PubMed | Massachusetts Institute of Technology, Hamner Institutes for Health Sciences, University of Swansea, University of Health Center and 2 more.
Type: | Journal: Mutation research. Reviews in mutation research | Year: 2016
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.
Rajan T.V.,University of Health Center |
Kerstetter J.,University of Connecticut |
Feinn R.,Quinnipiac University |
Kenny A.,University of Connecticut Health Center
Aging Male | Year: 2014
There are increasing data indicating profound ethnic differences in the levels of virilization of males [1-4]. It is well understood that the intensity of testosterone-mediated effects is modulated by sex hormone binding globulin (SHBG)  and the CAG repeat lengths in the androgen receptor (AR) gene . We determined the serum testosterone, estradiol and SHBG levels and average CAG repeat lengths among a group of healthy older Indian men living in Connecticut, USA and compared these parameters with those of a reference group of white Caucasian men. We also compared various parameters that represent the end-manifestations of testosterone activity-serum prostate-specific antigen (PSA) levels, lean body mass, skeletal mineralization and visceral fat. Our data suggest that men from the Indian subcontinent are smaller, manifest lower levels of circulating free testosterone, lower mean PSA levels and lean body mass, but are comparable to white Caucasian men in terms of SHBG, estradiol, levels of visceral fat and CAG repeat length. These data suggest that Indian men manifest a lower level of virilization compared to white Caucasian males and that this might be due to lower mean circulating testosterone levels rather than higher AR CAG repeat length or SHBG. © 2014 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.
Khalil I.,Gene Network science |
Brewer M.A.,University of Health Center |
Neyarapally T.,Gene Network science |
Runowicz C.D.,University of Health Center
Gynecologic Oncology | Year: 2010
Ovarian cancer is one of the most common gynecologic malignancies and is the 5th leading cause of cancer mortality in women in the United States. Understanding the biology and molecular pathogenesis of ovarian epithelial tumors is key to developing improved prognostic indicators and effective therapies. The selection of ovarian serous carcinomas as one of the three cancer types for extensive genomic and proteomic characterization of The Cancer Genome Atlas (TCGA) project offers an important opportunity to extend our knowledge of ovarian cancer. The data portal includes molecular characterization, high throughput sequencing, and clinical data. Models to determine which of these genes act as "key drivers" of ovarian carcinogenesis and which are innocent "passengers" are needed. Standard statistical approaches often fail to differentiate between these driver and passenger genes, given that the correlation between sets of genes or genes and endpoints alone does not establish causality. As contrasted to basic correlations analyses, biological network models offer the ability to resolve causality by elucidating the directional linkages between genetics, molecular characterizations of the system, and clinical measures. This article describes the use of a novel, supercomputer-driven approach named REFS™ to learn network models directly from the TGCA ovarian cancer data set and simulate these models to learn the "key drivers" of ovarian carcinogenesis. The model can be validated by out-of-sample testing, and may provide a powerful new tool for ovarian cancer research. © 2009 Elsevier Inc. All rights reserved.
Peluso J.J.,University of Health Center |
Decerbo J.,University of Health Center |
Lodde V.,University of Health Center |
Lodde V.,University of Milan
Steroids | Year: 2012
Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in the granulosa and luteal cells of rodent and primate ovaries. Interestingly, its molecular weight as assessed by Western blot is dependent on its cellular localization with a ≈27 kDa form being detected in the cytoplasm and higher molecular weight forms being detected in the nucleus. The higher molecular weight forms of PGRMC1 are sumoylated suggesting that they are involved in regulating gene transcription, since sumoylation of nuclear proteins often is associated with regulation of transcriptional activity of the sumoylated protein. In order to identify a set of candidate genes that are regulated by PGRMC1, a human granulosa/luteal cell line (hGL5 cells) was treated with PGRMC1 siRNA and changes in gene expression monitored by microarray analysis. The microarray analysis revealed that PGRMC1 generally functioned as a repressor of transcription, since depletion of PGRMC1 resulted in a disproportionate increase in the number of transcripts. Moreover, a pathway analysis implicated PGRMC1 in the regulation of apoptosis, which is consistent with PGRMC1's known biological action. More importantly these results support the concept that PGRMC1 influences gene transcription. Additional studies reveal that progesterone (P4) acting through a PGRMC1-dependent mechanism suppresses the activity of the transcription factor, Tcf/Lef, thereby identifying one molecular pathway through which P4-PGRMC1 can regulate gene transcription and ultimately apoptosis. © 2011 Elsevier Inc. All rights reserved.
Peluso J.J.,University of Health Center
Steroids | Year: 2011
Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. © 2011 Elsevier Inc. All rights reserved.
Ricketts J.R.,University of Health Center |
Rothe M.J.,University of Health Center |
Grant-Kels J.M.,University of Health Center
International Journal of Dermatology | Year: 2011
Many cutaneous conditions can mimic infection. If these lesions are not accurately recognized, they may be treated with antimicrobial agents, which adds cost, potential risk, and inconvenience to the patient and the healthcare system. The presenting signs and symptoms of many ulcerating, pustular, morbilliform, bullous, neoplastic, granulomatous, autoimmune, and neutrophilic conditions, as well as clinical vasculitis, cellulitis, folliculitis, and panniculitis, have been mistaken for infection. This review emphasizes the clinical presentation, physical exam, and diagnostic workup of many of these conditions to assist the clinician in ascertaining the correct diagnosis. In addition, general treatment options are provided for each disease category. © 2011 The International Society of Dermatology.
