European Journal of Immunology, EarlyView.
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Τρίτη 8 Μαΐου 2018
Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism
Regulation of Intestinal Epithelial Cells Properties and Functions by Amino Acids
Intestinal epithelial cells (IECs) line the surface of intestinal epithelium, where they play important roles in the digestion of food, absorption of nutrients, and protection of the human body from microbial infections, and others. Dysfunction of IECs can cause diseases. The development, maintenance, and functions of IECs are strongly influenced by external nutrition, such as amino acids. Amino acids play important roles in regulating the properties and functions of IECs. In this article, we briefly reviewed the current understanding of the roles of amino acids in the regulation of IECs' properties and functions in physiological state, including in IECs homeostasis (differentiation, proliferation, and renewal), in intestinal epithelial barrier structure and functions, and in immune responses. We also summarized some important findings on the effects of amino acids supplementation (e.g., glutamine and arginine) in restoring IECs' and intestine functions in some diseased states. These findings will further our understanding of the important roles of amino acids in the homeostasis of IECs and could potentially help identify novel targets and reagents for the therapeutic interventions of diseases associated with dysfunctional IECs.
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Homicide victims concealed in a freezer
Abstract
Freezing as a method for hiding a body is rare. We report here a homicide case in which three bodies were concealed in a freezer. This presented the pathologist with the problem of how to thaw the bodies and simultaneously avoid decomposition of the uppermost body. The problem was solved by slow thawing in a refrigerated morgue and by removing the bodies one after the other from top to bottom. The victims were a 27-year old mother and her two daughters, 7 and 9 years of age. The perpetrator was the 34-year old now-divorced husband and father. All were refugees from Syria. The perpetrator fled back to Syria. He was later arrested in Syria, confessed the crime and was sentenced to life imprisonment. The autopsy findings is discussed and compared to finding reported in the scientific literature.
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Unexpected findings and misdiagnoses in coroner’s autopsies performed for trauma at the University of the West Indies, Kingston, Jamaica
Abstract
There has been significant improvement in medical diagnostic technology, but discrepancy rates between clinical and postmortem diagnoses remain relatively high. This study aimed to identify misdiagnoses and missed (unexpected) findings documented during complete coroner's autopsies performed for trauma at the University of the West Indies (UWI) and evaluate their influence on patient outcome. We retrospectively reviewed the reports of all coroner's autopsies performed for trauma, between 2003 and 2012, at the UWI. For each case, we extracted age, gender, trauma type, mechanism and topography, clinical and postmortem diagnoses and hospitalization duration. The data were used to calculate frequencies, proportions and discrepancy rates. 955 coroner's autopsies were performed during the 10-year period; reports were available for 933. 396 of these were performed for trauma; 365 met the inclusion criteria. 260 (71.2%) of the 365 autopsies had at least one discrepancy. There were 746 clinical and 1118 autopsy diagnoses; 382 were discrepant (372 missed [unexpected] diagnoses, 6 mis-diagnoses and 4 over-diagnoses). The discrepancy rate (misdiagnoses and missed diagnoses) was 33.8%, and the majority (55%) occurred in patients hospitalized for <1 day. Cardiopulmonary diseases were the most commonly missed diagnoses. The discrepancy rate was intermediate to those previously reported in the literature. The short hospitalization duration in most patients suggests that limited time for clinical investigation may be a contributor to discrepancy. However, increased awareness among clinicians of the common major missed diagnoses should enhance their early diagnosis, even when clinical signs are subtle, hopefully producing improved patient outcome.
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Different patterns of confabulation in left visuo-spatial neglect
Abstract
Confabulating patients produce statements and actions that are unintentionally incongruous to their history, background, present and future situation. Here we present the very unusual case of a patient with right hemisphere damage and signs of left visual neglect, who, when presented with visual stimuli, confabulated both for consciously undetected and for consciously detected left-sided details. Advanced anatomical investigation suggested a disconnection between the parietal and the temporal lobes in the right hemisphere. A disconnection between the ventral cortical visual stream and the dorsal fronto-parietal networks in the right hemisphere may contribute to confabulatory behaviour by restricting processing of left-sided stimuli to pre-conscious stages in the ventral visual stream.
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Minimally Invasive Surgery for Intracerebral Hemorrhage
Abstract
Purpose of Review
Recent success in preliminary clinical studies evaluating various forms of minimally invasive surgery for spontaneous intracerebral hemorrhage (ICH) has renewed interest in the surgical treatment of this disease process.
Recent Findings
In December of 2016, phase 2 of the Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation (MISTIE) study demonstrated that this form of stereotactic thrombolysis safely reduces clot burden and may improve functional outcome 6 months after injury. A smaller arm of this study, the Intraoperative Stereotactic Computer Tomography-Guided Endoscopic Surgery (ICES) study, also demonstrated feasibility and good functional outcome for endoscopic minimally invasive evacuation.
Summary
Early-phase clinical studies evaluating various forms of minimally invasive surgery for intracerebral hemorrhage evacuation have shown safety and feasibility with a preliminary signal towards improved functional long-term outcome. Results from phase 3 studies addressing various minimally invasive techniques are imminent and will shape how intracerebral hemorrhage is treated.
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Role of the ultrasonographic ‘whirlpool sign’ in intestinal volvulus: a systematic review and meta‐analysis
ANZ Journal of Surgery, EarlyView.
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Transanal total mesorectal excision for locally advanced pT4b rectal cancers
ANZ Journal of Surgery, EarlyView.
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Otoplasty techniques in children: a comparative study of outcomes
ANZ Journal of Surgery, EarlyView.
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Two successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma: a case report
Abstract
Background
Astrocytomas are the most common malignant glial tumors. With improved prognosis, it is possible for patients to pursue pregnancy post-treatment. However, with potential gonadotoxicity of oncology treatments, fertility preservation prior to chemotherapy and/or radiation therapy should be considered. This requires close collaboration between the oncologist and reproductive endocrinologist. To our knowledge this is the first report of successful pregnancies following fertility preservation for AA.
Case presentation
33-year-old nulligravid woman with newly diagnosed anaplastic astrocytoma (AA; WHO grade III, IDH1-negative) sought fertility preservation. Prior to chemotherapy and radiation for AA, the patient underwent in vitro fertilization (IVF) for fertility preservation, resulting in 8 vitrified embryos. Following chemo-radiation, the patient underwent two rounds of frozen embryo transfers (FET), each resulting in a successful singleton pregnancy.
Conclusion
This case illustrates the realistic possibility, in carefully selected patients with brain tumors, of oocyte or embryo cryo-preservation prior to chemo-radiation and subsequent pregnancies.
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Predicted Glycerol 3-Phosphate Dehydrogenase Homologs and the Glycerol Kinase GlcA Coordinately Adapt to Various Carbon Sources and Osmotic Stress in Aspergillus fumigatus
Glycerol plays an important role in the adaptation of fungi to various microenvironments and stressors, including heat shock, anoxic conditions and osmotic stress. Glycerol 3-phosphate dehydrogenase (G3PDH) is able to catalyze dihydroxyacetone phosphate to glycerol 3-phosphate (G3P), which is subsequently dephosphorylated into glycerol. However, current knowledge about the functions of G3PDH homologs in glycerol biosynthesis in Aspergillus fumigatus is limited. Here, we show that the A. fumigatus G3PDH gene, gfdA, is crucial for normal colony growth in glucose media under both normoxic and hypoxic conditions. In addition, failure of the overexpression of the gfdA homolog, gfdB, to rescue the phenotype of a gfdA null mutant suggests that gfdA plays a predominant role in the synthesis of G3P and glycerol. However, in a wild-type background, overexpressing either gfdA or gfdB is able to significantly enhance biomass production of mycelia, suggesting that gfdA and gfdB have similar functions in promoting the use of glucose. Interestingly, overexpression of the gene encoding the predicted glycerol kinase, GlcA, which is capable of phosphorylating glycerol to form G3P, significantly rescues the growth defects of gfdA null mutants in glucose media, indicating that the growth defects of gfdA null mutants might be due to the absence of G3P rather than glycerol. Moreover, Western blotting analysis revealed that GfdA is inducibly expressed by osmotic mediators. However, in the absence of gfdA, osmotic stress can rescue colony growth defects and allow colonies to partially bypass the gfdA requirement in a high osmolarity glycerol pathway-dependent manner. Therefore, the findings of this study elucidate how saprophytic filamentous fungi have developed pathways distinct from those of budding yeasts to adapt to varied carbon sources and survive environmental stresses.
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Optimal collimator rotation based on the outline of multiple brain targets in VMAT
Abstract
Background
The aim of this study was to investigate the dosimetric quality in volumetric modulated arc therapy (VMAT) plans with optimal collimator angles that can represent the outline of multiple brain targets.
Methods
Twenty patients with multiple target volumes in the brain cases were selected retrospectively. To better represent the outline of the multiple brain targets, four conformal arc plans were generated for each patient using one full arc with four collimator settings. The optimal collimator angles calculated from the integrated multi-leaf collimator (MLC) aperture that had the smallest aperture size for certain collimator settings of the conformal arc plan were selected. VMAT plans with the optimal collimator angles with angular sections of 40° and 60° (Colli-VMAT (40°), Colli-VMAT (60°)) were generated, followed by evaluation of field sizes, dose-volumetric parameters and total monitor units (MUs).
