tbuckley/cabot-search huggingface dataset:
Effect of Long-Acting Somatostatin Analog (Somatulin) on Renal Hyperfiltration in Patients With IDDM
Authors: Marloes L Jacobs, Frans H M Derkx, Theo Stijnen, Steven W J Lamberts, Rob F A Weber
Journal: Diabetes Care (1997)

OBJECTIVE To investigate whether long-acting somatostatin (SMS) can suppress renal hyperfiltration in patients with IDDM. RESEARCH DESIGN AND METHODS A double-blind, randomized treatment of nine patients with IDDM was used. Selection criteria were renal hyperfiltration (glomerular filtration rate [GFR] ≥ 129 ml · min−1 · 1.73 m2) and absence of hypertension and macroalbuminuria. Treatment was either with a long-acting SMS analog (Somatulin, 30 mg) or with placebo, given by intramuscular injections every 10 days for 9 months. GFR, effective renal plasma flow (ERPF), IGF-I, and 24-h growth hormone (GH) profiles were used as evaluation parameters. RESULTS Five patients were randomized to Somatulin, four patients to placebo. One of the patients treated with Somatulin stopped after 3 months because of persistent abdominal discomfort after the injections. Somatulin treatment for 3 months lowered GFR and ERPF compared with placebo (P &amp;lt; 0.05). After 9 months, the differences were no longer significant. After 3 months, IGF-I concentrations were decreased in all Somatulin-treated patients. GH secretion tended to increase in the placebo group. CONCLUSIONS The administration of long-acting Somatulin to patients with IDDM and renal hyperfiltration leads to only a temporary reduction of ERPF/GFR.
Cardiovascular complications of cirrhosis
Authors: S Moller, J H Henriksen
Journal: Gut (2008)

Cardiovascular complications of cirrhosis include cardiac dysfunction and abnormalities in the central, splanchnic and peripheral circulation, and haemodynamic changes caused by humoral and nervous dysregulation. Cirrhotic cardiomyopathy implies systolic and diastolic dysfunction and electrophysiological abnormalities, an entity that is different from alcoholic heart muscle disease. Being clinically latent, cirrhotic cardiomyopathy can be unmasked by physical or pharmacological strain. Consequently, caution should be exercised in the case of stressful procedures, such as large volume paracentesis without adequate plasma volume expansion, transjugular intrahepatic portosystemic shunt (TIPS) insertion, peritoneovenous shunting and surgery. Cardiac failure is an important cause of mortality after liver transplantation, but improved liver function has also been shown to reverse the cardiac abnormalities. No specific treatment can be recommended, and cardiac failure should be treated as in non-cirrhotic patients with sodium restriction, diuretics, and oxygen therapy when necessary. Special care should be taken with the use of ACE inhibitors and angiotensin antagonists in these patients. The clinical significance of cardiovascular complications and cirrhotic cardiomyopathy is an important topic for future research, and the initiation of new randomised studies of potential treatments for these complications is needed.
TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Authors: Takaomi Sanda, Jeffrey W. Tyner, Alejandro Gutierrez, Vu N. Ngo, Jason Glover, Bill H. Chang, Arla Yost, Wenxue Ma, Angela G. Fleischman, Wenjun Zhou, Yandan Yang, Maria Kleppe, Yebin Ahn, Jessica Tatarek, Michelle A. Kelliher, Donna S. Neuberg, Ross L. Levine, Richard Moriggl, Mathias Müller, Nathanael S. Gray, Catriona H.M. Jamieson, Andrew P. Weng, Louis M. Staudt, Brian J. Druker, A. Thomas Look
Journal: Cancer Discovery (2013)

Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway.In recent years, "pathway dependence" has been revealed in specific types of human cancer, which can be important because they pinpoint proteins that are particularly vulnerable to antitumor-targeted inhibition (so-called Achilles’ heel proteins). Here, we use RNAi technology to identify a novel oncogenic pathway that involves aberrant activation of the TYK2 tyrosine kinase and its downstream substrate, STAT1, which ultimately promotes T-ALL cell survival through the upregulation of BCL2 expression
Pancreas Cancer and Smoking, Beverage Consumption, and Past Medical History&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: T M Mack, M C Yu, R Hanisch, B E Henderson
Journal: JNCI Journal of the National Cancer Institute (1986)

