tbuckley/cabot-search huggingface dataset:
Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion
Authors: Jinquan Cai, Zhixian Wu, Xiumin Xu, Lianming Liao, Jin Chen, Lianghu Huang, Weizhen Wu, Fang Luo, Chenguang Wu, Alberto Pugliese, Antonello Pileggi, Camillo Ricordi, Jianming Tan
Journal: Diabetes Care (2015)

OBJECTIVE To determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Between January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 × 106/kg UC-MSC, 106.8 × 106/kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUCC-Pep) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life. RESULTS The treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUCC-Pep increased 105.7% (6.6 ± 6.1 to 13.6 ± 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 ± 6.8 to 7.7 ± 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 ± 1,012.8 to 2,205.5 ± 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 ± 630.2 to 1,431.7 ± 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA1c decreased 12.6% (8.6 ± 0.81% [70.0 ± 7.1 mmol/mol] to 7.5 ± 1.0% [58.0 ± 8.6 mmol/mol], P &amp;lt; 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 ± 0.9% [72.0 ± 7.5 mmol/mol] to 8.8 ± 0.9% [73 ± 7.5 mmol/mol], P &amp;lt; 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 ± 51.1 to 151.2 ± 22.1 mg/dL, P &amp;lt; 0.002) and 4.3% in control subjects (192.4 ± 35.3 to 184.2 ± 34.3 mg/dL, P &amp;lt; 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 ± 0.2 to 0.6 ± 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 ± 0.2 to 0.9 ± 0.2 IU/day/kg, P &amp;lt; 0.01 vs. SCT). CONCLUSIONS Transplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D.
Lung cancer recruitment of CD14+ cells results in an immunosuppressive phenotype and improved tumor survival under stress conditions
Authors: Erin Schenk, Allan Dietz
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts We have previously shown that a higher burden of CD14+HLA-DRlo/neg cells in the peripheral blood of cancer patients is associated with systemic immune suppression and a poor outcome. We have also reported that CD14+ cells isolated from healthy donors are converted to the
Plasma Microrna Predicts B-Cell Lymphoma up to 12 Months before Diagnosis – Data from the Danish Blood Donor Study
Authors: Steffen Jørgensen, Dorte Tholstrup, Jakob Werner Hansen, Homburg Mikkelsen Keld, Henrik Hjalgrim, Peter de Nully Brown, Christian Erikstrup, Mikkel Steen Petersen, Kaspar Rene Nielsen, Erik Sørensen, Jesper Troelsen, Henrik Ullum, Kirsten Grønbæk, Ole Birger Pedersen
Journal: Blood (2014)
Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma
Authors: M. Lazzarino, E. Orlandi, M. Montillo, A. Tedeschi, G. Pagnucco, C. Astori, A. Corso, E. Brusamolino, L. Simoncini, E. Morra, C. Bernasconi
Journal: Annals of Oncology (1999)
Drug points: Nortriptyline intoxication induced by terbinafine
Authors: P-H M v. d. Kuy, P M Hooymans, A J B Verkaaik
Journal: BMJ (1998)

We present a case of nortriptyline intoxication secondary to terbinafine treatment.

A 74 year old man with depression was treated with nortriptyline for several months (other drug treatment was cisapride, hydrochlorothiazide, and ranitidine). Serum nortriptyline concentration was maintained at 200 ng/ml for more than 3 months as his depression had recurred when the dose was lowered.

He complained of increasing fatigue, vertigo, loss of energy, …
Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032
Authors: Matthew Taylor, Scott Antonia, Johanna Bendell, Emiliano Calvo, Dirk Jäger, Filippo de Braud, Patrick A Ott, M Catherine Pietanza, Leora Horn, Dung T Le, Michael A Morse, José A López-Martin, Paolo A Ascierto, Olaf Christensen, Jason S Simon, Chen-Sheng Lin, Joseph Paul Eder
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Treatment options for SCLC after failing platinum-based (PLT) chemotherapy (CT) are limited. Combined blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab
Leukotriene D 4 and prostaglandin E 2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3
Authors: Vinay Kondeti, Nosayba Al-Azzam, Ernest Duah, Charles K. Thodeti, Joshua A. Boyce, Sailaja Paruchuri
Journal: Journal of Allergy and Clinical Immunology (2015)
Imipramine and electrocardiographic abnormalities in hyperactive children
Authors: B G Winsberg, S Goldstein, L E Yepes, J M Perel
Journal: American Journal of Psychiatry (1975)

