tbuckley/cabot-search huggingface dataset:
Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles.
Authors: A D'Andrea, C Chang, J H Phillips, L L Lanier
Journal: The Journal of Experimental Medicine (1996)

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) and T cells that specifically recognize defined groups of polymorphic human histocompatibility leukocyte antigen (HLA) class I molecules. Interactions between KIRs on NK or T cells and major histocompatibility complex (MHC) class I molecules on potential target cells inhibit cell-mediated cytotoxicity, presumably by delivering a negative signal preventing lymphocyte activation. In this study we examined whether KIRs also regulate cytokine production induced in response to T cell receptor-dependent T cell activation. CD4+ and CD8+ T cell clones were stimulated by bacterial superantigens in the presence or absence of monoclonal antibodies (mAbs) against the KIR NKB1 or MHC class I molecules, and production of tumor necrosis factor alpha and interferon gamma was evaluated. When bacterial superantigen was presented by an autologous antigen-presenting cell (APC) to a KIR+ T cell clone, cytokine production was always enhanced in the presence of anti-MHC class I mAb. Similarly, anti-KIR mAb also augmented cytokine production, provided that the APC expressed a HLA class I allele recognized by the KIR. These results suggest that recognition of autologous MHC class I molecules by KIR+ T cells provides a regulatory mechanism acting to modulate the potency of their responses to antigenic challenge.
Effect of Risedronate on the Risk of Hip Fracture in Elderly Women
Authors: Michael R. McClung, Piet Geusens, Paul D. Miller, Hartmut Zippel, William G. Bensen, Christian Roux, Silvano Adami, Ignac Fogelman, Terrence Diamond, Richard Eastell, Pierre J. Meunier, Richard D. Wasnich, Maria Greenwald, Jean-Marc Kaufman, Charles H. Chesnut, Jean-Yves Reginster
Journal: New England Journal of Medicine (2001)

Risedronate increases bone mineral density in elderly women, but whether it prevents hip fracture is not known.
Progression of Pregnancy-Dependent Mouse Mammary Tumors after Long Dormancy Periods. Involvement of Wnt Pathway Activation
Authors: Albana Gattelli, María Cecilia Cirio, Ana Quaglino, Carolina Schere-Levy, Natalia Martinez, María Binaghi, Roberto P. Meiss, Lucio H. Castilla, Edith C. Kordon
Journal: Cancer Research (2004)

Abstract Mouse mammary tumor virus (LA) induces pregnancy-dependent mammary tumors that progress toward autonomy. Here we show that in virgin females, pregnancy-dependent tumor transplants are able to remain dormant for up to 300 days. During that period, these tumors synthesize DNA, express high levels of estrogen and progesterone receptors (ER+PR+) and are able to resume growth after hormone stimulation. Surprisingly, in a subsequent transplant generation, all these tumors are fully able to grow in virgin females, they express low levels of ER and PR (ER−PR−) and have a monoclonal origin; i.e., show all of the features we have described previously in pregnancy-independent tumors. Histologically, mouse mammary tumor virus (LA)-induced tumors are morphologically similar to genetically engineered mouse (GEM) mammary tumors that overexpress genes belonging to the Wnt pathway. Interestingly, in the virus-induced neoplasias, pregnancy-independent passages arising after a dormant phase usually display a lower level of glandular differentiation together with epithelial cell trans-differentiation, a specific feature associated to Wnt pathway activation. In addition, dormancy can lead to the specific selection of Int2/Fgf3 mutated and overexpressing cells. Therefore, our results indicate that during hormone-dependent tumor dormancy, relevant changes in cell population occur, allowing rapid progression after changes in the animal internal milieu.
Prospective, Multicenter, Randomized Trial of a New Organizational Modality for Providing Information and Support to Cancer Patients
Authors: Rodolfo Passalacqua, Caterina Caminiti, Francesco Campione, Francesca Diodati, Renata Todeschini, Giancarlo Bisagni, Roberto Labianca, Matteo Dalla Chiesa, Raffaella Bracci, Marcello Aragona, Fabrizio Artioli, Luigi Cavanna, Alceste Masina, Francesco De Falco, Barbara Marzocchini, Carmelo Iacono, Antonio Contu, Francesco Di Costanzo, Oscar Bertetto, Maria A. Annunziata
Journal: Journal of Clinical Oncology (2009)