Results
Patient-averaged values of field sizes for Colli-VMAT (40°) (111.5 cm2) were lowest and 1.3 times smaller than those for Std-VMAT (143.6 cm2). Colli-VMAT plans improved sparing of most normal organs but for brain stem and left parotid gland. For the total MUs, the averaged values obtained with the Colli-VMAT (40°) (390 ± 148 MU) were smaller than those obtained with the Std-VMAT (472 ± 235 MU).
Conclusions
The Colli-VMAT plans with smaller angular sections could be suitable in the clinic for multiple brain targets as well as for irregularly shaped targets. Determination of the optimal collimator rotation generally showed good normal tissue sparing and MU reduction for multiple brain targets.
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Curation of the pancreatic ductal adenocarcinoma subset of The Cancer Genome Atlas is essential for accurate conclusions about survival related molecular mechanisms
Purpose: Publically available databases, e.g. The Cancer Genome Atlas (TCGA), containing clinical and molecular data from large number of patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes. Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA. Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historical median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC. Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases and web-tool developers is of crucial importance for generating accurate conclusions.
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{Delta}Np63{gamma}/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers
Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the Np63 isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of Np63 modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.
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MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer
Purpose: Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phospho-proteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and pro-metastatic signaling. However, CDK4/6 inhibitor resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.
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PHASE IB/II STUDY OF SECOND LINE THERAPY WITH PANITUMUMAB, IRINOTECAN AND EVEROLIMUS (PIE) IN KRAS WILD TYPE METASTATIC COLORECTAL CANCER
Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. Experimental Design: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using Kaplan-Meier method and analysed as intention to treat. A pre-planned exploratory biomarker analysis was performed. Results: 49 patients were enrolled. Dose level 1 (irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate day) was declared the MTD with no dose limiting toxicities (DLT) in 6 patients. 40 patients were treated at dose level 1: median age 60 years (37-76), 65% male, 45 and 52.5% respectively ECOG 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia 20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4 toxicities were hypomagnesemia 5% and neutropenia 3%. RR was 48%, stable disease 43%. Median PFS was 5.6 months and median OS 10.8 months. 25 patients were RAS/RAF WT and had a RR of 60%, median PFS of 6.4 months and OS 11.8 months. Conclusions: The toxicity of the PIE regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination.
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A method to summarize toxicity in cancer randomized clinical trials
Background/Aims: Despite development of clinical "value frameworks" by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a weighted toxicity score (WTS). Methods: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicity. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model. Results: Nineteen of 58 trials were placebo-controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model employing a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference, and could be used to adjust dose/schedule as patients are accrued to a clinical trial. Conclusion: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy.
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Nutritional composition of gluten-free food versus regular food sold in the Italian market
Some concerns have been raised about the nutritional composition of gluten-free (GF) food.
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Evidence of inter-tissue differences in the DNA damage response and the pro-oncogenic role of NF{kappa}B in mice with disengaged BRCA1-PALB2 interaction
The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair (HRR), defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here we analyzed several aspects of the DNA damage response in multiple tissues of Palb2 mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation (IR), the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species (ROS) and constitutive activation of NFκB, an anti-apoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NFκB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a pro-survival and pro-oncogenic role of NFκB in PALB2 mutant cells.
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Alternatively activated macrophages upregulate mesothelial expression of P-selectin to enhance adhesion of ovarian cancer cells
Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a co-culture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAMs) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling under flow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from HGSOC patients confirmed increased MIP-1β and P-selectin, suggesting that this novel multi-cellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti- CCR5 and P-selectin therapies developed for other indications.
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The first report of Nematode ( Contracaecum ) and two Acanthocephala ( Serrasentis sagittifer , Tenuiosentis niloticus ) in Persian Gulf’s Japanese threadfin bream ( Nemipterus japonicus )
Abstract
In this study, 649 Japanese threadfin bream (Nemipterus japonicus) were captured from the Persian Gulf and necropsied. The helminths of each organ were cleared by clearing solutions and stained by proper staining methods. Identification of the parasites was conducted according to identification keys. Totally, 109 (17%) of fishes were infected with parasites, and infection in intestine was higher than in other organs. In the present study, one Nematode (Contracaecum), two Acanthocephala (Serrasentis sagittifer, Tenuiosentis niloticus), and three larvae were isolated. Although Serrasentis sagittifes was reported in previous studies in Iran, Tenuiosentis niloticus and Contracaecum are reported for first time in Iranian fishes.
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The prognostic value of discontinuous EEG patterns in postanoxic coma
Early outcome prediction of comatose patients after cardiac arrest remains a challenge. The EEG is a sensitive and reliable tool, especially within the first 24 hours after cardiac arrest (Hofmeijer and Van Putten, 2016). A timely restoration of continuous, normal amplitude background activity is essential for good neurological recovery. Consistently among various studies, a continuous EEG pattern within 12 hours after cardiac arrest predicts a good outcome, whereas a persistent isoelectric or low-voltage EEG at 24 hours predicts a poor outcome (Sivaraju et al., 2015; Sondag et al., 2017; Spalletti et al., 2016).
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Sleep and Circadian Rhythms in Severely Brain-Injured Patients – A Comment
Lately, several publications have focused on circadian rhythms and sleep in patients with disorders of consciousness (DOC), namely patients who, following severe brain injury, are in an unresponsive wakefulness syndrome/a vegetative state (UWS/VS) or in a minimally conscious state (MCS) (Cologan et al., 2013; de Biase et al., 2014; Forgacs et al., 2014; Landsness et al., 2011; Pavlov et al., 2017; Rossi Sebastiano et al., 2018). Circadian rhythms, i.e., variations in biological processes with a period length of about 24 hours, have been discovered in virtually all biological organisms.
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Feasibility of an EEG-based brain-computer interface in the intensive care unit
Clinicians may fail to detect early signs of consciousness in patients with acute severe brain injuries. Several studies have reported a misdiagnosis rate of approximately 40% when using assessments tools such as the Glasgow Coma Scale to assess a patient's level of consciousness in the intensive care unit (ICU), as compared to comprehensive behavioral evaluations with the Coma Recovery Scale-Revised (CRS-R; (Andrews et al., 1996; Giacino et al., 2004; Schnakers et al., 2009b)). However, even the CRS-R has limitations, as it relies on motor and language abilities, which makes accurate diagnosis challenging in patients with motor impairment, aphasia (Majerus et al., 2009) or fluctuation of vigilance (Giacino et al., 2002; Piarulli et al., 2016).
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Approaches to Sleep in Severely Brain Damaged Patients: Opposite or Complementary? Reply to “Sleep and Circadian Rhythms in Severely Brain-Injured Patients - A Comment”
We thank Schabus, Wislowska, Angerer and Blume (Schabus et al. 2018; in the following SWAB) for their stimulating comments to the article of Rossi Sebastiano et al. (2018), as well as to our own comments to that article (Kotchoubey and Pavlov 2018). SWAB made several important and constructive suggestions concerning the study of sleep in patients with Disorders of Consciousness (DoC) and other severely brain damaged patients. Unfortunately, it remains not quite clear from their text whether they conceive of their suggestions as complements to (and improvement of) the approach realized by other authors (e.g., Rossi Sebastiano et al., 2015, 2018; Pavlov et al., 2017), or as an alternative to it.
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Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease
Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors
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No Association Between Consumption of Sweetened Beverages and Later Risk of Crohn’s Disease or Ulcerative Colitis
Consumption of sweetened beverages has been associated with inflammation, based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC).
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Liquid nitrogen spray cryotherapy for dysphagia palliation in patients with inoperable esophageal cancer
Dysphagia is a debilitating symptom in patients with inoperable esophageal cancer contributing to poor quality of life and worsening nutritional status. The 2 most commonly used palliative modalities for dysphagia are radiation therapy (RT) and esophageal stent placement. However, RT is limited by adverse events (AEs) and total dose, and stent placement has a high rate of AEs including reflux, migration, and chest pain. A relatively new modality of liquid nitrogen endoscopic spray cryotherapy has been described as salvage when other options have been exhausted and when patients are no longer receiving systemic therapy.
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Comparison of endoscopic submucosal dissection and surgery for superficial esophageal squamous cell carcinoma: A propensity score-matched analysis
Endoscopic submucosal dissection (ESD) has been widely accepted for treating superficial esophageal squamous cell carcinoma (SESCC). However, long-term outcomes of ESD and esophagectomy for SESCC have not been compared. We compared the clinical outcomes of ESD and esophagectomy in a matched cohort.
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A novel submucosal injection solution for endoscopic resection of large colorectal lesions: a randomized, double-blind trial
SIC-8000 (Eleview) is a new FDA-approved solution for submucosal injection developed to provide long-lasting cushion to facilitate endoscopic resection maneuvers. Our aim was to compare the efficacy and safety of SIC-8000 with those of saline solution, when performing endoscopic mucosal resection (EMR) of large colorectal lesions.