The authors report seven cases of electrocardiographic abnormalities occurring in 7- to 10-year-old children receiving imipramine pharmacotherapy for behavior disorders. Three of the children evidenced a first-degree atrioventricular block. The abnormalities were less pronounced in the other four children. Imipramine plasma levels during steady state were not found to be directly related to the extent of the electrocardiographic changes within the obtained plasma values. The authors emphasize the necessity of careful clinical surveillance of children receiving imipramine pharmacotherapy.
Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer
Authors: Laurie A. Davidson, Evelyn S. Callaway, Eunjoo Kim, Brad R. Weeks, Yang-Yi Fan, Clinton D. Allred, Robert S. Chapkin
Journal: Cancer Research (2015)

Abstract p53 has been shown to mediate cancer stem–like cell function by suppressing pluripotency and cellular dedifferentiation. However, there have been no studies to date that have addressed the specific effects of p53 loss in colonic adult stem cells. In this study, we investigated the consequences of conditionally ablating p53 in the highly relevant Lgr5+ stem cell population on tumor initiation and progression in the colon. In a mouse model of carcinogen (AOM)-induced colon cancer, tamoxifen-inducible Lgr5-driven deletion of p53 reduced apoptosis and increased proliferation of crypt stem cells, but had no effect on tumor incidence or size. Conversely, in a mouse model of colitis-associated cancer, in which mice are exposed to AOM and the potent inflammation inducer DSS, stem cell–specific p53 deletion greatly enhanced tumor size and incidence in the colon. These novel findings suggest that the loss of p53 function in stem cells enables colonic tumor formation only when combined with DNA damage and chronic inflammation. Furthermore, we propose that stem cell targeting approaches are valuable for interrogating prevention and therapeutic strategies that aim to specifically eradicate genetically compromised stem cells. Cancer Res; 75(24); 5392–7. ©2015 AACR.
Toward Precision Medicine in Pulmonary Arterial Hypertension
Authors: Eric D. Austin, James E. Loyd
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Pulmonary arterial hypertension (PAH) remains a progressive and fatal pulmonary vascular disease despite advances in care during the last two decades (1–3). Detrimental pulmonary vascular remodeling, in concert with persistent vasoconstriction and additional perivascular changes, occurs as a result of a variety of identified and unidentified local and systemic factors, including enhanced endothelin-1 expression and levels (4–6). Pharmacologic antagonism of the endothelin receptor (via endothelin receptor antagonists [ERAs]) has been an important cornerstone of the therapeutic options available to combat PAH, with improvements in survival, time to clinical worsening, hemodynamics, and functional performance (7). However, unexplained variability remains with regard to individual clinical response to ERAs and other PAH-specific therapies (8, 9). In this issue of the Journal, Benza and colleagues (pp. 1345–1354) advance our understanding of ERA response via the discovery that certain common genetic variations in the endothelin pathway may identify subgroups of patients more or less likely to favorably respond to ERAs (10). This approach may ultimately provide a step toward the application of pharmacogenetics to individualize each patient’s PAH treatment.
Survival, Response Duration, and Activity By Braf Mutation (Mt) Status in a Phase 1 Trial of Nivolumab (Anti-Pd-1, Bms-936558, Ono-4538) and Ipilimumab (Ipi) Concurrent Therapy in Advanced Melanoma (Mel)
Authors: H. Kluger, M. Sznol, M. Callahan, M. Postow, R. Gordon, N.H. Segal, N. Rizvi, A. Lesokhin, M.B. Atkins, J. Kirkwood, M. Burke, A. Ralabate, A. Rivera, S. Kronenberg, B.U. Agunwamba, W. Feely, Q. Hong, S. Krishnan, J. Wolchok
Journal: Annals of Oncology (2014)
A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)
Authors: Georgina V Long, Reinhard Dummer, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert HI Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J Olszanski, Thomas F Gajewski, John M Kirkwood, Olga Kuznetsova, Lisa Chen, David R Kaufman, Jeffrey Chou, F Stephen Hodi
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint
Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.
Authors: Y Wang, J Pouysségur, M J Dunn
Journal: Journal of the American Society of Nephrology (1994)

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.
Genomewide Association Studies and Assessment of the Risk of Disease
Authors: Teri A. Manolio
Journal: New England Journal of Medicine (2010)

Over the past 5 years, genomewide association studies have yielded a wealth of insight into genes and chromosomal loci that contribute to susceptibility to disease. This article, the second in the Genomic Medicine series, describes the design of these studies and considers the extent to which the data they provide are useful in predicting the risk of disease.
Characteristics of 36 subjects reporting compulsive sexual behavior
Authors: D W Black, L L Kehrberg, D L Flumerfelt, S S Schlosser
Journal: American Journal of Psychiatry (1997)

