Until recently, no studies have examined vocabulary outcomes of children with hearing loss that have met all three components of the EHDI guidelines:
http://ift.tt/2vpBoVF
Σάββατο 15 Ιουλίου 2017
Effect of Glucocorticoids on Ultrastructure of Myocardial Muscle in the Course of Experimentally Induced Acute Myocardial Ischemia
The search for effective methods of myocardial cytoprotection against ischemia is the most significant issue in modern cardiology and cardiac surgery. Glucocorticoids are deemed very strong modulators of inflammatory response and thus can potentially protect heart muscle from postreperfusion injury and myocardial ischemia during cardiac surgery. Ultrastructural examination of the left ventricle heart samples revealed that the intravenous application of dexamethasone and hydrocortisone proved to exert cytoprotective effect on cardiomyocytes during experimentally induced acute ischemia in rats.
http://ift.tt/2vp9etF
The uS8, uS4, eS31, and uL14 Ribosomal Protein Genes Are Dysregulated in Nasopharyngeal Carcinoma Cell Lines
The association of ribosomal proteins with carcinogenesis of nasopharyngeal carcinoma (NPC) has been established in a limited subset of ribosomal protein genes. To date, three ribosomal protein genes, eL27 (L27), eL41 (L41), and eL43 (L37a), have been found to be differentially expressed in cell lines derived from NPC tumors. This raises the possibility of more ribosomal protein genes that could be associated with NPC. In this study, we investigated the expression profiles of eight ribosomal protein genes, uS8 (S8), uS4 (S9), eS31 (S27a), eL6 (L6), eL18 (L18), uL14 (L23), eL24 (L24), and eL30 (L30), in six NPC-derived cell lines (HONE-1, SUNE1, HK1, TW01, TW04, and C666-1). Their expression levels were compared with that of a nonmalignant nasopharyngeal epithelial cell line (NP69) using quantitative real-time PCR (RT-qPCR) assay. Of the eight genes studied, the expressions of four ribosomal protein genes uS8 (S8), uS4 (S9), eS31 (S27a), and uL14 (L23) were found to be significantly downregulated in NPC cell lines relative to NP69. Our findings provide novel empirical evidence of these four ribosomal protein genes as NPC-associated genetic factors and reinforce the relevance of ribosomal proteins in the carcinogenesis of nasopharyngeal cancer.
http://ift.tt/2vpuCPH
Nitrous oxide cryotherapy for treatment of esophageal squamous cell neoplasia: initial multicenter international experience with a novel portable cryoballoon ablation system (with video)
Early esophageal squamous cell neoplasia (ESCN) can be successfully treated by endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), or radiofrequency ablation (RFA). A new portable, battery-powered cryotherapy system using nitrous oxide (cryoballoon focal ablation system (CbFAS) has been used for Barrett's esophagus. It consists of a small hand-held device containing liquid nitrous oxide, which converts to gas within a low-pressure–compliant through-the-scope balloon and freezes targeted mucosa in contact with the balloon.
http://ift.tt/2v4Q9xR
Thrombotic Microangiopathy: A Multidisciplinary Team Approach
Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia along with organ dysfunction, and pathologically, by the presence of microthrombi in multiple microvascular beds. Delays in diagnosis and initiation of therapy are common due to the low incidence, variable presentation, and poor awareness of these diseases, underscoring the need for interdisciplinary approaches to clinical care for TMA. We describe a new approach to improve clinical management via a TMA team that originally stemmed from an Affinity Research Collaborative team focused on thrombosis and hemostasis.
http://ift.tt/2v50tFW
Treatment of Uremic Pruritus: A Systematic Review
Uremic pruritus is a common and burdensome symptom afflicting patients with advanced chronic kidney disease (CKD) and has been declared a priority for CKD research by patients. The optimal treatments for uremic pruritus are not well defined.
