tbuckley/cabot-search huggingface dataset:
Induction of autoimmunity in good and poor responder mice with mouse thyroglobulin and lipopolysaccharide.
Authors: P S Esquivel, N R Rose, Y C Kong
Journal: The Journal of Experimental Medicine (1977)

The administration of soluble mouse thyroglobulin (MTg) in conjunction with bacterial lipopolysaccharide (LPS) led to the termination of natural tolerance to MTg in mice. The extent of autoimmunity correlated with responsiveness to MTg, previously shown by the injection of MTg in complete Freund's adjuvant (CFA) to be dependent upon the H-2 haplotype. In good responder B10.BR (H-2k) mice given MTg either with LPS or in CFA, high antibody levels to MTg and extensive mononuclear cell infiltration in the thyroid were observed. In contrast, congenic poor responder B10.D2 (H-2d) mice given MTg plus LPS showed low levels of antibody to MTg, compared to those receiving MTg in CFA, and insignificant cellular infiltration of the thyroid. In no instance did autoimmunity develop in either good or poor responder strain given MTg, LPS, or CFA along although LPS was antigenic in both of these congenic strains. Since the genetic difference in responsiveness to MTg is known to be T-cell based, the involvement of T cells in LPS-treated mice was suspected. This was further ascertained by the use of athymic poor responder (BALB/c) mice and thymectomized, irradiated, and bone marrow-reconstituted B10.BR mice. Antibodies to MTg were detected only in heterozygous (nu/+) mice and good responder mice reconstituted with both thymus and bone marrow cells. In addition, significant cellular infiltration in the thyroid occurred only in fully reconstituted good responder mice. Thus, the adjuvant effect of LPS on responsiveness to MTg required T cells. Since unmodified MTg and LPS abrogated selftolerance to MTg, the need for cross-reactive T cells could be excluded. These observations suggest the presence of self-reactive T cells.
HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression
Authors: Naoki Izawa, Wenwen Wu, Ko Sato, Hiroyuki Nishikawa, Akihiro Kato, Narikazu Boku, Fumio Itoh, Tomohiko Ohta
Journal: Cancer Research (2011)

DNA replication, recombination, and repair are highly interconnected processes the disruption of which must be coordinated in cancer. HERC2, a large HECT protein required for homologous recombination repair, is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here, we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, endogenous HERC2 interacts with Claspin, a protein essential for G(2)-M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase progression and additional HERC2 depletion reduced the effect of Claspin depletion. In addition, HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing, and led to a decrease in MCM2 phosphorylation. In a HERC2-dependent manner, treatment of cells with replication inhibitor aphidicolin enhanced MCM2 phosphorylation. Taken together, our results suggest that HERC2 regulates DNA replication progression and origin firing by facilitating MCM2 phosphorylation. These findings establish HERC2 as a critical function in DNA repair, checkpoint activation, and DNA replication.
Characterization of the Effects of Arginine and Glucose on Glucagon and Insulin Release from the Perfused Rat Pancreas
Authors: John E. Gerich, M. Arthur Charles, Gerold M. Grodsky
Journal: Journal of Clinical Investigation (1974)

