tbuckley/cabot-search huggingface dataset:
Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate
Authors: Deborah A Thomas, Stefan H Faderl, Jorge E Cortes, Susan O'Brien, Francis J. Giles, Steven M. Kornblau, Guillermo Garcia-Manero, Michael J. Keating, Michael Andreeff, Sima Jeha, Miloslav Beran, Srdan Verstovsek, Sherry Pierce, Laurie Letvak, August Salvado, Richard Champlin, Moshe Talpaz, Hagop Kantarjian
Journal: Blood (2003)
Phase I Trial of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Refractory, Locally Advanced or Metastatic Solid Tumors
Authors: Patricia M. LoRusso, Charles M. Rudin, Josina C. Reddy, Raoul Tibes, Glen J. Weiss, Mitesh J. Borad, Christine L. Hann, Julie R. Brahmer, Ilsung Chang, Walter C. Darbonne, Richard A. Graham, Kenn L. Zerivitz, Jennifer A. Low, Daniel D. Von Hoff
Journal: Clinical Cancer Research (2011)

The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed.Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed.Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin.GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted.
Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience
Authors: Phil A Hart, Mark D Topazian, Thomas E Witzig, Jonathan E Clain, Ferga C Gleeson, Robin R Klebig, Michael J Levy, Randall K Pearson, Bret T Petersen, Thomas C Smyrk, Aravind Sugumar, Naoki Takahashi, Santhi S Vege, Suresh T Chari
Journal: Gut (2012)

There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder.We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX).We obtained details of disease relapse and treatment in 116 type 1 AIP patients from clinic visits, medical records and telephone interviews. We compared relapse free survival in those treated with IMs versus those treated with steroids alone, assessed patients' response to RTX, and identified treatment-related complications.During a median follow-up of 47 months, 52/116 AIP patients experienced 76 relapse episodes. The first relapse was treated with another course of steroids in 24 patients, and with steroids plus IM in another 27 patients; subsequent relapse-free survival until a second relapse was similar in the two groups (p=0.23). 38 patients received an IM for >2 months; failure or intolerance of IM therapy occurred in 17 (45%). 12 patients with steroid or IM intolerance/resistance were treated with RTX, an antiCD20 antibody; 10 (83%) experienced complete remission and had no relapses while on maintenance therapy. Treatment-limiting side effects related to RTX were uncommon.In type 1 AIP relapses are common. Relapse-free survival is similar in those treated with steroids plus IM compared to those treated with steroids alone. Nearly half the patients on IMs will relapse during treatment. RTX is effective in the treatment of both IM resistant and steroid intolerant patients.
Contrasting patterns of streptococcal superantigen-induced T-cell proliferation in guttate vs. chronic plaque psoriasis
Authors: S.C. Davison, M.H. Allen, E. Mallon, J.N.W.N. Barker
Journal: British Journal of Dermatology (2001)

Background Streptococcal infection is strongly associated with guttate psoriasis (GP) and may also exacerbate chronic plaque psoriasis (CPP), possibly through the release of superantigenic toxins. Objectives To investigate superantigen‐induced generation of cutaneous lymphocyte associated antigen (CLA) ‐positive lymphocytes in GP compared with CPP. Methods Peripheral blood lymphocyte (PBL) expression of CLA and T‐cell receptor Vβ chain was assessed in patients with CPP and with active and resolved GP. Expression of superantigen‐reactive Vβ families was compared with in vitro superantigen‐induced peripheral blood mononuclear cell (PBMC) proliferation. Results Peripheral blood mononuclear cells from patients with active GP showed a twofold increased proliferation after stimulation with streptococcal pyogenic toxins A and streptococcal pyogenic toxins C compared with controls (P < 0·01), whereas the response to the staphylococcal toxins and mitogenic stimulation was the same in all groups. Peripheral blood lymphocytes (PBL) from patients with active GP showed increased use of the superantigen‐reactive families Vβ2 (P < 0·01) and Vβ17 (P < 0·05), which was not evident in the other patient groups or controls. This pattern of Vβ expression was only observed in CLA‐positive T cells. Furthermore, there was a positive correlation between Vβ2 expression and enhanced proliferation after stimulation with SPEA (r = 0·82, P < 0·01) and SPEC (r = 0·74, P < 0·05) in active GP. Conclusions This study supports the concept that streptococcal infection precipitates acute GP at least in part through superantigen driven generation of Vβ‐restricted CLA‐positive skin homing lymphocytes, whereas we could find no evidence for a similar mechanism occurring in the maintenance of stable CPP.
Evolutionary psychology, ecological rationality, and the unification of the behavioral sciences
Authors: John Tooby, Leda Cosmides
Journal: Behavioral and Brain Sciences (2007)

