Women’s Health Research Faculty Publications Copyright (c) 2013 University of Massachusetts Medical School All rights reserved. http://escholarship.umassmed.edu/wfc_pp Recent documents in Women’s Health Research Faculty Publications en-us Sat, 01 Jun 2013 01:47:16 PDT 3600 Impact of dose, frequency of administration, and equol production on efficacy of isoflavones for menopausal hot flashes: a pilot randomized trial http://escholarship.umassmed.edu/wfc_pp/543 http://escholarship.umassmed.edu/wfc_pp/543 Thu, 30 May 2013 08:45:47 PDT OBJECTIVE: The relatively modest benefit of vasomotor symptom relief in clinical trials of isoflavones may reflect once-daily dosing and low percentages of participants who are able to metabolize daidzein into equol, a potentially more biologically active isoflavone. This pilot study examined whether symptom reduction was greater with more frequent administration and with higher daily doses. In addition, we explored possible effect modification by equol producer status.

METHODS: We randomized 130 perimenopausal (no menses in the past 3 mo) and postmenopausal (≥12 mo of amenorrhea) women with a mean of five or more moderate/severe hot flashes per day to treatment arms with varying total daily isoflavone doses and dosing frequency, separately for equol producers and nonproducers. Participants recorded the daily frequency and severity of hot flashes. Analyses compared mean daily hot flash intensity scores (sum of hot flashes weighted by severity) by total daily dose and by dosing frequency. Dose- and frequency-related differences were also compared for equol producers and nonproducers.

RESULTS: Hot flash intensity scores were lowest in women randomized to the highest total daily dose (100-200 mg) and in women randomized to the highest dosing frequency (twice daily to thrice daily), with greater benefits on nighttime scores than on daytime scores. Dose- and frequency-related differences were somewhat larger in equol producers than in nonproducers.

CONCLUSIONS: These results suggest that a twice-daily to thrice-daily dosing frequency may improve the benefit of isoflavones for vasomotor symptom relief, particularly in equol producers and for nighttime symptoms. Larger studies are needed to confirm these findings.

]]> Sybil L. Crawford et al. Hot Flashes Isoflavones Equol Soy Foods Menopause Vasomotor System Screening mammograms should not be underestimated http://escholarship.umassmed.edu/wfc_pp/542 http://escholarship.umassmed.edu/wfc_pp/542 Mon, 25 Feb 2013 08:48:02 PST Comment on: Likelihood that a woman with screen-detected breast cancer has had her "life saved" by that screening. Arch Intern Med. 2011 Dec 12;171(22):2043-6.

]]> Mary E. Costanza Breast Neoplasms *Early Detection of Cancer Female Humans *Mammography *SEER Program Survivors Improving population health through integration of primary care and public health: providing access to physical activity for community health center patients http://escholarship.umassmed.edu/wfc_pp/541 http://escholarship.umassmed.edu/wfc_pp/541 Mon, 25 Feb 2013 08:48:01 PST OBJECTIVES: Our community health center attempted to meet public health goals for encouraging exercise in adult patients vulnerable to obesity, diabetes, hypertension, and other chronic diseases by partnering with a local YMCA.

METHODS: During routine office visits, providers referred individual patients to the YMCA at no cost to the patient. After 2 years, the YMCA instituted a $10 per month patient copay for new and previously engaged health center patients.

RESULTS: The copay policy change led to discontinuation of participation at the YMCA by 80% of patients. Patients who persisted at the YMCA increased their visits by 50%; however, more men than women became frequent users after institution of the copay. New users after the copay were also more likely to be younger men. Thus the copay skewed the population toward a younger group of men who exercised more frequently. Instituting a fee appeared to discourage more tentative users, specifically women and older patients who may be less physically active.

CONCLUSIONS: Free access to exercise facilities (rather than self-paid memberships) may be a more appropriate approach for clinicians to begin engaging inexperienced or uncertain patients in regular fitness activities to improve health.