Four hundred and ninety pancreas cancer patients representative of confirmed cases in Los Angeles County residents of working age were compared to healthy controls individually matched by age, sex, race, and neighborhood. Home interviews were conducted on occupation, smoking, food and beverage consumption, and medical history. Cigarette smoking was a strong and consistent predictor of pancreas cancer occurrence; the effect disappeared after a decade of nonsmoking, and there was no increase in risk among current smokers as daily dose increased. There was no link between pancreas cancer and past consumption of tea, carbonated beverages, beer, or spirits; and an association with coffee consumption was inconsistent. A strong association between pancreas cancer and history of subtotal gastrectomy at any past time could not be explained by chance or any other factor. Pancreas cancer patients had experienced fewer allergies of any kind.
Autoimmune Diseases and Severe Infections as Risk Factors for Schizophrenia: A 30-Year Population-Based Register Study
Authors: Michael E. Benros, Philip R. Nielsen, Merete Nordentoft, William W. Eaton, Susanne O. Dalton, Preben B. Mortensen
Journal: American Journal of Psychiatry (2011)

Objective: Autoimmune diseases have been associated with an increased risk of schizophrenia. It has been suggested that brain-reactive autoantibodies are part of the mechanisms behind this association. Furthermore, an increased permeability of the blood-brain barrier has been observed during periods of infection and inflammation. The authors therefore investigated whether autoimmune diseases combined with exposures to severe infections may increase the risk of schizophrenia Method: Nationwide population-based registers in Denmark were linked, and the data were analyzed in a cohort study using survival analysis. All analyses were adjusted for calendar year, age, and sex. Incidence rate ratios and accompanying 95% confidence intervals (CIs) as measures of relative risk were used. Results: A prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29; 95% CI=1.18–1.41). Any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60; 95% CI=1.56–1.64). When the two risk factors were combined, the risk of schizophrenia was increased even further (incidence rate ratio=2.25; 95% CI=2.04–2.46). The risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91–3.94). The results remained significant after adjusting for substance use disorders and family history of psychiatric disorders. Hospital contact with infection occurred in nearly 24% of individuals prior to a schizophrenia diagnosis. Conclusions: Autoimmune disease and the number of infections requiring hospitalization are risk factors for schizophrenia. The increased risk is compatible with an immunological hypothesis in subgroups of schizophrenia patients.
Phenotypic and Functional Changes in Regenerated Porcine Coronary Endothelial Cells
Authors: Marie-Pierre Fournet-Bourguignon, Maria Castedo-Delrieu, Jean-Pierre Bidouard, Stephane Leonce, Delphine Saboureau, Isabelle Delescluse, Jean-Paul Vilaine, Paul M. Vanhoutte
Journal: Circulation Research (2000)

Abstract —Porcine coronary arteries with regenerated endothelium exhibit impaired endothelium-dependent relaxations. Experiments were designed to analyze the structural and functional changes occurring in regenerated endothelial cells. Primary cultures from regenerated endothelium contained giant endothelial cells, with an increased number of cells with diameter &gt;14.5 μm, a reduced ability to proliferate, and signs of apoptosis. The uptake of fluorescent acetylated LDL was increased 2-fold in cultures from regenerated endothelium. The increased uptake of acetylated LDL was confirmed ex vivo in injured coronary arteries. In cultures from regenerated endothelium, cGMP production was decreased under basal conditions and during stimulation with serotonin, bradykinin, and A23187. Thus, during regeneration, there is accelerated senescence of endothelial cells accompanied by increased incorporation of modified LDL and reduction of NO production without decrease in endothelial NO synthase expression. These alterations help to explain the altered endothelium-dependent responses 28 days after balloon injury.
Simultaneous colonisation of Helicobacter pylori with and without mutations in the 23S rRNA gene in patients with no history of clarithromycin exposure
Authors: M Matsuoka, Y Yoshida, K Hayakawa, S Fukuchi, K Sugano
Journal: Gut (1999)

