximum Lyapunov exponents were high at fast walking speeds and very short stride length conditions. This result implies that fast walking speeds and very short stride length were associated with lower local dynamic stability of temporal coordination. We concluded that fast walking is associated with lower local dynamic stability of temporal coordination of kinematic synergies.
https://ift.tt/2P3YsHz
Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis
Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis
Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis, Published online: 02 November 2018; doi:10.1038/s41419-018-1171-z
Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axishttps://ift.tt/2CXzfr1
Estrogen receptor β upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma
Estrogen receptor β upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma
Estrogen receptor β upregulated by lncRNA-<i>H19</i> to promote cancer stem-like properties in papillary thyroid carcinoma, Published online: 02 November 2018; doi:10.1038/s41419-018-1077-9
Estrogen receptor β upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinomahttps://ift.tt/2P5hHRi
Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor
Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor
Suppressive effect of syndecan ectodomains and <i>N</i>-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor, Published online: 02 November 2018; doi:10.1038/s41419-018-1167-8
Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factorhttps://ift.tt/2CXF33Z
Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-ι/GLI1 pathway
Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-ι/GLI1 pathway
Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-ι/GLI1 pathway, Published online: 02 November 2018; doi:10.1038/s41419-018-1145-1
Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-ι/GLI1 pathwayhttps://ift.tt/2P4QcXL
New Research From Psychological Science
Read about the latest research published in Psychological Science:
Contingent Attentional Engagement: Stimulus- and Goal-Driven Capture Have Qualitatively Different Consequences
Alon Zivony and Dominique Lamy
Zivony and Lamy examined whether shifting attention to a location resulted in attentional engagement (i.e., extracting the features at that location). They presented a cue (four dots) that either shared the target color (e.g., the dots were red) or did not (e.g., the dots were white), and the cue appeared either where the target would appear or elsewhere. They then presented a target defined by its known color (e.g., a red letter) along with three distractors (three orange or pink letters). Participants were asked to identify the letter in the target color. Results indicated that the cue captured attention both when it shared the target's color and when it did not. However, when the cue signaled the location of a distractor that shared the features of the target (e.g., the target was a red "H" and the distractor in the cued location was an orange "H"), participants took longer to identify the target, and they were less accurate when the cue shared the target color than when it did not. This compatibility effect shows that attentional engagement might come at a cost, Zivony and Lamy argue, and supports the idea that attention can be shifted without being engaged.
Chimpanzee Cooperation Is Fast and Independent From Self-Control
Alexandra G. Rosati, Lauren M. DiNicola, and Joshua W. Buckholtz
Rosati and colleagues tested 40 chimpanzees in six tasks to examine the cognitive basis of cooperation. They analyzed chimpanzee's performance in three cooperative tasks: a resource-donation task in which they could choose to share food or not, an instrumental-helping task in which they could choose to hand an instrument to a human experimenter, and a punishment task in which they could punish a thief. In these tasks, the animals made prosocial choices faster than they made selfish choices, and the most prosocial chimpanzees made the fastest prosocial responses. However, performance in the three tasks did not depend on each other. Rosati et al. also measured chimpanzee's self-control in a go/no-go task and by having them decide between eating an immediate small portion of food or a delayed large portion, and found no link between self-control and prosocial choices. Finally, they measured social responsivity in a task in which chimpanzees could approach social or nonsocial stimuli (e.g., a person or photos of chimpanzees, and objects or food items, respectively), and they found that chimpanzees who approached social stimuli the fastest had shown more instrumental help but less food-sharing behavior in the cooperative tasks. Taken together, these results suggest that different cognitive processes are involved in cooperation and that cooperation does not depend on self-control. Moreover, chimpanzees and humans seem to share some key cognitive processes for cooperation.