]]> Matthew A. Silva et al. Adult Age Factors *Community Health Centers *Exercise Fees and Charges Female Health Promotion Humans Male Motor Activity *Primary Health Care *Public Health Sex Factors Media as a source of information on pregnancy and childbirth http://escholarship.umassmed.edu/wfc_pp/540 http://escholarship.umassmed.edu/wfc_pp/540 Mon, 25 Feb 2013 08:48:00 PST Media can have a powerful eff ect on women’s knowledge, beliefs and expectations about pregnancy and birth. Media can consist of movies,television programs and advertisements, magazines,and more, recently, the Internet. As providers of care to women, it’s important that we have an understanding of the sources of information women and their partners use to guide their expectations for their care and their role in making decisions. We should also be aware of the images, messages and information that media present to women about pregnancy and birth. In this issue’s “A Second Look” column, we examine two research reports focusing on media and pregnancy information—one focused on the Internet (Lagan, Sinclair, & Kernohan, 2010) and the other on television (Morris & McInerney, 2010); both looked at the influence these could have on information and images of childbirth.

]]> Rosemary T. Theroux Female *Health Knowledge, Attitudes, Practice Health Promotion Humans Internet Male *Mass Media Parturition Patient Education as Topic Pregnancy Questionnaires Television Not just another annual exam: thoughts on the nurse-patient relationship http://escholarship.umassmed.edu/wfc_pp/539 http://escholarship.umassmed.edu/wfc_pp/539 Mon, 25 Feb 2013 08:47:59 PST Well-woman check-ups, also known as annual examinations, offer advance practice nurses an opportunity to assess health and promote wellness of women across the lifespan. Although regarded as a “routine” office visit by some, the following story of an encounter at an annual exam demonstrates the importance of these visits. There can be far-reaching effects on both the client and nurse from these visits.

]]> Rosemary T. Theroux *Empathy Female Humans Nurse's Role *Nurse-Patient Relations University of Massachusetts Medical School http://escholarship.umassmed.edu/wfc_pp/538 http://escholarship.umassmed.edu/wfc_pp/538 Sun, 09 Dec 2012 14:50:36 PST A snapshot of the medical education program leading to the MD degree at the University of Massachusetts Medical School.

]]> Michele P. Pugnaire et al. *Curriculum *Education, Medical Massachusetts *Schools, Medical Metal-free ALS variants of dimeric human Cu,Zn-superoxide dismutase have enhanced populations of monomeric species http://escholarship.umassmed.edu/wfc_pp/537 http://escholarship.umassmed.edu/wfc_pp/537 Sun, 09 Dec 2012 14:50:35 PST Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS). Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis approach, the perturbations on the global stability in response to mutation can be partitioned between the monomer folding and association steps, and the effects of mutation on the populations of the folded and unfolded monomeric states can be determined. The 2- to 10-fold increase in the population of the folded monomeric state for A4V, L38V and L106V and the 80- to 480-fold increase in the population of the unfolded monomeric states for all but S134N would dramatically increase their propensity for aggregation through high-order nucleation reactions. The wild-type-like populations of these states for the metal-binding region S134N variant suggest that even wild-type SOD1 may also be prone to aggregation in the absence of metals.

]]> Anna-Karin E. Svensson et al. Amyotrophic Lateral Sclerosis Binding Sites Humans Kinetics Metals *Mutation, Missense Protein Folding Protein Multimerization Superoxide Dismutase Thermodynamics Provision of contraceptive services to homeless women: results of a survey of health care for the homeless providers http://escholarship.umassmed.edu/wfc_pp/535 http://escholarship.umassmed.edu/wfc_pp/535 Sun, 09 Dec 2012 14:50:33 PST Homeless women have both a higher rate of pregnancy and a higher proportion of unintended pregnancies than other American women. The authors sought to learn about contraception services offered by providers of health care to homeless women and barriers to provision of long-acting, reversible contraception in these settings. A survey of the 31 member organizations in the national Health Care for the Homeless Practice-Based Research Network was conducted, inquiring about services provided and barriers to service provision. Among the 20 responding organizations (65% response rate), 17 directly provided contraceptive services; two referred patients elsewhere, and one provided no contraceptive services. All 17 that provided such services provided condoms; 15 provided oral contraceptives; 14 provided injectable contraception; 6 provided intrauterine devices, and 2 provided contraceptive implants. Barriers to providing the last two methods included lack of provider training, lack of resources for placement, costs, and concerns about complications. The present survey results suggested very limited access for homeless women across the country to the two most effective means of long-acting, reversible contraception. Modest investments of resources could reduce a number of barriers to providing these services.