No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials.This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed.Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance.This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.
Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion.
Authors: T Brand, H S Sharma, K E Fleischmann, D J Duncker, E O McFalls, P D Verdouw, W Schaper
Journal: Circulation Research (1992)

The molecular basis of myocardial adaptation to ischemia and reperfusion is poorly understood. It is thought that nuclear proto-oncogenes act as third messengers, converting cytoplasmic signal transduction into long-term changes of gene expression. We studied the expression of six nuclear proto-oncogenes (Egr-1, c-fos, fosB, c-jun, junB, and c-myc) in myocardium subjected to ischemia and reperfusion in anesthetized pigs. Stunning was achieved by two 10-minute left anterior descending coronary artery occlusions separated by 30 minutes of reperfusion. Hearts were excised after the first occlusion, after the first reperfusion, and at 30, 120, 150, and 210 minutes of reperfusion after the second occlusion. Total RNA was prepared from stunned as well as normally perfused myocardial tissue and subjected to Northern blotting. The response of the six nuclear proto-oncogenes varied.fosB gene expression was never detected. The c-myc gene was expressed, but its level was unchanged by ischemia. c-jun expression was slightly increased by ischemia (3.1 +/- 0.6-fold). The c-fos, Egr-1, and junB genes were highly induced, being fivefold to sevenfold higher in experimental than in control tissue. In three animals pretreated with the beta 1-antagonist metoprolol and then subjected to the above experimental protocol, the induction of proto-oncogenes was similar to that in nonblocked controls. Our results show that the myocardial adaptive response to ischemic stress includes the induction of at least four transcription factors that may be further operative in repair processes and angiogenesis.
Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression
Authors: Daniel W. Chung, David W. Volk, Dominique Arion, Yun Zhang, Allan R. Sampson, David A. Lewis
Journal: American Journal of Psychiatry (2015)

Objective: Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons and is associated with lower parvalbumin levels in schizophrenia. Method: Tissue samples enriched in calretinin and parvalbumin interneurons were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4, respectively, from matched pairs of schizophrenia and comparison subjects. Transcript levels for pan-ErbB4, four ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2), parvalbumin, and calretinin were quantified by quantitative polymerase chain reaction (qPCR) in each layer. Transcript levels for myocardial infarction associated transcript (MIAT), which regulates ErbB4 splicing, were quantified in gray matter by qPCR and in parvalbumin interneurons by microarray. Results: Calretinin and parvalbumin mRNAs were preferentially expressed in layers 2 and 4, respectively. In schizophrenia subjects, lower parvalbumin levels, higher CYT-1 and JM-a levels, and lower CYT-2 and JM-b levels were detected selectively in layer 4. In layer 4, the JM-a/JM-b ratio was inversely correlated with parvalbumin levels in schizophrenia subjects. MIAT levels were preferentially higher in parvalbumin interneurons in schizophrenia subjects. Conclusions: These findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.
Selection of patients for liver transplantation and allocation of donated livers in the UK
Authors: J Neuberger, A Gimson, M Davies, M Akyol, J O'Grady, A Burroughs, M Hudson
Journal: Gut (2007)

<h3>Background:</h3> The increasing shortfall between the number of patients who would benefit from liver transplantation and the availability of donor livers means that rationing has to occur. The processes of selection of patients for transplantation and for allocation of donor livers should be done according to ethical and, where possible, evidence-based criteria so that there is clarity and that the competing requirements of equity, justice, utility and benefit can be balanced. <h3>Methods:</h3> To achieve these goals for patients in the United Kingdom in need of transplantation, we have developed guidelines for the selection of patients to the national waiting list based on the risk of death without a transplant and the ability of the procedure to improve the recipient’s quality of life. Guidelines have been developed for both those with acute liver failure and chronic liver disease. Allocation will depend on matching of the donor liver to the recipient. <h3>Results:</h3> The proposed system, to be introduced into the UK compares with some other systems, where different models for selection and allocation have been introduced.
Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies
Authors: David Olmos, Douglas Barker, Rohini Sharma, Andre T. Brunetto, Timothy A. Yap, Anne B. Taegtmeyer, Jorge Barriuso, Hanine Medani, Yan Y. Degenhardt, Alicia J. Allred, Deborah A. Smith, Sharon C. Murray, Thomas A. Lampkin, Mohammed M. Dar, Richard Wilson, Johann S. de Bono, Sarah P. Blagden
Journal: Clinical Cancer Research (2011)

GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies.Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies.The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.
Myocardial Connective Tissue Metabolism in Response to Injury: HISTOLOGICAL AND CHEMICAL STUDIES OF MUCOPOLYSACCHARIDE AND COLLAGEN IN RAT HEARTS AFTER ISOPROTERENOL-INDUCED INFARCTION
Authors: JOSEPH T. JUDD, BERNARD C. WEXLER, GEORGE WILLIAMSON, MARY BICKERS, MYRA SPRINGS
Journal: Circulation Research (1969)

Arteriosclerotic and nonarteriosclerotic rats were given isoproterenol sufficient to cause massive myocardial injury. Hearts, livers, and kidneys were taken for analysis of the connective tissues at various intervals. Mucopolysaccharide was identified as Hale-positive material digestible with testicular hyaluronidase. Hexosamine and hydroxyproline were determined by chemical means. The changes in the connective tissue following infarction were divided into two phases. The first, occurring 1 to 2 days after the induction of necrosis, was characterized by extensive edema, accumulation of hexosamine, and by histologically demonstrable mucopolysaccharide. The second phase, 3 to 7 days after infarction, was characterized by changes typical of wound healing in general, involving both mucopolysaccharide and collagen deposition in foci of myocardial scar tissue formation. The increase in hexosamine was the same in arteriosclerotic breeder animals, which required one-half the dose of isoproterenol, as in virgin animals receiving the full dose of isoproterenol. Since the dose was selected to produce relatively the same degree of necrosis in each type of animal, it was thought that the increase in hexosamine was directly related to the injury and not to the isoproterenol per se . No comparable increase in hexosamine was observed in either the liver or kidney.
Gender Differences in UVB-Induced Skin Carcinogenesis, Inflammation, and DNA Damage
Authors: Jennifer M. Thomas-Ahner, Brian C. Wulff, Kathleen L. Tober, Donna F. Kusewitt, Judy A. Riggenbach, Tatiana M. Oberyszyn
Journal: Cancer Research (2007)

The American Cancer Society reports the incidence of squamous cell carcinoma in males to be thrice the incidence in females. This increased squamous cell carcinoma incidence has been attributed to men accumulating more sun exposure and using less sun protection than women. To date, there have been no controlled studies examining the effect of gender on skin tumor development following equal doses of UVB. Gender differences in UVB-induced skin carcinogenesis were examined using the Skh-1 mouse model. After chronic exposure to equal doses of UVB, male mice developed tumors earlier and had more tumors than female mice; tumors in male mice tended to be larger, and the total tumor burden was greater than in females. In addition, tumors in males were of more advanced histologic grade compared with those of female mice. To evaluate the contribution of differences in inflammation and DNA damage to differences in skin carcinogenesis, male and female Skh-1 mice were exposed once to 2,240 J/m(2) UVB and examined 48 h after exposure. Surprisingly, male mice developed less of an inflammatory response, as determined by skin fold thickness and myeloperoxidase activity, compared with females. Interestingly, male mice showed more cutaneous oxidative DNA damage than the females and lower antioxidant levels. These results show a gender bias in skin carcinogenesis and suggest that the gender difference in tumor development is more influenced by the extent of oxidative DNA damage and antioxidant capacities than by inflammatory response.
Antimalarial immunity in Saimiri monkeys. Immunization with surface components of asexual blood stages.
Authors: L H Perrin, B Merkli, M Loche, C Chizzolini, J Smart, R Richle
Journal: The Journal of Experimental Medicine (1984)