http://ift.tt/2uvxX3a
Assessment of BRAF V600E mutation in pulmonary Langerhans cell histiocytosis in tissue biopsies and bronchoalveolar lavages by droplet digital polymerase chain reaction
Abstract
The neoplastic nature of pulmonary Langerhans cell histiocytosis (PLCH) is still debated. As the detection of BRAF V600E and MAP2K1 mutations in patients with PCLH is now considered for such assessment, the aim of our study was to evaluate digital droplet polymerase chain reaction (ddPCR) in PCLH diagnosis. We retrospectively analyzed BRAFV600E detection in a cohort of 42 PCLH tissues and 18 bronchoalveolar lavages (BALs) by ddPCR, immunohistochemistry, high-resolution melting PCR (HRM), and next-generation sequencing (NGS). The presence of BRAFV600E mutation was assessed by at least two concordant techniques to further evaluate specificity and sensitivity of each method. The BRAF V600E mutation prevalence was detected in 18 out of 41 cases by ddPCR, 10 out of 36 cases by HRM PCR, and 16 out of 31 cases by NGS. BRAFV600E immunohistochemistry sensitivity was 94%, and specificity was 79%. HRM PCR sensitivity was only 59%, and specificity was 100%. NGS sensitivity and specificity were 100% for interpretable cases (n = 31), but in 11 cases, this technique was non-contributive. The analysis of BAL samples by ddPCR revealed a BRAFV600E mutation both in tissue and in BAL samples in one patient, a wild-type status both in tissue and in BAL samples in two patients, and a wild-type BRAF status in BAL and a BRAFV600E mutation in tissue samples in four patients. The study supports the usefulness of ddPCR for BRAF status assessment in either tissue or BAL samples to increase the accuracy of PLCH diagnosis.
http://ift.tt/2tdNRz5
A simplified clinical prediction rule for prognosticating independent walking after spinal cord injury: a prospective study from a Canadian multicenter spinal cord injury registry
Publication date: Available online 14 July 2017
Source:The Spine Journal
Author(s): Katharine E. Hicks, Yichen Zhao, Nader Fallah, Carly Rivers, Vanessa Noonan, Tova Plashkes, Eugene K. Wai, Darren M. Roffey, Eve Tsai, Jerome Paquet, Najmedden Attabib, Travis Marion, Henry Ahn, Philippe Phan
BackgroundContext: Traumatic spinal cord injury (SCI) is a debilitating condition with limited treatment options for neurological or functional recovery. The ability to predict the prognosis of walking post-injury with emerging prediction models could aid in rehabilitation strategies and reintegration into the community.PurposeTo re-validate an existing clinical prediction model for independent ambulation (van Middendorp et al. 2011) utilising acute and long-term post-injury follow-up data, and to investigate the accuracy of a simplified model using prospectively collected data from a Canadian multicenter SCI database, the Rick Hansen Spinal Cord Injury Registry (RHSCIR).Study DesignProspective cohort study.Participant SampleThe analysis cohort consisted of 278 adult individuals with traumatic SCI enrolled in the RHSCIR for whom complete neurological examination data and Functional Independence Measure (FIM) outcome data was available.Outcome MeasuresThe FIM locomotor score was used to assess independent walking ability (defined as modified or complete independence in walk or combined walk/wheelchair modality) at one-year follow-up for each participant.MethodsA logistic regression (LR) model based on age and four neurological variables was applied to our cohort of 278 RHSCIR participants. Additionally, a simplified LR model was created. The Hosmer-Lemeshow goodness of fit test was used to check if the predictive model is applicable to our data set. The performance of the model was verified by calculating the area under the receiver operating characteristic curve (AUC). The accuracy of the model was tested using a cross-validation technique. This study was supported by a grant from The Ottawa Hospital Academic Medical Organization (TOHAMO) ($50,000 over 2 years). The RHSCIR is sponsored by the Rick Hansen Institute and is supported by funding from Health Canada, Western Economic Diversification Canada, and the provincial governments of Alberta, British Columbia, Manitoba, and Ontario. ET and JP report receiving grants from the Rick Hansen Institute (approximately $60,000 and $30,000 per year, respectively). DMR reports receiving remuneration for consulting services provided to Palladian Health, LLC and Pacira Pharmaceuticals, Inc ($20,000-$30,000 annually), although neither relationship presents a potential conflict of interest with the submitted work. KEH received a grant for involvement in the present study from the Government of Canada as part of the Canada Summer Jobs Program ($3,000). JP reports receiving an educational grant from Medtronic Canada outside of the submitted work ($75,000 annually). TM reports receiving educational fellowship support from AO Spine, AO Trauma, and Medtronic; however, none of these relationships are financial in nature. All remaining authors have no conflicts of interest to disclose.ResultsThe fitted prediction model generated 85% overall classification accuracy, 79% sensitivity and 90% specificity. The prediction model was able to accurately classify independent walking ability (AUC 0.889, 95% CI 0.846-0.933, p<0.001) compared to the existing prediction model, despite the use of a different outcome measure (FIM versus SCIM) to qualify walking ability. A simplified, three-variable LR model based on age and two neurological variables had an overall classification accuracy of 84% with 76% sensitivity and 90% specificity, demonstrating comparable accuracy to its five-variable prediction model counterpart. The AUC was 0.866 (95% CI 0.816-0.916, p<0.01), only marginally less than that of the existing prediction model.ConclusionsA simplified predictive model with similar accuracy to a more complex model for predicting independent walking was created which improves utility in a clinical setting. Such models will allow clinicians to better predict the prognosis of ambulation in individuals who have sustained a traumatic SCI.