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Technical feasibility and oncological safety of diagnostic endoscopic resection for superficial esophageal cancer
Active use of endoscopic resection (ER) for cM3-SM2 esophageal cancer may enable sufficient extent of esophageal resection and help determine the need for lymph node dissection based on histopathological findings. However, ER preceding esophagectomy may have an adverse impact on outcomes. This study was designed to determine the technical feasibility and oncological safety of diagnostic ER.
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FDA Permits Marketing of New Device for Treating GI Bleeding
TUESDAY, May 8, 2018 -- The U.S. Food and Drug Administration has approved the new Hemospray device to help control bleeding of the gastrointestinal (GI) tract. The new device "provides an additional, non-surgical option for treating upper and lower...
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Intravesical Gemcitabine Therapy Cuts Bladder Cancer Recurrence
TUESDAY, May 8, 2018 -- Immediate post-resection intravesical installation of gemcitabine is associated with reduced recurrence over four years for patients with suspected low-grade non-muscle-invasive urothelial cancer, according to a study...
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USPSTF: Decision to Undergo PSA Screening Should Be Individual
TUESDAY, May 8, 2018 -- The U.S. Preventive Services Task Force (USPSTF) concludes that the decision to undergo periodic prostate-specific antigen (PSA) screening for prostate cancer should be an individual one for men aged 55 to 69 years. These...
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Regulatory Requirements Drive Dissatisfaction With EHRs
TUESDAY, May 8, 2018 -- Regulatory requirements are likely to be an important aspect of physician dissatisfaction with electronic health records (EHRs) that is driving burnout, according to an Ideas and Opinions piece published online May 8 in the...
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Exceptional Glycemic Control With Very Low-Carbohydrate Diet
TUESDAY, May 8, 2018 -- For children and adults with type 1 diabetes mellitus (T1DM), consuming a very low-carbohydrate diet (VLCD) is associated with exceptional glycemic control, according to a study published online May 7 in Pediatrics. Belinda...
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Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma
Histologically tubulo-papillary structures with glycogen-rich clear cytoplasm in gastric adenocarcinoma with enteroblastic differentiation (GAED) are well-known, but a solid growth pattern can also be observed as a minor component. In contrast, hepatoid adenocarcinoma (HAC) of the stomach shows many overlapping features, including solid pattern and alpha-fetoprotein expression. In this study, we employed next-generation sequencing (NGS) to establish a molecular/clinicopathological concept of GAED and clarify whether these two tumors should be grouped together in one category.
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Usefulness of the “continuous insufflation method” for observing the cervical esophagus
Digestive Endoscopy, EarlyView.
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A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences
To investigate the prospective associations between early childhood lead exposure and subsequent risk of attention deficit hyperactivity disorder (ADHD) in childhood and its potential effect modifiers.
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A Child with Diminished Linear Growth and Waddling Gait
A 6-year-old girl presented with disproportionate short stature and windswept deformity of the lower limbs accompanied by flat feet, short broad hands (Figure 1), and waddling gait. Her weight (2750 g) and length (49 cm) at birth were within normal range. She was born to normal-stature parents and had a healthy 9-year-old sister. Her psychophysical development was uneventful until the age of 18 months, when she presented with disturbance in walking and joint pain in the lower limbs. At the same time, her height growth rate started to be significantly slower.
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Associations of Coexisting Conditions with Healthcare Spending for Children with Cerebral Palsy
To determine which coexisting conditions have the strongest associations with healthcare use and spending among children with cerebral palsy (CP).
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Stippled Calcifications over Bilateral Epiphyses of Humeri
An infant girl born preterm presented with upper limb shortening and respiratory distress after birth. She was born via cesarean delivery due to oligohydramnios and malposition with a gestational age of 35 weeks and body weight at birth of 2360 g. A radiograph of the chest showed stippled calcifications in the epiphyses of bilateral humeri (Figure, arrows). Due to the abnormality on chest radiography, whole-exome sequencing was performed for a suspected genetic disorder. Later, it reported compound heterozygous mutations in the peroxisome biogenesis factor 7 gene (PEX7).
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Prescription Drug Shortages: Implications for Ambulatory Pediatrics
To describe contemporary drug shortages affecting general ambulatory pediatrics.
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Well-Child Visits of Medicaid-Insured Children with Medical Complexity
Well-child visits (WCVs) help optimize children's health. We measured annual WCVs for children with medical complexity (CMC) and correlated WCVs with hospitalizations.
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Association between Furosemide Exposure and Patent Ductus Arteriosus in Hospitalized Infants of Very Low Birth Weight
To evaluate the association between furosemide exposure and patent ductus arteriosus (PDA) in a large, contemporary cohort of hospitalized infants with very low birth weight (VLBW).
https://ift.tt/2HZcSFz
Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes
To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D).
https://ift.tt/2rvJjQD
Treating Obstructive Sleep Apnea and Chronic Intermittent Hypoxia Improves the Severity of Nonalcoholic Fatty Liver Disease in Children
To determine the effects of treating obstructive sleep apnea/nocturnal hypoxia on pediatric nonalcoholic fatty liver disease (NAFLD) severity and oxidative stress.
https://ift.tt/2I0jpQp
What Parents Want to Know after Preterm Birth
When faced with the birth of a child born very preterm, most parents' first question is, "Will our baby live?" Then, "If so, how will she be?" or "What will his life be like?" And finally, "What will our lives look like now?" Generally, parents do not ask, "Will our child have neurodevelopmental impairment?" or "Will our child have a Bayley cognitive composite score less than 85?"
https://ift.tt/2rwKpLY
PRESERVE: The End or the Beginning of a New Era in Prevention of Contrast-Associated Acute Kidney Injury?
Acute kidney injury (AKI) following the administration of iodinated contrast media has been widely recognized and studied since the initial reports in the 1950s.1 The decrease in glomerular filtration rate (GFR) occurs almost immediately upon exposure to contrast media and is reflected in an increase in serum creatinine (or cystatin C) level, usually within 24 to 48 hours before creatinine levels gradually return to near baseline within 5 to 7 days. Despite the predominantly transient nature of the increase in creatinine level, this AKI has been associated with a variety of short- and long-term adverse outcomes, including extended hospitalization and health care costs.
https://ift.tt/2wr6nG0
Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC)
Abstract
Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.
https://ift.tt/2I9mmtF
The Pathophysiology of Acquired Aplastic Anemia
Idiopathic acquired aplastic anemia is a rare, life-threatening bone marrow failure syndrome characterized by cytopenias and hypocellular bone marrow. The pathophysiology is unknown; the most favored model is of a dysregulated immune system leading to autoreactive T-cell destruction of hematopoietic stem and progenitor cells in a genetically susceptible host. The authors review the literature and propose that the major driver of acquired aplastic anemia is a combination of hematopoietic stem and progenitor cells intrinsic defects and an inappropriately activated immune response in the setting of a viral infection. Alterations in bone marrow microenvironment may also contribute to the disease process.
https://ift.tt/2I2YRXa
Cellular messengers communicate with bacteria in the mouth
Cellular messengers in saliva may be able to regulate the growth of oral bacteria responsible for diseases, such as periodontitis and meningitis. A new study suggests that a body's cellular messengers play an important role in managing the amount of good and bad bacteria in the mouth.
https://ift.tt/2FXpMOf
Neurovascular Stents Used for Stent-Assisted Coiling (SAC): Letter to Health Care Providers - Recommendations Associated With the Use of These Devices in the Treatment of Unruptured Brain Aneurysms
[Posted 5/8/2018] AUDIENCE: Neurology, Risk Manager ISSUE: FDA received reports associated with the use of these devices in the treatment of unruptured brain aneurysms that suggest some events of peri-procedural stroke and/or death may have been...
https://ift.tt/2rv7AGL
Neurovascular Stents Used for Stent-Assisted Coiling (SAC): Letter to Health Care Providers - Recommendations Associated With the Use of These Devices in the Treatment of Unruptured Brain Aneurysms
[Posted 5/8/2018] AUDIENCE: Neurology, Risk Manager ISSUE: FDA received reports associated with the use of these devices in the treatment of unruptured brain aneurysms that suggest some events of peri-procedural stroke and/or death may have been...
https://ift.tt/2rv7AGL
Re-irradiation in lung disease by SBRT: a retrospective, single institutional study
Abstract
Background
The loco regional relapse is frequent in the lung disease. The aim of this study was to evaluate the outcomes of re-irradiation by SBRT in terms of Local Control (LC) and toxicities.
Methods
From April 2011 to December 2016, twenty-two patients received a re-irradiation by SBRT. Twenty- seven lesions were treated. The medium BED(10) of re-irradiation was 100.6 Gy (range: 48–151.2 Gy) and the medium EQD2(10) was 93.8 Gy (range: 40–126 Gy). In the previous treatment the medium BED(10) was 97.2 Gy (range: 40–120 Gy), the medium EQD2(10) was 81 Gy (range: 32.5–100 Gy). The median time between the first and the second treatment was 18 months.
Results
Local Control was reached in 18 out of 27 (66%) re-irradiated lesions, with rates of 67 and 54% at 1- year and 2- years respectively. The treatment was well tolerated; the maximum recorded toxicity was Grade 3.
