tbuckley/cabot-search huggingface dataset:
Systemic Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E–Null Diabetic Mice
Authors: Paola Secchiero, Riccardo Candido, Federica Corallini, Serena Zacchigna, Barbara Toffoli, Erika Rimondi, Bruno Fabris, Mauro Giacca, Giorgio Zauli
Journal: Circulation (2006)

Although in vitro studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) might be involved in vascular biology, its potential role in the pathogenesis and/or treatment of atherosclerosis has not been investigated.Both recombinant human TRAIL and an adeno-associated virus vector expressing human TRAIL were used to deliver TRAIL in apolipoprotein E (apoE)-null mice in which diabetes mellitus was induced by destruction of islet cells with streptozotocin. Diabetes in apoE-null mice was associated with a significant increase in atherosclerotic plaque area and complexity in the aorta as assessed by a marked increase in interstitial collagen, cellular proliferation, and macrophage infiltration and a focal loss of endothelial coverage. Repeated intraperitoneal injections of recombinant human TRAIL and a single intravenous injection of adeno-associated virus-human TRAIL significantly attenuated the development of atherosclerotic plaques in apoE-null animals. TRAIL also markedly affected the cellular composition of plaque lesions by inducing apoptosis of infiltrating macrophages and increasing the vascular smooth muscle cell content. Moreover, TRAIL promoted the in vitro migration of cultured human aortic vascular smooth muscle cells but not of monocytes or macrophages. Conversely, TRAIL selectively induced apoptosis of human cultured macrophages but not of vascular smooth muscle cells.Overall, data from the present study indicate that atherosclerosis in diabetic apoE-null mice is ameliorated by systemic TRAIL administration and that adeno-associated virus-mediated TRAIL gene delivery might represent an innovative method for the therapy of diabetic vascular diseases.
Revealing the role of CD4+ T cells in viral immunity
Authors: Andrea J. Sant, Andrew McMichael
Journal: The Journal of Experimental Medicine (2012)

Protective immunity to chronic and acute viral infection relies on both the innate and adaptive immune response. Although neutralizing antibody production by B cells and cytotoxic activity of CD8+ T cells are well-accepted components of the adaptive immune response to viruses, identification of the specific role of CD4+ T cells in protection has been more challenging to establish. Delineating the contribution of CD4+ T cells has been complicated by their functional heterogeneity, breadth in antigen specificity, transient appearance in circulation, and sequestration in tissue sites of infection. In this minireview, we discuss recent progress in identifying the multiple roles of CD4+ T cells in orchestrating and mediating the immune responses against viral pathogens. We highlight several recent reports, including one published in this issue, that have employed comprehensive and sophisticated approaches to provide new evidence for CD4+ T cells as direct effectors in antiviral immunity.
Sperm Function and Structure and Seminal Plasma Prostanoid Concentrations in Men With IDDM
Authors: Pankaj Shrivastav, John Swann, Jamie Y Jeremy, Cecil Thompson, Robert W Shaw, Paresh Dandona
Journal: Diabetes Care (1989)

Semen from 18 men with insulin-dependent diabetes mellitus (IDDM) aged 20-40 yr was compared with that from 15 age-matched control subjects. Although semen volume, sperm count, and spermatozoal motility were similar in the two groups, semen from diabetic men had significantly greater numbers of abnormal spermatozoa and significantly lower ability to penetrate hamster eggs. Concentrations of prostaglandins E2, F2 alpha, and I2 and thromboxane A2 were significantly elevated in the seminal plasma from semen of diabetic subjects compared with control subjects. These observations indicate the need for a careful assessment of fertility in diabetic men, the mechanisms underlying the abnormalities in spermatozoa, and the relationship of these abnormalities to the increase in prostanoid concentrations in diabetic men.
The Ras Inhibitor Farnesylthiosalicylic Acid as a Potential Therapy for Neurofibromatosis Type 1
Authors: Batya Barkan, Sigal Starinsky, Eitan Friedman, Reuven Stein, Yoel Kloog
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that dislodges all active Ras isoforms from the membrane. We assessed the ability of FTS to reverse the transformed phenotype of neurofibromatosis type 1 (NF1)–associated tumor cell lines of malignant peripheral nerve sheath tumor (MPNST). Experimental Design: nf1 mutations were genotyped, allelic losses were analyzed, and neurofibromin expression levels were determined in MPNST cell lines ST88-14, S265P21, and 90-8. The effects of FTS on GTP-bound Ras (Ras-GTP) and its prominent downstream targets, as well as on cell morphology, anchorage-dependent and anchorage-independent growth, and tumor growth in mice, were assessed. Results: The MPNST cell lines were biallelic, NF1 inactive, and neurofibromin deficient. We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RalA in all NF1-deficient MPNST cell lines (NF1 cells) to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line. These effects of FTS led to lower steady-state levels of Ras-GTP and its activated targets. Both anchorage-dependent and anchorage-independent growth of NF1 cells were dose dependently inhibited by FTS, and the inhibition correlated positively with Ras-GTP levels. NF1 cells were found to possess strong actin stress fibers, and this phenotype was also corrected by FTS. NF1 tumor growth in a nude mouse model was inhibited by oral FTS. Conclusions: FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1.
Validity of the Simple-Measure for Assessing Psoriasis Activity (S-MAPA) for objectively evaluating disease severity in patients with plaque psoriasis
Authors: Zelma C. Chiesa Fuxench, Kristina Callis Duffin, Michael Siegel, Abby S. Van Voorhees, Joel M. Gelfand
Journal: Journal of the American Academy of Dermatology (2015)
Hypothermia during sports swimming in water below 11°C: Table 1
Authors: W R Keatinge, M Khartchenko, N Lando, V Lioutov
Journal: British Journal of Sports Medicine (2001)