]]> Barry G. Saver et al. Contraception Contraceptive Agents, Female Contraceptive Devices Family Planning Services Female Health Care Surveys *Health Services Accessibility Healthcare Disparities *Homeless Persons Humans Patient Acceptance of Health Care Pregnancy Pregnancy, Unplanned Questionnaires United States A novel pleckstrin homology domain-containing protein enhances insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes http://escholarship.umassmed.edu/wfc_pp/536 http://escholarship.umassmed.edu/wfc_pp/536 Sun, 09 Dec 2012 14:50:33 PST Protein kinase B/Akt protein kinases control an array of diverse functions, including cell growth, survival, proliferation, and metabolism. We report here the identification of pleckstrin homology-like domain family B member 1 (PHLDB1) as an insulin-responsive protein that enhances Akt activation. PHLDB1 contains a pleckstrin homology domain, which we show binds phosphatidylinositol PI(3,4)P(2), PI(3,5)P(2), and PI(3,4,5)P(3), as well as a Forkhead-associated domain and coiled coil regions. PHLDB1 expression is increased during adipocyte differentiation, and it is abundant in many mouse tissues. Both endogenous and HA- or GFP-tagged PHLDB1 displayed a cytoplasmic disposition in unstimulated cultured adipocytes but translocated to the plasma membrane in response to insulin. Depletion of PHLDB1 by siRNA inhibited insulin stimulation of Akt phosphorylation but not tyrosine phosphorylation of IRS-1. RNAi-based silencing of PHLDB1 in cultured adipocytes also attenuated insulin-stimulated deoxyglucose transport and Myc-GLUT4-EGFP translocation to the plasma membrane, whereas knockdown of the PHLDB1 isoform PHLDB2 failed to attenuate insulin-stimulated deoxyglucose transport. Furthermore, adenovirus-mediated expression of PHLDB1 in adipocytes enhanced insulin-stimulated Akt and p70 S6 kinase phosphorylation, as well as GLUT4 translocation. These results indicate that PHLDB1 is a novel modulator of Akt protein kinase activation by insulin.

]]> Qiong L. Zhou et al. 3T3-L1 Cells Adipocytes Animals Blood Proteins Enzyme Activation Gene Expression Regulation Gene Silencing Glucose Glucose Transporter Type 4 Humans Insulin Intracellular Signaling Peptides and Proteins Mice Phosphatidylinositol Phosphates Phosphoproteins Phosphorylation Protein Structure, Tertiary Protein Transport Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 70-kDa Sequence Homology, Amino Acid Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection http://escholarship.umassmed.edu/wfc_pp/534 http://escholarship.umassmed.edu/wfc_pp/534 Sun, 09 Dec 2012 14:50:32 PST The pathophysiology of dengue virus infection remains poorly understood, although secondary infection is strongly associated with more severe disease. In the present study, we performed a nested, case-control study comparing the responses of pre-illness peripheral blood mononuclear cells between children who would subsequently develop either subclinical or symptomatic secondary infection 6-11 months after the baseline blood samples were obtained and frozen. We analyzed intracellular cytokine production by CD4(+) and CD8(+) cells in response to stimulation with dengue antigen. We found higher frequencies of dengue virus-specific TNFalpha, IFNgamma-, and IL-2-producing T cells among schoolchildren who subsequently developed subclinical infection, compared with those who developed symptomatic secondary dengue virus infection. Although other studies have correlated immune responses during secondary infection with severity of disease, to our knowledge this is the first study to demonstrate a pre-infection dengue-specific immune response that correlates specifically with a subclinical secondary infection.

]]> Steven Hatch et al. Adolescent Case-Control Studies Child Cytokines Dengue Dengue Virus Humans T-Lymphocytes Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes http://escholarship.umassmed.edu/wfc_pp/533 http://escholarship.umassmed.edu/wfc_pp/533 Sun, 09 Dec 2012 14:50:31 PST BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.

METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.

CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.