Conclusions
Re- irradiation by SBRT may represent an option for the treatment of lung disease with good results in terms of LC and toxicity.
https://ift.tt/2wqCPZ6
Control of Eating Behavior Using a Novel Feedback System
Subjects eat food from a plate placed on a scale connected to a computer that records the weight loss of the plate during the meal. Feedback on the computer screen allows the subject to adapt her/his eating behavior to reference curves thus normalizing body weight.
https://ift.tt/2rsWsuN
Tickling, a Technique for Inducing Positive Affect When Handling Rats
https://ift.tt/2I4yDj3
Novel Passive Clearing Methods for the Rapid Production of Optical Transparency in Whole CNS Tissue
https://ift.tt/2rtX9Ux
EMCrit – Retract SSC 2018 – You Only Have Yourself to Blame if You Do Not Take Action
please read this post--if you care about your practice and your patients
EMCrit Project by Scott Weingart.
https://ift.tt/2Il4I9X
Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy
Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.
https://ift.tt/2rvxWbH
External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study
Abstract
To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.
https://ift.tt/2I3PjaA
Associations between endothelial progenitor cells, clinical characteristics and coronary restenosis in patients undergoing percutaneous coronary artery intervention
Endothelial progenitor cells (EPCs) are produced in the bone marrow and mobilized to the peripheral blood playing a key role in endothelial repair. The objective of this study was to evaluate circulating EPC b...
https://ift.tt/2HZX99g
Prevalence and phenotypic characterization of Enterococcus species isolated from clinical samples of pediatric patients in Jimma University Specialized Hospital, south west Ethiopia
This study was done to determine the prevalence and phenotypic characterization of Enterococcus species isolated from clinical samples of pediatric patients in Jimma University Specialized Hospital, Southwest Eth...
https://ift.tt/2ruppps
Preeclampsia and gestational weight gain in the Norwegian Fit for Delivery trial
Excessive gestational weight gain is linked to risk of preeclampsia, but it is not clear whether the association is causal. The purpose of this paper was to examine gestational weight gain in the Norwegian Fit...
https://ift.tt/2KLL4SW
Incidence and outcomes of acute kidney injury in octogenarians in Jordan
Improvements in the health care system, resulted in a greater number of geriatric patients diagnosed with acute kidney injury (AKI). We evaluated the incidence and outcome of AKI in octogenarians, as studies i...
https://ift.tt/2rt1vKV
Undergraduate medical research in the Gulf Cooperation Council (GCC) countries: a descriptive study of the students’ perspective
There is a lack of research-oriented physicians in several Arab countries and especially in Gulf region countries. In this context, it is important to explore medical students' perceptions and motivations towa...
https://ift.tt/2KM6QWj
Type 2 Diabetes Ups Risk of Renal Cancer in Women, but Not Men
TUESDAY, May 8, 2018 -- Type 2 diabetes is independently associated with a greater risk of renal cell carcinoma (RCC) in women, but not in men, according to a study published online April 20 in Diabetes Care. Rebecca E. Graff, Sc.D., from Harvard...
https://ift.tt/2rtFUTj
Primary, Secondary Implant Equal for Fibula Free Tissue Transfer
TUESDAY, May 8, 2018 -- For patients with a fibula free tissue transfer (FFTT) for osteoradionecrosis (ORN) and osteonecrosis (ON) of the mandible, the rate of complications is similar for patients undergoing primary and secondary dental...
https://ift.tt/2K4RSKa
Automated Algorithm Accurately IDs Plus Disease in ROP
TUESDAY, May 8, 2018 -- A fully automated algorithm can accurately diagnose plus disease in retinopathy of prematurity (ROP), according to a study published online May 2 in JAMA Ophthalmology. James M. Brown, Ph.D., from Massachusetts General...
https://ift.tt/2ruklC0
Evidence Lacking for Impact of PDMPs on Drug Overdoses
TUESDAY, May 8, 2018 -- There is insufficient evidence available for examining the correlation between prescription drug monitoring programs (PDMPs) and non-fatal or fatal overdoses, according to a review published online May 8 in the Annals of...
https://ift.tt/2K6fgaf
Approaches to Firearms for Persons With Dementia Discussed
TUESDAY, May 8, 2018 -- Approaches to addressing the potential complications of owning firearms for persons with dementia (PWD) are presented in an article published online May 8 in the Annals of Internal Medicine. Noting that 7.8 to 11.8 million...
https://ift.tt/2rvsm9Z
After-School Activities Beneficial for Children With ADHD
TUESDAY, May 8, 2018 -- For children with attention-deficit/hyperactivity disorder (ADHD), participation in after-school activities (ASA) is associated with reduced odds of moderate-to-severe ADHD and having seven or more missed school days,...
https://ift.tt/2K3sNz2
Risk of Pediatric Mental Illness Up After Injury Hospitalization
TUESDAY, May 8, 2018 -- Medicaid-insured children are at increased risk for mental health diagnoses and psychotropic prescriptions after hospitalization for an injury compared with pre-hospitalization, according to a study published online May 7 in...
https://ift.tt/2IrWInG
High Number of Years of Life Lost Due to Police Violence in U.S.
TUESDAY, May 8, 2018 -- The number of years of life lost (YLLs) due to police violence in the United States is substantial and disproportionately impacts young people of color, according to a study published online May 7 in the Journal of...
https://ift.tt/2K0gBz9.
Teen Sexting Linked to Intimate Partner Violence, Sexual Abuse
TUESDAY, May 8, 2018 -- Teen sexting is associated with sexual abuse, with higher victimization in girls and intimate partner violence perpetration in boys, according to a study presented at the annual meeting of the Pediatric Academic Societies,...
https://ift.tt/2Iuoe3A
Long-Term Cardiovascular Risk for Endometrial Cancer Survivors
TUESDAY, May 8, 2018 -- Endometrial cancer survivors have an elevated risk of various adverse long-term cardiovascular outcomes, according to a study published online May 8 in the Journal of the National Cancer Institute. Sean Soisson, from the...
https://ift.tt/2K3ZI6R
Cognition and bimanual performance in children with unilateral cerebral palsy: protocol for a multicentre, cross-sectional study
Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two...
https://ift.tt/2FX839J
Atypical central retinal artery occlusion as the first presentation of POEMS syndrome: a case report
POEMS syndrome is a plasma cell disorder, which clinically manifests from paraneoplastic syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. The most comm...
https://ift.tt/2jFnNWb
ImageTrend announces new partnership with state of Tennessee
LAKEVILLE, Minn. — ImageTrend, Inc. is proud to announce a new partnership with the state of Tennessee for their EMS data collection and trauma registry reporting. The state's Department of Health, Office of Emergency Medical Services selected ImageTrend through a competitive RFP process. The Volunteer State will be utilizing the company's industry-leading Elite ePCR and Patient Registry ...
https://ift.tt/2Im7XO9
Clonal Analysis of Embryonic Hematopoietic Stem Cell Precursors Using Single Cell Index Sorting Combined with Endothelial Cell Niche Co-culture
https://ift.tt/2ruHa7Q
Preparation Steps for Measurement of Reactivity in Mouse Retinal Arterioles Ex Vivo
https://ift.tt/2HYFoai
Serological evaluation for Chagas disease in migrants from Latin American countries resident in Rome, Italy
Chagas disease (CD) is a systemic parasitic infection caused by the protozoan Trypanosoma cruzi, whose chronic phase may lead to cardiac and intestinal disorders. Endemic in Latin America where it is transmitted ...
https://ift.tt/2wokVX8
Investigating knowledge regarding antibiotics and antimicrobial resistance among pharmacy students in Sri Lankan universities
Antimicrobial resistance (AMR) is a major challenge for global health care. Pharmacists play a key role in the health care setting to help support the quality use of medicines. The education, training, and exp...
https://ift.tt/2rtelJM
HBV and HIV viral load but not microbial translocation or immune activation are associated with liver fibrosis among patients in South Africa
Co-infection with HIV negatively impacts the progression of chronic hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis. Sub-Saharan Africa represents arguably the most imp...
https://ift.tt/2K4lYNE
Angiocentric lymph proliferative disorder (lymphomatoid granulomatosis) in a person with newly-diagnosed HIV infection: a case report
Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has ...
https://ift.tt/2rrCkcq
High prevalence of HIV-1 transmitted drug resistance among therapy-naïve Burmese entering travelers at Dehong ports in Yunnan, China
The overall success of Human immunodeficiency virus type 1 (HIV-1) antiretroviral therapy (ART) was heavily challenged upon the occurrence of drug resistance. Dehong Prefecture witnessed not only the first rep...
https://ift.tt/2K42t8d
The roles of mid-myocardial and epicardial cells in T-wave alternans development: a simulation study
The occurrence of T-wave alternans in electrocardiographic signals was recently linked to susceptibility to ventricular arrhythmias and sudden cardiac death. Thus, by detecting and comprehending the origins of...
https://ift.tt/2K41WDf
Anti-stress effects of human placenta extract: possible involvement of the oxidative stress system in rats
Human placenta hydrolysate (hPH) has been utilized to improve menopausal, fatigue, liver function. Its high concentration of bioactive substances is known to produce including antioxidant, anti-inflammatory an...
