tbuckley/cabot-search huggingface dataset:
Automated Quantitative Analysis of Tissue Microarrays Reveals an Association between High Bcl-2 Expression and Improved Outcome in Melanoma
Authors: Kyle A. DiVito, Aaron J. Berger, Robert L. Camp, Marisa Dolled-Filhart, David L. Rimm, Harriet M. Kluger
Journal: Cancer Research (2004)

Abstract The addition of B-cell lymphoma 2 (Bcl-2) antisense to dacarbazine in the treatment of metastatic melanoma demonstrates improved response rates and progression-free survival when compared with dacarbazine alone. Studies on small cohorts of melanoma patients have shown variability in Bcl-2 expression (60%–96% positive). We performed quantitative analysis of Bcl-2 expression in a large patient cohort to assess the association with outcome. Tissue microarrays containing intact melanoma specimens representing 402 patients (339 with associated survival data) were analyzed with our AQUA system for automated quantitative analysis. Automated, quantitative analysis uses S100 to define pixels as melanoma (tumor mask) within the array spot and measures intensity of Bcl-2 expression using a Cy5 conjugated antibody within the mask. A continuous index score is generated, which is directly proportional to the number of molecules per unit area. Scores were divided into quartiles and correlated with clinical variables. High Bcl-2 expression was associated with better outcome in the entire cohort and among metastatic specimens only (P = 0.004 and P = 0.015, respectively). Expression was higher in primary than in metastatic specimens (P &amp;lt; 0.0001). There was no association between Bcl-2 expression and Breslow depth or Clark level. The diverse results within the literature may be due to use of small cohorts or variability in staining technique. These results suggest studies are needed to evaluate the association between quantitative assessment of Bcl-2 expression and response to Bcl-2 targeting therapy toward the goal of improved response rates to these drugs.
Micrometastases in Sentinel Lymph Nodes: Few Data Make for Hard Decisions
Authors: Karen Rowan
Journal: JNCI Journal of the National Cancer Institute (2009)

with 1% for those who had ALND or axilla radiotherapy. The sentinel lymph node, which is the fi rst node that lymph fl uid enters after draining from the breast, is the most common site of breast cancer metastasis, and patients who are node negative — meaning that the biopsy turns up no cancer in the sentinel node — have a better prognosis than those who are node positive. Under present U.S. guidelines, patients with micrometastases, which range from 0.2 mm to 2.0 mm, are considered to be node positive, and some experts say they should be treated as all other node-positive patients: Their biopsy should be followed by
Human Monocytes, but not Dendritic Cells Derived from Them, Are Defective in Base Excision Repair and Hypersensitive to Methylating Agents
Authors: Manuela Briegert, Bernd Kaina
Journal: Cancer Research (2007)

Abstract Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N′-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O6-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O6-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIα, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression. [Cancer Res 2007;67(1):26–31]
Early disturbance of calcium translocation across the plasma membrane in toxic liver injury
Authors: Bernhard H. Lauterburg
Journal: Hepatology (1987)

An increased influx and/or a decreased extrusion of calcium across the plasma membrane resulting in an increase in cytosolic-free calcium could play an important role in the initiation of irreversible cell injury. Therefore, the translocation of calcium across the plasma membrane was probed in the perfused rat liver using multiple indicator dilution methodology. The sucrose space corresponding to the extracellular space amounted to 0.35 ± 0.13 ml per gm liver, and the water space corresponding to the extra- and intracellular spaces was 0.97 ± 0.08 ml per gm. The calcium space was always slightly larger (0.42 ± 0.10 ml per gm) than the sucrose space. The calcium space further increased during perfusion with the calcium ionophore A 23187, whereas the sucrose space remained unchanged. Two hours after administration to intact rats of acetaminophen (2 gm per kg) and carbon tetrachloride (2 ml per kg), respectively, the calcium space had increased markedly relative to the sucrose space and relative to the water space, indicating an increased accessibility of the cells to extracellular calcium. Similarly, reperfusion of livers after 90 min of ischemia was associated with an increase in calcium space relative to the sucrose and water spaces. These studies indicate that, in three models of acute liver injury, the net influx of calcium across the plasma membrane is increased early in the evolution of the injury before irreversible damage occurs.
Tolerance and autoimmunity to erythroid differentiation (B-G) major histocompatibility complex alloantigens of the chicken.
Authors: C Havele, T G Wegmann, B M Longenecker
Journal: The Journal of Experimental Medicine (1982)

