tbuckley/cabot-search huggingface dataset:
Effect of chemotherapy and immunotherapy on tumor-specific immunity in melanoma.
Authors: M S Mitchell, M B Mokyr, J M Davis
Journal: Journal of Clinical Investigation (1977)

The effects of chemotherapy, with nitrosoureas or dimethyl-triazeno-imidazole-carboxamide (DTIC), or immunotherapy with Bacillus Calmette-Guérin (BCG), on cell-mediated immunity (CMI), and serum blocking factor (BF) to melanoma cells were studied in 23 patients. Studies were performed with autologous or allogenic melanoma target cells obtained from recent biopsy, in 16 mm diameter plastic wells. Assays for lymphocyte-mediated cytotoxicity and BF were performed at weekly intervals over the course of 3-4 mo, with some studies extending beyond 3 yr. The specificity of cytotoxicity was good with these methods. Nine patients given nitrosoureas, predominantly methyl-chloroethyl-cyclohexyl-nitrosourea, showed a transient decline in CMI from 42.2 to 14% 3 wk after administration of a single dose of the agent, with a rapid recovery within 1 week. 10 patients given 5-day courses of DTIC at 3-wk intervals showed no decline in CMI after two courses, and 7 of the 10 had no decline even after three courses. Three of the four patients who achieved a remission lost BF previously present: BF reappeared in both patients studied during a subsequent relapse. BCG intradermally or intralesionally elevated CMI within 2 mo after initiation of therapy, but despite continuation of the injections CMI returned to base line in all but two of the nine patients studied. These results indicate that chemotherapy for melanoma with nitrosoureas or DTIC at these schedules is not profoundly immunosuppressive towards tumor-specific immunity, as measured by our procedures. Putative immunotherapy with BCG at these schedules was likewise only transiently stimulatory.
Primary hepatic schwannoma mimicking malignancy on fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography
Authors: Young Chul Kim, Mi-Suk Park
Journal: Hepatology (2009)

A 52-year-old male presented to our hospital with a focal hepatic mass that was incidentally detected on the screening ultrasound and computed tomography (CT). The patient did not have a relevant medical history or any related complaints. All levels of serum tumor markers, including alfa-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 125, and carbohydrate antigen 19-9 were within normal limits. CT, computed tomography; FDG, 2-fluoro-2-deoxy-D-glucose; PET, positron emission tomography. Ultrasonography revealed a well-encapsulated, hypoechoic round lesion in the left lobe of the liver. On CT, a well-defined, hypoattenuating mass was indicated with enhancement of the capsule adjacent to the left portal vein (Fig. A). Positron emission tomography (PET) demonstrated increased 2-fluoro-2-deoxy-D-glucose (FDG) uptake in this lesion, suggesting a malignant tumor or inflammatory mass (Fig. B). The patient underwent lateral segmentectomy, and a cross-section of surgical specimen showed a well-demarcated, yellowish, solid round mass measuring 3 cm × 4.5 cm with minimal myxoid component and capsulation (Fig. C). A microscopic specimen obtained at the junction of the tumor and the liver (arrowhead), consisting of densely packed spindle cells (arrow) surrounded by a capsule, was compatible with the findings of schwannoma (Fig. D). An immunohistochemical study was performed on the mass. The tumor cells, which showed a whorl pattern, were positive for immunochemical staining with S-100 protein (Fig. E). However, the tumor cells were negative for smooth muscle actin, c-kit, and CD34. Hepatic schwannoma is a very rare benign mesenchymal tumor that originates from a variety of hepatic sympathetic and parasympathetic nerves distributed in the intralobular connective tissues along the portal veins.1, 2 The histologic hallmarks of a schwannoma are the presence of a true capsule and mixture of Antoni A (hypercellular area) and Antoni B (hypocellular area with a more myxoid matrix and water content) regions. This tumor usually presents as an encapsulated, homogeneous, hypo-enhancing mass located along the portal veins on CT scan. As the tumor becomes larger, however, it shows variable heterogeneity depending on secondary degeneration of cystic change, calcification, and hemorrhage formation. Visual qualitative assessment of FDG-PET images usually reveal high tumor-to-background ratios for schwannomas with high cellularity, which limits the utility of PET for distinguishing schwannomas from malignant tumors.3 Hepatic schwannomas should be differentiated from other primary mesenchymal tumors such as leiomyomas and gastrointestinal stromal tumors which are positive for muscle markers (actin/desmin) and c-kit, respectively, on immunohistochemical staining.
Natural resistance of lethally irradiated F1 hybrid mice to parental marrow grafts is a function of H-2/Hh-restricted effectors.
Authors: J P Daley, I Nakamura
Journal: The Journal of Experimental Medicine (1984)