]]> Joel M. O'Bryan et al. Alanine Transaminase Antigens, CD Aspartate Aminotransferases Drug Therapy, Combination Flow Cytometry Hepatitis C Humans In Situ Hybridization, Fluorescence Interferon-alpha Ribavirin T-Lymphocytes *Telomere Viral Load Enhanced humoral and hla-a2-restricted dengue virus-specific t cell responses in humanized blt nsg mice http://escholarship.umassmed.edu/wfc_pp/532 http://escholarship.umassmed.edu/wfc_pp/532 Sun, 09 Dec 2012 14:50:30 PST Dengue is a mosquito borne viral disease of humans, and animal models that recapitulate human immune responses and/or dengue pathogenesis are needed to understand the pathogenesis of the disease. We recently described an animal model for dengue virus (DENV) infection using humanized NOD-scid IL2rgamma(null) mice (NSG) engrafted with cord blood hematopoietic stem cells (HSC). We sought to further improve this model by co-transplantation of human fetal thymus and liver tissues into NSG (BLT-NSG) mice. Enhanced DENV-specific antibody titers were found in the sera of BLT-NSG mice compared to human cord blood HSC-engrafted NSG mice. Furthermore, B cells generated during the acute phase and in memory from splenocytes of immunized BLT-NSG mice secreted DENV-specific IgM antibodies with neutralizing activity. Human T cells in engrafted BLT-NSG mice secreted IFN-gamma in response to overlapping DENV peptide pools and HLA-A2 restricted peptides. BLT-NSG mice will provide a much-needed platform to assess human immune responses to DENV vaccines and the effects of prior immunity on subsequent DENV infections. (c) 2012 The Authors. Immunology (c) 2012 Blackwell Publishing Ltd, Immunology.

]]> Smita Jaiswal Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice http://escholarship.umassmed.edu/wfc_pp/531 http://escholarship.umassmed.edu/wfc_pp/531 Sun, 09 Dec 2012 14:50:29 PST Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-alpha, (HIF-1alpha) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1alpha in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels, and increased serum alanine aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. There was increased hepatic HIF-1alpha messenger RNA (mRNA), protein, and DNA-binding activity in alcohol-fed mice compared with controls. Mice engineered with hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1alpha mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic triglyceride compared with WT mice. In contrast, hepatocyte-specific deletion of HIF-1alpha [HIF-1alpha(Hep(-/-) )], protected mice from alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1alpha(Hep(-/-) ), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor alpha mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1alpha(Hep(-/-) ) ethanol-fed/LPS-challenged mice. The chemokine monocyte chemoattractant protein-1 (MCP-1) was cooperatively induced by alcohol feeding and LPS in WT but not HIF-1alpha(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1alpha protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1alpha prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1alpha in hepatocyte lipid accumulation.

CONCLUSION: Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1alpha activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1alpha activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.

]]> Bharath D. Nath et al. Animals Fatty Liver, Alcoholic Hepatocytes Hypoxia-Inducible Factor 1, alpha Subunit *Lipid Metabolism Mice Epigenetic regulation in alcoholic liver disease http://escholarship.umassmed.edu/wfc_pp/530 http://escholarship.umassmed.edu/wfc_pp/530 Sun, 09 Dec 2012 14:50:28 PST Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.

]]> Pranoti Mandrekar Epigenesis, Genetic Ethanol Gene Expression Humans Liver Liver Diseases, Alcoholic Oxidative Stress Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice http://escholarship.umassmed.edu/wfc_pp/528 http://escholarship.umassmed.edu/wfc_pp/528 Sun, 09 Dec 2012 14:50:27 PST Endotoxin-mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS-induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17-DMAG prevented LPS-induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA-binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased cluster of differentiation 14 mRNA and LPS-induced nuclear factor kappa light-chain enhancer of activated B cells (NFkappaB) DNA binding without affecting Toll-like receptor 4 mRNA in liver. Mechanistic studies revealed that 17-DMAG-mediated inhibition of TNFalpha showed no effect on LPS-induced NFkappaB promoter-driven reporter activity, but significantly decreased TNFalpha promoter-driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to the TNFalpha promoter, but not the IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFalpha, but not IL-6. We show that HSF1 indirectly regulates IL-6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17-DMAG-mediated down-regulation of NFkappaB-binding activity, TNFalpha, and IL-6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition.

CONCLUSION: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS-induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS-induced liver injury.

