tbuckley/cabot-search huggingface dataset:
Increasing Incidence of Diabetes After Gestational Diabetes
Authors: Jeannet Lauenborg, Torben Hansen, Dorte Møller Jensen, Henrik Vestergaard, Lars Mølsted-Pedersen, Peter Hornnes, Henning Locht, Oluf Pedersen, Peter Damm
Journal: Diabetes Care (2004)

OBJECTIVE—To study the incidence of diabetes among women with previous diet-treated gestational diabetes mellitus (GDM) in the light of the general increasing incidence of overweight and diabetes and to identify risk factors for the development of diabetes. RESEARCH DESIGN AND METHODS—Women with diet-treated GDM during 1978–1985 (old cohort, n = 241, also followed up around 1990) or 1987–1996 (new cohort, n = 512) were examined in 2000–2002. Women were classified by a 2-h, 75-g oral glucose tolerance test according to the World Health Organization criteria or an intravenous glucagon test supplemented by measurement of GAD antibodies. Historical data from index-pregnancy and anthropometrical measurements were collected. RESULTS—A total of 481 (63.9%) women were examined (median 9.8 years [interquartile range 6.4–17.2]) after index pregnancy. Diabetes and impaired glucose tolerance (IGT)/impaired fasting glucose were present in 40.0 and 27.0% of women, respectively. In the new cohort, 40.9% had diabetes compared with 18.3% in the old cohort at the 1990 follow-up (P &amp;lt; 0.0005). Prepregnancy BMI was significantly higher in the new compared with the old cohort (26.0 [22.5–30.8] vs. 22.9 kg/m2 [20.2–28.0], P &amp;lt; 0.0005). Among others, new-cohort membership, prepregnancy overweight (BMI ≥25 kg/m2), and IGT postpartum were identified as independent predictors of diabetes by multiple logistic regression analyses. CONCLUSIONS—The incidence of diabetes among Danish women with previous diet-treated GDM was very high and had more than doubled over a 10-year period. This seems to be due to a substantial increase in BMI in women with GDM.
B cell–specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers
Authors: Thinh Huy Tran, Mikiyo Nakata, Keiichiro Suzuki, Nasim A Begum, Reiko Shinkura, Sidonia Fagarasan, Tasuku Honjo, Hitoshi Nagaoka
Journal: Nature Immunology (2009)
Metabolic Complications of Childhood Obesity
Authors: Ram Weiss, Francine Ratner Kaufman
Journal: Diabetes Care (2008)

The growing number of obese children and adolescents across the world creates a diagnostic challenge to caregivers. The early clinical manifestations of abnormalities related to childhood obesity, attributed to obesity-driven insulin resistance, are impaired glucose metabolism and nonalcoholic fatty liver disease. Both have no symptoms and demand a high index of suspicion and the proper choice of tests for establishing the diagnosis. The clinician should gather information derived from thoroughly taken history and a focused physical examination to stratify patients by their risk. Focused lifestyle modification-aimed interventions are showing promising results in improving the metabolic profile of obese children. Early diagnosis may help allocate resources for intensive interventions that may benefit individuals at greatest risk for early obesity-related morbidity.
Alteration of colony‐stimulating factor output, endotoxemia, and granulopoiesis in cyclic neutropenia
Authors: Peter L. Greenberg, Ine Bax, Jack Levin, Tony M. Andrews
Journal: American Journal of Hematology (1976)

Abstract Cellular and humoral factors involved in the regulation of granulopoiesis were evaluated in two patients with cyclic neutropenia by utilizing the agar‐gel marrow culture technique to serially study marrow granulocytic colony‐forming capacity (CFC) and the urinary output of colony‐stimulating factor (CSF). CSF output varied inversely with peripheral neutrophil counts and directly with monocyte counts and evidence for infection (endotoxemia and/or staphylococcal abscesses). Following autologous infusion of one patient's plasma obtained during a period of neutropenia, increased urinary excretion of CSF occurred concomitant with increments in both marrow CFC and the proportion of granulocytic progenitor cells in DNA synthesis. Neutrophil periodicity was not altered by the administration of the neutropenic plasma. These findings are consistent with the hypothesis that cyclic neutropenia is caused by a quantitatively decreased entry of stem cells or granulocytic progenitor cells into granulopoiesis.
A Tale of Two Cells: Discovering the Origin of Prostate Cancer
Authors: Ken Garber
Journal: JNCI Journal of the National Cancer Institute (2010)