The Power of Attention: Using Eye Gaze to Predict Other-Regarding and Moral Choices
Minou Ghaffari and Susann Fiedler
Recent studies indicate that other-regarding choices (e.g., helping a stranger) and moral choices are affected by eye gaze. Thus, along with top-down processes (controlled processes in which one weighs information), bottom-up processes (in which one focuses on the characteristics of the choices' presentation) also seem to drive information search and, consequently, the decision. Ghaffari and Fiedler asked participants to make other-regarding choices (in which their interests conflicted with others' interests) and moral choices (in which any choice encompassed undesirable outcomes). They used an eye tracker to measure participants' eye fixations as an indicator of the choice process, and, in some cases, prompted participants to make a choice when their last fixation was directed at a randomly allocated target option. Participants were more likely to choose their last-fixated choice when their fixation was not interrupted and, to a lesser extent, when their last fixation was randomly allocated by the researchers. Also, experimentally manipulated final fixations predicted choices, revealing the influence of bottom-up processes. Thus, attention seems to be a product and a driver of decision making, and choices may be influenced by guiding attention.
https://ift.tt/2DfC9sp
Proposal for the Classification of Peri-Implant Femoral Fractures: Retrospective cohort study
Publication date: Available online 1 November 2018
Source: Injury
Author(s): Miquel Videla-Cés, José-Miguel Sales-Pérez, Rubén Sánchez-Navés, Eudald Romero-Pijoan, Sebastián Videla, on behalf of the "Peri-implant Femoral Fractures Study Group"
Abstract
Background
Peri-implant fractures occur in association with an implant used to treat a previous injury and that is still attached to the bone. Peri-implant fractures are considered to be relatively "new" fractures and they lack any classification system that is accepted in practice. Generally, the fracture classification systems currently used in our clinical practice were not developed or validated using rigorous scientific evaluation methods.
Aim
To provide data for a proposed classification of peri-implant femoral fractures.
Methods
This is an international and multicentre study (12 centres) based on a cohort of consecutive peri-implant fractures with the criterion being: a fracture in any segment of the femur in association with previously-used osteosynthesis material, whether a nail, plate or screws. A proposed system for the classification was tested, based on a topographical classification using alphanumeric coding, following a similar nomenclature to that explained in the "Vancouver-Classification-for-Total-Hip-Arthroplasty-Periprosthetic-Fractures", and classified according to whether the implant is a nail, a screw or a plate, and the location of the fracture in relation to the original implant and the affected femoral segment.
The study coordinator performed the first classification exercise, which was discussed subsequently for the study coordinator group to reach a consensus. A descriptive analysis of the fractures was produced. The proportion of peri-implant femoral fractures was estimated, and 95% confidence interval (95%CI) was calculated.
Results
Between January 2013 and December 2016, data on a total of 143 peri-implant femoral fractures were collected.
Only 5 (3.5%) fractures had to be discussed to reach a consensus. The most common peri-implant femoral fractures were located at the diaphyseal segment (#32) and associated with nails or plates: 51%, 73/143, 95%CI:43-59%; at the proximal segment (#31): 39%, 56/143, 95%CI:32-47%; and at the distal femoral segment (#33): 10%, 14/143, 95%CI:6-16%. The highest proportion of peri-implant femoral fractures corresponded to #31-AN (trochanteric and neck area) and #32-CNP (diaphysis fractures distant from the implant, often distal and spiral).
Conclusion
The proposed classification for peri-implant femoral fractures appears to be useful and easy to accomplish. Future studies will be necessary to validate it and demonstrate the effectiveness of its application in clinical practice.
https://ift.tt/2P3HGIT
Does external fixator pin site distance from definitive implant affect infection rate in pilon fractures?: Possible option at the reviewers’/editors’ discretion: ‘Deep infection in pilon fractures: analysis of external fixator pin site distance from definitive implant and other risk factors’
Publication date: Available online 1 November 2018
Source: Injury
Author(s): Michael M. Hadeed, Cody L. Evans, Brian C. Werner, Wendy M. Novicoff, David B. Weiss
Abstract
Introduction
Tibial pilon fractures are often treated with initial external fixation followed by delayed definitive fixation. It has been postulated that the external fixator pin site may correlate with infection risk. The purpose of this study was to determine whether external fixator pin-site distance from definitive implants impacts the risk of deep infection in pilon fractures.
Materials and Methods
A retrospective cohort study was completed at a single level 1 trauma center. All patients ages 15-65 who underwent open reduction and internal fixation (ORIF) of a distal tibial fracture (AO/OTA Classification 43) from 2007-2013 were included. The final study population was 133 patients. The impact of external fixation pin location (relative to the definitive implant location) on postoperative infection was measured.