https://ift.tt/2KKz2ZT
Acute and chronic toxicity of a polyherbal preparation – Jueyin granules
The potential toxicity of Chinese herbal medicine has attracted more attention in recent years. Jueyin granules (JYG), a polyherbal formula, have been proven to be an effective agent for treating psoriasis in bot...
https://ift.tt/2roWCCy
Sheng Jiang San, a traditional multi-herb formulation, exerts anti-influenza effects in vitro and in vivo via neuraminidase inhibition and immune regulation
Sheng Jiang San (SJS), a multi-herb formulation, is used in treating high fever, thirsty and anxiety in ancient China and it is sometimes used to treat seasonal influenza nowadays. However, there is no evidenc...
https://ift.tt/2HYojgC
Artemisia Capillaris leaves inhibit cell proliferation and induce apoptosis in hepatocellular carcinoma
Natural product is one of the most important sources of drugs used in pharmaceutical therapeutics. Artemisia capillaris has been traditionally used as a hepatoprotective and anti-inflammatory agent. In this study...
https://ift.tt/2ruBOcK
Ampicillin and Sulbactam for Injection USP, 3 g Single-Dose Vials by AuroMedics Pharma: Recall - Presence of Red Particulate Matter
[Posted 05/08/2018] AUDIENCE: Risk Manager, Infectious Disease, Pharmacy, Nursing ISSUE: AuroMedics Pharma is voluntarily recalling two lots of Ampicillin and Sulbactam for Injection USP, 3 g/Single-Dose vials, to the hospital/user level. The recall...
https://ift.tt/2FYCXig
Piperacillin and Tazobactam for Injection, USP 3.375 g Vials by AuroMedics Pharma: Recall - Vials Contain Particulate Matter
[Posted 05/08/2018] AUDIENCE: Risk Manager, Infectious Disease, Pharmacy, Nursing ISSUE: AuroMedics Pharma is voluntarily recalling two lots of Piperacillin and Tazobactam for Injection, USP 3.375 g (Piperacillin Sodium equivalent to 3 g of...
https://ift.tt/2KJIeO5
Ampicillin and Sulbactam for Injection USP, 3 g Single-Dose Vials by AuroMedics Pharma: Recall - Presence of Red Particulate Matter
[Posted 05/08/2018] AUDIENCE: Risk Manager, Infectious Disease, Pharmacy, Nursing ISSUE: AuroMedics Pharma is voluntarily recalling two lots of Ampicillin and Sulbactam for Injection USP, 3 g/Single-Dose vials, to the hospital/user level. The recall...
https://ift.tt/2FYCXig
Piperacillin and Tazobactam for Injection, USP 3.375 g Vials by AuroMedics Pharma: Recall - Vials Contain Particulate Matter
[Posted 05/08/2018] AUDIENCE: Risk Manager, Infectious Disease, Pharmacy, Nursing ISSUE: AuroMedics Pharma is voluntarily recalling two lots of Piperacillin and Tazobactam for Injection, USP 3.375 g (Piperacillin Sodium equivalent to 3 g of...
https://ift.tt/2KJIeO5
What Is a Healthy Mind? Art Informs Recovery at a State Psychiatric Hospital
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https://ift.tt/2FSx99T
Severe metabolic acidosis after out-of-hospital cardiac arrest: risk factors and association with outcome
Metabolic acidosis is frequently observed as a consequence of global ischemia–reperfusion after out-of-hospital cardiac arrest (OHCA). We aimed to identify risk factors and assess the impact of metabolic acido...
https://ift.tt/2K6nIWD
Association of intensive care unit delirium with sleep disturbance and functional disability after critical illness: an observational cohort study
In medical intensive care unit (MICU) patients, the predictors of post-discharge sleep disturbance and functional disability are poorly understood. ICU delirium is a risk factor with a plausible link to sleep ...
https://ift.tt/2IlTTEu
Increase in intra-abdominal pressure during airway suctioning-induced cough after a successful spontaneous breathing trial is associated with extubation outcome
A patient's ability to clear secretions and protect the airway with an effective cough is an important part of the pre-extubation evaluation. An increase in intra-abdominal pressure (IAP) is important in gener...
https://ift.tt/2K31zZj
Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America
Abstract
Background
This study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort.
Methods
Demographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer ≤ 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type.
Results
Among 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range [IQR]: 32–47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio [aHR] = 1.63, p = 0.02), age (aHR = 1.02 per year, p = 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year, p = 0.01).
Conclusion
ADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.
https://ift.tt/2rqTpn0
A short history of nearly every sense - The evolutionary history of vertebrate sensory cell types
Abstract
Evolving from filter feeding chordate ancestors, vertebrates adopted a more active life style. These ecological and behavioral changes went along with an elaboration of the vertebrate head including novel complex paired sense organs such as the eyes, inner ears and olfactory epithelia. However, the photoreceptors, mechanoreceptors and chemoreceptors used in these sense organs have a long evolutionary history and homologous cell types can be recognized in many other bilaterians or even cnidarians. After briefly introducing some of the major sensory cell types found in vertebrates, this review summarizes the phylogenetic distribution of sensory cell types in metazoans and presents a scenario for the evolutionary history of various sensory cell types involving several cell type diversification and fusion events. It is proposed that the evolution of novel cranial sense organs in vertebrates involved the redeployment of evolutionarily ancient sensory cell types for building larger and more complex sense organs.https://ift.tt/2FWpkQh
Improvement of the Shock Absorption Ability of a Face Guard by Incorporating a Glass-Fiber-Reinforced Thermoplastic and Buffering Space
This study aimed to evaluate the shock absorption ability of trial face guards (FGs) incorporating a glass-fiber-reinforced thermoplastic (GF) and buffering space. The mechanical properties of 3.2 mm and 1.6 mm thick commercial medical splint materials (Aquaplast, AP) and experimental GF prepared from 1.6 mm thick AP and fiberglass cloth were determined by a three-point bending test. Shock absorption tests were conducted on APs with two different thicknesses and two types of experimental materials, both with a bottom material of 1.6 mm thick AP and a buffering space of 30 mm in diameter (APS) and with either (i) 1.6 mm thick AP (AP-APS) or (ii) 1.6 mm thick GF (GF-APS) covering the APS. The GF exhibited significantly higher flexural strength (64.4 MPa) and flexural modulus (7.53 GPa) than the commercial specimens. The maximum load of GF-APS was 75% that of 3.2 mm AP, which is widely used clinically. The maximum stress of the GF-APS only could not be determined as its maximum stress is below the limits of the analysis materials used (
https://ift.tt/2K1GKNV
Computer-aided diagnosis for ( 123 I)FP-CIT imaging: impact on clinical reporting
Abstract
Background
For (123I)FP-CIT imaging, a number of algorithms have shown high performance in distinguishing normal patient images from those with disease, but none have yet been tested as part of reporting workflows. This study aims to evaluate the impact on reporters' performance of a computer-aided diagnosis (CADx) tool developed from established machine learning technology.
Three experienced (123I)FP-CIT reporters (two radiologists and one clinical scientist) were asked to visually score 155 reconstructed clinical and research images on a 5-point diagnostic confidence scale (read 1). Once completed, the process was then repeated (read 2). Immediately after submitting each image score for a second time, the CADx system output was displayed to reporters alongside the image data. With this information available, the reporters submitted a score for the third time (read 3). Comparisons between reads 1 and 2 provided evidence of intra-operator reliability, and differences between reads 2 and 3 showed the impact of the CADx.
Results
The performance of all reporters demonstrated a degree of variability when analysing images through visual analysis alone. However, inclusion of CADx improved consistency between reporters, for both clinical and research data. The introduction of CADx increased the accuracy of the radiologists when reporting (unfamiliar) research images but had less impact on the clinical scientist and caused no significant change in accuracy for the clinical data.
Conclusions
The outcomes for this study indicate the value of CADx as a diagnostic aid in the clinic and encourage future development for more refined incorporation into clinical practice.
https://ift.tt/2rtsypf
Metastatic Gallbladder Melanoma Presenting as Acute Emphysematous Cholecystitis
Malignant melanoma is an aggressive tumor with a high potential for distant metastases, including spread to the gallbladder where it represents more than half of all metastases detected at autopsy. Yet, it is rarely symptomatic in life and is a rare cause of acute cholecystitis. Emphysematous cholecystitis is a rare, potentially fatal variant of acute cholecystitis characterized by the presence of gas in the gallbladder lumen or wall. We report a 77-year-old woman with acute emphysematous cholecystitis as the initial feature of recurrent melanoma metastatic to the gallbladder. This exceptional association highlights the need to consider a relapse of malignancy when assessing unexplained abdominal symptoms in any patient with a prior history of melanoma.