Plasmodium falciparum polypeptides of 200 and 140 K mol wt exposed at the surface of merozoites and/or schizonts were purified by affinity chromatography and by electroelution from sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Monkeys were separated into three groups of four and immunized either with one of the two polypeptides or with saline (control). After intravenous challenge with 2.5 X 10(7) P. falciparum asexual blood stages, two monkeys of the control group had to be treated and two recovered spontaneously after peak parasitemia of 9 and 11%. The four monkeys immunized with the 140 K polypeptide recovered without treatment after peak parasitemia between 1.5 and 4.5%. Monkeys immunized with the 200 K polypeptide had similar peak parasitemia except one monkey who suffered from a large skin excoriation and who recovered spontaneously after a peak parasitemia of 11%. Prechallenge sera of the immunized monkeys reacted only with the polypeptide used for immunization except for one serum of the 140 K group, which precipitated an additional polypeptide of 39 K, and a polypeptide of 31 K weakly precipitated by the four sera of monkeys immunized with the 200 K polypeptide. The relatedness between the 200 and 140 K polypeptides was investigated using tryptic digestion and reverse phase chromatography. No clear analogy was found between the two polypeptides, which suggests that immunization with either of two independent surface components of P. falciparum asexual blood stages is able to induce at least a partial protective immunity in immunized hosts.
Structured Type 1 Diabetes Education Delivered Within Routine Care
Authors: Debbie Cooke, Rod Bond, Julia Lawton, David Rankin, Simon Heller, Marie Clark, Jane Speight
Journal: Diabetes Care (2012)

OBJECTIVE To determine whether improvements in glycemic control and diabetes-specific quality of life (QoL) scores reported in research studies for the type 1 diabetes structured education program Dose Adjustment For Normal Eating (DAFNE) are also found when the intervention is delivered within routine U.K. health care. RESEARCH DESIGN AND METHODS Before and after evaluation of DAFNE to assess impact on glycemic control and QoL among 262 adults with type 1 diabetes. RESULTS There were significant improvements in HbA1c from baseline to 6 and 12 months (from 9.1 to 8.6 and 8.8%, respectively) in a subgroup with suboptimal control. QoL was significantly improved by 3 months and maintained at both follow-up points. CONCLUSIONS Longer-term improved glycemic control and QoL is achievable among adults with type 1 diabetes through delivery of structured education in routine care, albeit with smaller effect sizes than reported in trials.
Interleukin-6 and Soluble Interleukin-6 Receptor Levels as Markers of Disease Extent and Prognosis in Neuroblastoma
Authors: Rachel A. Egler, Susan M. Burlingame, Jed G. Nuchtern, Heidi V. Russell
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To explore the relationships between interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) levels and disease extent and clinical outcome in childhood neuroblastoma. Experimental Design: Pretreatment peripheral blood (PB; n = 53) and bone marrow (n = 18) samples from patients with neuroblastoma were assayed by ELISA for IL-6 and sIL-6R. PB values were compared with healthy pediatric controls (n = 28). Results: PB IL-6 levels were significantly elevated in patients with high-risk disease compared with those with low and intermediate risk disease (23.9 versus 4.3 pg/mL; P &amp;lt; 0.001) and the normal control group (23.9 versus 3.3 pg/mL; P &amp;lt; 0.001). Similarly, bone marrow IL-6 levels were higher in high-risk patients when compared with low- and intermediate-risk patients (15 versus 0 pg/mL; P &amp;lt; 0.02). Other factors correlated with higher IL-6 levels were age of &amp;gt;18 months, bony metastases, and unfavorable histology. sIL-6R levels were not significantly correlated with disease stage. Patients with detectable PB IL-6 at diagnosis had significantly lower event-free survival rates (P &amp;lt; 0.008). sIL-6R levels &amp;lt;2.5 × 104 pg/mL were also associated with a significantly worse event-free survival (P = 0.016). Conclusion: Elevated PB IL-6 levels correlated with features of high-risk neuroblastoma and poor prognosis in this population. Decreased PB sIL-6R levels correlated with the presence of metastatic disease. Further study of these markers in children with neuroblastoma seems warranted.
Lenient versus Strict Rate Control in Patients with Atrial Fibrillation
Authors: Isabelle C. Van Gelder, Hessel F. Groenveld, Harry J.G.M. Crijns, Ype S. Tuininga, Jan G.P. Tijssen, A. Marco Alings, Hans L. Hillege, Johanna A. Bergsma-Kadijk, Jan H. Cornel, Otto Kamp, Raymond Tukkie, Hans A. Bosker, Dirk J. Van Veldhuisen, Maarten P. Van den Berg
Journal: New England Journal of Medicine (2010)

Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation.We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years.The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups.In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)