I n July, researchers in the lab of Owen Witte, M.D., at the University of California, Los Angeles, reported in Science that human prostate basal cells, transformed and then transplanted into mice, could form tumors. But in September 2009, a different group reported in Nature that prostate cancer in mice originated from a rare population of luminal cells. Basal versus luminal: irreconcilable? Apparently not. “Neither of them contradicts each other at all,” said Lynette Wilson, Ph.D., a professor in the departments of cell biology and urology at New York University. It’s possible that there are different prostate cancer cells of origin, she said. And the two papers are together a big step forward for a fi eld badly lacking such basic knowledge. That’s because the cellular origins of prostate cancer are still largely unknown. “The prostate cancer fi eld is struggling because, unlike [for] the breast, there is not a clear consensus about prostatic cell lineage,” said Gail Risbridger, Ph.D., a professor in the department of anatomy and developmental biology at Monash University in Melbourne, Australia. In breast cancer, six different subtypes have been mapped out, each arising from a distinct step in the differentiation of breast tissue from a common precursor cell. But we do not yet have such a map for prostate cancer. “This whole fi eld is still in its infancy,” Wilson said. Closing this knowledge gap could be the key to distinguishing between aggressive and indolent cancers and in developing individualized treatments — research that’s much further along in some other cancers. “It is conceivable that by identifying cell types of origin, you could distinguish different types of prostate cancer that differ in terms of their prognosis and/or treatment response,” said Michael Shen, Ph.D., a professor of medicine and genetics and development at Columbia University in New York. Shen led the group that reported in Nature last year that a rare population of luminal cells in mice gave rise to prostate cancer. That study and the recent report in Science open the door to new experiments that should pin down the exact cell types in which human prostate cancer originates.
β2-Adrenergic receptors in propranolol therapy: Does down-regulation do it?
Authors: Andrew K. Burroughs
Journal: Hepatology (1987)

The density and affinity of beta-2-adrenoceptors on mononuclear cells from peripheral blood were studied in fifteen patients with cirrhosis of different severity and in thirteen controls. There was no significant difference between cirrhotic patients and controls in density or affinity of beta-2 binding sites. Within the cirrhotic group, however, the number of binding sites per cell was significantly lower in patients with severe ascites than in patients with mild to moderate or no ascites. This down-regulation of beta-adrenoceptors could influence the haemodynamic response to beta-blockers.
THE CERVICAL SYMPATHETIC AND ITS RELATION TO THE THYROID GLAND IN EXOPHTHALMIC GOITRE
Authors: R. C. Shaw
Journal: BMJ (1929)

IN tllis counltry tlheories as to the cauisatioii of exophtlialnmic goitre have p)rincipally been focused oni the thyroid gland, anid as a riesult of such hypothetical basis for the disease Qperative treatmne(nt has beeni almost entirely dii.ected towards this structure.On tlhe other liand, a very cursorV r eview of -tlhe literature of the etiology of this disease, especially fromi Continental and American sources, demon- strates the fact that in the minids of a very large proportion of investigators ani explanation based oni a miiorbid change in the thyroid alone is iniadequate to account for tlle complex plhen-omena of the disease, and accordingly maniy theories have been propounded introducinig a nieurogenic or toxico-neurogenic factor.Surgery has followed up this reasoning bv attempting to effect a cure thrlough extirpation of presumably diseased nervous'pathways of the cervical sympatheticsysitein. 'Wlhat, briefly, are the e.sults of surgical intervention directed towards two totally different aiiatomical structures?Since the conmmencement of the present century a large 'series of operations-for exophthalimiic goitre have -been carried ouit both oni the synimpthetic and the thyroid aid-the outcome of botlh )rocedures has been a 'reasoniable proportion of absolute (eires or of caises wheie thliee hass been prionounced aneliorlation of thie symptomns.In order to exemplify bviefly-this point tlhe followintg observations may be cited.Chalier in 1926 r-eported a ser ies of nineteen cases of .ervicalsmpnatbectomy for toxic goitre.The end-results'ill be seeln from the following table.Cured ... ... ... ... 3 Greatly iffprove ... .. ... ... 9 'however, is even ow, at the en-d of seven months, by no means complete.CASE II.A. healthy man, aged 38, whlen first seen .byone of uls gave the following hlistory.
Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression
Authors: H. Yu
Journal: JNCI Journal of the National Cancer Institute (2000)

