tbuckley/cabot-search huggingface dataset:
Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals
Authors: Ruth I. Connor, Kristine E. Sheridan, Daniel Ceradini, Sunny Choe, Nathaniel R. Landau
Journal: The Journal of Experimental Medicine (1997)

Recent studies have identified several coreceptors that are required for fusion and entry of Human Immunodeficiency Virus type 1 (HIV-1) into CD4+ cells. One of these receptors, CCR5, serves as a coreceptor for nonsyncytium inducing (NSI), macrophage-tropic strains of HIV-1, while another, fusin or CXCR-4, functions as a coreceptor for T cell line–adapted, syncytiuminducing (SI) strains. Using sequential primary isolates of HIV-1, we examined whether viruses using these coreceptors emerge in vivo and whether changes in coreceptor use are associated with disease progression. We found that isolates of HIV-1 from early in the course of infection predominantly used CCR5 for infection. However, in patients with disease progression, the virus expanded its coreceptor use to include CCR5, CCR3, CCR2b, and CXCR-4. Use of CXCR-4 as a coreceptor was only seen with primary viruses having an SI phenotype and was restricted by the env gene of the virus. The emergence of variants using this coreceptor was associated with a switch from NSI to SI phenotype, loss of sensitivity to chemokines, and decreasing CD4+ T cell counts. These results suggest that HIV-1 evolves during the course of infection to use an expanded range of coreceptors for infection, and that this adaptation is associated with progression to AIDS.
A Selective Small Molecule Inhibitor of c-Met, PHA665752, Inhibits Tumorigenicity and Angiogenesis in Mouse Lung Cancer Xenografts
Authors: Neelu Puri, Andrey Khramtsov, Salman Ahmed, Vidya Nallasura, Jeremy T. Hetzel, Ramasamy Jagadeeswaran, Greg Karczmar, Ravi Salgia
Journal: Cancer Research (2007)

Abstract The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non–small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non–small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by &amp;gt;85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer. [Cancer Res 2007;67(8):3529–34]
Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy
Authors: Takuro Arimura, J. Martijn Bos, Akinori Sato, Toru Kubo, Hiroshi Okamoto, Hirofumi Nishi, Haruhito Harada, Yoshinori Koga, Mousumi Moulik, Yoshinori L. Doi, Jeffrey A. Towbin, Michael J. Ackerman, Akinori Kimura
Journal: Journal of the American College of Cardiology (2009)
Infection of Mice with <i>Mycobacterium bovis</i>–Bacillus Calmette-Guérin (BCG) Suppresses Allergen-induced Airway Eosinophilia
Authors: Klaus Josef Erb, John W. Holloway, Alexandra Sobeck, Heidrun Moll, Graham Le Gros
Journal: The Journal of Experimental Medicine (1998)

It has been proposed that the increase in prevalence and severity of atopic disorders inversely correlates with exposure to infectious diseases such as tuberculosis. We have investigated this issue by combining an intranasal Mycobacterium bovis–Bacillus Calmette-Guérin (BCG) infection with a murine model of allergen, (ovalbumin [OVA]) induced airway eosinophilia. BCG infection either 4 or 12 wk before allergen airway challenge resulted in a 90–95 and 60–70% reduction in eosinophilia within the lungs, respectively, compared to uninfected controls. The inhibition of airway eosinophilia correlated with a reduced level of IL-5 production by T cells from the lymph node draining the site of OVA challenge. Interestingly, BCG infection of the lung had no effect on IgG1 and IgE OVA-specific serum immunoglobulin or blood eosinophil levels. Furthermore, BCG-induced inhibition of airway eosinophilia was strongly reduced in interferon (IFN)-γ receptor–deficient mice and could be partially reversed by intranasal IL-5 application. Intranasal BCG infections could also reduce the degree of lung eosinophilia and IL-5 produced by T cells after Nippostrongylus brasiliensis infection. Taken together, our data suggest that IFN-γ produced during the T helper cell (Th)1 immune response against BCG suppresses the development of local inflammatory Th2 responses in the lung. Most importantly, this inhibition did not extend to the systemic immunoglobulin response against OVA. Our data support the view that mycobacterial infections have the potential to suppress the development of atopic disorders in humans.
Naltrexone in the Treatment of Alcohol Dependence
Authors: John H. Krystal, Joyce A. Cramer, William F. Krol, Gail F. Kirk, Robert A. Rosenheck
Journal: New England Journal of Medicine (2001)