Results
As a continuous variable, the distance between the closest pin site and plate was 62.1 +/- 44.1 mm in the infected cohort and 62.2 +/- 49.7 mm in the non-infected cohort (p = 0.991). Further analysis was performed by grouping the distances into less than 0 mm (i.e. overlapping), >0.0 – 25.0 mm, >25.0 – 50.0 mm, >50.0 – 75.0 mm, >75.0 – 100.0 mm, and >100.0 mm of separation. No significant differences were noted with regards to the risk for infection.
Conclusions
Staged care has been shown to be an effective treatment strategy for AO/OTA type 43 fractures. There are many variables to consider when placing an external fixator construct. In this cohort, pin site distance from definitive implant location was not associated with an increase in deep infections.
Level of Evidence
Level III
https://ift.tt/2CX9pn5
Correction to: Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca 2+ -dependent pathway in mouse Neuro-2a neuroblastoma cells
The original version of this article contained a mistake in the figure. The Ca2 + confocal image for the 2-APB/Apicidin-120 min in Fig. 5d is incorrect. The correction does not influence either the validity of the published data or the conclusion described in the article. The corrected Fig. 5d is given below.
https://ift.tt/2JyHbR0
Correction to: Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca 2+ -, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells
The original version of this article contained mistakes in figures. The western blot data for pro-caspase-3 and cleaved caspase-3 (Fig. 1d), β-actin (Fig. 1d), PLCγ1 (Fig. 5d), and eIF2α (Fig. 7d) are incorrect. The corrected Figs. 1d, 5d, and 7d are shown below. The corrections do not influence either the validity of the published data or the conclusion described in the article.
https://ift.tt/2DkBMwL
Targeting CTCFL/BORIS for the immunotherapy of cancer
Abstract
Cancer vaccines have great potential in the fight against metastatic malignancies. Current anti-tumor immunotherapy is hindered by existing tolerance to tumor-associated antigens (TAA) and tumor escape using various mechanisms, highlighting the need for improved targets for immunotherapy. The cancer–testis antigen CTCFL/BORIS was discovered 16 years ago and possesses all features necessary for an ideal TAA. Recently CTCFL/BORIS has received additional attention as a target expressed in cancer stem cells (CSC). These cells drive tumor growth recurrence, metastasis, and treatment resistance. CTCFL/BORIS silencing leads to senescence and death of CSC. Therefore, an immunotherapeutic strategy that targets CTCFL/BORIS may lead to the selective destruction of CSC and potential eradication of metastatic disease. The high immunotherapeutic potential of CTCFL/BORIS antigen was shown in a stringent 4T1 mouse model of breast cancer. Using these highly metastatic, poorly immunogenic carcinoma cells inoculated into T-helper2 prone mice, we showed that DC fed with recombinant CTCFL/BORIS as an immunogen inhibited tumor growth and reduced the number of metastases in distant organs. About 20% of CTCFL/BORIS immunized animals were tumor free. 50% of animals remained metastasis free. Those having metastasis showed at least tenfold fewer metastases compared to controls. In a rat model of breast cancer, we showed that alphavirus-based CTCFL/BORIS immunotherapy was capable of cancer elimination as we were able to cure 50% of animals. Based on the above data, we believe that translation of CTCFL/BORIS-targeting immunotherapeutic strategies to the clinic will provide new avenues for improving survival of breast cancer patients with advanced metastatic disease.
