tbuckley/cabot-search huggingface dataset:
BRCA1 Activates a G2-M Cell Cycle Checkpoint following 6-Thioguanine–Induced DNA Mismatch Damage
Authors: Kazuhiko Yamane, Jane E. Schupp, Timothy J. Kinsella
Journal: Cancer Research (2007)

Abstract Human DNA mismatch repair (MMR) is involved in the response to certain chemotherapy drugs, including 6-thioguanine (6-TG). Consistently, MMR-deficient human tumor cells show resistance to 6-TG damage as manifested by a reduced G2-M arrest and decreased apoptosis. In this study, we investigate the role of the BRCA1 protein in modulating a 6-TG–induced MMR damage response, using an isogenic human breast cancer cell line model, including a BRCA1 mutated cell line (HCC1937) and its transfectant with a wild-type BRCA1 cDNA. The MMR proteins MSH2, MSH6, MLH1, and PMS2 are similarly detected in both cell lines. BRCA1-mutant cells are more resistant to 6-TG than BRCA1-positive cells in a clonogenic survival assay and show reduced apoptosis. Additionally, the mutated BRCA1 results in an almost complete loss of a G2-M cell cycle checkpoint response induced by 6-TG. Transfection of single specific small interfering RNAs (siRNA) against MSH2, MLH1, ATR, and Chk1 in BRCA1-positive cells markedly reduces the BRCA1-dependent G2-M checkpoint response. Interestingly, ATR and Chk1 siRNA transfection in BRCA1-positive cells shows similar levels of 6-TG cytotoxicity as the control transfectant, whereas MSH2 and MLH1 siRNA transfectants show 6-TG resistance as expected. DNA MMR processing, as measured by the number of 6-TG–induced DNA strand breaks using an alkaline comet assay (±z-VAD-fmk cotreatment) and by levels of iododeoxyuridine-DNA incorporation, is independent of BRCA1, suggesting the involvement of BRCA1 in the G2-M checkpoint response to 6-TG but not in the subsequent excision processing of 6-TG mispairs by MMR. [Cancer Res 2007;67(13):6286–92]
Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia
Authors: Priscila P Zenatti, Daniel Ribeiro, Wenqing Li, Linda Zuurbier, Milene C Silva, Maddalena Paganin, Julia Tritapoe, Julie A Hixon, André B Silveira, Bruno A Cardoso, Leonor M Sarmento, Nádia Correia, Maria L Toribio, Jörg Kobarg, Martin Horstmann, Rob Pieters, Silvia R Brandalise, Adolfo A Ferrando, Jules P Meijerink, Scott K Durum, J Andrés Yunes, João T Barata
Journal: Nature Genetics (2011)
Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder
Authors: Anne-France Dekairelle, Bertrand Tombal, Jean-Pierre Cosyns, Jean-Luc Gala
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To investigate the value of p53 functional analysis of separated alleles in yeast (FASAY) as a witness of p53/p21 pathway alteration and as a predictor of recurrence in superficial transitional cell carcinomas. Experimental Design: p53 transcriptional activity was prospectively analyzed in 52 newly diagnosed transitional cell carcinoma using FASAY competent for the transactivation of p21 and bax promoters. TP53 and p21 gene expression was quantified by real-time PCR, and expression of corresponding proteins was assessed by immunohistochemistry. In addition to tumor stage and grade, the predictive value of FASAY, real-time PCR, and immunohistochemistry for tumor recurrence was assessed by Cox survival analysis. Results: A total (p21 and bax) or partial (bax only) loss of transcriptional activity was observed in 15 of 52 (29%) and 4 of 52 (7.7%) cases, respectively, a partial loss being consistently associated with R283H mutation. p53 nuclear overexpression grossly overestimated (∼40%) or underestimated (∼10%) the true incidence of p53 transcriptional abnormalities, especially in Ta-T1 grade 1 to 2 tumors. Loss of p21 transactivation significantly correlated with decreased p21 gene expression and lack of expression of p21 (P = 0.001). FASAY had a better predictive value for recurrence than p53 immunohistochemistry (Cox hazard ratio, 6.57 versus 3.95; P = 0.0002 versus 0.019, respectively), whereas neither p21 immunohistochemistry (hazard ratio, 1.9; P = 0.29) nor TP53 or p21 gene expression were significant predictors of recurrence. The prognostic difference between FASAY and p53 immunohistochemistry was maintained in the subgroup of Ta-T1 grade 3 tumors. Conclusions: FASAY is a valuable surrogate marker for assessing p53/p21 pathway alteration and predicts transitional cell carcinoma recurrence better than p53 immunohistochemistry.
A case of candidal umbilical granuloma
Authors: A. ANSTEY, G.P. SPICKETT, N. BEECHEY-NEWMAN, L. GOWERS, H. MOLLOY
Journal: British Journal of Dermatology (1991)