Elassar A.,University of Connecticut Health Center |
Liu X.,University of Health Center |
Scranton V.,University of Connecticut Health Center |
Wu C.A.,University of Connecticut Health Center |
And 2 more authors.
Fertility and Sterility | Year: 2012
Objective: To determine the relationship between progesterone receptor membrane component-1 (PGRMC1) expression and the outcome of IVF treatment. Design: A prospective study in which PGRMC1 messenger RNA (mRNA) levels, methylation status of the Pgrmc1 promoter, and the presence of point mutations within Pgrmc1 were obtained from granulosa (GC)/luteal cells of women undergoing controlled ovarian hyperstimulation (COH). Setting: Fertility center/basic science laboratory. Patient(s): Eighty-five patients undergoing IVF treatment and 10 women who were undergoing COH for the purpose of oocyte donation were included in this study. Intervention(s): None. Main Outcome Measure(s): The PGRMC1 measurements were correlated with clinical outcomes, such as number of follicles, number of retrieved oocytes, and ongoing pregnancy rates (PR). Result(s): The PGRMC1 mRNA levels within GC/luteal cells of 18% of IVF patients were >2.25-fold higher than those of oocyte donors. Individuals with elevated PGRMC1 mRNA levels had 30% fewer large follicles and fewer oocytes retrieved. The elevated PGRMC1 mRNA levels were associated with an increase in the methylation of Pgrmc1 promoter. Conclusion(s): In patients with elevated PGRMC1 mRNA levels, gonadotropin-induced follicle development is attenuated, although sufficient numbers of follicles develop to allow for ET and subsequent pregnancy. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
Datta D.,University of Health Center |
Normandin E.,St Francis Hospital and Medical Center |
Zuwallack R.,St Francis Hospital and Medical Center
Annals of Thoracic Medicine | Year: 2015
Dyspnea on exertion is a commonly encountered problem in clinical practice. It is usually investigated by resting tests such as pulmonary function tests and echocardiogram, which may at times can be non-diagnostic. Cardiopulmonary exercise testing (CPET) measures physiologic parameters during exercise which can enable accurate identification of the cause of dyspnea. Though CPET has been around for decades and provides valuable and pertinent physiologic information on the integrated cardiopulmonary responses to exercise, it remains underutilized. The objective of this review is to provide a comprehensible overview of the underlying principles of exercise physiology, indications and contraindications of CPET, methodology and interpretative strategies involved and thereby increase the understanding of the insights that can be gained from the use of CPET.
Berger N.,University of Health Center |
Nichols J.,University of Health Center |
Yap V.,University of Health Center |
Datta D.,University of Health Center
Connecticut Medicine | Year: 2015
Spontaneous pneumomediastinum (SPM) is the presence of air in the mediastinum without any precipitating factor or predisposing disease. It is an uncommon, usually benign condition predominantly seen in young males. It typically presents with chest pain or dyspnea. It occurs after intrathoracic pressure changes leads to alveolar rupture and dissection of air along the tracheobronchial tree. It is reported to occur in 1/30,000 to 1/40,000 hospital admissions. Despite its low incidence, SPM should be considered in the differential diagnosis of acute chest pain or dyspnea in young patients. Diagnosis requires a high index of suspicion, as evidence of its occurrence may not be present on examination or chest X-ray. Patients with SPM respond well to medical treatment, with no recurrence in the majority of cases. We report a case of a young healthy male who developed a spontaneous pneumomediastinum and pneumopericardium while playing volleyball and did well with conservative management. © 2015, Connecticut State Medical Society. All rights reserved.
PubMed | University of Health Center
Type: Case Reports | Journal: The clinical respiratory journal | Year: 2016
Idiopathic pulmonary haemosiderosis (IPH) is a rare disorder of unknown cause characterised by haemoptysis, diffuse alveolar infiltrates and iron-deficiency anaemia. IPH predominantly affects children; it is rare in adults, in whom it usually manifests before 30 years. In adults, course is protracted with a better prognosis, in contrast to children. Even rarer is the Lane-Hamilton syndrome, a condition in which IPH is associated with celiac disease. Only 15 cases of Lane-Hamilton syndrome affecting adults are reported in literature. Treatment of IPH is based on anecdotal case reports and case series because of its rare occurrence. High-dose steroids reportedly reduce morbidity and mortality and delays or stops disease progression; more effectively in adults than children. In Lane-Hamilton syndrome, a gluten-free diet for the celiac disease in addition to steroids for IPH, is the mainstay of therapy. The optimal treatment duration of steroid therapy is not known but anecdotally a more prolonged course results in improved outcome. We report a case of a young woman who presented with exertional dyspnoea, intermittent haemoptysis, severe anaemia and lung infiltrates but no gastrointestinal complaints. After extensive work-up, she was diagnosed with Lane-Hamilton syndrome based on a diagnosis of IPH made from lung biopsy and concomitant celiac disease because of positive anti-gliadin antibody and endomyosial antibody and jejunal biopsy. She was treated with sustained low-dose steroid therapy for a year and a gluten-free diet with resolution of her symptoms, anaemia and lung infiltrates. At 4 years of follow-up, she remains stable, without recurrence.