http://ift.tt/2tWKdqs
A Combination of Testosterone and White Blood Cell Count as a Predictive Factor of Overall Survival in Localized Prostate Cancer
Abstract
Background
It has been shown that neutrophil count or an elevated neutrophil-to-lymphocyte ratio (NLR) as well as testosterone levels are separately associated with increased mortality in patients with localized prostate cancer.
Objective
We tested a combination of testosterone levels and white blood cell (WBC) counts to predict overall survival (OS) in a prospective cohort of patients treated with radiotherapy for localized prostate cancer.
Patients and Methods
The 381 patients included in this study were prospectively enrolled in phase 2 or 3 studies. Multivariate Cox proportional hazards models were used to analyze the influence of WBC count and testosterone level on biochemical recurrence and OS. Cutoff levels of ≤10.4 nmol/L (300 ng/dL) for testosterone and a median value of 6.2 (×109/L) for WBC count were used.
Results
The median follow-up for biochemical recurrence and OS were 72 and 78 months, respectively. A WBC count of ≥6.2 alone was not associated with OS (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.30–1.46). When combined with a testosterone level of >10.3 nmol/L, a WBC count of ≥6.2 was associated with increased mortality (HR 2.96; 95% CI 1.45–6.06) when compared with a WBC count of <6.2 (p-interaction = 0.01). The HR for biochemical recurrence for patients with a testosterone level >10.3 nmol/L combined with a lymphocyte level above or equal to the median was nearly identical to the HR of a testosterone level >10.3 nmol/L with a WBC above or equal to the median. There was no association between testosterone level and the NLR.
Conclusions
A high WBC and lymphocyte count combined with normal testosterone levels increases the overall mortality of patients treated with radiotherapy for localized prostate cancer within the first 6–7 years post-treatment. Validation in larger cohorts is necessary.
http://ift.tt/2ukHeuq
Identification of BRCA1 As a Potential Biomarker for Insulin-Like Growth Factor-1 Receptor Targeted Therapy in Breast Cancer.
Identification of BRCA1 As a Potential Biomarker for Insulin-Like Growth Factor-1 Receptor Targeted Therapy in Breast Cancer.
Front Endocrinol (Lausanne). 2017;8:148
Authors: Cohen-Sinai T, Cohen Z, Werner H, Berger R
Abstract
The insulin-like growth factor-1 receptor (IGF1R) emerged in recent years as a promising therapeutic target in oncology. Identification of potential biomarkers capable of predicting response to IGF1R-targeted therapy is of cardinal importance. Tumor suppressor BRCA1 has important roles in multiple pathways, including gene transcription, DNA damage repair, and control of apoptosis. Early studies have identified the IGF1R gene as a downstream target for inhibitory regulation by wild-type, but not mutant, BRCA1. The aim of the present study was to evaluate the hypothesis that the mutational status of BRCA1 may influence the ability of IGF1R-directed therapies to efficiently inhibit the IGF1R axis. Using breast cancer-derived cell lines expressing a wild-type or a mutant BRCA1, we demonstrate that the capacity of MK-0646, a monoclonal antibody antagonist to the human IGF1R, to inhibit insulin-like growth factor-1-stimulated IGF1R and downstream mediators' phosphorylation was impaired in mutant BRCA1-expressing cell lines. In addition, the antibody was able to reduce proliferation of wild-type BRCA1-expressing cells but had a reduced inhibitory effect in mutant BRCA1-expressing cells. In summary, our data indicate that the mutational status of BRCA1 must be taken into account when selecting patients for IGF1R targeting protocols.