For two decades, the integrated causal model of evolutionary psychology (EP) has constituted an interdisciplinary nucleus around which a single unified theoretical and empirical behavioral science has been crystallizing – while progressively resolving problems (such as defective logical and statistical reasoning) that bedevil Gintis's beliefs, preferences, and constraints (BPC) framework. Although both frameworks are similar, EP is empirically better supported, theoretically richer, and offers deeper unification.
Absence of Mitochondrial Superoxide Dismutase Results in a Murine Hemolytic Anemia Responsive to Therapy with a Catalytic Antioxidant
Authors: Jeff S. Friedman, Vivienne I. Rebel, Ryan Derby, Kirsten Bell, Ting-Ting Huang, Frans A. Kuypers, Charles J. Epstein, Steven J. Burakoff
Journal: The Journal of Experimental Medicine (2001)

Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2−, and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2+/+, Sod2−/−, and Sod2+/− fetal liver recipients. However, animals receiving Sod2−/− cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress–induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.
Antiretroviral Treatment for Adult HIV Infection in 2002
Authors: Patrick G. Yeni, Scott M. Hammer, Charles C. J. Carpenter, David A. Cooper, Margaret A. Fischl, Jose M. Gatell, Brian G. Gazzard, Martin S. Hirsch, Donna M. Jacobsen, David A. Katzenstein, Julio S. G. Montaner, Douglas D. Richman, Michael S. Saag, Mauro Schechter, Robert T. Schooley, Melanie A. Thompson, Stefano Vella, Paul A. Volberding
Journal: JAMA (2002)

New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care.In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization.The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel.Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.
Do present damage and health perception in patients with systemic lupus erythematosus predict extent of future damage?: a prospective study
Authors: Thomas Stoll, Nurhan Sutcliffe, Richard Klaghofer, David A Isenberg
Journal: Annals of the Rheumatic Diseases (2000)

To study whether either initial damage, disease activity, disease duration, age, a drug score, or health status would predict an increase in damage in patients with systemic lupus erythematosus (SLE) within the next three years.A three year prospective longitudinal study of a cohort of 141 consecutive patients with SLE attending a specialist lupus outpatient clinic from their first assessment between July 1994 and February 1995. Disease activity was assessed using the BILAG system, health status by the Medical Outcome Survey Short Form 20 with an extra question about fatigue (SF-20+), and damage by the SLICC/ACR Damage Index (SDI). Damage was reassessed three years later. Statistical analysis was carried out using logistic regression analysis (logXact).133 female and 8 male patients with SLE (97 white subjects, 16 Afro-Caribbeans, 22 Asians, and 6 others) were included. Their mean (SD) age at inclusion was 41.1 (12.5) years and their disease duration 10.2 (6. 3) years. The mean measures at inclusion were: total BILAG 5.2 (range 0-17), total SDI 1.2 (0-7), drug score 1.2 (0-3); SF-20+: physical 58 (0-100), role 54 (0-100), social functioning 71 (0-100), mental health 64 (16-100), health perception 44 (0-100), pain 53 (0-100), fatigue 59 (0-100). Four patients were lost to follow up because they had moved. At three years in 33 patients the total SDI had increased to a mean of 1.5 (0-7) (n=130). Moreover, seven patients had the maximum damage as they had died during the follow up period. The only variables with an independent and significant contribution in predicting damage at three years were the total damage score (odds ratio (OR)=1.46; 95% CI 1.04 to 2.05), and health perception (OR=0.96; 95% CI 0.93 to 0.99) at inclusion.Of all the variables at inclusion only the total damage score and SF-20+: health perception, significantly predicted an increase in damage, for patients with SLE, three years later.
Surge in Newly Identified Diabetes Among Medicaid Patients in 2014 Within Medicaid Expansion States Under the Affordable Care Act
Authors: Harvey W. Kaufman, Zhen Chen, Vivian A. Fonseca, Michael J. McPhaul
Journal: Diabetes Care (2015)