To characterize the mechanisms by which arginine and glucose affect pancreatic alpha and beta cell function, the effects of these agents over their full dose response, both alone and in various combinations, were studied using the perfused rat pancreas. Arginine (0-38 mM), in the absence of glucose, stimulated biphasic glucagon (IRG) secretion (Km approximately 3-4 mM) at concentrations less than 1 mM and caused nonphasic insulin (IRI) release (Km approximately 12-13 mM) but only at concentrations greater than 6 mM. Glucose (0-27.5 mM) alone stimulated biphasic IRI release (Km approximately 9-10 mM) at concentrations in excess of 5.5 mM and caused nonphasic inhibition of IRG secretion (Kt approximately 5-6 mM) at concentrations as low as 4.1 mM. These results demonstrate fundamental differences in pancreatic alpha and beta cell secretory patterns in response to glucose and arginine and suggest that glucagon secretion is more sensitive to the effect of both glucose and arginine. Various concentrations of arginine in the presence of 5.5 mM glucose stimulated biphasic IRG and IRI release: IRG responses were diminished and IRI responses were enhanced compared with those seen with arginine in the absence of glucose. Glucose (0-27.5 mM) in the presence of 3.2 or 19.2 mM arginine caused similar inhibition of IRG secretion (Km approximately 5-6 mM) and stimulation of IRI release (Km approximately 9-10 mM) as that seen with glucose alone, although greater IRG and IRI release occurred. This augmentation of IRI secretion was greater than that expected from mere additive effects of glucose and arginine. Classical Lineweaver-Burk analysis of these results indicates that glucose is a non-competitive inhibitor arginine-stimulated glucagon secretion and suggests that glucose and arginine affect pancreatic alpha and beta cell function via different mechanisms. In addition, comparison of simultaneous insulin and glucagon secretion patterns under various conditions suggests that endogenous insulin per se has little or no direct effect on IRG secretion and that endogenous glucagon does not appreciably affect pancreatic beta cell function.
Inhibition of the cardiac electrogenic sodium bicarbonate cotransporter reduces ischemic injury
Authors: N Khandoudi
Journal: Cardiovascular Research (2001)

Objective: Although it is believed that sodium-driven acid–base transport plays a central role in the development of the reperfusion injury that follows cardiac ischemia, research to date has demonstrated only a role for Na+/H+ exchange (NHE). However, Na+-driven HCO–3 transport, which is quantitatively as important as NHE in cardiac cells, has not been examined. Methods and Results: Here the results show that a neutralizing antibody raised against the human heart electrogenic Na+/HCO3− cotransporter (hhNBC) blocked the recovery of pH after acidic pulse both in HEK-293 cells expressing hhNBC and in rat cardiac myocytes demonstrating the presence of an electrogenic NBC in rat cardiac myocytes similar to hhNBC. Administration of anti-NBC antibody to ischemic-reperfused rat hearts markedly protects systolic and diastolic functions of the heart during reperfusion. Furthermore, using a quantitative real-time RT-PCR (TaqMan) and Western blot analysis we demonstrated that in human cardiomyopathic hearts, mRNA and protein levels of hhNBC increase, whereas mRNA levels of the electroneutral Na+/HCO3− cotransporter (NBCn1) remain unchanged. Conclusion: Our data provide evidence that inhibition of hhNBC, whose role in cardiac pathologies could be amplified by overexpression, represents a novel therapeutic approach for ischemic heart disease.
Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss.
Authors: A M Parfitt, C H Mathews, A R Villanueva, M Kleerekoper, B Frame, D S Rao
Journal: Journal of Clinical Investigation (1983)

We devised a new method for examining the structural changes that occur in trabecular bone in aging and in osteoporosis. With simultaneous measurement of total perimeter and bone area in thin sections, indirect indices of mean trabecular plate thickness (MTPT) and mean trabecular plate density (MTPD) can be derived, such that trabecular bone volume = MTPD X MTPT. MTPD is an index of the probability that a scanning or test line will intersect a structural element of bone, and is the reciprocal of the mean distance between the midpoints of structural elements, multiplied by pi/2. We applied this method to iliac bone samples from 78 normal subjects, 100 patients with vertebral fracture, and 50 patients with hip fracture. The reduction in trabecular bone volume observed in normal subjects with increasing age was mainly due to a reduction in plate density, with no significant decrease in plate thickness. The further reduction in trabecular bone volume observed in patients with osteoporotic vertebral fracture was mainly due to a further reduction in plate density. There was a relatively smaller reduction in plate thickness that was statistically significant in males but not in females. Only in patients with hip fracture did trabecular thinning contribute substantially to the additional loss of trabecular bone in osteoporosis relative to age. These data indicate that age-related bone loss occurs principally by a process that removes entire structural elements of bone; those that remain are more widely separated and some may undergo compensatory thickening, but most slowly become reduced in thickness. We propose that the process of removal is initiated by increased depth of osteoclastic resorption cavities which leads to focal perforation of trabecular plates; this is followed by progressive enlargement of the perforations with conversion of plates to rods. The resulting structural changes are more severe in osteoporotic patients than in normal subjects, but have been completed in most patients before they develop symptoms.
Somatic Induction of Pten Loss in a Preclinical Astrocytoma Model Reveals Major Roles in Disease Progression and Avenues for Target Discovery and Validation
Authors: Andrew Xiao, Chaoying Yin, Chunyu Yang, Antonio Di Cristofano, Pier Paolo Pandolfi, Terry Van Dyke
Journal: Cancer Research (2005)