A case is reported of a 14-year-old boy with a mass arising from the umbilicus, which was a large, well-organized candidal granuloma. Cell markers showed normal numbers and distribution of peripheral T and B lymphocytes but there was no reaction to intradermal injection of Candida, suggesting a specific T-cell defect such as occurs in chronic mucocutaneous candidiasis.
Plasma hepcidin of Ethiopian highlanders with steady-state hypoxia
Authors: Erika L. Lundgrin, Allison J. Janocha, Carl D. Koch, Amha Gebremedhin, Anna Di Rienzo, Gorka Alkorta-Aranburu, Gary M. Brittenham, Serpil C. Erzurum, Cynthia M. Beall
Journal: Blood (2013)
Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death
Authors: Imran N. Mungrue, Robert Gros, Xiaomang You, Asif Pirani, Azar Azad, Tamas Csont, Richard Schulz, Jagdish Butany, Duncan J. Stewart, Mansoor Husain
Journal: Journal of Clinical Investigation (2002)

Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.
Neutrophil survival is prolonged in the airways of healthy infants and infants with RSV bronchiolitis
Authors: A. Jones, J.M. Qui, E. Bataki, H. Elphick, S. Ritson, G.S. Evans, M.L. Everard
Journal: European Respiratory Journal (2002)

Large numbers of neutrophils in the airway of infants infected by respiratory syncytial virus (RSV) are recruited by chemokines, such as interleukin-8, and specific inflammatory molecules can delay apoptosis increasing their longevity. The aim of this study was to investigate whether airway secretions in RSV bronchiolitis contain factors that influence neutrophil apoptosis. Nasal lavage fluid (NLF) was obtained from 24 infants with RSV bronchiolitis (31 infant controls and 12 adults). Neutrophils isolated from healthy adult volunteers were incubated with the NLF in Dulbecco modified Eagle medium (DMEM) for 24 h, and apoptosis and necrosis were quantified using Hoechst 33342 and propidium iodide viability dyes. The presence of putative factors that delay neutrophil apoptosis was investigated using inhibitors to leukotriene-B 4 , lipopolysaccharide and the IL-8 receptor CXCR2, and blocking antibodies to granulocyte-monocyte colony-stimulating factor. Characterisation of NLF involved tests of thermal instability, proteolysis, deoxyribonuclease digestion and molecular filtration. NLF from infants with RSV bronchiolitis and controls significantly delayed neutrophil apoptosis, whereas NLF from healthy adults did not. None of these inhibitor molecules blocked this delay in apoptosis but activity was heat liable and &gt;3 kDa. The study showed that nasal lavage fluid from infants significantly delays neutrophil apoptosis. The speculation is that the prolonged survival of neutrophils in the infant airway contributes to the characteristic accumulation of neutrophils in the airways of infants with respiratory infections.
The New Psychosurgery
Authors: Henry T. Ricketts
Journal: JAMA (1973)

Readers of the article by Mark and Neville (p 765) would do well to refer to a critique that appeared in<i>Science</i>(179:1109, 1973) where the author, Constance Holden, deals with the pros and cons of recent developments in psychosurgery. One learns that there is no agreement on its definition. Twenty or 30 years ago, the term might have been applied to the operation of prefrontal lobotomy, performed, too often in vain, to cure or ameliorate certain forms of psychosis for which there was no other remedy. Now, the targets, no longer cerebral lobes or portions thereof, are the deeply buried cingulum, thalamus, and amygdala—the supposed seats of such mysterious entities as emotion, behavior, and imagination. In place of the scalpel and electrocautery to whack away at brain tissue, we have the stereotaxically-placed electrode that can zero in precisely on any of these hidden islands and either stimulate or destroy
The Cost-Effectiveness and Population Outcomes of Expanded HIV Screening and Antiretroviral Treatment in the United States
Authors: Elisa F. Long, Margaret L. Brandeau, Douglas K. Owens
Journal: Annals of Internal Medicine (2010)