To assess precautions needed to avoid dangerous hypothermia in endurance sports swims in water below 11 degrees C, using rectal temperature, anthropometric measurements, and voluntary swim times during a six day marathon relay swim.The time in the water and the decrease in rectal temperature were measured during the longest of three to five relay swims by each of eight experienced swimmers in 9.4-11.0 degrees C water. Height, weight, and four skinfold thicknesses were measured.Swimmers with less subcutaneous fat terminated their swims after significantly less time in the water than those with thicker skinfold thickness, even though their rectal temperatures were not significantly lower. The lowest rectal temperature recorded was 34.3 degrees C.Subjective sensation in these experienced swimmers gave reliable guidance on safe durations for swims, and all voluntarily left the water with rectal temperatures that present no threat to people able to rewarm in safe surroundings. Endurance swims in highly competitive conditions or water below 9 degrees C may require continuous temperature monitoring for safety.
Diet-induced hypoxia responsive element demethylation increases CEACAM6 expression, favouring Crohn's disease-associated<i>Escherichia coli</i>colonisation
Authors: Jérémy Denizot, Alexis Desrichard, Allison Agus, Nancy Uhrhammer, Nicolas Dreux, Valérie Vouret-Craviari, Paul Hofman, Arlette Darfeuille-Michaud, Nicolas Barnich
Journal: Gut (2014)

<h3>Objective</h3> Adherent-invasive <i>Escherichia coli</i> (AIEC) are abnormally predominant on Crohn9s disease (CD) ileal mucosa. AIEC strains adhere to enterocytes via interaction between type 1 pili and CEACAM6 receptors abnormally expressed on CD ileal mucosa, leading to gut inflammation. We analysed whether epigenetic mechanisms are involved in the upregulation of CEACAM6 expression in intestinal epithelial cells (IECs). <h3>Design</h3> Methylation of CEACAM6 promoter was analysed using bisulfite sequencing and site-specific methylation by SnapShot. pCpGfree reporter system was used to analyse CEACAM6 promoter activity. Transgenic mice expressing human CEACAM6 fed either standard food or a low-methyl diet (LMD) were orally challenged with 10<sup>9</sup> AIEC LF82. After 3 days, gut-associated AIEC and proinflammatory cytokines were quantified. <h3>Results</h3> Analysis of CEACAM6 gene promoter revealed potentially methylated dinucleotide CpGs within HIF-1-responsive elements (HREs). Methylation levels of CpG within CEACAM6 promoter were inversely correlated with CEACAM6 expression in IEC expressing various levels of CEACAM6. We show the critical role of HRE methylation and transcription factor HIF-1 in the regulation of CEACAM6 gene in IEC. This was confirmed in transgenic mice expressing human CEACAM6 fed a LMD. LMD-dependent HRE demethylation led to abnormal gut expression of CEACAM6, favouring AIEC colonisation and subsequent inflammation. <h3>Conclusions</h3> HRE hypomethylation in CEACAM6 promoter correlates with high expression in IEC. Our findings suggest that abnormal DNA methylation leading to CEACAM6 increased expression and AIEC-mediated gut inflammation can be related to changes in nutritional habits, such as low intake in methyl donor molecules, leading to abnormal epigenetic marks in mouse model mimicking CD susceptibility.
Aggravation of bleomycin-induced pulmonary fibrosis in senescence-accelerated mouse
Authors: Baohui Lou, Qiao Ye, Huaping Dai, Kewu Huang, Chen Wang
Journal: European Respiratory Journal (2012)