The natural resistance of F1 hybrid mice against parental bone marrow grafts is thought to be mediated by natural killer (NK)-like effector cells. However, unlike the NK cell activity against a wide range of tumors and normal cells, hybrid resistance is characterized by the immunogenetic specificity controlled by a set of unique noncodominant genes denoted as Hh. Two alternative hypotheses can account for the specificity. Thus, the specificity may reflect either the Hh restriction of effectors or the Hh gene control of mechanisms regulating non-Hh-restricted effector activity. In this study, therefore, we tested the recognition specificity of putative effectors mediating hybrid resistance in lethally irradiated H-2b/d and H-2b/k F1 hybrid mice to the engraftment of parental H-2b bone marrow. As a direct means of defining the effector specificity, rejection of parental bone marrow grafts was subjected to competitive inhibition in situ by irradiated tumor cells. Of the 16 independent lines of lymphoma and other hemopoietic tumor cells tested, the ability to inhibit hybrid resistance was the exclusive property of all tumors derived from mice homozygous for the H-2Db region, regardless of whether the tumor cells were susceptible or resistant to NK cell-mediated cytotoxicity in vitro. Four cell lines heterozygous for the H-2Db were noninhibitory, including one that is susceptible to natural killing. Pretreatment of the F1 hosts with an interferon inducer augmented the resistance with no alteration in the recognition specificity of effector cells. Therefore, natural resistance to parental H-2b bone marrow grafts was mediated by effectors restricted by the H-2Db/Hh-1b gene(s), and not by the nonrestricted NK cells detectable in conventional in vitro assays.
Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Organic Nitrates in Patients With Chronic Heart Failure Treated With Angiotensin-Converting Enzyme Inhibition
Authors: Uri Elkayam, Janet V. Johnson, Avraham Shotan, Syed Bokhari, Alejandro Solodky, Menahem Canetti, Omar Rashid Wani, Ilyas Somer Karaalp
Journal: Circulation (1999)