]]> Aditya Ambade et al. Benzoquinones Cytokines DNA-Binding Proteins HSP90 Heat-Shock Proteins Lactams, Macrocyclic Liver Liver Diseases An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice http://escholarship.umassmed.edu/wfc_pp/529 http://escholarship.umassmed.edu/wfc_pp/529 Sun, 09 Dec 2012 14:50:27 PST The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum alanine aminotransferase in WT and CCR2KO, but not MCP-1KO, mice. Alcohol-induced liver steatosis and triglyceride were attenuated in alcohol-fed MCP-1KO, but high in CCR2KO mice, compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6, KC/IL-8, intercellular adhesion molecule 1, and cluster of differentiation 68 was induced in alcohol-fed WT, but inhibited in MCP-1KO, mice independent of nuclear factor kappa light-chain enhancer of activated B cell activation in KCs. Oxidative stress, but not cytochrome P450 2E1, was prevented in chronic alcohol-fed MCP-1KO mice, compared to WT. Increased expression of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma was accompanied by nuclear translocation, DNA binding, and induction of fatty acid metabolism genes acyl coenzyme A oxidase and carnitine palmitoyltransferase 1A in livers of alcohol-fed MCP-1KO mice, compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARalpha messenger RNA and peroxisome proliferator response element binding in hepatocytes independent of CCR2. Conclusion: Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of proinflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism.

]]> Pranoti Mandrekar et al. Acyl-CoA Oxidase Animals Carnitine O-Palmitoyltransferase Cell Line, Tumor Chemokine CCL2 Cytokines Fatty Liver, Alcoholic Female Hepatocytes Humans Kupffer Cells Lipopolysaccharides Liver Liver Diseases, Alcoholic Mice Mice, Inbred C57BL Mice, Knockout Oxidative Stress Peroxisome Proliferator-Activated Receptors Receptors, CCR2 Oxidative stress and inflammation: essential partners in alcoholic liver disease http://escholarship.umassmed.edu/wfc_pp/527 http://escholarship.umassmed.edu/wfc_pp/527 Sun, 09 Dec 2012 14:50:26 PST Alcoholic liver disease (ALD) is a multifaceted disease that is characterized by hepatic steatosis or fat deposition and hepatitis or inflammation. Over the past decade, multiple lines of evidence have emerged on the mechanisms associated with ALD. The key mechanisms identified so far are sensitization to gut-derived endotoxin/lipopolysaccharide resulting in proinflammatory cytokine production and cellular stress due to oxidative processes, contributing to the development and progression of disease. While oxidative stress and inflammatory responses are studied independently in ALD, mechanisms linking these two processes play a major role in pathogenesis of disease. Here we review major players of oxidative stress and inflammation and highlight signaling intermediates regulated by oxidative stress that provokes proinflammatory responses in alcoholic liver disease.

]]> Aditya Ambade et al. Liver Diseases, Alcoholic Oxidative Stress Inflammation Two closely related Env antigens from the same patient elicited different spectra of neutralizing antibodies against heterologous HIV-1 isolates http://escholarship.umassmed.edu/wfc_pp/526 http://escholarship.umassmed.edu/wfc_pp/526 Sun, 09 Dec 2012 14:50:25 PST Identification of immunogens capable of eliciting broadly neutralizing antibody (NAb) responses against HIV-1 is a major goal toward the development of an AIDS vaccine. Despite significant progress in understanding the structural features of the HIV-1 envelope glycoprotein (Env) and the discovery of multiple broadly neutralizing monoclonal antibodies with defined antigenic structures, the design of optimal Env immunogens to elicit broad NAbs remains a major challenge. As the structural determinants of Env immunogenicity remain unclear, we assessed two closely related Env antigens isolated from the same HIV-1-infected patient with different phenotypic features to identify what may result in a favorable immunogenic profile. One Env, B33, isolated from brain, was highly macrophage tropic with a high CD4 affinity, while the other, LN40, isolated from the lymph nodes, was poorly macrophage tropic with a low CD4 affinity. Using a DNA prime-protein boost approach, rabbits primed with LN40 Env antigen had a NAb response against heterologous primary isolates, while B33 Env antigens were capable of eliciting NAbs against only homologous and sensitive viral isolates. Further analysis revealed that the specificity of NAbs elicited by the LN40 antigen mapped to limited residues within or flanking the CD4 binding site. Certain key structural determinants were identified that could differentiate primary Env immunogens based on their potential to elicit broader NAbs. This progress will facilitate the rational design of effective HIV-1 vaccine formulations with optimal Env antigens.