https://ift.tt/2FVs3tr
eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells
Abstract
The nitric oxide (NO) secreted by vascular endothelium is required for the maintenance of cardiovascular homeostasis. Diminished release of NO generated by endothelial NO synthase contributes to endothelial dysfunction. Hypoxia and ischemia reduce endothelial eNOS expression via posttranscriptional mechanisms that result in NOS3 transcript destabilization. Here, we examine whether microRNAs contribute to this mechanism. We followed the kinetics of hypoxia-induced changes in NOS3 mRNA and eNOS protein levels in primary human umbilical vein endothelial cells (HUVECs). Utilizing in silico predictive protocols to identify potential miRNAs that regulate eNOS expression, we identified miR-200b as a candidate. We established the functional miR-200b target sequence within the NOS3 3′UTR, and demonstrated that manipulation of the miRNA levels during hypoxia using miR-200b mimics and antagomirs regulates eNOS levels, and established that miR-200b physiologically limits eNOS expression during hypoxia. Furthermore, we demonstrated that the specific ablation of the hypoxic induction of miR-200b in HUVECs restored eNOS-driven hypoxic NO release to the normoxic levels. To determine whether miR-200b might be the only miRNA that had this effect, we utilized Next Generation Sequencing (NGS) to follow hypoxia-induced changes in the miRNA levels in HUVECS and found 83 novel hypoxamiRs, with two candidate miRNAs besides miR-200b that could potentially influence eNOS levels. Taken together, the data establish miR-200b-eNOS regulation as a first hypoxamiR-based mechanism that limits NO bioavailability during hypoxia in endothelial cells, and show that hypoxamiRs could become useful therapeutic targets for cardiovascular diseases and other hypoxic-related diseases including various types of cancer.
https://ift.tt/2FUewT7
Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE)
Abstract
Background
Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced rectal cancer with improved local control. However, systemic recurrence despite neoadjuvant CRT remained unchanged. The only significant prognostic factor proven to be important was pathologic complete response (pCR) after neoadjuvant CRT. Several efforts have been tried to improve survival of patients who treated with neoadjuvant CRT and to achieve more pCR including adding cytotoxic chemotherapeutic agents, chronologic modification of chemotherapy schedule or adding chemotherapy during the perioperative period. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase pCR rate, subsequently could show better oncologic outcomes.
Methods
Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to undergo TME followed by 8 cycles of adjuvant chemotherapy (control arm) or receive 3 cycles of consolidation chemotherapy before TME, and receive 5 cycles of adjuvant chemotherapy (experimental arm). The primary endpoints are pCR and 3-year disease-free survival (DFS), and the secondary endpoints are radiotherapy-related complications, R0 resection rate, tumor response rate, surgery-related morbidity, and peripheral neuropathy at 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in pCR (15 to 30%) and in 3-year DFS (65 to 80%), compared with the control arm. The accrual period is 2 years and the follow-up period is 3 years. Based on the superiority design, one-sided log-rank test with α-error of 0.025 and a power of 80% was conducted. Allowing for a drop-out rate of 10%, 358 patients (179 per arm) will need to be recruited. Patients will be followed up at every 3 months for 2 years and then every 6 months for 3 years after the last patient has been randomized.
Discussion
KONCLUDE trial aims to investigate whether consolidation chemotherapy shows better pCR and 3-year DFS than adjuvant chemotherapy alone for the patients who received neoadjuvant CRT for locally advanced rectal cancer. This trial is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer.
Trial registration
Clinicaltrials.gov NCT02843191 (First posted on July 25, 2016).
https://ift.tt/2I8M5Tn
M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas
Abstract
Background
Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis.
Methods
Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data.
Results
TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively.
Conclusion
M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma.
https://ift.tt/2rsEjNB
Spontaneous renal hemorrhage secondary to choriocarcinoma in a man with congenital hypospadias and cryptorchidism: a case report and literature review
Abstract
Background
Choriocarcinoma is a rare malignant germ-cell tumour, most commonly found in adult women. It infrequently presents as spontaneous renal haemorrhage (SRH). Genital malformation and SRH secondary to choriocarcinoma has previously been only reported in females. We present what we believe to be the first case of a male patient with genital malformation (hypospadias and cryptorchidism) and SRH at presentation of choriocarcinoma.
Case presentation
A 25-year-old man presented to the department with intense pain in the right flank region and lower back. Initial investigations showed spontaneous renal haemorrhage, for which an emergency partial nephrectomy was performed. Clinical, radiological, and pathological investigations suggested a diagnosis of testicular choriocarcinoma with metastases to the right kidney, both lungs, and brain. Initial treatment was with a chemotherapy regimen of cisplatin, etoposide and bleomycin and whole brain radiotherapy; however, 6 months after diagnosis the patient developed liver metastasis, after which time the BEP protocol was switched to ITP with oral apatinib. Despite best efforts, the liver and lung metastasis continued to grow and a decision was made to discontinue active treatment and provide only palliative care until the patient passed away.
Conclusion
Choriocarcinoma is a difficult cancer to diagnose pre-operatively. In male patients with early metastasis, prognosis may be much poorer than in the commoner gestational choriocarcinoma. A multidisciplinary with comprehensive post-surgical intervention is of great importance in the treatment of these patients.
https://ift.tt/2I3eiL7
Incidence of breast and colorectal cancer among immigrants in Ontario, Canada: a retrospective cohort study from 2004-2014
Abstract
Background
Studies have shown that morbidity and mortality rates due to cancer among recent immigrants are lower than those among the native-born population. The objectives of this study were to describe the incidence of colorectal and breast cancer among immigrants from major regions of the world compared to Canadian-born residents of the province of Ontario and to examine the role of length of stay and neighborhood income.
Methods
Retrospective cohort study including all individuals 18 years and over residing in Ontario from 2004 to 2014. Age-standardized incidence rates (ASIR) were calculated for immigrants from each world region versus Canadian-born residents and stratified by neighborhood income quintile and length of stay. Binomial regression analysis was used to determine the association of neighbourhood income, length of stay, and location of birth with colorectal and breast cancer incidence.
Results
Canadian immigrants born in South Asia had the lowest colorectal and breast cancer incidence (colorectal: women: ASIR = 0.14; men: ASIR = 0.18; breast: ASIR = 1.00) compared to long-term residents during the study period (colorectal: women: ASIR = .57; men: ASIR = .72; breast cancer ASIR = 1.61). In multivariate analyses, neighboorhood income did not consistently play a significant role in colorectal cancer incidence; however higher neighbourhood income was a risk factor for breast cancer among immigrant women (adjusted relative risk for highest neighboorhood income quintile versus lowest income quintile =1.21, 95% CI = 1.18–1.24). Increased length of stay was associated with higher risk of cancer. After adjusting for age, neighborhood income, and length of stay, those born in Europe and Central Asia had the highest risk of colorectal cancer compared to those born in East Asia and Pacific and those born in the Middle East had the greatest additional risk of breast cancer.
Conclusions
After correcting for age, breast and colorectal cancer incidence rates among immigrants differ according to their region of birth and recent immigrants to Ontario have lower colorectal and breast cancer incidence rates than their native-born peers. However, those advantages diminish over time. These findings call for Ontario to generate tools and interventions to maintain the health of the immigrant population, particularly for those groups with a higher incidence of cancer.
https://ift.tt/2jJs9vA
Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma
Abstract
Background
SETDB1 is a histone H3K9 methyltransferase, which plays a significant role in the occurrence and progression of tumors. Previous studies have confirmed that T-lymphom invasion and metastasis gene (Tiam1) is a protein associated with the metastasis of hepatocellular carcinoma (HCC); however, we have not yet been successful in elucidating the specific mechanism of HCC.
Methods
Yeast two-hybrid test was conducted to screen proteins that interacted with Tiam1 gene. Glutathione-S-transferase (GST) pull-down and crosslinking-immunoprecipitation (CLIP) assays were performed to determine whether SETDB1 can interact with Tiam1 gene. A series of related experiments were performed to explore role of SETDB1 on cell proliferation, migration, and invasion in HCC. Recovery experiment was performed to investigate the effect of Tiam1 knockdown on cell proliferation and migration, which was caused by SETDB1 overexpression in HCC cells. The expression of SETDB1 was frequently upregulated in HCC tissues and positively correlated with Tiam1.
Results
GST pull-down and CLIP assays were performed to elucidate the interaction between SETDB1 and Tiam1. Cell proliferation, migration, and epithelial mesenchymal transformation (EMT) in HCC cells was promoted with the overexpression of SETDB1. Following the knockdown of Tiam1 gene, the effect of SETDB1 on cell proliferation and migration was reversed in HCC cells. The expression of SETDB1 was frequently up-regulated in HCC tissues, and it was positively correlated with Tiam1 gene.
Conclusions
Ours is the first study to prove that SETDB1 promotes the proliferation and migration of cells by forming SETDB1-Tiam1 compounds. We found that SETDB1-Tiam1 compounds were involved in a novel pathway, which regulated epigenetic modification of gene expression in HCC samples.
https://ift.tt/2wkL4WQ
Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer
Abstract
Background
An important component of the RAS signalling pathway, the RAS p21 oncogene, is frequently hyperactivated in breast cancer. Its expression in tumor tissue has been linked to poor clinical outcome. This study was designed to evaluate the clinical relevance of RAS p21 levels in peripheral blood in a large cohort of metastatic breast cancer patients.