Organic nitrates are widely used in the treatment of chronic heart failure (CHF). No information, however, is available regarding their effect in patients already treated with ACE inhibitors.In a randomized, double-blind, crossover design, we studied the effects of high-dose (50 to 100 mg) transdermal nitroglycerin (NTG) and placebo given daily for 12 hours in 29 patients with CHF (NYHA functional classes II to III). Exercise time (4 hours after patch application) showed a progressive improvement during NTG administration, with an increase of 38+/-35 seconds (9+/-7%) at the end of the first month (P=NS), 76+/-28 seconds (16+/-6%) at the end of the second month (P=0.01), and 117+/-34 seconds (27+/-6%) at the end of the third month (P=0.003). No significant change was seen during placebo administration (12+/-20, 5+/-26, and 19+/-28 seconds, all P=NS). Exercise time 8 hours after NTG application measured at 3 months was also significantly longer, with a difference of 87+/-28 seconds (P=0.006), but not with placebo (23+/-36 seconds, P=0.53). Assessment of quality of life and need for additional diuretics or hospitalizations for CHF failed to demonstrate a significant difference between the 2 treatment periods. In contrast, NTG decreased left ventricular end-diastolic (-2.1+/-0.1%, P<0.05) and end-systolic (-3.2+/-1.3%, P<0.05) dimensions and augmented LV fractional shortening (24.7+/-10.5%, P<0.03). The effect of placebo on these parameters was not statistically significant.High-dose nitrate therapy significantly improves exercise tolerance and left ventricular size and systolic function in patients with chronic, mild to moderate CHF already treated with ACE inhibitors. These findings support the role of organic nitrates as an adjunctive therapy to ACE inhibitors in patients with chronic CHF.
Renal insufficiency and its relation to ischemic and bleeding outcomes with tirofiban versus abciximab in the TARGET trial
Authors: Peter B. Berger, David J. Moliterno, Jennifer White, Patricia J. Best, Albert W. Chan, Steen D. Kristensen, David R. Holmes, Peter M. DiBattiste, Howard C. Herrmann, Eric J. Topol
Journal: Journal of the American College of Cardiology (2002)
Protein Tyrosine Phosphatases: Structure and Function, Substrate Specificity, and Inhibitor Development
Authors: Zhong-Yin Zhang
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Protein tyrosine phosphatases (PTPs) are signaling enzymes that control a diverse array of cellular processes. Malfunction of PTP activity is associated with a number of human disorders. Recent genetic and biochemical studies indicate that PTPs represent a novel platform for drug discovery. Detailed knowledge of PTP substrate specificity and the wealth of structural data on PTPs provide a solid foundation for rational PTP inhibitor design. This review summarizes a correlation of PTP structure and function from mutagenesis experiments. The molecular basis for PTP1B and MKP3 substrate recognition is discussed. A powerful strategy is presented for creating specific and high-affinity bidentate PTP inhibitors that simultaneously bind both the active site and a unique adjacent site. Finally, recent advances in the development of potent and selective inhibitors for PTP1B and Cdc25 are described.
Multimedia Teaching of Introductory Psychiatry
Authors: PAUL R. MILLER, JOE P. TUPIN
Journal: American Journal of Psychiatry (1972)

Preliminary experience and empirical measures suggest that second-year psychiatry can be taught effectively with a multimedia mix of videotaped interviews with patients, an inventory of critical symptoms, a diagnostic chart illustrating clustering of symptoms in the basic diagnosis, and rapid computer analysis and feedback. Traditional methods are also used conjointly. Multimedia teaching provides several channels of informational input and engages the student's interest and motivation by making him an active participant in the learning process.
Aplastic anemia and hepatitis C: Molecular biology exonerates another suspect
Authors: Jorge J. Gumucio, Dale Bachwich, Jules Dienstag
Journal: Hepatology (1993)

Objective. – To test the hypothesis that the rare, often fatal, syndrome of hepatitis-associated aplasia is associated with hepatitis C virus infection. Design. – Case series. Setting.-Tertiary referral centers in the United States, Japan, Italy, and Germany. Patients. – Twenty-eight patients with onset of aplastic anemia within 90 days after seeking medical attention for jaundice, or having serum transaminase levels 150% or more of normal (hepatitis-associated aplasia patients) and three patients who developed aplastic anemia following liver transplantation for non-A, non-B, hepatitis. Outcome Measures. - Presence of hepatitis C in serum, bone marrow, and liver samples, detected by the polymerase chain reaction; antibody testing; and percentage of activated peripheral cytotoxic T lymphocytes determined by immunophenotyping. Results. – Hepatitis ribonucleic acid was present in the serum samples of 10 (36%) patients with hepatitis-associated aplasia. However, hepatitic C virus viremia was associated with transfusions received after the onset of aplasia: seven (58%) of 12 patients with hepatitis-associated aplasia who had received 21 or more units of blood products at the time of serum sampling were viremic, compared with only three (19%) of 16 patients with hepatitis-associated aplasia who had received 20 or less units of blood products (P <.05). Hepatitis C virus was not found in blood and bone marrow samples of three National Institutes of Health case patients tested at the time of diagnosis. None of three livers from non-A, non-B hepatitis patients who developed aplastic anemia after liver transplantation contained hepatitis C virus ribonucleic acid. Activated CD8+ T lymphocytes were elevated three- to 20-fold early in the course of hepatitis-associated aplasia. Conclusions. – Our results implicate a novel, non-A, non-B, and non-C agent in both hepatitis-associated aplasia and fulminant hepatitis.
Haplotype Structure of the Stigmatic Self-Incompatibility Gene in Natural Populations of Arabidopsis lyrata
Authors: D. Charlesworth
Journal: Molecular Biology and Evolution (2003)