Although naltrexone, an opiate-receptor antagonist, has been approved by the Food and Drug Administration for the treatment of alcohol dependence, its efficacy is uncertain.
Specific immunotherapy downregulates peripheral blood CD4 and CD8 T-lymphocyte activation in grass pollen-sensitive asthma
Authors: M Majori, S Bertacco, ML Piccoli, R Melej, V Pileggi, A Pesci
Journal: European Respiratory Journal (1998)

Several lines of evidence indicate that specific immunotherapy may act by modifying the immune responses of T-lymphocytes to the antigen. To evaluate the effect of specific immunotherapy on the activation of T-lymphocytes by cluster of differentiation cells (CD4+ and CD8+) in peripheral blood, the expression of two surface activation markers, the p55 interleukin-2 receptor (CD25) and human leucocyte antigen (HLA)-DR, was studied prospectively on circulating CD4+ and CD8+ T-cell subsets in subjects with grass-pollen sensitive asthma before and after 1 yr of treatment with specific immunotherapy. Twenty five asthmatic patients with pollen sensitivity other than grass, studied out of their pollen season, served as the control group. Specific immunotherapy improved clinical indices of disease activity including symptom scores and medication use during the pollen season of the treatment year. It had a marked effect in reducing the expression of the two activation markers, CD25 and HLA-DR, in both CD4+ (p=0.002 and p=0.005, respectively) and CD8+ (p=0.01 and p=0.01, respectively) T-cell subsets, in parallel with a significant decrease in CD23 expression on B-cells (p=0.008) and in grass-specific immunoglobulin E levels (p=0.01) in the peripheral blood of subjects with grass pollen-sensitive asthma. The decreased T-lymphocyte activation observed in immunotherapy-treated subjects after the treatment year was significant (p=0.05) in comparison with the control group. These data add to the view that the efficacy of specific immunotherapy may be attributed to the downregulation of T-cell responses.
Risk Factors for Prostate Cancer Detection After a Negative Biopsy: A Novel Multivariable Longitudinal Approach
Authors: Peter H. Gann, Angela Fought, Ryan Deaton, William J. Catalona, Edward Vonesh
Journal: Journal of Clinical Oncology (2010)

To introduce a novel approach for the time-dependent quantification of risk factors for prostate cancer (PCa) detection after an initial negative biopsy.Data for 1,871 men with initial negative biopsies and at least one follow-up biopsy were available. Piecewise exponential regression models were developed to quantify hazard ratios (HRs) and define cumulative incidence curves for PCa detection for subgroups with specific patterns of risk factors over time. Factors evaluated included age, race, serum prostate-specific antigen (PSA) concentration, PSA slope, digital rectal examination, dysplastic glands or prostatitis on biopsy, ultrasound gland volume, urinary symptoms, and number of negative biopsies.Four hundred sixty-five men had PCa detected, after a mean follow-up time of 2.8 years. All of the factors were independent predictors of PCa detection except for PSA slope, as a result of its correlation with time-dependent PSA level, and race. PSA (HR = 3.90 for > 10 v 2.5 to 3.9 ng/mL), high-grade prostatic intraepithelial neoplasia/atypical glands (HR = 2.97), gland volume (HR = 0.39 for > 50 v < 25 mL), and number of repeat biopsies (HR = 0.36 for two v zero repeat biopsies) were the strongest predictors. Men with high-risk versus low-risk event histories had a 20-fold difference in PCa detection over 5 years.Piecewise exponential models provide an approach to longitudinal analysis of PCa risk that allows clinicians to see the interplay of risk factors as they unfold over time for individual patients. With these models, it is possible to identify distinct subpopulations with dramatically different needs for monitoring and repeat biopsy.
Cost-Effectiveness of HIV Treatment in Resource-Poor Settings — The Case of Côte d'Ivoire
Authors: Sue J. Goldie, Yazdan Yazdanpanah, Elena Losina, Milton C. Weinstein, Xavier Anglaret, Rochelle P. Walensky, Heather E. Hsu, April Kimmel, Charles Holmes, Jonathan E. Kaplan, Kenneth A. Freedberg
Journal: New England Journal of Medicine (2006)