https://ift.tt/2Qf8OkC
Targeting CTCFL/BORIS for the immunotherapy of cancer
Abstract
Cancer vaccines have great potential in the fight against metastatic malignancies. Current anti-tumor immunotherapy is hindered by existing tolerance to tumor-associated antigens (TAA) and tumor escape using various mechanisms, highlighting the need for improved targets for immunotherapy. The cancer–testis antigen CTCFL/BORIS was discovered 16 years ago and possesses all features necessary for an ideal TAA. Recently CTCFL/BORIS has received additional attention as a target expressed in cancer stem cells (CSC). These cells drive tumor growth recurrence, metastasis, and treatment resistance. CTCFL/BORIS silencing leads to senescence and death of CSC. Therefore, an immunotherapeutic strategy that targets CTCFL/BORIS may lead to the selective destruction of CSC and potential eradication of metastatic disease. The high immunotherapeutic potential of CTCFL/BORIS antigen was shown in a stringent 4T1 mouse model of breast cancer. Using these highly metastatic, poorly immunogenic carcinoma cells inoculated into T-helper2 prone mice, we showed that DC fed with recombinant CTCFL/BORIS as an immunogen inhibited tumor growth and reduced the number of metastases in distant organs. About 20% of CTCFL/BORIS immunized animals were tumor free. 50% of animals remained metastasis free. Those having metastasis showed at least tenfold fewer metastases compared to controls. In a rat model of breast cancer, we showed that alphavirus-based CTCFL/BORIS immunotherapy was capable of cancer elimination as we were able to cure 50% of animals. Based on the above data, we believe that translation of CTCFL/BORIS-targeting immunotherapeutic strategies to the clinic will provide new avenues for improving survival of breast cancer patients with advanced metastatic disease.
https://ift.tt/2Qf8OkC
This is a call to oncologists for action
Abstract
Cancer cases are growing in an exponential way, likewise the prices of new cancer drugs. Continuing in this way, in the near future, it will be impossible to provide optimum care for all cancer patients. Therefore, it is important to establish mechanisms that enable the National Health Systems to provide the best options of treatment, either through the elaboration of decision-binding frameworks or through other initiatives that guarantee the best quality care for all oncology patients to overcome, in the best possible way, this difficult illness. Here, we review current proposals that have been established by different cancer organizations worldwide, their similarities, their differences and whether they are helpful in a real clinical setting. Facing present reality and despite these organizations' huge efforts, these proposals are not being implemented at all and it does not seem feasible that they will in the short run. In the same way, we support and argue why oncologists should have a crucial and a preponderant role to establish the best way of guaranteeing an equal access to the latest oncology care.
https://ift.tt/2RvlmEt
Does NEMO/IKKγ protein have a role in determining prognostic significance in uveal melanoma?
Abstract
Purpose
Uveal melanoma, although a rare form of cancer, is the most common primary malignancy of the eye in adults. Nuclear factor-κB (NF-κB) is a transcription factor that transactivates genes involved in the regulation of cell growth, apoptosis, angiogenesis, and metastasis, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. NF-κB can also be activated by DNA damage pathway through NEMO protein. Therefore, the objective of this study is to elucidate the role of NEMO/IKKγ protein in uveal melanoma patients.
Methods
Seventy-five formalin-fixed paraffin-embedded prospective tissues of uveal melanoma were included in the present study. These cases were reviewed and investigated for the expression of NEMO/IKKγ protein by immunohistochemistry and validated by western blotting along with the qRT-PCR for mRNA expression. Expression levels were correlated with the clinicopathological parameters and patients' outcome.
Results
Immunohistochemistry showed cytoplasmic expression of NEMO/IKKγ expression in only 22 out of 75 (29.33%) cases. This result was confirmed by western blotting, and correlated well with the immunohistochemical expression of NEMO/IKKγ protein (48 kDa). In addition, downregulation of this gene was found in 87.93% of the cases when compared with the normal tissues. On statistical analysis, loss of NEMO/IKKγ protein was correlated with neovascularization, high mitotic count, and presence of vascular loop (p < 0.05). There was less overall survival rate with low expression of NEMO/IKKγ protein in patients with uveal melanoma.
Conclusion
This was the first study suggesting the relevant role of NEMO/IKKγ protein, and highlights the prognostic significance with outcome in uveal melanoma patients. This protein might be used as a screening biomarker in these patients after large-scale validation and translational studies.
https://ift.tt/2PDfjjS
Clinical subtypes and prognosis in breast cancer according to parity: a nationwide study in Korean Breast Cancer Society
Abstract
Purpose
We explored the association between parity and the risk of developing a specific subtype of breast cancer. We also assessed the association between parity and prognosis according to subtypes.