We describe analyses of almost full-length sequences (including both the kinase domain and the S-domain) of the putative SRK incompatibility gene of the self-incompatible plant Arabidopsis lyrata. In A. lyrata, the SRKS-domain controls the pistil recognition specificity, as in self-incompatible Brassica species. In alleles from plants derived from natural A. lyrata populations, nonsynonymous and synonymous site diversity values are very high in both domains; even in exons 3 to 7 of the kinase domain, which probably have no recognition functions, 39% of the amino acids are polymorphic. Within populations, diversity between alleles is high, as expected for an incompatibility locus, which should be under frequency-dependent selection within populations, whereas within the different putative allelic classes polymorphism is very low, as predicted from theoretical models when recombination is rare. Nonsynonymous site variability declines in the kinase domain with increasing distance from the S-domain border, although synonymous diversity remains high, and the introns are unalignable. A decline in nonsynonymous diversity is expected due to selective constraints in the kinase domain, in combination with recombination (allowing diversity to decrease at sites distant from those under balancing selection). However, it is unclear whether recombination occurs in the SRK locus, and interpretation of the observed diversity pattern is complicated by apparent gene conversion with a paralogous gene (or genes). Patterns of linkage disequilibrium in our SRK sequences do not support the conclusion that recombination occurs, which was suggested from previous analyses based on Brassica SLG sequences.
Comparison of radiotherapy alone and radiotherapy with chemotherapy using adriamycin and 5-fluorouracil in bronchogenic carcinoma.
Authors: G Anderson, T J Deeley, C Smith, J Jani
Journal: Thorax (1981)

Eighty-two patients with histologically confirmed lung cancer were randomly allocated to receive either radiotherapy alone (2400-3200 rads, depending upon cell type) or the same dose of radiotherapy followed by four cycles of adriamycin and 5-fluorouracil. Eighty-one patients were evaluated and for the group as a whole survival was better in the undifferentiated group assigned to receive adjuvant chemotherapy but survival in the patients with squamous tumours was not significantly prolonged. The chemotherapy was not unduly toxic.
Treatment with gallium nitrate: Evidence for interference with iron metabolism in vivo
Authors: Paul A. Seligman, Patrick L. Moran, Rhoda B. Schleicher, E. David Crawford
Journal: American Journal of Hematology (1992)

Abstract Gallium, when bound to transferrin, has been previously shown to cause tumor cell cytotoxicity by preventing cellular uptake of transferrin bound iron in vitro. Patients treated with constant infusion gallium nitrate for carcinoma show a rise in serum iron within 6 hr of the start of treatment. Serum iron returns to baseline by 24 hr post‐infusion. Atomic analysis of iron and gallium content of Sephadex G‐150 fractions of treatment sera indicate that about an equamolar amount of gallium and iron are associated with transferrin. These gallium and iron concentrations result in inhibition of transferrin mediated iron uptake in vitro, and in vivo allow for &gt;90% saturation of transferrin with metal. All seven patients who completed two courses of gallium therapy exhibited hypochromic microcytic anemia (mean fall in hemoglobin 3.5 grams %). Evidence for red cell iron depletion was confirmed by an increase (mean 3.3‐fold) in zinc protoporphyrin levels. Since transferrin receptor increases on gallium treated iron requiring cells in vitro, we assessed cell surface transferrin receptor on peripheral blood lymphocytes by measuring fluorescent transferrin receptor antibody binding. A population of highly transferrin receptor positive cells peaks at 48 hr into the infusion. DNA analysis as well as double staining indicate the majority of transferrin receptor positive cells are unstimulated B lymphocytes. These studies provide the first documentation that constant infusion gallium treatment results in significant interference with iron metabolism and evidence for tissue iron depletion in vivo. These changes may correlate with therapeutic effects of gallium such as tumor response. © 1992 Wiley‐Liss, Inc.
Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
Authors: Joseph A. Sparano, Stacy Moulder, Aslamuzzaman Kazi, Domenico Coppola, Abdissa Negassa, Linda Vahdat, Tianhong Li, Christine Pellegrino, Susan Fineberg, Pam Munster, Mokenge Malafa, David Lee, Shira Hoschander, Una Hopkins, Dawn Hershman, John J. Wright, Celina Kleer, Sofia Merajver, Said M. Sebti
Journal: Clinical Cancer Research (2009)

Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified.Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (alpha = 0.05, beta = 0.10).Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01).Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.
Role of RyR2 Phosphorylation in Heart Failure and Arrhythmias
Authors: Steven R. Houser
Journal: Circulation Research (2014)

This Controversies in Research article discusses the hypothesis that protein kinase A (PKA)-mediated phosphorylation of the Ryanodine Receptor (RyR) at a single serine (RyRS2808) is essential for normal sympathetic regulation of cardiac myocyte contractility and is responsible for the disturbed Ca 2+ regulation that underlies depressed contractility in heart failure. Studies supporting this hypothesis have associated hyperphosphorylation of RyRS2808 and heart failure progression in animals and humans and have shown that a phosphorylation defective RyR mutant mouse (RyRS2808A) does not respond normally to sympathetic agonists and does not exhibit heart failure symptoms after myocardial infarction. Studies to confirm and extend these ideas have failed to support the original data. Experiments from many different laboratories have convincingly shown that PKA-mediated RyRS2808 phosphorylation does not play any significant role in the normal sympathetic regulation of sarcoplasmic reticulum Ca2+ release or cardiac contractility. Hearts and myocytes from RyRS2808A mice have been shown to respond normally to sympathetic agonists, and to increase Ca 2+ influx, Ca 2+ transients, and Ca 2+ efflux. Although the RyR is involved in heart failure–related Ca 2+ disturbances, this results from Ca 2+ -calmodulin kinase II and reactive oxygen species–mediated regulation rather than by RyR2808 phosphorylation. Also, a new study has shown that RyRS2808A mice are not protected from myocardial infarction. Collectively, there is now a clear consensus in the published literature showing that dysregulated RyRs contribute to the altered Ca 2+ regulatory phenotype of the failing heart, but PKA-mediated phosphorylation of RyRS2808 has little or no role in these alterations.
Implication of <i>IL-2/IL-21</i> region in systemic sclerosis genetic susceptibility
Authors: Lina-Marcela Diaz-Gallo, Carmen P Simeon, Jasper C Broen, Norberto Ortego-Centeno, Lorenzo Beretta, Madelon C Vonk, Patricia E Carreira, Sofia Vargas, José Andrés Román-Ivorra, Miguel A González-Gay, Carlos Tolosa, Francisco Javier López-Longo, Gerard Espinosa, Esther F Vicente, Roger Hesselstrand, Gabriela Riemekasten, Torsten Witte, Jörg H W Distler, Alexandre E Voskuyl, Annemie J Schuerwegh, Paul G Shiels, Annika Nordin, Leonid Padyukov, Anna-Maria Hoffmann-Vold, Raffaella Scorza, Claudio Lunardi, Paolo Airo, Jacob M van Laar, Nicolas Hunzelmann, Birgit S Gathof, Alexander Kreuter, Ariane Herrick, Jane Worthington, Christopher P Denton, Xiaodong Zhou, Frank C Arnett, Carmen Fonseca, Bobby PC Koeleman, Shervin Assasi, Timothy R D J Radstake, Maureen D Mayes, Javier Martín
Journal: Annals of the Rheumatic Diseases (2012)

Objective The interleukin 2 ( IL-2 ) and interleukin 21 ( IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (p c =6.6E-4 and p c =7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (p c =1.7E-03 and p c =8E-4, respectively). Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.