Twenty-six states and the District of Columbia expanded Medicaid in January 2014 pursuant to the Affordable Care Act (ACA); 24 states did not. This created an opportunity to examine the impact of Medicaid expansion on the number of Medicaid patients with newly identified diabetes among enrollees (19-64 years of age) who had laboratory testing through Quest Diagnostics.Newly identified diabetes was defined as an ICD-9 diagnosis code of 250.x (diabetes) or hemoglobin A1c of >6.4% (46 mmol/mol) within the first 6 months of a calendar year and the absence of both in the preceding calendar year within our data repository.We identified 215,398 and 218,890 patients who met our definition of newly diagnosed diabetes within the first 6 months of 2013 (control period) and 2014 (study period), respectively (a 1.6% increase). We identified 26,237 Medicaid-enrolled patients with new diabetes in the control period vs. 29,673 in the study period: an increase of 13%. The number of Medicaid-enrolled patients with newly identified diabetes increased by 23% (14,625 vs. 18,020 patients) in the 26 states (and District of Columbia) that expanded Medicaid compared with an increase of 0.4% (11,612 vs. 11,653 patients) in the 24 states that did not expand Medicaid during this period. Similar differences were observed in younger and older adults and for both men and women.This study suggests that in the states that expanded Medicaid under the ACA, an increased number of Medicaid patients with diabetes are being diagnosed and treated earlier. This could be anticipated to lead to better long-term outcomes.
Postoperative Chemotherapy for N2 Non–Small-Cell Lung Cancer: Conclusions Are Not Black and White, but Gray
Authors: Nasser H. Hanna, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2006)

We agree with Dr Halm that an isolated measurement of CA19-9 concentration has limited value in the treatment decision of individual patients, and that there is a very broad range in the concentrations of this serum marker.It is because of the skewed distribution of the CA19-9 values that median, rather than mean, is routinely utilized in studies involving this marker.We in fact do state the range and quartiles of the values in the results section, and levels of nearly 19,000 were found in one of our patients.In addition to confirming previous studies that have correlated CA19-9 concentrations with tumor stage and survival, our study 1 shows by multivariate Cox model that a decrease in CA19-9 after resection, and an absolute value of less than 200 U/mL, are both independent prognostic factors predicting increased survival.The power of these two variables was as strong as T stage and absence of lymph node metastases.It is for this reason that we propose that postoperative CA19-9 values may be useful to stratify pancreatic cancer patients for adjuvant trials.
Pepsin secretion in man after Histalog stimulation
Authors: M. D. Turner, P. J. Mayer, L. L. Miller, H. L. Segal
Journal: Gut (1970)