Background: Although recent guidelines call for expanded routine screening for HIV, resources for antiretroviral therapy (ART) are limited, and all eligible persons are not currently receiving treatment. Objective: To evaluate the effects on the U.S. HIV epidemic of expanded ART, HIV screening, or interventions to reduce risk behavior. Design: Dynamic mathematical model of HIV transmission and disease progression and cost-effectiveness analysis. Data Sources: Published literature. Target Population: High-risk (injection drug users and men who have sex with men) and low-risk persons aged 15 to 64 years in the United States. Time Horizon: Twenty years and lifetime (costs and quality-adjusted life-years [QALYs]). Perspective: Societal. Intervention: Expanded HIV screening and counseling, treatment with ART, or both. Outcome Measures: New HIV infections, discounted costs and QALYs, and incremental cost-effectiveness ratios. Results of Base-Case Analysis: One-time HIV screening of low-risk persons coupled with annual screening of high-risk persons could prevent 6.7% of a projected 1.23 million new infections and cost $22 382 per QALY gained, assuming a 20% reduction in sexual activity after screening. Expanding ART utilization to 75% of eligible persons prevents 10.3% of infections and costs $20 300 per QALY gained. A combination strategy prevents 17.3% of infections and costs $21 580 per QALY gained. Results of Sensitivity Analysis: With no reduction in sexual activity, expanded screening prevents 3.7% of infections. Earlier ART initiation when a CD4 count is greater than 0.350 × 109 cells/L prevents 20% to 28% of infections. Additional efforts to halve high-risk behavior could reduce infections by 65%. Limitation: The model of disease progression and treatment was simplified, and acute HIV screening was excluded. Conclusion: Expanding HIV screening and treatment simultaneously offers the greatest health benefit and is cost-effective. However, even substantial expansion of HIV screening and treatment programs is not sufficient to markedly reduce the U.S. HIV epidemic without substantial reductions in risk behavior. Primary Funding Source: National Institute on Drug Abuse, National Institutes of Health, and Department of Veterans Affairs.
916-65 Clearance of Thallium-201 from the Blood After Peak Exercise: No Difference in Washout Kinetics Between Early and Late Reinjection
Authors: Berthe L.F. van Eck-Smit, Ernst E. van der Wall, Patrick P.A.M. Verhoeven, Aeilko H. Zwinderman, Ernest K.J. Pauwels
Journal: Journal of the American College of Cardiology (1995)
Terminal deoxynucleotidyltransferase distribution in neoplastic and hematopoietic cells.
Authors: M F Greenwood, M S Coleman, J J Hutton, B Lampkin, C Krill, F J Bolium, P Holland
Journal: Journal of Clinical Investigation (1977)

In the present study, terminal deoxynucleotidyltransferase was examined in the peripheral blood and (or) bone marrow of 115 children with a variety of neoplastic, hematologic, and other unrelated disorders. Terminal deoxynucleotidyltransferase activity was present at 4.08+/-0.74 U/108 cells in 23 morphologicall normal bone marrow samples from childhood controls. Terminal transferase was present at greater than 23 U/108 nucleated cells and at greater than31 U/108 blasts in the bone marrow of all children with acute lymphoblastic leukemia studied at initial diagnosis and at disease relapse. Terminal deoxynucleotidyltransferase was detectable at low levels, less than 7.5 U/108 cells, in all remission marrow smaples. Bone marrow terminal transferase activity was markedly elevated in all untreated acute lymphoblastic leukemia patients, whereas low levels which were difficult to interpret were present in the peripheral blood samples of two patients at diagnosis and six patients at relapse who had low absolute lymphoblast counts. Because of greater variation in the lymphoblast content of peripheral blood, bone marrow assays are more reliable in detecting disease activity. Marrow terminal deoxynucleotidyltransferase values obtained during the active phase of acute lymphoblastic leukemia were significantly greater than those found in other types of leukemia, bone marrow malignancies, and hematologic disorders. Terminal transferase determinations in blast cells of two patients with leukemic conversion of non-Hodgkin's lymphoma and in tumor cells from one patient with Burkitt's lymphoma were within the control range. These dat further define the usefulness of terminal deoxynucleotidyltrnasferase assay in the differentiation and classication of hematologic malignancies.
THE PATHOGENESIS OF TUMORS OF THE LIVER PRODUCED BY BUTTER YELLOW
Authors: Eugene L. Opie
Journal: The Journal of Experimental Medicine (1944)