The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.
Roflumilast in Asian patients with COPD: A randomised placebo-controlled trial
Authors: David Hui, Aziah Mahayiddin, Camilo Roa, Kheng Hoe Kwa, Dirk Bredenbröker, Udo-Michael Goehring, Han-Pin Kuo, Sang-Do Lee
Journal: European Respiratory Journal (2011)

Background/Rationale:  Roflumilast (ROF) is the first oral, selective phosphodiesterase 4 inhibitor licensed for the treatment of severe COPD associated with chronic bronchitis and a history of frequent exacerbations. This study (NCT00242320) examined the efficacy, safety and tolerability of ROF in Asian patients with COPD.   Methods:  Patients with moderate to severe COPD (post-bronchodilator FEV 1  30–80% predicted) were recruited from 32 outpatient centres in Hong Kong, Malaysia, the Philippines, South Korea and Taiwan. Patients were randomly assigned (1:1) to oral ROF, 500μg once daily, or placebo, in a 12-week treatment period, following a single-blind baseline period in which all patients received placebo for 4 weeks. The primary endpoint was mean change in post-bronchodilator FEV 1  from baseline to each post-randomisation visit. Safety endpoints included clinical laboratory tests, vital signs, physical examination (including electrocardiogram) and monitoring of adverse events (AEs).   Results:  Of 551 patients recruited, 410 were randomised and treated (ROF, n=203; placebo, n=207). ROF improved post-bronchodilator FEV 1  by 79mL vs placebo (p 1 , pre-and post-bronchodilator FEV 6 , forced vital capacity and peak expiratory flow also significantly favoured ROF over placebo. In both groups, >90% patients completed treatment without exacerbations. AEs were more common with ROF than placebo, but were comparable with those in previous studies.   Conclusions:  ROF, 500μg once daily, improves lung function in Asian patients with COPD. The safety and tolerability of ROF was similar to that observed in a Caucasian population.
Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance
Authors: Olivia Simma, Eva Zebedin, Nina Neugebauer, Carola Schellack, Andreas Pilz, Souyet Chang-Rodriguez, Karen Lingnau, Eva Weisz, Eva Maria Putz, Winfried F. Pickl, Thomas Felzmann, Mathias Müller, Thomas Decker, Veronika Sexl, Dagmar Stoiber
Journal: Cancer Research (2008)

Abstract We showed previously that Tyk2−/− natural killer cells lack the ability to lyse leukemic cells. As a consequence, the animals are leukemia prone. Here, we show that the impaired tumor surveillance extends to T cells. Challenging Tyk2−/− mice with EL4 thymoma significantly decreased disease latency. The crucial role of Tyk2 for CTL function was further characterized using the ovalbumin-expressing EG7 cells. Tyk2−/− OT-1 mice developed EG7-induced tumors significantly faster compared with wild-type (wt) controls. In vivo assays confirmed the defect in CD8+ cytotoxicity on Tyk2 deficiency and clearly linked it to type I IFN signaling. An impaired CTL activity was only observed in IFNAR1−/− animals but not on IFNγ or IL12p35 deficiency. Accordingly, EG7-induced tumors grew faster in IFNAR1−/− and Tyk2−/− but not in IFNγ−/− or IL12p35−/− mice. Adoptive transfer experiments defined a key role of Tyk2 in CTL-mediated tumor surveillance. In contrast to wt OT-1 cells, Tyk2−/− OT-1 T cells were incapable of controlling EG7-induced tumor growth. [Cancer Res 2009;69(1):203–11]
Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2–Positive Cancer
Authors: Patricia M. LoRusso, Denise Weiss, Ellie Guardino, Sandhya Girish, Mark X. Sliwkowski
Journal: Clinical Cancer Research (2011)