]]> Michael Vaine et al. Animals Antibodies, Neutralizing Brain HIV Antibodies HIV Infections HIV-1 Humans Immunization Immunization, Secondary Lymph Nodes Rabbits Viral Tropism env Gene Products, Human Immunodeficiency Virus dosage Effect of Paget's disease on survival in breast cancer: an exploratory study http://escholarship.umassmed.edu/wfc_pp/525 http://escholarship.umassmed.edu/wfc_pp/525 Sun, 09 Dec 2012 14:50:24 PST OBJECTIVE: To explore whether Paget's disease (PD) has an effect on outcome in patients with breast cancer.

DESIGN: Retrospective analysis of comprehensive pathology database, medical records, and slides of samples showing pathologic features.
SETTING: UMass Memorial Health Care.

PATIENTS: All patients with breast cancer and PD with records in a prospectively maintained database between January 1, 1990, and December 31, 2008, were identified. Each participant was matched (criteria: age within 5 years, year of treatment, and stage of breast cancer) with 2 controls (1:2 ratio).

MAIN OUTCOME MEASURES: Overall and disease-free survival were analyzed using Kaplan-Meier statistics and Cox proportional hazards modeling, accounting for matching in the latter analyses by using robust standard error estimates. RESULTS: Mean (SD) follow-up was 47 (33) months. Treatment involved mastectomy in 29 (91%) PD vs 16 (25%) non-PD patients (P < .001), radiotherapy in 14 (44%) PD vs 53 (83%) non-PD patients (P < .001), and hormonal therapy in 14 (44%) PD vs 33 (52%) non-PD patients (P = .004). Biological markers were not significantly different except for ERBB2 (formerly HER2 or HER2/neu) overexpression in 14 (44%) PD vs 16 (25%) non-PD patients (P = .008). The PD group had an overall 5-year survival of 81.2% vs 93.8% of the non-PD group (Kaplan-Meier log-rank, P = .03). The unadjusted hazard ratio for the PD vs non-PD group was 5.31 (95% CI, 1.74-16.27; P = .003). The corresponding hazard ratio after adjusting for local and systemic treatment was 2.26 (95% CI, 0.46-11.06; P = .32).

CONCLUSIONS: These exploratory data show that PD may have a negative effect on breast cancer survival. This finding needs to be substantiated in larger data sets.

]]> Sonia Ortiz-Pagan et al. Breast Neoplasms Disease-Free Survival Female Follow-Up Studies Humans Massachusetts Middle Aged Neoplasm Staging Paget's Disease, Mammary Prognosis Retrospective Studies Risk Factors *SEER Program Survival Rate Institutional review board variability in minimal-risk multicenter urogynecology studies http://escholarship.umassmed.edu/wfc_pp/523 http://escholarship.umassmed.edu/wfc_pp/523 Sun, 09 Dec 2012 14:50:22 PST OBJECTIVES: To investigate variability among local institutional review boards (IRBs) in the review process of standardized multicenter urogynecologic studies with common protocols.

METHODS: Descriptive study of the IRB review and approval process for common urogynecologic protocols of 4 minimal-risk multicenter studies conducted within the Fellow's Pelvic Research Network (FPRN), including prospective cohort, retrospective review, and case-control studies.

RESULTS: Most of the 22 network sites (73%) were in academic institutions. The level of IRB review varied by site and study design. Institutional review boards had local requirements regarding standard format and language that resulted in 86% of consent documents and 33% of protocols being changed before submission. Institutional review boards queried most (55%) submissions, with significantly more queries for prospective studies compared to retrospective studies (78.6% vs 35.3%; P = 0.03). After submission, IRB requirements necessitated changes for 71% of consents and 28% of protocols. There were no substantive changes made to any consent document or protocol. There was considerable variability in time between IRB submission and approval (10 +/- 3 days; range, 7-12 days for exempt; 22 +/- 17 days; range, 1-57 days for expedited; and 34 +/- 32 days; range, 13-81 days for full board reviews).

CONCLUSIONS: We detected considerable variability in IRB review of standardized multicenter protocols across minimal-risk study designs. Reduction in variability may improve expediency of multicenter studies while maintaining the highest level of protections for research participants.

]]> Heidi S. Harvie et al. Academies and Institutes Clinical Protocols Consent Forms Ethics Committees, Research Guideline Adherence *Gynecology Humans Multicenter Studies as Topic *Research Design Risk Adjustment *Urology