A conspicuous feature of the cirrhosis that is produced by butter yellow is the new formation of bile ducts that sprout from ducts of the larger portal spaces and penetrate between "portal units" to anastomose with liver cell columns at the periphery of these units. Hyperplasia of the liver may occur with butter yellow administration in the absence of cirrhosis or other change associated with widespread destruction of liver tissue; it occurs as diffuse or focal lesions and affects both parenchymal cells and newly formed ducts. Focal hyperplasia is a precursor of trabecular and adenomatous hepatomas which arise as multiple tumors. Butter yellow causes localized cystic dilatation of newly formed bile ducts unaccompanied by acute or chronic inflammation and liver cells adjacent to them may undergo hyperplasia. Cystic ducts by proliferation of their epithelium may form cyst-adenomas. Butter yellow causes newly formed ducts to undergo dilatation, and with acute inflammation and fibrosis to produce circumscribed macroscopically recognizable lesions (cholangiofibrosis). Cholangiofibrosis is the precursor of tumors that reproduce the histological characters of small bile ducts (cholangiomas), and often proceed to the formation of scirrhous carcinoma. Hepatomas, cyst-adenomas, and cholangiomas may become malignant with formation of metastases in which the characteristics of the parent tumor are reproduced.
Subtotal Colectomy for Refractory Pseudomembranous Enterocolitis
Authors: William C. Boyd
Journal: JAMA (1976)

Pseudomembranous enterocolitis resulting from therapy with antibiotics such as clindamycin and lincomycin hydrochloride monohydrate does not always respond to drug and vigorous medical support. We describe two seriously ill patients who recovered after subtotal colectomy with ileostomy.
Relation of Steroid Hormones to Glucose Tolerance and Plasma Insulin Levels in Men: Importance of visceral adipose tissue
Authors: André Tchernof, Jean-Pierre Després, André Dupont, Alain Bélanger, André Nadeau, Denis Prud'homme, Sital Moorjani, Paul J Lupien, Fernand Labrie
Journal: Diabetes Care (1995)

Low plasma testosterone levels are associated with hyperinsulinemia and glucose intolerance in men. However, it is unclear whether these abnormalities are related to the concomitant alteration in regional adipose tissue (AT) accumulation associated with reduced androgen levels.We measured plasma steroid levels in a sample of 79 men, ranging from lean to obese (aged 29-42 years), for whom an oral glucose tolerance test (OGTT), anthropometric and computed tomography (CT) measurements of body fatness, and AT distribution were performed. Sex hormone binding globulin (SHBG) and the following steroids were measured after extraction from plasma and chromatography: dehydroepiandrosterone, androstenedione, androst-5-ene-3 beta,17 beta-diol, testosterone, estrone, and estradiol (E2).Several significant negative correlations were found between adrenal C19 steroid precursors, testosterone, SHBG, and fasting insulin levels, as well as between plasma glucose and insulin concentrations measured during the OGTT (-0.25 < or = r < or = -0.35, 0.05 > or = P > or = 0.001). The best steroid correlate of plasma glucose and insulin homeostasis indexes was the E2: testosterone ratio (0.34 < or = r < or = 0.42, 0.005 > or = P > or = 0.001). However, after correction of steroid levels for either fat mass, body mass index (BMI), or visceral AT area, as measured by CT, no significant residual associations were noted between testosterone, adrenal C19 steroid, SHBG, and estrogen levels and indexes of plasma glucose-insulin homeostasis, although the positive association between the E2: testosterone ratio and glucose area remained significant after adjustment for total body fat mass and BMI. Furthermore, 15 pairs of obese subjects, matched for visceral AT area, showing either low or high levels of the steroids studied, did not differ in fasting insulin and postglucose plasma insulin levels or in glucose tolerance.These results suggest that the previously reported relationships between androgen levels and indexes of plasma glucose-insulin homeostasis are mediated, to a large extent, by concomitant alterations in levels of total body fat and visceral AT in men.
Dermatoglyphics in the Rubella Syndrome
Authors: Milton Alter
Journal: JAMA (1966)

Epidermal ridges on hands and feet (dermatoglyphics) develop during the first trimester of gestation and remain unchanged thereafter for life. As the rubella virus has a teratogenic effect during this period, it is postulated that an alteration in dermatoglyphics might be present in rubella-damaged individuals. Analysis of dermatoglyphics in 28 rubella-damaged individuals revealed a higher frequency of whorl patterns, a reduced a-b ridge count, a wider atd angle, a tendency towards more patterns on the palm, and a higher frequency of transitional and simian lines than in normals. This study suggests that dermatoglyphics may serve as a marker of a deleterious intrauterine experience during early gestation.
Hereditary deficiency of the fifth component of complement in man. II. Biological properties of C5-deficient human serum.
Authors: S I Rosenfeld, J Baum, R T Steigbigel, J P Leddy
Journal: Journal of Clinical Investigation (1976)