Abstract Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)–targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1–containing agents are eagerly awaited. Clin Cancer Res; 17(20); 6437–47. ©2011 AACR.
A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis
Authors: Sébastien Gibot, Marie-Nathalie Kolopp-Sarda, Marie-C. Béné, Pierre-Edouard Bollaert, Alain Lozniewski, Françoise Mory, Bruno Levy, Gilbert C. Faure
Journal: The Journal of Experimental Medicine (2004)

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently discovered receptor expressed on the surface of neutrophils and a subset of monocytes. Engagement of TREM-1 has been reported to trigger the synthesis of proinflammatory cytokines in the presence of microbial products. Previously, we have identified a soluble form of TREM-1 (sTREM-1) and observed significant levels in serum samples from septic shock patients but not controls. Here, we investigated its putative role in the modulation of inflammation during sepsis. We observed that sTREM-1 was secreted by monocytes activated in vitro by LPS and in the serum of animals involved in an experimental model of septic shock. Both in vitro and in vivo, a synthetic peptide mimicking a short highly conserved domain of sTREM-1 appeared to attenuate cytokine production by human monocytes and protect septic animals from hyper-responsiveness and death. This peptide seemed to be efficient not only in preventing but also in down-modulating the deleterious effects of proinflammatory cytokines. These data suggest that in vivo modulation of TREM-1 by sTREM peptide might be a suitable therapeutic tool for the treatment of sepsis.
Kinetics of Allergen-Induced Airway Eosinophilic Cytokine Production and Airway Inflammation
Authors: GAIL M. GAUVREAU, RICK M. WATSON, PAUL M. O'BYRNE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Airway eosinophilia is the hallmark of asthma exacerbation. Coordination of cytokines such as interleukin (IL)-5, eotaxin and regulated on activation, normal T-cell expressed and secreted (RANTES) seem to be necessary for eosinophil extravasation including adhesion, chemotaxis, and activation. The purpose of this study was to characterize both the kinetics of allergen-induced inflammatory cell recruitment to the airways and cytokines selective for eosinophil chemotaxis, activation, or resolution. Eight atopic asthmatic individuals demonstrating a dual response to inhaled allergen completed a diluent-controlled crossover study. The subjects showed significant allergen-induced early and late airway asthmatic responses (p < 0.001), and an increase in the number of sputum eosinophils and metachromatic cells (p < 0.05). The number of eosinophils immunopositive for IL-5, eotaxin, and RANTES increased 7 h after allergen inhalation (p < 0.05), coincident with the peak number of activated eosinophils. Sputum cells immunopositive for IL-10 decreased significantly following allergen challenge (p = 0.04), and correlated negatively with sputum eosinophils (r = − 0.34, p = 0.02). This study shows that allergen-induced increases in sputum eosinophils are associated with the presence of cytokines specific for the activation and chemotaxis of eosinophils, and suggests that cooperation of eosinophilic cytokines may be important for the accumulation and regulation of activated eosinophils at the site of allergic inflammation.
Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs
Authors: Bernice Wright, Jeremy P.E. Spencer, Julie A. Lovegrove, Jonathan M. Gibbins
Journal: Cardiovascular Research (2012)

Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti-thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small-molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy.
Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species
Authors: Angelo De Milito, Elisabetta Iessi, Mariantonia Logozzi, Francesco Lozupone, Massimo Spada, Maria Lucia Marino, Cristina Federici, Maurizio Perdicchio, Paola Matarrese, Luana Lugini, Anna Nilsson, Stefano Fais
Journal: Cancer Research (2007)

Abstract Proton pumps like the vacuolar-type H+ ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose- and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI. [Cancer Res 2007;67(11):5408–17]