PMID: 28706506 [PubMed]
http://ift.tt/2t1kmft
Pancreas adenocarcinoma: novel therapeutics.
Pancreas adenocarcinoma: novel therapeutics.
Chin Clin Oncol. 2017 Jun;6(3):30
Authors: Krantz BA, Yu KH, O'Reilly EM
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third highest cause of cancer-related deaths in the US, and is projected to be second only to non-small cell lung cancer (NSCLC) by the 2020s. Current therapies have a modest impact on survival and median overall survival (mOS) across all stages of disease remains under a year. Over the last decade, however, great strides have been made in the understanding of PDAC pathobiology including the role of the tumor microenvironment (TME), DNA damage repair and mechanism of immunosuppression. Exciting novel therapeutics are in clinical development targeting the TME to increase cytotoxic drug delivery, decrease immunosuppressive cell presence and attack cancer stem cells (CSCs). Immune checkpoint inhibitors, cancer vaccines and other immunotherapies are actively being studied and novel combinations of targeted agents are being pursued. There is a sense of optimism in the oncology community that these scientific advances will translate into improved outcomes for patients with PDAC in the proximate future. In this review, we examine various novel therapeutics under clinical development with a focus on stromal disrupting agents, immunotherapeutics and DNA damage repair strategies.
PMID: 28705007 [PubMed - in process]
http://ift.tt/2uubGD0
Targeting cancer using KAT inhibitors to mimic lethal knockouts.
  | Related Articles |
Targeting cancer using KAT inhibitors to mimic lethal knockouts.
Biochem Soc Trans. 2016 Aug 15;44(4):979-86
Authors: Brown JA, Bourke E, Eriksson LA, Kerin MJ
Abstract
Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.
PMID: 27528742 [PubMed - indexed for MEDLINE]
http://ift.tt/2uknQgZ
Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer
Abstract
Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.
http://ift.tt/2tTCrPw
Clarithromycin co-administration does not increase irinotecan (CPT-11) toxicity in colorectal cancer patients
Abstract
Purpose
Irinotecan (CPT-11) is used to treat advanced colorectal cancer. The drug is activated by carboxylesterases and rendered inactive by CYP3A4. Recently, the efficacy of combining CPT-11 and anti-epidermal growth factor receptor (EGFR) agents was confirmed in patients with KRAS wild-type metastatic colorectal cancer. Clarithromycin (CAM) is a strong CYP3A inhibitor often used to prevent rash associated with anti-EGFR therapy. The objective of this study was to evaluate the risk of increased neutropenia and diarrhea in combining CPT-11 and CAM.
Methods
Retrospective analyses were conducted at Osaka National Hospital (Osaka, Japan) on the records of colorectal cancer patients treated with a CPT-11-containing regimen between November 2006 and January 2014. The incidence of neutropenia and diarrhea was compared between patients who received CPT-11 and CAM and patients who received CPT-11 without CAM.
Results
One-hundred and twenty-eight patients were included in this study, of whom 21 were concomitantly treated with CAM and 107 were not. There was no difference in the incidence of grade 3–4 neutropenia between the CAM co-administration group (10%) and the non-CAM group (16%) [Odds ratio: 0.56 (95% confidence interval: 0.12–2.62), p = 0.45]. No difference in the incidence of grade 3–4 diarrhea was found between the CAM co-administration group (0%) and the non-CAM group (4%) (p = 0.37).