Abstract High-grade astrocytomas are invariably deadly and minimally responsive to therapy. Pten is frequently mutated in aggressive astrocytoma but not in low-grade astrocytoma. However, the Pten astrocytoma suppression mechanisms are unknown. Here we introduced conditional null alleles of Pten (Ptenloxp/loxp) into a genetically engineered mouse astrocytoma model [TgG(ΔZ)T121] in which the pRb family proteins are inactivated specifically in astrocytes. Pten inactivation was induced by localized somatic retroviral (MSCV)-Cre delivery. Depletion of Pten function in adult astrocytoma cells alleviated the apoptosis evoked by pRb family protein inactivation and also induced tumor cell invasion. In primary astrocytes derived from TgG(ΔZ)T121; Ptenloxp/loxp mice, Pten deficiency resulted in a marked increase in cell invasiveness that was suppressed by inhibitors of protein kinase C (PKC) or of PKC-ζ, specifically. Finally, focal induction of Pten deficiency in vivo promoted angiogenesis in affected brains. Thus, we show that Pten deficiency in pRb-deficient astrocytoma cells contributes to tumor progression via multiple mechanisms, including suppression of apoptosis, increased cell invasion, and angiogenesis, all of which are hallmarks of high-grade astrocytoma. These studies not only provide mechanistic insight into the role of Pten in astrocytoma suppression but also describe a valuable animal model for preclinical testing that is coupled with a primary cell-based system for target discovery and drug screening.
Effects of malnutrition on rat myocardial beta-adrenergic and muscarinic receptors.
Authors: L Ransnäs, C Drott, K Lundholm, A Hjalmarson, B Jacobsson
Journal: Circulation Research (1989)

Malnutrition, as well as malignancy, induces alterations in heart metabolism and performance. Previous studies have implicated adrenergic mechanisms as the cause. The present study was undertaken to investigate if the adenylate cyclase system in the rat heart was affected by malnutrition. Three different animal groups with malnutrition were compared with a control group: rats with acute starvation for 14-96 hours, rats with protein-calorie malnutrition for 2 weeks, and rats with tumors. Stimulation by beta-adrenergic receptors and inhibition by muscarinic receptors of adenylate cyclase activity were not altered by malnutrition. However, conditions used for in vitro adenylate cyclase determinations were, of necessity, not physiological. Neither did the number of beta-adrenergic and muscarinic receptors change. When competition-binding experiments were performed, differences comprising agonist affinity and affinity state distribution were noted among the groups. The myocardial beta-adrenergic receptors formed a reduced number of high-affinity sites in all groups as compared with the control rats. All high-affinity sites displayed a more than 10-fold increase in affinity toward isoproterenol and an impaired sensitivity to guanine nucleotides except in heart membranes derived from rats starved less than 48 hours. While the protein-calorie restricted and the tumor-bearing rats had myocardial beta-adrenergic receptors that were unresponsive to guanine nucleotides, after 48 hours of starvation the rats exhibited an attenuated guanine-nucleotide-induced affinity shift. No changes associated with malnutrition in myocardial membrane levels of the of the stimulatory guanine-nucleotide-binding protein were detected by cholera-toxin-induced ADP-ribosylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract P188: Urinary Sodium and Potassium Excretion and Cardiovascular Diseases in Patients with Chronic Kidney Disease: the Chronic Renal Insufficiency Cohort study
Authors: Katherine T Mills, Jing Chen, Wei Yang, Lawrence Appel, John Kusek, Arnold B Alper, Patrice Delafontaine, Martin G Keane, Emile R Mohler, Akinlolu O Ojo, Mahboob Rahman, Ana C Ricardo, Elsayed Z Soliman, Susan Steigerwalt, Raymond R Townsend, Jiang He
Journal: Circulation (2014)