It was recently reported that A to G transition mutations at positions 2143 and 2144 in the 23S rRNA gene are associated with clarithromycin resistance in Helicobacter pylori.To study the incidence and mechanism of development of clarithromycin resistance by analysing these mutations.Eighty two H pylori positive patients who had an endoscopic examination and no history of treatment with macrolide antibiotics.Clarithromycin resistance was screened for by polymerase chain reaction-restriction fragment length polymorphism of the 23S rRNA gene coupled with antibiotic susceptibility testing. In clinical isolates with mutations or resistance, mutations in individual colonies were analysed by direct sequencing.Of the 79 amplicons (DNA fragments amplified by polymerase chain reaction), Alw26I and MboII digestion disclosed the mutation in four (5%) and one (1%) respectively. However, the Alw26I cleavage was incomplete in two of the four amplicons, as was the MboII cleavage. Individual colony analysis of the isolates with incomplete cleavage patterns showed the presence of both wild type and mutated strains in the 23S rRNA genes.Both clarithromycin sensitive and resistant strains colonised in some patients with no history of exposure to macrolides. The results suggest that resistant strains may not be formed but selected by clarithromycin administration.
A potential role for insulin resistance in experimental pulmonary hypertension
Authors: James West, Kevin D. Niswender, Jennifer A. Johnson, Meredith E. Pugh, Linda Gleaves, Joshua P. Fessel, Anna R. Hemnes
Journal: European Respiratory Journal (2012)

Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2 R899X was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2 R899X mice treated with dexamethasone. Compared to controls, Bmpr2 R899X mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0±0.4 versus 2.2±1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2 R899X mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
Differential Impact of Combination Antiretroviral Therapy in Preventing Kaposi's Sarcoma With and Without Visceral Involvement
Authors: Sophie Grabar, Bruno Abraham, Aba Mahamat, Pascal Del Giudice, Eric Rosenthal, Dominique Costagliola
Journal: Journal of Clinical Oncology (2006)

To study the impact of different potent combined antiretroviral treatment (cART) on the incidence of HIV-associated Kaposi's sarcoma (KS) with and without visceral involvement.Patients were selected from the French Hospital Database on HIV, a large hospital cohort. The risk of KS was estimated by using Cox proportional hazards models adjusting for age, the CD4 cell nadir, the HIV exposure category, prior AIDS, cART, and the type of cART regimen. cART regimens were distinguished according to whether they contained protease inhibitor (PI), non-nucleoside analog (NNRTI), both, or only nucleoside analog (NRTI). Separate analyzes were conducted according to the initial visceral involvement of KS.Among the 54,999 patients included in this study (182,756 person-years of follow-up), 1,634 patients were diagnosed with KS during follow-up, of whom 421 had visceral involvement at diagnosis. The KS incidence rate fell from 32 per 1,000 person-years in 1993 to 1994 to 3 per 1,000 person-years after 1999. PI-containing and NNRTI-containing cART regimens were associated with similar reductions in the risk of KS (hazard ratio, 0.68; 95%CI, 0.61 to 0.75; HR, 0.62; 95% CI, 0.54 to 0.71, respectively). The risk of visceral KS fell more strongly than the risk of cutaneous KS (> 50% and < 30%, respectively).The incidence of KS, and especially visceral KS, has fallen sharply since the advent of cART. This effect is likely due to immune restoration rather than to a specific effect on the tumoral process, as PI-containing and NNRTI-containing regimens had similar preventive efficacy.
Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)
Authors: R Loch Macdonald, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Andreas Raabe, Peter Vajkoczy, Isabel Wanke, Doris Bach, Aline Frey, Angelina Marr, Sébastien Roux, Neal Kassell
Journal: The Lancet Neurology (2011)
Glinski and the Aetiology of Simmonds's Disease
Authors: J. D. Robertson
Journal: BMJ (1951)