Conclusions
This study did not identify an increase in CPT-11 toxicity by co-administration with CAM.
http://ift.tt/2uua6AO
Effectiveness of Apneic Oxygenation During Intubation: A Systematic Review and Meta-analysis
We conduct a systematic review and meta-analysis to evaluate the effectiveness of apneic oxygenation during emergency intubation.
http://ift.tt/2tW6WCQ
A Custom-Developed Emergency Department Provider Electronic Documentation System Reduces Operational Efficiency
Electronic health record implementation can improve care, but may also adversely affect emergency department (ED) efficiency. We examine how a custom, ED provider, electronic documentation system (eDoc), which replaced paper documentation, affects operational performance.
http://ift.tt/2tdad3z
Do Intravenous Benzodiazepines or Benzodiazepines by an Alternative Route (Nonintravenous) Abort Seizures Faster?
The authors included 11 studies, with 10 randomized controlled trials and 1 observational longitudinal study for analysis, with 1,633 patients. Ten of the 11 articles were predominantly pediatric, although a single study accounting for more than half the patients analyzed in the meta-analysis (893 patients) comprised both children and adults with mean age 43 years among patients receiving benzodiazepines by alternative routes and 44 years in the intravenous group.2 Comparison of failure, defined by failure to stop seizure, favored benzodiazepines administered by alternative routes (odds ratio 0.72; 95% CI 0.56 to 0.92).
http://ift.tt/2tdaa7T
Patients’ Perspectives on Outcomes of Care After Discharge From the Emergency Department: A Qualitative Study
Much effort has been expended to understand what care experiences patients value in the emergency department (ED), yet little is known about which outcomes patients value after ED care. Our goal is to define outcomes of ED care that are valued by patients discharged from the ED, with the goal of informing the development of a patient-reported outcome measure for ED care.
http://ift.tt/2tW8Cw4
Is Early Goal-Directed Therapy or Standard Therapy More Effective in Decreasing Mortality Among Patients With Sepsis?
In the systematic review, 19,998 patients were included from 6 randomized trials (n=4,342) and 31 observational studies (n=15,656). The pooled analysis demonstrated a 23% reduction in the risk of mortality in patients treated with early goal-directed therapy (relative risk=0.77; 95% confidence interval 0.71 to 0.83; P<.001). This reduction was not observed in the randomized studies (relative risk=0.92; 95% confidence interval 0.78 to 1.07; P=.27). A meta-regression analysis of potential differences between the randomized and the observational studies revealed that the only factors associated with the mortality differences between early goal-directed therapy and control were the following: time to first antibiotic, and antibiotic administration within 6, 4, and 3 hours (Table 1).
http://ift.tt/2tda8wN
What Elements Suggest Infectious Mononucleosis?
Authors screened 670 abstracts and selected 117 for full-text review, of which 11 met inclusion criteria. A total of 4,769 patients were included, of whom 2,345 had serologically confirmed mononucleosis. Three studies were prospective cohort studies, 3 were retrospective laboratory studies without clinical information, and 5 were case series with confirmed mononucleosis. Of the studied elements, atypical lymphocytes had the greatest positive LR (Table). None of the examined elements were sufficient to exclude the diagnosis.
http://ift.tt/2tVXbEC
“Sometimes You Feel Like the Freak Show”: A Qualitative Assessment of Emergency Care Experiences Among Transgender and Gender-Nonconforming Patients
Transgender, gender-variant, and intersex (trans) people have decreased access to care and poorer health outcomes compared with the general population. Little has been studied and documented about such patients' emergency department (ED) experiences and barriers to care. Using survey and qualitative research methods, this study aims to identify specific areas for improvement and generate testable hypotheses about the barriers and challenges for trans individuals needing acute care.
http://ift.tt/2tdvudo
Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer
Abstract
Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.
http://ift.tt/2tTCrPw
From Last to First — Could the U.S. Health Care System Become the Best in the World?
New England Journal of Medicine, Ahead of Print.
http://ift.tt/2uk62ms
From Last to First — Could the U.S. Health Care System Become the Best in the World?