As antiretroviral therapy is increasingly used in settings with limited resources, key questions about the timing of treatment and use of diagnostic tests to guide clinical decisions must be addressed.
Italian Randomized Trial Among Women With Hysterectomy: Tamoxifen and Hormone-Dependent Breast Cancer in High-Risk Women
Authors: U. Veronesi, P. Maisonneuve, N. Rotmensz, A. Costa, V. Sacchini, R. Travaglini, G. D'Aiuto, F. Lovison, G. Gucciardo, M. G. Muraca, M. A. Pizzichetta, S. Conforti, A. Decensi, C. Robertson, P. Boyle, None The Italian Tamoxifen Study Group
Journal: JNCI Journal of the National Cancer Institute (2003)

Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P =.003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P =.89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P =.002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials.
Role of Hedgehog Signaling in Ovarian Cancer
Authors: Resham Bhattacharya, Junhye Kwon, Bushra Ali, Enfeng Wang, Sujata Patra, Viji Shridhar, Priyabrata Mukherjee
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In humans, several distinctive cancers result from mutations that aberrantly activate hedgehog (HH) signal transduction. Here, we investigate the role of HH signaling in ovarian cancer. Experimental Design: We assessed the expression of different components of hedghehog pathway in primary tumor samples and cell lines. We used specific hedghehog pathway blocker to study the effect on clonal growth and proliferation of ovarian cancer cell both in vitro and in vivo. Results: We show that the up-regulation of several HH pathway components is a common feature of primary ovarian tumors and cell lines. However, expression of PATCHED1 (PTCH1), a direct transcriptional target of the HH pathway, is down-regulated in ovarian cancer in direct contrast to the expression observed in other adult solid tumors. Cyclopamine, a specific HH pathway inhibitor, inhibits the proliferation and clonal growth of ovarian tumor cells in vitro and arrests ovarian tumor growth in vivo. Expression of BMI-1, a polycomb gene, is down-regulated in ovarian cancer cells following cyclopamine treatment. Overexpression of PTCH1 phenocopied the effects of cyclopamine; it down-regulated BMI-1 and reduced clonal growth in ovarian cancer cell lines. Furthermore, knocking down BMI-1 using small interfering RNA also inhibited the clonal growth of all the ovarian cancer cell lines tested. Conclusions: In brief, the constitutive low-level expression of PTCH1 contributes to proliferation and clonal growth of ovarian cancer cells by an aberrant HH signal. Because the HH pathway can be inhibited by specific inhibitors, these findings point toward possible new treatments to inhibit ovarian cancer growth.
Simvastatin and sildenafil combine to attenuate pulmonary hypertension
Authors: L. Zhao, A. Sebkhi, O. Ali, B. Wojciak-Stothard, L. Mamanova, Q. Yang, J. Wharton, M. R. Wilkins
Journal: European Respiratory Journal (2009)