The first known human kindred with hereditary deficiency of the fifth component of complement (C5) was documented in the accompanying report. This study examines several biological properties of C5-deficient (C5D) human serum, particularly sera obtained from two C5D homozygotes. The proband, who has inactive systemic lupus erythematosus is completely lacking C5, while her healthy half-sister has 1-2% of normal levels. Both sera were severely impaired in their ability to generate chemotactic activity for normal human neutrophils upon incubation with aggregated human gamma-globulin or Escherichia coli endotoxin. This function was fully restored in the sibling's serum, and substantially improved in the proband's serum, by addition of highly purified human C5 to normal serum concentrations. Sera from eight family members who were apparently heterozygous for C5 deficiency gave normal chemotactic scores. The ability of C5D serum to opsonize Saccharomyces cerevisiae (baker's yeast) or Candida albicans for ingestion by normal neutrophils was completely normal. In addition, C5D serum was capable of promoting normal phagocytosis and intracellular killing of Staphylococcus aureus. The proband's serum was incapable of mediating lysis of erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria in both the sucrose hemolysia and acid hemolysis tests, and also lacked bactericidal activity against sensitized or unsensitized Salmonella typhi. The sibling's serum, containing only 1-2% of normal C5, effectively lysed S. typhi, but only at eightfold lower serum dilutions as compared to normals. These findings underscore the critical role of C5 in the generation of chemotactic activity and in cytolytic reactions, as opposed to a nonobligatory or minimal role in opsonization, at least for the organisms under study.
Intraluminal gastric pH in chronic pancreatitis.
Authors: P Bovo, G Cataudella, V Di Francesco, B Vaona, M Filippini, M Marcori, G Montesi, L Rigo, L Frulloni, M P Brunori
Journal: Gut (1995)

The aim of this study was to assess the circadian variations of intragastric pH in 28 inpatients with chronic pancreatitis (mean (SD) age 46.8 (12.4) years) and in 14 controls (45.4 (9.8)). pH Metry was performed using a monocrystalline antimony electrode placed in the body of the stomach under fluoroscopic control and connected up to a recorder (MKII Digitrapper, Synectics). The evaluation parameters, expressed as median and interquartile range, were: total period, postprandial periods (P1 and P2), interdigestive, and nocturnal phases. Patients with chronic pancreatitis were subdivided into three groups on the basis of severity of exocrine pancreatic insufficiency (secretin-caerulein test: lipase output at 60-90 min)--that is, those with severe insufficiency (chronic pancreatitis-SI: 13 patients, lipase output < 10% normal values and pancreolauryl test < 20%), those with only mild insufficiency (chronic pancreatitis-MI: seven patients), and those with normal secretion (chronic pancreatitis-NF: eight patients). The chronic pancreatitis-SI patients present significantly greater gastric acidification in the postprandial periods compared with controls (P1: p < 0.001; P2: p < 0.01), and with chronic pancreatitis-MI plus chronic pancreatitis-NF subjects (P1: p < 0.01; P2: p < 0.05), taken together. In conclusion, gastric acidity, exocrine pancreatic insufficiency, and impaired digestion are closely related during the course of chronic pancreatitis.
PREMOTOR AND PARIETAL CORTEX: Corticocortical Connectivity and Combinatorial Computations
Authors: Steven P. Wise, Driss Boussaoud, Paul B. Johnson, Roberto Caminiti
Journal: Annual Review of Neuroscience (1997)

▪ Abstract The dorsal premotor cortex is a functionally distinct cortical field or group of fields in the primate frontal cortex. Anatomical studies have confirmed that most parietal input to the dorsal premotor cortex originates from the superior parietal lobule. However, these projections arise not only from the dorsal aspect of area 5, as has long been known, but also from newly defined areas of posterior parietal cortex, which are directly connected with the extrastriate visual cortex. Thus, the dorsal premotor cortex receives much more direct visual input than previously accepted. It appears that this fronto-parietal network functions as a visuomotor controller—one that makes computations based on proprioceptive, visual, gaze, attentional, and other information to produce an output that reflects the selection, preparation, and execution of movements.