The authors describe the sociodemographic features, phenomenology, and psychiatric comorbidity of 36 subjects reporting compulsive sexual behavior.Twenty-eight men and eight women who responded to advertisements for "persons ... who have a problem with compulsive sexual behavior" completed structured and semistructured assessments, including the Diagnostic Interview Schedule for DSM-III-R disorders (axis I) and the Structured Interview for DSM-III-R Personality Disorders, Revised (axis II).The typical subject was a 27-year-old man who reported experiencing compulsive sexual behavior for nearly 9 years. Sexual behavior was described as excessive and poorly controlled and was associated with either subjective distress or impairment in interpersonal or occupational functioning or as overly time-consuming. Fourteen subjects (39%) reported a history of major depression or dysthymia, 15 (42%) a history of phobic disorder, and 23 (64%) a history of substance use disorder. Personality disorders were quite frequent, particularly the paranoid, histrionic, obsessive-compulsive, and passive-aggressive subtypes. The compulsive sexual behavior was quite varied and included both paraphilic (e.g., cross-dressing) and nonparaphilic (e.g., compulsive masturbation) types.Compulsive sexual behavior may be a clinically useful concept, but it describes a heterogeneous group of individuals with substantial psychiatric comorbidity and diverse behavioral problems.
Outdoor Air Pollution, Low Birth Weight, and Prematurity
Authors: Martin Bobak
Journal: Environmental Health Perspectives (2000)

This study tested the hypothesis, suggested by several recent reports, that air pollution may increase the risk of adverse birth outcomes. This study analyzed all singleton live births registered by the Czech national birth register in 1991 in 67 districts where at least one pollutant was monitored in 1990-1991 (n = 108,173). Maternal exposures to sulfur dioxide (SO(2)), total suspended particles (TSP), and nitrous oxides (NO(x)) in each trimester of pregnancy were estimated as the arithmetic means of all daily measurements taken by all monitors in the district of birth of each infant. Odds ratios of low birth weight (< 2,500 g), prematurity (< 37 weeks of gestation), and intrauterine growth retardation (IUGR; < 10th percentile of birth weight for gestational age and sex) were estimated by robust logistic regression. The median (and 25th and 75th percentile) trimester exposures were 32 (18, 56) microg/m(3) for SO(2); 72 (55, 87) microg/m(3) for TSP; and 38 (23, 59) microg/m(3) for NO(x). Low birth weight (prevalence 5.2%) and prematurity (prevalence 4.8%) were associated with SO(2) and somewhat less strongly with TSP. IUGR was not associated with any pollutant. The effects on low birth weight and prematurity were marginally stronger for exposures in the first trimester, and were not attenuated at all by adjustment for socioeconomic factors or the month of birth. Adjusted odds ratios of low birth weight were 1.20 [95% confidence interval (CI), 1.11-1.30] and 1.15 (CI, 1.07-1.24) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester; adjusted odds ratios of prematurity were 1.27 (CI, 1.16-1.39) and 1.18 (CI, 1.05-1.31) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester. Low gestational age accounted for the association between SO(2) and low birth weight. These findings provide further support for the hypothesis that air pollution can affect the outcome of pregnancy.
The FDA’s new clothes
Authors: Donald W Light, Joel Lexchin
Journal: BMJ (2015)

The FDA does not protect patients from harmful or ineffective drugs, but approves both

The Vioxx disaster in the early 2000s triggered a crisis of mistrust in the US Food and Drug Administration (FDA), as evidence emerged that it had downplayed or ignored evidence of serious cardiovascular harm associated with Vioxx (rofecoxib), a cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drug.

The result was a renewed emphasis on drug safety throughout a product’s lifecycle. At the same time, drug companies, which provide most of the funds for the FDA’s review of their drugs, kept pushing for faster approvals and new uses for old drugs, supposedly so that more patients could benefit. Any possible risks in getting new drugs to market more quickly would be offset by more intensive monitoring once they were being prescribed.

Two linked papers (doi:10.1136/bmj.h4633, 10.1136/bmj.h4679) provide valuable accounts of how the FDA is using faster reviews for what it deems to be important new drugs and using supplemental approvals for existing drugs more widely.1 2 This is just what patients and their doctors are said to want—more patients benefiting from taking more new drugs sooner, generating revenue for the companies to fund more breakthrough research.