Introduction: Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) compared to the general population. Prior studies have produced contradictory results for the associations of sodium and potassium intake with the risk of CVD. In addition, these associations have not been investigated in patients with CKD. Hypothesis: We assessed the prospective associations between urinary sodium and potassium excretion and CVD event rates among patients with CKD. Methods: The Chronic Renal Insufficiency Cohort Study (CRIC) is a prospective cohort study of 3,939 participants with CKD from seven locations in the United States. Dietary sodium and potassium intake are assessed by averaging three 24-hour urinary measures and calibrating to sex-specific mean 24-hour urinary creatinine excretion. Composite CVD event is defined as myocardial infarction (MI), stroke, or congestive heart failure (CHF). CVD events are reported every six months and confirmed by medical record adjudication. Results: Over an average 6.5 years of follow-up, 660 CVD events were observed. The highest quartile (&gt;197.7 mmol/24 hours) of adjusted sodium excretion had a hazard ratio (HR) of 1.52 (95% confidence interval 1.23, 1.88; p for trend across quartiles 70.5 mmol/24 hours) of adjusted potassium excretion had a HR of 1.46 (1.14, 1.87; p for trend across quartiles 0.0009) for composite CVD events compared to the lowest quartile (≤41.2 mmol/24 hours). When modeled continuously, every 100-mmol/24 hours higher adjusted sodium excretion was associated with an increased HR of 1.25 (1.14, 1.36) for composite CVD events, 1.25 (1.13, 1.39) for CHF, 1.32 (1.08, 1.61) for stroke, and 1.09 (0.93, 1.27) for MI. In addition, every 50-mmol/24 hour higher adjusted potassium intake was associated with an increased HR of 1.25 (1.10, 1.41) for composite CVD events, 1.32 (1.15, 1.52) for CHF, 1.11 (0.81, 1.54) for stroke, and 1.00 (0.79, 1.27) for MI. Conclusions: Our study found that high dietary sodium and potassium are both associated with an increased risk of CVD among patients with CKD. These findings suggest that reductions in high dietary sodium and potassium intake might reduce the risk of CVD among patients with CKD.
Cerebral Microembolization After Bioprosthetic Aortic Valve Replacement
Authors: Talal Al-Atassi, Khanh Lam, Melissa Forgie, Munir Boodhwani, Fraser Rubens, Paul Hendry, Roy Masters, William Goldstein, Pierre Bedard, Thierry Mesana, Marc Ruel
Journal: Circulation (2012)

No human physiological data exists on whether aspirin only is as effective as warfarin plus aspirin in preventing cerebral microembolization in the early postoperative period after bioprosthetic aortic valve replacement (bAVR).We prospectively enrolled 56 patients who had no other indication for oral anticoagulation, who underwent bAVR and received, in an open-label fashion, either daily warfarin (for INR 2.0-3.0) plus 81 mg of aspirin (n=28) or 325 mg of aspirin only (n=28). Cerebral microembolization was quantified at 4 hours (baseline) and at 1 month postoperatively, by recording 1-hour bilateral middle cerebral artery (MCA) microembolic signals (MES). Platelet-function analysis (PFA) of closure times (CT) on collagen was also used as a marker of platelet-dependent activation. Follow-up to 1 year was complete. Preoperative demographics and baseline platelet function were equivalent in both groups. There was no mortality, stroke, or transient ischemic attack at 1 year in either group. No significant differences were found in the proportion of patients with MES among those receiving warfarin plus aspirin versus aspirin only, at baseline (68% versus 82%, respectively; P=0.4) and at 1 month (46% versus 43%; P=1.0) after bAVR. The total MES and PFA were also equivalent between groups, at baseline and follow-up.Early after bAVR, the effects of these 2 antithrombotic regimens on cerebral microembolization and platelet function are equivalent. These data bring new mechanistic support to the premise that aspirin only may safely be used early after bAVR in patients who have no other indication for oral anticoagulation.
A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization during Tumor Growth and Metastasis
Authors: Dezheng Dong, Christopher Stapleton, Biquan Luo, Shigang Xiong, Wei Ye, Yi Zhang, Niyati Jhaveri, Genyuan Zhu, Risheng Ye, Zhi Liu, Kevin W. Bruhn, Noah Craft, Susan Groshen, Florence M. Hofman, Amy S. Lee
Journal: Cancer Research (2011)