Methods
Two hundred fifty-one patients with metastatic breast cancer were enrolled in this prospective, multicentre, open-label, non-randomized study. Blood samples were collected before start of first-line or later-line treatment. RAS p21 was determined using a sandwich-type ELISA immunoassay. For the determination of the cutoff, blood samples from age-matched healthy controls were analyzed. A value above 452 pg/ml was regarded as elevated (mean + 2 x SD). In the univariate survival analysis, two other cutoffs were considered as well (50th and 75th percentile of patients, i.e. 229 pg/ml and 320 pg/ml). Circulating tumor cells (CTCs) were detected using the CellSearch system.
Results
29 of 251 (12%) patients had RAS p21 levels above the cut-off level of 452 pg/ml. Clinical-pathological parameters, such as hormone receptor and HER2 status, line of therapy and CTC status, did not correlate with RAS p21 levels. Elevated RAS p21 was significantly associated with shorter progression-free and overall survival in the univariate analysis (median PFS: 3.9 months [95%-CI: 1.8–6.0] for patients with elevated RAS p21 levels versus 8.5 months [95%-CI: 7.4–9.5] with non-elevated levels [p = 0.01]; median OS: 7.1 months [95%-CI: 0.3–14.2] versus not reached [p = 0.002], respectively). When RAS p21 cutoffs other than 452 pg/ml were considered, elevated RAS p21 was significantly associated with OS but not with PFS. Classical clinical-pathological factors were included into a multivariate Cox regression analysis. In addition, factors previously shown to influence survival in a univariate analysis, such as serum HER2, CAIX and TIMP1, were included as well. In the multivariate analysis, RAS p21, presence of ≥5 CTCs per 7.5 ml blood, higher grading and higher line of therapy remained independent predictors of shorter OS.
Conclusions
Metastatic breast cancer patients with elevated levels of circulating RAS p21 have significantly worse clinical outcome. Hypothetically, these patients might benefit from therapeutic strategies targeting RAS pathway.
Trial registration
Current Controlled Trials ISRCTN59722891 (DETECT); trial registration date: April, 17th 2010; the trial was registered retrospectively.
https://ift.tt/2rs4hkk
Angiopoietin-like 4 promotes osteosarcoma cell proliferation and migration and stimulates osteoclastogenesis
Abstract
Background
Osteosarcoma is the most common primary bone cancer in children and young adults. It is highly aggressive and patients that present with metastasis have a poor prognosis. Angiopoietin-like 4 (ANGPTL4) drives the progression and metastasis of many solid tumours, but has not been described in osteosarcoma tissue. ANGPTL4 also enhances osteoclast activity, which is required for osteosarcoma growth in bone. We therefore investigated the expression and function of ANGPTL4 in human osteosarcoma tissue and cell lines.
Methods
Expression of ANGPTL4 in osteosarcoma tissue microarrays was determined by immunohistochemistry. Hypoxic secretion of ANGPTL4 was tested by ELISA and Western blot. Regulation of ANGPTL4 by hypoxia-inducible factor (HIF) was investigated using isoform specific HIF siRNA (HIF-1α, HIF-2α). Effects of ANGPTL4 on cell proliferation, migration (scratch wound assay), colony formation and osteoblastogenesis were assessed using exogenous ANGPTL4 or cells stably transfected with ANGPTL4. Osteoclastogenic differentiation of CD14+ monocytes was assessed by staining for tartrate-resistant acid phosphatase (TRAP), bone resorption was assessed by lacunar resorption of dentine.
Results
ANGPTL4 was immunohistochemically detectable in 76/109 cases. ANGPTL4 was induced by hypoxia in 6 osteosarcoma cell lines, under the control of the HIF-1α transcription factor. MG-63 cells transfected with an ANGPTL4 over-expression plasmid exhibited increased proliferation and migration capacity and promoted osteoclastogenesis and osteoclast-mediated bone resorption. Individually the full-length form of ANGPTL4 could increase MG-63 cell proliferation, whereas N-terminal ANGPTL4 mediated the other pro-tumourigenic phenotypes.
Conclusions
This study describes a role(s) for ANGPTL4 in osteosarcoma and identifies ANGPTL4 as a treatment target that could potentially reduce tumour progression, inhibit angiogenesis, reduce bone destruction and prevent metastatic events.
https://ift.tt/2wttYGm
Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells
Abstract
Background
Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines.
Methods
Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model.
Results
All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib – treatment.
Conclusions
Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors.
https://ift.tt/2rudqJ6
Cancer incidence in Yemen from 1997 to 2011: a report from the Aden cancer registry
Abstract
Background
This study aims to report on the trend and incidence of cancers in Yemen (Aden) using data from Aden Cancer Registry (ACR), as a population-based cancer registry in Yemen over a period of 15 years (1997–2011). Such comprehensive, valid and detailed information on cancer trend is badly needed for planning a cancer control program in the country.
Methods
All cancer cases were abstracted from patients' medical records – based on clinical, histopathology, and radiological diagnosis. Data were coded using the International Classification of Diseases for Oncology (ICD-O) and the International Classification of Childhood Cancer (ICCC-3) to code childhood tumors. The CanReg4 program was used to analyze the data for 15 years study period.
Results
A total of 6974 cases were included in this study, 47% were males and 53% females. The overall annual incidence rate was 21.6/100,000 populations; however, the incidence in males was little lower than in females (20.0 and 22.9 per 100,000 populations, respectively). The top five cancers among males were leukaemia (10.5%), nonhodgkin lymphoma [(NHL), 10.1%], colon (7.5%), Hodgkin diseases [(HD), 6.1%] and stomach cancer (5.1%). For females, breast cancer was the top (30.0%), followed by leukaemia (7.6%), NHL (6.6%), colonic (4.9%) and ovarian cancer (4.5%).
Conclusion
Our findings reveal that, there is urgent need to commence the early screening of breast cancer due to its high frequency among Yemeni women. The government should give more support for cancer registries in the country to sustain its vital contribution to cancer care.
https://ift.tt/2wttL62
Combination Immunotherapy in Non-small Cell Lung Cancer
Abstract
Purpose of Review
Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach.
Recent Findings
Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results. Additional studies targeting other immune pathways like TIGIT, LAG-3, and cellular therapies are ongoing.
Summary
Combination immunotherapy has the potential to improve outcomes in NSCLC. Data from early clinical trials is promising and reveals that these agents can be administered together safely without a significant increase in toxicity. Further studies are needed to evaluate their long-term safety and efficacy and to determine appropriate patient selection.
https://ift.tt/2K17EWm
CD36 Mediates Cell-Surface Antigens to Promote Thymic Development of the Regulatory T Cell Receptor Repertoire and Allo-tolerance
How cooperative antigen presentation between medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) occurs remains unknown. Perry et al. show that CD36, a scavenger receptor expressed on CD8α+ DCs, mediates acquisition and presentation of cell-surface antigens from mTECs for T cell receptor repertoire development and allo-tolerance during bone marrow transplantation.
https://ift.tt/2jEU93r
Cell-Specific Imd-NF-κB Responses Enable Simultaneous Antibacterial Immunity and Intestinal Epithelial Cell Shedding upon Bacterial Infection
The intestinal epithelium is constantly renewed through cell shedding and stem cell activation, and this renewal maintains intestinal barrier integrity. Zhai et al. show that in Drosophila, activation of the Imd-NF-κB pathway upon bacterial infection not only induces the expression of antimicrobial peptides, but also controls epithelial shedding, suggesting an evolutionarily conserved crosstalk between immunity and epithelial turnover.
https://ift.tt/2FVCPjk
The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
TREM2 is a microglial innate immune receptor whose functions during brain development are still unknown. Filipello et al. demonstrate that TREM2 is essential for microglia to eliminate supernumerary synapses in the developing brain. TREM2 protein was also reduced in autistic patients, suggesting that the receptor may be involved in neurodevelopmental diseases.
https://ift.tt/2KKHLLF
Proteomic Analyses of Human Regulatory T Cells Reveal Adaptations in Signaling Pathways that Protect Cellular Identity
Using high-resolution mass spectrometry and transcriptomics, Cuadrado et al. provide a molecular characterization of regulatory and conventional CD4+ T cell subsets, yielding markers to distinguish cells with different properties and insights into mechanisms that prevent regulatory T cells from exhibiting undesirable functional activities of the related but functionally antithetical conventional T cells.
https://ift.tt/2FU9TIF
Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity
Lymph node stromal cells support diverse processes, but bulk assessments obscure their niche-specific functions. Rodda et al. identify transcriptional profiles for nine lymph node stromal cell clusters using single-cell RNA sequencing, validate subset markers in situ, and suggest niche-restricted functions.
https://ift.tt/2KJoBFT
De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder
Abstract
Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.
https://ift.tt/2FS8UZr
Effect of emulsifying stability of myofibrillar protein on the gel properties of emulsified surimi gel
Food Science &Nutrition, EarlyView.
https://ift.tt/2jGNc1V
Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC
Future Oncology, Ahead of Print.
https://ift.tt/2K1q5dl
Patterns of failure after resection of extrahepatic bile duct cancer: implications for adjuvant radiotherapy indication and treatment volumes
Abstract
Background
The role of adjuvant radiotherapy (RT) and setting proper RT target volumes have not been clearly demonstrated for extrahepatic bile duct (EHBD) cancer, due to the rarity of the disease and the lack of randomized trials. This study was conducted to evaluate the indication and treatment volume for adjuvant RT in EHBD cancer patients by identifying the prognostic factors for loco-regional (LR) failure, and analyze the patterns of LR failure.