The dentate hilus has been extensively studied in relation to its potential role in memory and in temporal lobe epilepsy. Little is known, however, about the synapses formed between the two major cell types in this region, glutamatergic mossy cells and hilar interneurons, or the organization of local circuits involving these cells. Using triple and quadruple simultaneous intracellular recordings in rat hippocampal slices, we find that mossy cells evoke EPSPs with high failure rates onto hilar neurons. Mossy cells show profound synapse specificity; 87.5% of their intralamellar connections are onto hilar interneurons. Hilar interneurons also show synapse specificity and preferentially inhibit mossy cells; 81% of inhibitory hilar synapses are onto mossy cells. Hilar IPSPs have low failure rates, are blocked by the GABA<sub>A</sub> receptor antagonist gabazine, and exhibit short-term depression when tested at 17 Hz. Surprisingly, more than half (57%) of the mossy cell synapses we found onto interneurons were part of reciprocal excitatory/inhibitory local circuit motifs. Neither the high degree of target cell specificity, nor the significant enrichment of structured polysynaptic local circuit motifs, could be explained by nonrandom sampling or somatic proximity. Intralamellar hilar synapses appear to function primarily by integrating synchronous inputs and presynaptic burst discharges, allowing hilar cells to respond over a large dynamic range of input strengths. The reciprocal mossy cell/interneuron local circuit motifs we find enriched in the hilus may generate sparse neural representations involved in hippocampal memory operations.
Preliminary results from a phase I/II study of the combination of lenalidomide and DTIC in patients with metastatic malignant melanoma previously untreated with systemic chemotherapy
Authors: A. Y. Bedikian, K. Kim, N. Papadopoulos, W. Hwu, A. Ervin-Haynes, D. Pietronigro, J. Zeldis, P. Hwu
Journal: Journal of Clinical Oncology (2007)

8533 Background: In metastatic melanoma (MM) no single agent has shown objective response greater than 21%, and none have made an impact on overall survival. DTIC is approved for MM with response rates of 7% to 21%. Lenalidomide, an immunomodulatory drug of the IMiDs class, was reported to enhance immune responses in MM patients. This study was designed to assess the safety and activity of lenalidomide in combination with DTIC in patients with metastatic melanoma (MM). Methods: Twenty-eight chemotherapy naive patients with unresectable stage III and IV MM enrolled in the study. All patients received 25 mg lenalidomide orally once daily on days 1–14 every 21 days and continued therapy as tolerated or until disease progression. DTIC was given IV over 1 hour on day 1 every 21 days. There were three dose levels for DTIC: 600 mg/m 2 , 800 mg/m 2 and 1,000 mg/m 2 . Each dose level had 3–6 patients enrolled. Thirteen additional patients were to be enrolled at the MTD. Response and progression were evaluated using the RECIST criteria every 6 weeks. Results: As of December 21, 2006 twenty-six patients were evaluable for response. Median age was 65 (46–83) and 13 were female. Median ECOG was 1. Two patients (8%) exhibited an objective response (2 partial responses (PR)), 10 had stable disease (SD) for a tumor control rate (TCR) of 46 % and 14 progressive disease (PD). Thirteen patients have been enrolled at the MTD of 25 mg lenalidomide + 800 mg/m 2 DTIC and most are still receiving therapy. Grade 3 or 4 adverse events occurred in 12 (43%) of the 28 patients receiving drug. Grade 3 events included: transient elevation of transaminases, increased temperature, headache, dizziness, low hemoglobin, and leg edema. Four patients (14%) experienced a Grade 4 adverse reaction (pulmonary emboli, low hemoglobin, cerebral hemorrhage, and cerebral ischemia). The most common Grade 1/2 adverse events included: fatigue, nausea, pruritis, muscle cramps, taste alteration, skin rash, and constipation. Conclusions: The MTD has been established at 25 mg lenalidomide + 800 mg/m 2 DTIC. Preliminary results indicate that lenalidomide in combination with DTIC has manageable side effects in patients with MM. Evaluation of efficacy is ongoing. No significant financial relationships to disclose.
Reply to R. Gertler et al
Authors: Kazuki Sudo, Elena Elimova, Heath D. Skinner, Wayne L. Hofstetter, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2014)

Clinical Oncology.The authors concluded that longer wait times from diagnosis to surgery have a negative impact on survival.However, in this study, almost 23% of the patients had histological types of endometrial cancer (clear-cell carcinoma, serous carcinoma, adenosquamous carcinoma, and sarcoma) that are known to behave differently than endometrial endometrioid carcinoma and also known to have a unfavorable prognosis.
Double-Blind, Placebo-Controlled Study of Quality of Life, Hematologic End Points, and Safety of Weekly Epoetin Alfa in Children With Cancer Receiving Myelosuppressive Chemotherapy
Authors: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Denise Williams, Wayne R. Rackoff
Journal: Journal of Clinical Oncology (2006)

Purpose To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer. Methods Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS). Results One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P ≥ .238; P ≥ .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups. Conclusion This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.