Put in the context of the FDA’s larger record, however, these studies give cause for concern about whether most new drugs are any more effective …
Adverse effects of intraperitoneal fluorouracil in patients with optimal residual ovarian cancer after second-look laparotomy: a Gynecologic Oncology Group Study.
Authors: L A Walton, J A Blessing, H D Homesley
Journal: Journal of Clinical Oncology (1989)

Twenty-seven patients with ovarian cancer who had failed combination chemotherapy were offered intraperitoneal (IP) fluorouracil (5-FU) as salvage therapy in an attempt to ascertain the efficacy of such a therapeutic method. All patients had minimal residual epithelial cancer. The median number of treatment cycles was six. Major problems with dialysate inflow and egress occurred in ten patients and required discontinuation of therapy. An additional ten patients experienced hematologic toxicity with a median nadir WBC of 2,300/microL. Therapy was altered but not discontinued because of this complication. Other adverse sequelae, such as abdominal pain, were manageable with medication. IP 5-FU is technically feasible on a multiinstitutional basis in residual ovarian cancer, but its therapeutic role remains to be defined.
Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure
Authors: Marco V. Perez, Aleksandra Pavlovic, Ching Shang, Matthew T. Wheeler, Clint L. Miller, Jing Liu, Frederick E. Dewey, Stephen Pan, Porama K. Thanaporn, Devin Absher, Jeffrey Brandimarto, Heidi Salisbury, Khin Chan, Rupak Mukherjee, Roda P. Konadhode, Richard M. Myers, Daniel Sedehi, Thomas E. Scammell, Thomas Quertermous, Thomas Cappola, Euan A. Ashley
Journal: Journal of the American College of Cardiology (2015)
Pulmonary-Respiratory Medicine
Journal: JAMA (2001)

Data collection: Data were provided by review of patients’ charts, interview of family doctors, external hospitals and in single cases interview of family members. Patients who came for controlling of the stent were also interviewed. Methods: Bronchoscopic procedure was done under general anaesthesia, intubation with a rigid bronchoscope, dilation by balloon, rigid scope or combination. Stent placement was mostly done under fluoroscopy. Stent removal and/or replacement were also done with a rigid bronchoscope under general anaesthesia. Only the procedures for placement of a Montgomery t-tube were done under local anaesthesia. Results: During the observation period the longest survival time so far was 18 years. In 19 patients the stent led to a relief of symptoms, mainly dyspnoea and stridor and was tolerated without major complications (Successful stenting). In 12 patients the stent had to be removed because of complications and another four patients died of stenting related complications. In 16 patients therefore stenting was called “not successful”. Conclusions: In comparison to patients with advanced malignant diseases, where stenting is supposed only palliative, patients with tracheo-bronchial diseases are not limited in their life expectancy from the local tracheal disease, if this can be treated. But often these patients are high risk patients concerning co-morbidities, technical and functional operability. In these patients a stent can therefore be an alternative to surgery. Nevertheless because of the high rate of complications, which can be also life threatening, the decision must be done carefully. Purpose: Review of stenting in benign tracheal stenosis in the long run concerning indications, tolerance of stents,
A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
Authors: C Papayannidis, D J DeAngelo, W Stock, B Huang, M N Shaik, R Cesari, X Zheng, J M Reynolds, P A English, M Ozeck, J C Aster, F Kuo, D Huang, P D Lira, K R McLachlan, K A Kern, G Garcia-Manero, G Martinelli
Journal: Blood Cancer Journal (2015)

A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
Dietary Magnesium, Not Calcium, Regulates Renal Thiazide Receptor
Authors: DARRELL D. FANESTIL, RONALD H. HYDE, PATRICIA BLAKELY, DUKE A. VAUGHN
Journal: Journal of the American Society of Nephrology (1999)

Abstract. This study reports for the first time a relationship between dietary Mg and the renal thiazide-sensitive Na-Cl cotransporter (TZR, measured by saturation binding with 3 H-metolazone). Ion-selective electrodes measured plasma ionized magnesium (P Mg + +), calcium (P Ca + +), and potassium (P K +). Restricting dietary Mg for 1 wk decreased P Mg + + 18%, TZR 25%, and renal excretion of magnesium (U Mg ) and calcium (U Ca ) more than 50% without changing P Ca + +, P K +, or plasma aldosterone. A low Mg diet for 1 d significantly decreased P Mg + +, TZR, U Mg and U Ca . Return of dietary Mg after 5 d of Mg restriction restored P Mg + + and TZR toward normal. In the control, Mg-deficient, and Mg-repleting animals, TZR correlated with P Mg + + ( r = 0.86) and with U Mg ( r = 0.87) but not U Ca ( r = 0.09). Increasing oral intake of Mg for 1 wk increased P Mg + + 14%, TZR 32%, U Mg 74%, and U Ca more than fourfold without changing P Ca + + or P K +. In contrast, increasing dietary Ca content from 0.02% to 1.91% did not change TZR, but increased U Ca fivefold without changing P Ca + +. Hormonal mediators (if any) involved in the relationship between dietary Mg and TZR remain to be elucidated, as does the relationship between TZR and tubular reabsorption of Mg.