Statins have been proposed to be a potential treatment for pulmonary arterial hypertension. If introduced into clinical practice, the statin would have to be used in conjunction with established therapy. We investigated the effects of combining simvastatin with a phosphodiesterase type-5 inhibitor, sildenafil, in the rat model of hypoxia-induced pulmonary hypertension. Rats were allocated to either: 1) a prevention protocol, to receive simvastatin 20 mg x kg(-1) x day(-1) by intraperitoneal injection or sildenafil 75 mg x kg(-1) x day(-1) orally or the combination (or vehicle) for 2 weeks beginning at the start of exposure to hypoxia (10% inspired oxygen); or 2) a treatment protocol, where the same agents were administered in the last 2 weeks of a 4-week period of hypoxia. In both protocols, the combination of sildenafil and simvastatin lowered pulmonary artery pressure and produced a significantly greater reduction in right ventricular hypertrophy and pulmonary vascular muscularisation than either drug alone. Moreover, the combination augmented significantly endothelial nitric oxide synthase expression and cGMP levels in the lung and right ventricle above that produced by either drug independently and resulted in greater inhibition of RhoA activity. These data suggest that simvastatin can be usefully combined with sildenafil in the treatment of pulmonary arterial hypertension to achieve greater therapeutic benefit.
Surface μ Heavy Chain Signals Down-Regulation of the V(D)J-Recombinase Machinery in the Absence of Surrogate Light Chain Components
Authors: Gunther R. Galler, Cornelia Mundt, Mathew Parker, Roberta Pelanda, Inga-Lill Mårtensson, Thomas H. Winkler
Journal: The Journal of Experimental Medicine (2004)

Early B cell development is characterized by stepwise, ordered rearrangement of the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the two alleles of these genes is used to produce a receptor, a phenomenon referred to as allelic exclusion. It has been suggested that pre–B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele. Using a mouse model, we show that expression of an inducible μHC transgene in Rag2−/− pro–B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts. Similar effects were also observed in the absence of surrogate LC (SLC) components, but not in the absence of the signaling subunit Ig-α. Furthermore, in wild-type mice and in mice lacking either λ5, VpreB1/2, or the entire SLC, the TdT protein is down-regulated in μHC+LC− pre–B cells. Surprisingly, μHC without LC is expressed on the surface of pro–/pre–B cells from λ5−/−, VpreB1−/−VpreB2−/−, and SLC−/− mice. Thus, SLC or LC is not required for μHC cell surface expression and signaling in these cells. Therefore, these findings offer an explanation for the occurrence of HC allelic exclusion in mice lacking SLC components.
Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; Production by EL 4 Leukemia Cells From C57BL/6 Mice: Mechanism for Tumor Dissemination&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M Mahan, J Meunier, M Newby, M R Young
Journal: JNCI Journal of the National Cancer Institute (1985)

Murine EL 4 leukemia cells contained and secreted prostaglandin E2 (PGE2). PGE2 was secreted into the culture media during in vitro growth, as well as into plasma during growth in the peritoneum of inbred C57BL/6 mice. For the study of the role of PGE2 in tumor dissemination, migration of EL 4 cells out of glass capillary tubes was used as an in vitro model for tumor spread in a host. PGE2 enhanced the in vitro migration of EL 4 cells while indomethacin, a prostaglandin synthesis inhibitor, reduced the extent of migration. When EL 4 cells were allowed to migrate into medium containing both indomethacin and PGE2, the cells exhibited an enhanced migration ability suggesting an extrinsic effect on cells by PGE2. The participation of tumor-derived PGE2 in promoting tumor spread in a host was supported by demonstration that EL 4 cells grown in indomethacin-treated mice secreted less PGE2 and had reduced in vivo dissemination ability. These results indicated that tumor spread was promoted by tumor-derived PGE2. The extent of migration and dissemination can be reduced by prostaglandin synthesis inhibitors such as indomethacin.
Improved survival after variceal bleeding in patients with cirrhosis over the past two decades
Authors: Nicolas Carbonell, Arnaud Pauwels, Lawrence Serfaty, Olivier Fourdan, Victor George Lévy, Raoul Poupon
Journal: Hepatology (2004)

