The mir-503 cluster is coordinately under-expressed in endometrial cancer

The microRNA-503 cluster, composed of six microRNAs (miR-424, miR503, miR-542, miR-450a-1, miR450a-2 and miR-450b), is located on the human X-chromosome at Xq26. This location is very near the gene encoding placenta-specific protein 1 (PLAC1) that we have shown is significantly over-expressed in several gynecologic cancers. We examined expression of the miR-503 cluster in a panel of endometrial endometrioid adenocarcinomas (EEAs) and found that all of the miRNAs are significantly under-expressed compared with benign tissue. Expression of the miRNAs is highly correlated suggesting that they are regulated from a single promoter. We have used DNA editing (CRISPR) of the miR-503 cluster promoter to down-regulate the entire cluster together. Additionally, known and validated targets of cluster members include a number of important oncogenes. Thus, suppression of miR-503 cluster members contributes to the establishment and maintenance of endometrial cancer. We further suggest that decreased miR-503 cluster expression is due to hyper-methylation of the promoter in tumor cells. Thus, we conclude that the miR-503 cluster is a potential therapeutic target in endometrial cancer

Computational analysis of expressed sequence tags for understanding gene regulation.

High-throughput sequencing has provided a myriad of genetic data for thousands of organisms. Computational analysis of one data type, expressed sequence tags (ESTs) yields insight into gene expression, alternative splicing, tissue specificity gene functionality and the detection and differentiation of pseudogenes. Two computational methods have been developed to analyze alternative splicing events and to detect and characterize pseudogenes using ESTs. A case study of rat phosphodiesterase 4 (PDE4) genes yielded more than twenty-five previously unreported isoforms. These were experimentally verified through wet lab collaboration and found to be tissue specific. In addition, thirteen cytochrome-like gene and pseudogene sequences from the human genome were analyzed for pseudogene properties. Of the thirteen sequences, one was identified as the actual cytochrome gene, two were found to be non-cytochrome-related sequences, and eight were determined to be pseudogenes. The remaining two sequences were identified to be duplicates. As a precursor to applying the two new methods, the efficiency of three BLAST algorithms (NCBI BLAST, WU BLAST and mpiBLAST) were examined for comparing large numbers of short sequences (ESTs) to fewer large sequences (genomic regions). In general, WU BLAST was found to be the most efficient sequence comparison tool. These approaches illustrate the power of ESTs in understanding gene expression. Efficient computational analysis of ESTs (such as the two tools described) will be vital to understanding the complexity of gene expression as more high-throughput EST data is made available via advances in molecular sequencing technologies, such as the current next-generation approaches

Postpartum Visit Attendance Increases the Use of Modern Contraceptives

Background. Delays in postpartum contraceptive use may increase risk for unintended or rapid repeat pregnancies. The postpartum care visit (PPCV) is a good opportunity for women to discuss family planning options with their health care providers. This study examined the association between PPCV attendance and modern contraceptive use using data from a managed care organization. Methods. Claims and demographic and administrative data came from a nonprofit managed care organization in Virginia (2008–2012). Information on the most recent delivery for mothers with singleton births was analyzed (N = 24,619). Routine PPCV (yes, no) and modern contraceptive use were both dichotomized. Descriptive analyses provided percentages, frequencies, and means. Multiple logistic regression was conducted and ORs and 95% CIs were calculated. Results. More than half of the women did not attend their PPCV (50.8%) and 86.9% had no modern contraceptive use. After controlling for the effects of confounders, women with PPCV were 50% more likely to use modern contraceptive methods than women with no PPCV (OR = 1.50, 95% CI = 1.31, 1.72). Conclusions. These findings highlight the importance of PPCV in improving modern contraceptive use and guide health care policy in the effort of reducing unintended pregnancy rates

Mobile resistome of human gut and pathogen drives anthropogenic bloom of antibiotic resistance

BACKGROUND:The impact of human activities on the environmental resistome has been documented in many studies, but there remains the controversial question of whether the increased antibiotic resistance observed in anthropogenically impacted environments is just a result of contamination by resistant fecal microbes or is mediated by indigenous environmental organisms. Here, to determine exactly how anthropogenic influences shape the environmental resistome, we resolved the microbiome, resistome, and mobilome of the planktonic microbial communities along a single river, the Han, which spans a gradient of human activities. RESULTS:The bloom of antibiotic resistance genes (ARGs) was evident in the downstream regions and distinct successional dynamics of the river resistome occurred across the spatial continuum. We identified a number of widespread ARG sequences shared between the river, human gut, and pathogenic bacteria. These human-related ARGs were largely associated with mobile genetic elements rather than particular gut taxa and mainly responsible for anthropogenically driven bloom of the downstream river resistome. Furthermore, both sequence- and phenotype-based analyses revealed environmental relatives of clinically important proteobacteria as major carriers of these ARGs. CONCLUSIONS:Our results demonstrate a more nuanced view of the impact of anthropogenic activities on the river resistome: fecal contamination is present and allows the transmission of ARGs to the environmental resistome, but these mobile genes rather than resistant fecal bacteria proliferate in environmental relatives of their original hosts. Video abstract