Methods
Ninety-three patients with EHBD cancer, who underwent resection without adjuvant RT, at 2 medical centers, between 2001 and 2016, were analyzed retrospectively. Univariable and multivariable analyses were performed to find the prognostic factors for LR recurrence. The initial patterns of failure were recorded, especially those of LR recurrence, and categorized according to the Japanese classification.
Results
The median follow-up duration was 30 months, and 38 (40.9%) patients experienced LR recurrence during this period. With regards to LR recurrence, close or positive resection margin (RM) status (p < 0.001) remained statistically significant in the multivariable analysis. The most common LR recurrence sites were the tumor bed (18.3%), and lymph node (LN) stations No. 8 (14.1%), No. 9 (12.7%), No. 12 (12.7%), No. 13 (5.6%), No. 14 (21.1%), No. 16 (14.1%), and No. 17 (1.4%).
Conclusions
A close or positive RM status may be suggestive of high LR recurrence rates. In such cases, adjuvant RT may improve outcomes. When adjuvant RT is performed, the treatment volume should be well-designed so as to encompass the tumor bed, as well as LN stations No. 8, No. 9, No. 12, No. 14, and No. 16.
https://ift.tt/2FVxWXz
Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma
Abstract
Background
With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor's generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the "clinical research group heavy ion therapy" and funded by the German Research Council (DFG, KFO 214).
Methods
Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months.
Results
In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7–56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8–45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08–34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2–87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6–55,3).
Conclusion
Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient.
https://ift.tt/2jGcSvn
The effects of enriched environment on the behavioral and corticosterone response to methamphetamine in adolescent and adult mice
Developmental Psychobiology, EarlyView.
https://ift.tt/2I1p9ZS
Different Activity Patterns in Retinal Ganglion Cells of TRPM1 and mGluR6 Knockout Mice
TRPM1, the first member of the melanoma-related transient receptor potential (TRPM) subfamily, is the visual transduction channel downstream of metabotropic glutamate receptor 6 (mGluR6) on retinal ON bipolar cells (BCs). Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB). In both TRPM1 and mGluR6 KO mouse retinas, OFF but not ON BCs respond to light stimulation. Here we report an unexpected difference between TRPM1 knockout (KO) and mGluR6 KO mouse retinas. We used a multielectrode array (MEA) to record spiking in retinal ganglion cells (RGCs). We found spontaneous oscillations in TRPM1 KO retinas, but not in mGluR6 KO retinas. We performed a structural analysis on the synaptic terminals of rod ON BCs. Intriguingly, rod ON BC terminals were significantly smaller in TRPM1 KO retinas than in mGluR6 KO retinas. These data suggest that a deficiency of TRPM1, but not of mGluR6, in rod ON bipolar cells may affect synaptic terminal maturation. We speculate that impaired signaling between rod BCs and AII amacrine cells (ACs) leads to spontaneous oscillations. TRPM1 and mGluR6 are both essential components in the signaling pathway from photoreceptors to ON BC dendrites, yet they differ in their effects on the BC terminal and postsynaptic circuitry.
https://ift.tt/2FS0mBP
Evaluation of the Effect of the Sulcus Angle and Lateral to Medial Facet Ratio of the Patellar Groove on Patella Tracking in Aging Subjects with Stable Knee Joint
Purpose. To determine whether the sulcus angle and the lateral to medial facet ratio correlate with patella lateral displacement and tilt in patients without patella instability. Methods. Computed tomography images of the lower limb of 64 patients without known arthropathy were collected. Three-dimensional models of the lower limb with a unified coordinate system were rebuilt by using Mimics software. The sulcus angle, lateral to medial facet ratio, lateral trochlear inclination of the patellar groove, tibial tuberosity-trochlear groove (TT-TG) distance, bisect offset index, and lateral tilt of the patella were measured. Pearson's correlation test was used to determine the relationship between the aforementioned parameters. Results. Data from 51 patients were analyzed. The sulcus angle was negatively correlated with lateral tilt inclination (, ) and positively correlated with the bisect offset index (, ) and patellar tilt (, ); the lateral to medial facet ratio was positively correlated with TT-TG distance (, ) and bisect offset index (, ). Conclusion. The sulcus angle and lateral to medial facet ratio of the patellar groove can influence patella tracking in patients with stable knee joints.
https://ift.tt/2jEGKZb
Cancers, Vol. 10, Pages 140: Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
Cancers, Vol. 10, Pages 140: Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface
Cancers doi: 10.3390/cancers10050140
Authors: Floriane Gibault Mathilde Coevoet Manon Sturbaut Amaury Farce Nicolas Renault Frédéric Allemand Jean-François Guichou Anne-Sophie Drucbert Catherine Foulon Romain Magnez Xavier Thuru Matthieu Corvaisier Guillemette Huet Philippe Chavatte Patricia Melnyk Fabrice Bailly Philippe Cotelle
Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP50–71-hTEAD1209–426 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis) and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells). A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes.
https://ift.tt/2ruxn1P
Circulating Tumor Cell Increase as a Biomarker of Disease Progression in Metastatic Castration-Resistant Prostate Cancer Patients with Low Baseline CTC Counts
Abstract
Background
The development of treatment response and surrogate biomarkers for advanced prostate cancer care is an unmet clinical need. Patients with baseline circulating tumor cell counts (BLCTCs)<5/7.5 mL represent a good prognosis subgroup, but are non-evaluable for response assessment (decrease in CTCs). The aim of the study is to determine the value of any increase in CTCs (CTC Progression) as an indicator of progression in prostate cancer patients with low pre-treatment CTCs (<5). Patients and Methods
We performed a post-hoc analysis of patients with BLCTCs < 5 treated in the COU-AA-301 (abiraterone or placebo + prednisone) and IMMC-38 (chemotherapy) trials. The association of CTC Progression (increase in CTCs at 4, 8 or 12 weeks) with overall survival (OS) was evaluated in multivariable Cox regression models. Performance of survival models with and without CTC Progression was evaluated by calculating ROC curve AUCs and weighted c-indices. Results
Overall, 511 patients with CTCs <5 (421 in COU-AA-301; 90 in IMMC-38) were selected; 212 (41.7%) had CTC Progression at 4, 8 or 12 weeks after treatment initiation. CTC Progression was associated with significantly worse OS (27.1 vs 15.1m; HR: 3.4 [95%CI:2.5-4.5; p < 0.001]); independent of baseline CTCs and established clinical variables. Adding CTC Progression to the OS model significantly improved ROC AUC (0.77 vs 0.66; p < 0.001). Models including CTC Progression had superior ROC AUC (0.77 vs 0.69; p < 0.001) and weighted c-index (0.750 vs 0.705; delta c-index: 0.045 [95%CI: 0.019-0.071]) values than those including CTC conversion (increase to CTCs ≥5). In COU-AA-301, the impact of CTC Progression was independent of treatment arm. Conclusions
Increasing CTCs during the first 12-weeks of treatment are independently associated with worse OS from advanced prostate cancer in patients with baseline CTCs < 5 treated with abiraterone or chemotherapy and improve models with established prognostic variables. These findings must be prospectively validated.https://ift.tt/2KMQexY
Biochemistry of N-mustard tumour control compounds reconsidered
The biochemicals and reactions involved in the present mechanism of degradation of tumour cells during chemotherapy are reconsidered and limitations noted. Alternative mechanisms and treatment methods are detailed. Correspondence to Daniel S. Robertson, BSc, Research Chemist, 205, Private Practitioner, Pickersleigh Road, Malvern, Worcestershire WR14 2QS, UK Tel: +44 168 457 5637; e-mail: danielstewartrobertson@gmail.com Received March 6, 2018 Accepted April 14, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2I4swvd
https://ift.tt/2I4swvd
Growth arrest and apoptosis induced by kinesin Eg5 inhibitor K858 and by its 1,3,4-thiadiazoline analogue in tumor cells
Tumors are complex and heterogeneous but, despite this, they share the ability to proliferate continuously, irrespective of the presence of growth signals, leading to a higher fraction of actively growing and dividing cells compared with normal tissues. For this reason, the cytotoxic antimitotic treatments remain an important clinical tool for tumors. Among these drugs, antitubulin compounds constitute one of the most effective anticancer chemotherapies; however, they cause dose-limiting side effects. Therefore, it is still necessary to develop compounds with new targets and new mechanisms of action to reduce side effects or chemoresistance. Mitosis-specific kinesin Eg5 can represent an attractive target for discovering such new anticancer agents because its role is fundamental in mitotic progression. Therefore, we analyzed the effects induced by an inhibitor of kinesin Eg5, K858, and by its 1,3,4-thiadiazoline analogue on human melanoma and prostate cancer cell lines. We found that both compounds have an antiproliferative effect, induce apoptosis, and can determine a downmodulation of survivin. Correspondence to Ida Silvestri, PhD, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy Tel/fax: +39 064 997 3335; e-mail: ida.silvestri@uniroma1.it Received October 6, 2017 Accepted April 12, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2rnX059
https://ift.tt/2rnX059
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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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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