Over the past two decades, new treatment modalities have been introduced for the management of variceal bleeding. The aim of this retrospective study in a single center was to assess whether these treatments have improved the prognosis for cirrhotic patients with variceal bleeding. We reviewed the clinical records of all patients with cirrhosis admitted to our Liver Intensive Care Unit due to variceal bleeding during the years 1980, 1985, 1990, 1995, and 2000. Whereas balloon tamponade was still the first-line treatment in 1980, patients treated in 2000 received a vasoactive agent, an endoscopic treatment, and an antibiotic prophylaxis in, respectively, 90%, 100%, and 94% of cases. The in-hospital mortality rate steadily decreased over the study period: 42.6%, 29.9%, 25%, 16.2%, and 14.5% in 1980, 1985, 1990, 1995, and 2000, respectively ( P &lt; .05). Mortality decreased from 9% in 1980 to 0% in 2000 in Child-Turcotte-Pugh class A patients, from 46% to 0% in class B patients, and from 70% to 32% in class C patients. This improved survival was associated with a decrease of rebleeding (from 47% in 1980 to 13% in 2000) and bacterial infection rates (from 38% to 14%). On multivariable analysis, endoscopic therapy and antibiotic prophylaxis were independent predictors of survival. In conclusion , in-hospital mortality of patients with cirrhosis and variceal bleeding decreased threefold over the past two decades, in concurrence with an early and combined use of pharmacological and endoscopic therapies and short-term antibiotic prophylaxis. (Hepatology 2004;40:652-659.)
Genetic predictors of controlled ovarian hyperstimulation: where do we stand today?
Authors: S. Altmäe, O. Hovatta, A. Stavreus-Evers, A. Salumets
Journal: Human Reproduction Update (2011)

BACKGROUNDNowadays, the use of IVF has improved the prospects of infertility treatment. The expected outcome of IVF depends greatly on the effectiveness of controlled ovarian hyperstimulation (COH), where exogenous gonadotrophins are used to induce folliculogenesis. The response to stimulation varies substantially among women and is difficult to predict. Several predictive markers of COH outcome have been proposed (e.g. maternal age and ovarian reserve), but the search for optimal predictors is ongoing. Pharmacogenetic studies demonstrate the effects of individual genetic variability on COH outcome and the potential for customizing therapy based on the patient's genome.
The Immune Regulatory Function of Lymphoproliferative Double Negative T Cells In Vitro and In Vivo
Authors: Megan S. Ford, Kevin J. Young, Zhuxu Zhang, Pamela S. Ohashi, Li Zhang
Journal: The Journal of Experimental Medicine (2002)

Lymphoproliferative (lpr) mice, which lack functional Fas receptor expression and develop autoimmune lymphoproliferative disease, have an accumulation of T cell receptor-αβ+CD4−CD8− (double negative T cells [DNTC]) in the periphery. The function of the accumulating DNTC is not clear. In this study we demonstrate that B6/lpr DNTC can dose dependently kill syngeneic CD8+ and CD4+ T cells from wild-type B6 mice through Fas/Fas ligand interactions in vitro. We also demonstrate that B6/lpr DNTC that are activated and expand in vivo are able to specifically down-regulate allogeneic immune responses mediated by syngeneic Fas+CD4+ and CD8+ T cells in vivo. B6/lpr DNTC that have been preactivated in vivo by infusion of either class I– (bm1) or class II– (bm12) mismatched allogeneic lymphocytes are able to specifically enhance the survival of bm1 or bm12, but not third-party skin allografts when adoptively transferred into naive B6+/+ mice. These findings clearly demonstrate that B6/lpr DNTC have a potent immune regulatory function in vitro and in vivo. They also provide new insights into the mechanisms involved in the development of autoimmune disease in lpr mice.
Beyond Humanitarian Bandages — Confronting Genocide in Sudan
Authors: Jerry Fowler
Journal: New England Journal of Medicine (2004)

The basic contours of what is happening in the Darfur region of western Sudan have been extensively documented. In May, I traveled to Chad, Sudan's neighbor to the west, and interviewed dozens of refugees spread out over hundreds of miles. The stories I heard were remarkably consistent. Person after person, the refugees told me that they had fled after attacks on their villages by Arab Janjaweed militias, which have burned hundreds of villages and murdered tens of thousands of civilians from so-called black African ethnic groups. The distinction between Arab and African has a heavy subjective component, but it is . . .