Glucose-regulated protein 78 (GRP78)/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis, and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we showed that Grp78 heterozygosity impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis and the Grp78(+/-) mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors, while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this article, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models in which wild-type (WT), syngeneic mammary tumor cells were injected into the host, we showed that Grp78(+/-) mice suppressed tumor growth and angiogenesis during the early phase but not during the late phase of tumor growth. Growth of metastatic lesions of WT, syngeneic melanoma cells in the Grp78(+/-) mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and showed severe reduction of tumor angiogenesis and metastatic growth, with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells showed that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis.
Incidence of inflammatory bowel disease in northern France (1988-1990).
Authors: C Gower-Rousseau, J L Salomez, J L Dupas, R Marti, M C Nuttens, A Votte, M Lemahieu, B Lemaire, J F Colombel, A Cortot
Journal: Gut (1994)

There were no data concerning the incidence of inflammatory bowel disease (IBD) in France. The aim of this study was to investigate the incidence of Crohn9s disease and ulcerative colitis in northern France. This prospective population based study was realised through the gastroenterologists of the region Nord-Pas de Calais and the Somme Department. Each gastroenterologist referred patients consulting for the first time with clinical symptoms compatible with IBD. Data were collected by an interviewer practitioner present at the gastroenterologist9s consulting room. Two independent expert gastroenterologists assessed each case in a blind manner and made a final diagnosis of Crohn9s disease, ulcerative colitis, ulcerative proctitis, or unclassifiable chronic colitis. From 1988 to 1990, 1291 cases of IBD were recorded: 674 (52%) Crohn9s disease, 466 (36%) ulcerative colitis including 162 proctitis (35%), and 151 (12%) unclassifiable chronic colitis. The mean annual incidence was 4.9 per 100,000 for Crohn9s disease and 3.2 for ulcerative colitis. The sex ratio F/M was 1.3 for Crohn9s disease and 0.8 for ulcerative colitis. The highest age specific incidence rate for Crohn9s disease was between 20 and 29 years: 13.1 for women and 9.8 for men. The highest age specific incidence rate for ulcerative colitis was between 20 and 39 years: 5.5 for women and 6.5 for men. This first French prospective study has shown an incidence rate for Crohn9s disease comparable with that seen in north European studies but lower than that seen for ulcerative colitis. These results could be related to the different environmental factors or the genetic background of the population studied, or both.
Respiratory rehabilitation: improvement of short- and long-term outcome
Authors: R. Gosselink
Journal: European Respiratory Journal (2002)

Studies over the last 5–10 yrs have clearly demonstrated the benefits of rehabilitation programmes on chronic obstructive pulmonary disease (COPD) patients' exercise capacity, quality of life, and utilisation of healthcare resources. Despite these achievements, several unanswered questions need to be addressed to further improve the outcome of rehabilitation in COPD. The effects of exercise training on survival, the effectiveness of various modalities of exercise training and the maintenance of the effects in the long-term remain largely unknown. In the current issue of the European Respiratory Journal , the latter two of these issues are addressed. Vogiatzis et al. 1 report on the feasibility of interval training as an alternative training modality for endurance training. Indeed, most training programmes in COPD rehabilitation are based on endurance training, which effectively means periods of sustained exercise for 20–30 min. High-intensity …