Objective:  Idiopathic pulmonary fibrosis (IPF) is predominantly a lung fibrotic disease of older adults, and the process underlying aging might significantly influence the development of pulmonary fibrosis. Bleomycin-induced lung injury was investigated in murine models of accelerated senescence (SAMP8) and of normal aging (SAMR1). The levels of Th1/Th2 related cytokine were also measured.   Methods:  Bleomycin or PBS was injected into the tracheal lumen of 12-month-old SAMP8, 4 and 12-month-old SAMR1 mice. Seven, 14 and 28 days after the injection, the mice were killed and the lungs were harvested for pathological examination, hydroxyproline assay and protein detect. Lung TGF-β1 expression was determined by western blot, and the levels of IL-4 and IFN-γ were detected by ELISA.   Results:  The aggravated bleomycin induced lung injury was observed in 12-month-old SAMP8 compared with 4 and 12-month-old SAMR1. Twenty eight days after injection of bleomycin, Ashcroft score was significant higher in 12-month-old SAMP8 than in 4 and 12-month-old SAMR1 ( P    Conclusions:  Bleomycin-induced pulmonary fibrosis in SAM was aggravated by aging. The old SAM with bleomycin-induced pulmonary fibrosis might be inclined to Th2-biased immune responses.  (This work was funded by National Natural Science Foundation of China Grants 81070046).
Distinct Apoptotic Signaling Characteristics of the Anti-CD40 Monoclonal Antibody Dacetuzumab and Rituximab Produce Enhanced Antitumor Activity in Non-Hodgkin Lymphoma
Authors: Timothy S. Lewis, Renee S. McCormick, Kim Emmerton, Jeffrey T. Lau, Shang-Fan Yu, Julie A. McEarchern, Iqbal S. Grewal, Che-Leung Law
Journal: Clinical Cancer Research (2011)

Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-x(L).Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination.
Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia
Authors: Urban Emmenegger, Gerard C. Morton, Giulio Francia, Yuval Shaked, Marcela Franco, Adina Weinerman, Shan Man, Robert S. Kerbel
Journal: Cancer Research (2006)

Abstract The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy. (Cancer Res 2006; 66(3): 1664-74)
Prepregnancy Care: A Shared Responsibility
Authors: Sara J. Meltzer
Journal: Diabetes Care (2010)

The effective management of pregnancies complicated by diabetes is a shared responsibility—an equal partnership between health care professionals and a responsible woman. Over the last 30 years, major advances in our understanding of the pathophysiology and care of diabetes has led to the hope that pregnancy outcomes for women with diabetes would be similar to the outcomes for women without diabetes as stated in the goal of the Saint Vincent's Declaration in 1989 (1). Unfortunately this has not been realized with the risk of congenital malformations, stillbirths, and neonatal death remaining as high as 3–10 times that of the background population (2–5).

For over a decade, major evidence-based guidelines have called for the counseling of women of child-bearing age with diabetes about the need for family planning and excellent control prior to conception (6–9). Also, preconception care provides the opportunity for the woman and her health caregivers to evaluate nutritional needs, the presence and extent of any micro-/macrovascular complications, and to adjust medications or diabetes management plans before pregnancy occurs.

Ideally, every woman with known diabetes would not only have prepregnancy counseling but actually receive effective prepregnancy care. This has been an elusive goal that is underlined in the article by Murphy et al. (10) in this issue of Diabetes Care . These investigators developed a remarkable “marketing” plan, which included a website, lively and encouraging pamphlets mailed directly to potential patients, as well as local and community educational activities for health professionals. Disappointingly, only 27% of the eligible women with pregestational diabetes actually presented for prepregnancy care. This mirrors similar attempts in Maine (34%) using a statewide community–based educational program for health providers and Ohio (37% in the third 5-year phase of a 15-year program) to optimize access and use of prepregnancy counseling and …
Iron Nutrition and Premenopausal Women: Effects of Poor Iron Status on Physical and Neuropsychological Performance
Authors: James P. McClung, Laura E. Murray-Kolb
Journal: Annual Review of Nutrition (2013)