Human gastric juice shows three separable pepsin fractions on chromatography on DEAE-cellulose. The response of these fractions to stimulation with beta-aminoethylpyrazole hydrochloride (Histalog) was studied. After a single intramuscular injection of Histalog (1.7 mg/kg body weight) there was an increase in the output of all three chromatographically distinguishable pepsin fractions. Little change was observed in the relative proportions of these three fractions and there was no evidence of selective stimulation of any individual fraction.
Comorbidities and Risk of Mortality in Patients with Chronic Obstructive Pulmonary Disease
Authors: Miguel Divo, Claudia Cote, Juan P. de Torres, Ciro Casanova, Jose M. Marin, Victor Pinto-Plata, Javier Zulueta, Carlos Cabrera, Jorge Zagaceta, Gary Hunninghake, Bartolome Celli
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk.To prospectively evaluate COPD comorbidities and mortality risk.We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a "comorbidome". A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index.Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08-1.18; P < 0.001) and non-COPD-related causes (HR, 1.18; 95% confidence interval, 1.15-1.21; P < 0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26-2.68; P < 0.001) in all BODE quartile.Comorbidities are frequent in COPD and 12 of them negatively influence survival. A simple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD.
Glycogen synthase kinase 3β inhibition enhances repair of DNA double-strand breaks in irradiated hippocampal neurons
Authors: Eddy S. Yang, Somaira Nowsheen, Tong Wang, Dinesh K. Thotala, Fen Xia
Journal: Neuro-Oncology (2011)

Prevention of cranial radiation-induced morbidity following the treatment of primary and metastatic brain cancers, including long-term neurocognitive deficiencies, remains challenging. Previously, we have shown that inhibition of glycogen synthase kinase 3β (GSK3β) results in protection of hippocampal neurons from radiation (IR)–induced apoptosis and attenuation of neurocognitive dysfunction resulting from cranial IR. In this study, we examined whether regulation of the repair of IR-induced DNA damage is one of the mechanisms involved in the radioprotective effects of neurons by inhibition of GSK3β. Specifically, this study showed that inhibition of GSK3β accelerated double strand-break (DSB) repair efficiency in irradiated mouse hippocampal neurons, as assessed by the neutral comet assay. This coincided with attenuation of IR-induced γ-H2AX foci, a well characterized in situ marker of DSBs. To confirm the effect of GSK3 activity on the efficacy of DSB repair, we further demonstrated that biochemical or genetic inhibition of GSK3 activity resulted in enhanced capacity in nonhomologous end-joining–mediated repair of DSBs in hippocampal neurons. Importantly, none of these effects were observed in malignant glioma cells. Taken together, these results suggested that enhanced repair of IR-induced DNA damage may be a novel mechanism by which inhibition of GSK3β specifically protects hippocampal neurons from IR-induced apoptosis. Furthermore, these findings warrant future investigations of the molecular mechanisms underlying the role of GSK3β in the DSB repair of normal neurons and the potential clinical application of neuroprotection with GSK3β inhibitors during cranial IR.
Age and Fecundity
Authors: H. Campbell
Journal: BMJ (1956)

The present study examined the effects of a centrally acting 5-HT1A receptor agonist flesinoxan on the renal sympathetic nerve control of the kidney while left renal perfusion pressure (RPP) was controlled at 80 mm Hg. In groups of chloralose/urethane-anesthetized Wistar rats, reduction in left kidney RPP significantly decreased the glomerular filtration rate (GFR), with much larger decreases in urine flow (UV) and absolute (UNaV) and fractional (FENa) sodium excretions, but raised systemic pressure as well as right kidney GFR and water and sodium excretion. In intact time-control rats, there were no time-dependent changes in left or right kidney GFR, UV, UNaV or FENa. Administration of bolus doses of flesinoxan at 30, 100 and 300 micrograms/kg i.v. in intact rats caused significant, dose-dependent decreases in mean systemic arterial pressure (23%) and heart rate (10%) (both P &lt; .001). Although RPP was unchanged, there were significant increases in left kidney UV (118%), UNaV (385%) and FENa (277%) (all P &lt; .005). Despite the substantial decrease in RPP at the right kidney, excretion of water and sodium was well preserved. In bilaterally renal-denervated rats, flesinoxan produced similar changes in blood pressure and heart rate but did not increase left kidney UV or sodium excretion, and the reduction in pressure caused significant decreases in right kidney UV, UNaV and FENa. These findings are consistent with the hypothesis that flesinoxan causes suppression of renal sympathetic tone, which leads to increased sodium and water excretion.