Methods
A total of 158,189 patients were enrolled in the Korean Breast Cancer Society Registry database between 1996 and 2015 in Korea. The database provided information on sex, age, number of parity, surgical method, stage, histological findings, presence of biologic markers, adjuvant therapy, and date and cause of death.
Results
The patients with higher parity showed a higher ratio of triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) subtypes. In univariate analysis, women with TNBC who had more than three children had a worse prognosis compared to other groups (HR 1.83; 95% CI 1.34–2.49; P < 0.001). This association was also observed in women younger than 50 years (HR 1.63; 95% CI 1.07–2.48; P = 0.021). In multivariate analysis stratified by subtypes, women who had more than three children were associated with a worse prognosis in TNBC in the total population (HR 1.53; 95% CI 1.11–2.12; P = 0.011). This association was also observed in patients younger than 50 years of age (HR 1.53; 95% CI 1.09–2.61; P = 0.017).
Conclusion
Women who had more than three children were more likely to develop hormone receptor-negative (HR−) subtypes. Women who had more than three children were associated with worse prognosis in patients younger than 50 years of age and in patients with TNBC.
https://ift.tt/2PAwMto
Digital Screen Time and Pediatric Sleep: Evidence from a Preregistered Cohort Study
To determine the extent to which time spent with digital devices predicts meaningful variability in pediatric sleep.
https://ift.tt/2Qe8ZN3
Circulating miRNA Panels for Specific and Early Detection in Bladder Cancer
Cancer Science, Volume 0, Issue ja, -Not available-.
https://ift.tt/2D004L8
Ways of improving precise knock-in by genome-editing technologies
Abstract
Despite the recent discover of genome-editing methods, today we can say these approaches have firmly entered our life. Two approaches—knocking out malfunctioning gene allele or correcting the mutation with precise knock-in—can be used in hereditary monogenic diseases treatment. The latter approach is relatively ineffective. Modern data about the ways of repair of double-strand DNA breaks formed by nucleases are presented in this review. The main part of the review is devoted to the ways of increasing precise and effective knock-in: inhibition of non-homologous end joining and stimulation of homology-directed repair key factors, use of small molecules with unknown mechanism of action, cell-cycle synchronization and cell-cycle-dependent activity of Cas9, donor molecule design, selection, alternative methods for insertion and other approaches.
https://ift.tt/2zltKze
Investigation of the changes in oscillatory power during task switching after mild traumatic brain injury
European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
https://ift.tt/2znlT48
Spatially Resolving the Condensing Effect of Cholesterol in Lipid Bilayers
We study the effect of cholesterol on the structure of dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayers. Using extensive molecular dynamics computer simulations at atomistic resolution we observe and quantify several structural changes upon increasing cholesterol content that are collectively known as the condensing effect: a thickening of the bilayer, an increase in lipid tail order, and a decrease in lateral area. We also observe a change in leaflet interdigitation and a lack thereof in the distributions of DPPC head group orientations.
https://ift.tt/2CWQJ6R
Dual role of the C-terminal domain in osmosensing by bacterial osmolyte transporter ProP
ProP is a member of the major facilitator superfamily, a proton-osmolyte symporter, and an osmosensing transporter. ProP proteins share extended cytoplasmic carboxyl terminal domains (CTDs) implicated in osmosensing. The CTDs of the best characterized, Group A ProP orthologues terminate in sequences that form intermolecular, antiparallel α-helical coiled-coils (e.g. ProPEc, from Escherichia coli). Group B orthologues lack that feature (e.g. ProPXc, from Xanthomonas campestris). ProPXc was expressed and characterized in E.
https://ift.tt/2P22sby
Common fragile site instability in normal cells: lessons and perspectives
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2SEMx12
A journey with common fragile sites: from S‐phase to telophase
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2zjUEY8
CINSARC SIGNATURE AS A PROGNOSTIC MARKER FOR CLINICAL OUTCOME IN SARCOMAS AND BEYOND
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2SErqvY
Cancer Diagnosis and Immunotherapy in the age of CRISPR
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2zioDQa
Immunohistochemical Correlates of Recurrent Genetic Alterations in Sarcomas
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2SF9bq0
miR‐155 expression in anti‐tumor immunity: the higher the better?
Genes, Chromosomes and Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2zlmnYo
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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