Iron is a nutritionally essential trace element that functions through incorporation into proteins and enzymes, many of which contribute to physical and neuropsychological performance. Poor iron status, including iron deficiency (ID; diminished iron stores) and iron deficiency anemia (IDA; poor iron stores and diminished hemoglobin), affects billions of people worldwide. This review focuses on physical and neuropsychological outcomes associated with ID and IDA in premenopausal women, as the prevalence of ID and IDA is often greater in premenopausal women than other population demographics. Recent studies addressing the physiological effects of poor iron status on physical performance, including work productivity, voluntary activity, and athletic performance, are addressed. Similarly, the effects of iron status on neurological performance, including cognition, affect, and behavior, are summarized. Nutritional countermeasures for the prevention of poor iron status and the restoration of decrements in performance outcomes are described.
Short-Term Weight Change and the Incidence of Diabetes in Midlife
Authors: Gita D. Mishra, Gretchen Carrigan, Wendy J. Brown, Adrian G. Barnett, Annette J. Dobson
Journal: Diabetes Care (2007)

Although there is consensus that excess adiposity is strongly associated with type 2 diabetes, its relationship with weight change is less clear. This study investigates the relative impact of BMI at baseline and short-term (2- or 3-year) weight changes on the incidence of diabetes.Prospective data were collected from a population-based cohort of middle-aged women participating in the Australian Longitudinal Study on Women's Health (n = 7,239 for this report). To date, participants have completed four mailed surveys (S1, 1996; S2, 1998; S3, 2001; and S4, 2004). Generalized estimating equations were used to model binary repeated-measures data to assess the impact of BMI at S1 and weight change (S1 to S2; S2 to S3) on 3-year incidence of diabetes at S3 and S4, respectively, adjusting for sociodemographic and lifestyle factors.BMI at S1 was strongly associated with the development of diabetes by S3 or S4. Compared with women who had a BMI <25 kg/m2, those with BMI > or =25 kg/m2 had higher incidence of diabetes (P < 0.0001), with odd ratios reaching 12.1 (95% CI 7.6-19.3) for women in the very obese group (BMI > or =35 kg/m2). There was no association between shorter-term weight gain or weight loss on first-reported diagnosis of diabetes (P = 0.08).Because women's risk of developing type 2 diabetes in midlife is more closely related to their initial BMI (when aged 45-50 years) than to subsequent short-term weight change, public health initiatives should target the prevention of weight gain before and during early adulthood.
Novel macrophage receptor for glucose-modified proteins is distinct from previously described scavenger receptors.
Authors: H Vlassara, M Brownlee, A Cerami
Journal: The Journal of Experimental Medicine (1986)

A high-affinity macrophage receptor has been identified that recognizes proteins modified by a common in vivo process, long-term nonenzymatic reaction of glucose with proteins (AGE proteins). This receptor for glucose-modified proteins is now shown to be distinct from previously described scavenger receptors, using competition and crosscompetition experiments between AGE-modified protein and a variety of in vitro-modified scavenger receptor ligands, including unmodified BSA, unmodified low-density lipoproteins (LDL), acetyl-LDL, maleyl-BSA, and formaldehyde-treated BSA. Furthermore, the specific pattern of AGE-protein receptor inhibition by the polyanionic compounds polyinosinic acid, polyadenylic acid, polyglutamic acid, polycytidylic acid, fucoidin, and heparin was distinctly different from that of acetyl-LDL. By thus selectively recognizing a time-dependent in vivo protein modification, macrophages may preferentially degrade senescent macromolecules, thereby having an important role in the regulation of extracellular protein turnover.
Inducible nitric oxide synthase is expressed in granuloma pyogenicum
Authors: None Shimizu, None Naito, None Urata, None Sekine, None Kondo, None Katayama
Journal: British Journal of Dermatology (1998)

It is known that granuloma pyogenicum (GP) grows rapidly but cherry angioma (CA) does not, although they show the same histological features of hyperplasia of the capillary vessels. Although some cytokines have been thought to be angiogenic factors, a nitric oxide (NO) synthase-dependent effector mechanism is reported to be involved in macrophage-derived angiogenesis in humans. Under the hypothesis that this mechanism is also involved in the more rapid growth of GP, we examined the expression of inducible NO synthase (iNOS) in GP as compared with that in CA. The expression of iNOS mRNA was detected in GP, but not in CA, by reverse transcription-polymerase chain reaction (RT-PCR) analysis. In situ hybridization (ISH) demonstrated iNOS mRNA expression in endothelial cells and to a lesser extent round cells and spindle cells in the myxomatous stroma in GP. Immunohistochemical study showed that iNOS protein was expressed in endothelial cells, infiltrating round cells and spindle cells in the stroma in GP. These results suggested that a NOS-dependent mechanism may be involved in angiogenesis and the rapid growth of GP.