Reactive granulomatous dermatitis associated with ovarian cancer and a review of its role as a harbinger for malignancy

Reactive granulomatous dermatitis (RGD) is a rare dermatosis with a variety of cutaneous manifestations unified by a dermal granulomatous infiltrate on histology. Rheumatoid arthritis and autoimmune disease are classic associations, but an increasing number of cases have been attributed to covert malignancy. Only 41 cases of paraneoplastic RGD have been documented to our knowledge and we present an additional case that manifested eight months prior to the diagnosis of ovarian cancer and clinically mimicked morphea. Histopathologic examination identifying palisaded CD68+ cells and collagen degeneration are helpful in diagnosing this entity which may mimic a host of other cutaneous processes, including metastatic disease. Cancer-directed therapies have been successful in clearing paraneoplastic RGD with or without the addition of corticosteroids, as RGD severity may be driven by the underlying malignancy. This case highlights the importance of utilizing histopathology to confirm the diagnosis given its nonspecific clinical findings, as well as the importance of considering malignancy and metastatic disease in patients diagnosed with RGD regardless of their cancer history

Epidural Hematoma Following Cervical Spine Surgery.

STUDY DESIGN: A multicentered retrospective case series. OBJECTIVE: To determine the incidence and circumstances surrounding the development of a symptomatic postoperative epidural hematoma in the cervical spine. METHODS: Patients who underwent cervical spine surgery between January 1, 2005, and December 31, 2011, at 23 institutions were reviewed, and all patients who developed an epidural hematoma were identified. RESULTS: A total of 16 582 cervical spine surgeries were identified, and 15 patients developed a postoperative epidural hematoma, for a total incidence of 0.090%. Substantial variation between institutions was noted, with 11 sites reporting no epidural hematomas, and 1 site reporting an incidence of 0.76%. All patients initially presented with a neurologic deficit. Nine patients had complete resolution of the neurologic deficit after hematoma evacuation; however 2 of the 3 patients (66%) who had a delay in the diagnosis of the epidural hematoma had residual neurologic deficits compared to only 4 of the 12 patients (33%) who had no delay in the diagnosis or treatment (P = .53). Additionally, the patients who experienced a postoperative epidural hematoma did not experience any significant improvement in health-related quality-of-life metrics as a result of the index procedure at final follow-up evaluation. CONCLUSION: This is the largest series to date to analyze the incidence of an epidural hematoma following cervical spine surgery, and this study suggest that an epidural hematoma occurs in approximately 1 out of 1000 cervical spine surgeries. Prompt diagnosis and treatment may improve the chance of making a complete neurologic recovery, but patients who develop this complication do not show improvements in the health-related quality-of-life measurements

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31

This report is a summary of \u27New Cancer Immunotherapy Agents in Development\u27 program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy

Incidence and Severity of Drug Interactions Before and After Switching Antiretroviral Therapy to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Treatment-Experienced Patients.

Background: Switching antiretroviral therapy (ART) in people with HIV (PWH) can influence their risk for drug-drug interactions (DDIs). The purpose of this study was to assess changes in the incidence and severity of DDIs among PWH who switched their ART to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Methods: This was a multicenter retrospective cohort study of PWH on ART and at least 1 concomitant medication (CM) who switched to BIC/FTC/TAF between 3/2018 and 6/2019. Using the University of Liverpool\u27s HIV Drug Interaction Database, 2 DDI analyses were performed for each patient. The first assessed patients\u27 preswitch ART regimens with their CM list. The second assessed the same CM list with BIC/FTC/TAF. Each ART-CM combination was given a score of 0 (no or potential weak interaction), 1 (potential interaction), or 2 (contraindicated interaction). A paired Results: Among 411 patients, 236 (57%) had at least 1 DDI present at baseline. On average, baseline DDI scores (SD) were 1.4 (1.8) and decreased by 1 point (95% CI, -1.1 to -0.8) after patients switched to BIC/FTC/TAF ( Conclusions: Treatment-experienced PWH eligible to switch their ART may experience significant declines in number and severity of DDIs if switched to BIC/FTC/TAF

A retinoic acid–dependent checkpoint in the development of CD4+ T cell–mediated immunity

Immune cell activation induces concurrent temporal and spatial retinoic acid signaling, and CD4+ T cell–specific loss of RA signals reduces effector function, migration, and polarity