New England Journal of Medicine, Ahead of Print.
http://ift.tt/2uk62ms
Accelerated kindling epileptogenesis in Tg4510 tau transgenic mice, but not in tau knockout mice
Summary
The biologic processes underlying epileptogenesis following a brain insult are not fully understood, but several lines of evidence suggest that hyperphosphorylation of tau may be an important factor in these processes. To provide further insight into the causal relationship between tau and epileptogenesis, this study applied amygdala kindling to rTg4510 mice that, concurrent with other pathologies, overexpress phosphorylated tau, tau knockout mice, or their respective wild-type controls. Mice were electrically stimulated twice daily, 5 days per week for 3 weeks. Electroencephalography was recorded to measure the primary afterdischarge duration, and the behavioral progression of kindling-induced seizures was assessed. rTg4510 mice (n = 10) had increased primary afterdischarge durations (p < 0.001), and significantly more rapid progression of kindling (p < 0.001), compared with wild-type mice (n = 10). Tau knockout mice (n = 7), however, did not differ from their wild-type counterparts (n = 8) on any of the seizure outcomes. These results suggest that Tg4510 mice are more vulnerable to epileptogenesis, but that the presence of tau itself is not necessary for kindling epileptogenesis to occur.
http://ift.tt/2v2JdBc
Prevalence and Significance of HMGA2 Expression in Esophageal Adenocarcinoma
Abstract
Aims
Esophageal adenocarcinoma (EAC) tumorigenesis has been primarily linked to loss-of-function mutations in tumor suppressor genes. Knowledge of specific oncogenes that drive tumor progression, and their relationship to outcomes, is limited. High Mobility Group AT-Hook 2 (HMGA2) has been reported to be amplified in a subset of EACs, but the clinicopathologic and prognostic implications of HMGA2 expression in EAC is unknown.
Methods and Results
We performed HMGA2 immunohistochemistry and fluorescence in-situ hybridization (FISH) in EAC to determine its clinicopathologic and prognostic significance. Ninety-one primary EAC resections without neoadjuvant treatment were identified and immunohistochemistry for HMGA2 was performed. The presence or absence of nuclear staining was evaluated and correlated with predetermined clinicopathologic parameters and patient outcomes. A selected subset of tumors was subjected to FISH to identify alterations at the HMGA2 locus. HMGA2 expression was present in 25/91 (27.4%) tumors. HMGA2 expressing cells were present in solid, poorly differentiated areas of the tumors at the invasive front, or as single infiltrating cells. FISH showed that 3-4 copies of HMGA2 are frequently present in EAC irrespective of HMGA2 protein expression and that high level HMGA2 amplification is a rare event. HMGA2 expression was associated with numerous adverse clinicopathologic parameters including higher T- and N-stage, the presence of lymphovascular invasion, and with a worse recurrence free and overall survival.
Conclusion
Our data suggests that HMGA2 is primarily regulated in EAC through non-chromosomal level alterations that lead to increased HMGA2 expression. HMGA2 positive EAC correlates with adverse pathologic features and worse patient outcomes.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tcLsEM
Prognostic significance of a comprehensive histologic evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients
Abstract
Aims
to evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.
Methods
reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 base-line BMBs. Then, we assigned to each case a comprehensive score (RCO score, ranging from 0 to 9) that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes.
Results and discussion
of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was more frequently associated with anemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. RCO score resulted strictly correlated with overall mortality (p=0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (Log-Rank test: p<0.001). Moreover, it proved to be more accurate than the European Consensus on grading of bone marrow fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis.
Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients.
Conclusion
the comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis, resulted prognostically significant, more accurate than ECGMF grade in identifying high-risk patients, and improved PPV when applied in addition to IPSS.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tVRKFK
Isochlorogenic acid A promotes melanin synthesis in B16 cell through the β-catenin signal pathway
Abstract
Isochlorogenic acid A, also called 3,5-dicaffeoylquinic acid (3,5-diCQA), is a widespread phenolic compound in the plant. Recent studies have shown that it has antioxidant and anti-inflammatory activity. In addition, oxidative stress and inflammation induced by solar ultraviolet radiation is a very significant reason for skin depigmentation. Therefore, in this study, we evaluated the effect of 3,5-diCQA on B16 cells and explored its molecular mechanism. Results showed that 3,5-diCQA upregulated intracellular melanin production in a time- and dose-dependent manner. Tyrosinase (TYR) activity was also increased after treatment with 3,5-diCQA in a dose-dependent manner. Expressions of TYR, TYR-related protein1, TYR-related protein2, and microphthalmia-associated transcription factor were upregulated in a dose-dependent manner after 48 h of treatment with 3,5-diCQA. Results also showed that 3,5-diCQA promoted the phosphorylation of Akt at Thr308 and glycogen synthase kinase-3β at Ser 9. Moreover, 3,5-diCQA increased the content of β-catenin in cell cytoplasm and nucleus by reducing the content of phosphorylated β-catenin (p-β-catenin). All these results suggest that 3,5-diCQA may mediate the acceleration of melanin synthesis by the β-catenin signal pathway.http://ift.tt/2utzBlL
DNA-binding properties of FOXP3 transcription factor
Abstract
FOXP3, a lineage-specific forkhead (FKH) transcription factor, plays essential roles in the development and function of regulatory T cells. However, the DNA-binding properties of FOXP3 are not well understood. In this study, FOXP3 fragments containing different domains were purified, and their DNA-binding properties were investigated using electrophoretic mobility shift assay and isothermal titration calorimetry (ITC). Both the FKH and leucine-zipper domains were required for optimal DNA binding for FOXP3. FOXP3 protein not only binds with DNA sequences containing one FKH consensus sequence, but also binds with DNA sequences with two direct repeats of consensus sequences separated by three-nucleotides (DRE3). Our results shed lights on the mechanisms by which FOXP3 recognizes cognate DNA elements, and would facilitate further structural and functional studies of FOXP3.http://ift.tt/2v2vUR2
Emerging role of HuR in inflammatory response in kidney diseases
Abstract
Human antigen R (HuR) is a member of the embryonic lethal abnormal vision (ELAV) family which can bind to the A/U rich elements in 3' un-translated region of mRNA and regulate mRNA splicing, transportation, and stability. Unlike other members of the ELAV family, HuR is ubiquitously expressed. Early studies mainly focused on HuR function in malignant diseases. As researches proceed, more and more proofs demonstrate its relationship with inflammation. Since most kidney diseases involve pathological changes of inflammation, HuR is now suggested to play a pivotal role in glomerular nephropathy, tubular ischemia-reperfusion damage, renal fibrosis and even renal tumors. By regulating the mRNAs of target genes, HuR is causally linked to the onset and progression of kidney diseases. Reports on this topic are steadily increasing, however, the detailed function and mechanism of action of HuR are still not well understood. The aim of this review article is to summarize the present understanding of the role of HuR in inflammation in kidney diseases, and we anticipate that future research will ultimately elucidate the therapeutic value of this novel target.http://ift.tt/2utqpxX
Bisphenol A induced apoptosis and transcriptome differences of spermatogonial stem cells in vitro
Abstract
Bisphenol A (BPA) is widely used as an industrial plasticizer, which is also an endocrine disruptor and considered to have adverse effects on reproduction. In male mammals, the long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). However, little is known about the effects of BPA on the viability of SSCs. To investigate the influence of BPA exposure on SSCs in vitro, we isolated SSCs from mouse and successfully established in vitro propagation of SSCs. After BPA treatment, we found that BPA reduced the viability of SSCs and induced SSC apoptosis. For revealing the transcriptome differences of the BPA-treated SSCs, we performed high-throughput RNA sequencing and found that 860 genes were differentially expressed among 18,272 observed genes. The gene ontology (GO) terms, regulation of programmed cell death and apoptotic process, were enriched in the differentially expressed genes (DEGs). Among the cluster of DEGs associated with the kyoto encyclopedia of genes and genomes (KEGG) apoptosis pathway, activating transcription factor 4 (Atf4) and DNA damage inducible transcript 3 (Ddit3) genes were significantly up-regulated in BPA-treated SSCs, which were proved by qPCR. Taken together, these findings suggest that BPA can increase the mRNA expression of pro-apoptosis genes and reduce the viability of SSCs by inducing apoptosis.http://ift.tt/2v2Jdkr
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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...