Hematopoietic chimeras were produced at four different stages of ontogeny between two allogeneic strains of chickens. All chimeras produced by parabiosis at day 12 of embryogenesis and the majority (83%) of the ones produced at day 15 by intravenous injection of allogeneic stem cells remained healthy, chimeric, and specifically tolerant at both the humoral and cell-mediated level throughout a long examination period. Chimeras generated at day 17 of embryogenesis demonstrated specific unresponsiveness at the cell-mediated level but produced specific anti-donor alloantibodies directed against erythrocyte-associated major histocompatibility complex (MHC) (B-G) antigens. These chimeras and a minority (17%) of the chimeras generated at day 15 of embryogenesis developed severe antibody-mediated autoimmune hemolytic anemia after the 5th mo of age and succumbed to massive bursal lymphomas and metastases by the 10th mo of age. The immunological and pathological characteristics of these birds appear to reflect an autoimmune state rather than one of tolerance. Erythroid chimeras generated at day 21 of ontogenic development displayed normal levels of GVH reactivity. These birds were eventually able to eliminate the chimeric state and remained healthy until deliberately killed. These results show that there is a critical period in embryogenesis during which the induction of allogeneic erythrocytic chimerism leads to the development, in adult life, of severe autoimmune anemia, B cell lymphomas, and death. B-G MHC antigens are erythroid differentiation antigens of the chicken. Polymorphic determinants on B-G antigens appear to be important cross-reactive determinants (with environmental bacteria), against which a high background immunity exists. Evidence is presented that the immune response to B-G antigens is responsible for the development of autoimmunity and other pathological events that follow and that tolerance to class I MHC antigens (B-F antigens) shared by lymphocytes erythrocytes is maintained at the same time that B-G tolerance is broken.
Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus
Authors: Anna Kanerva, Kurt R Zinn, Tandra R Chaudhuri, John T Lam, Kaori Suzuki, Taco G Uil, Tanja Hakkarainen, Gerd J Bauerschmitz, Minghui Wang, Bin Liu, Zhihong Cao, Ronald D Alvarez, David T Curiel, Akseli Hemminki
Journal: Molecular Therapy (2003)

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie–adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Δ24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Δ24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Δ24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Δ24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.
The influence of hyperinflation and systemic inflammation on the 6 minute walking distance in patients with COPD
Authors: Tadeusz Przybylowski, Renata Rubinsztajn, Marta Maskey-Warzechowska, Magdalena Paplinska-Goryca, Patrycja Nejman-Gryz, Krzysztof Karwat, Ryszarda Chazan
Journal: European Respiratory Journal (2013)

Dyspnea and impaired exercise tolerance are frequent in patients with COPD. Hyperinflation contributes to exercise intolerance by its negative impact on lung mechanics.  Aim: to evaluate the influence of hyperinflation on the 6 minute walking distance and the markers of systemic inflammation in patients with COPD.  The study group consisted of 149 patients with stable COPD (61F, 88M) aged 68±8.8 yrs.  All the patients underwent spirometry and bodypletysmography with bronchial reversibility testing and 6 minute walking test (6MWT). Hyperinflation was defined as RV%TLC > 48% and > 126% predicted. The following serum inflammatory markers were evaluated: C-reactive protein, IL-6, IL-8, TNF alpha, CC16, adiponectin and resistin.  The patients were divided into group A (patients without hyperinflation, n=53) and group B (patients with hyperinflation, n=96). Table 1 presents significant differences in the results of the 6 MWT between the two groups.  We found significant positive correlations between 6 MWD and serum IL-8 (R=-0.2,p=0.02), IL-6 (R=-0.3, p=0.002), TNF alpha (R=-0.2, p=0.04) and C-reactive protein (R=-0.2, p=0.03); SpO 2  6 min and resistine (R=0.2, p=0.006), CC16 (R=0.2, p=0.03); RV%TLC and IL6 (R=0.2, p=0.007) in the group as a whole.  Conclusions:  1/ Hyperinflation has a negative influence on exercise tolerance in COPD patients.  2/Systemic inflammation may also deteriorate exercise tolerance in COPD patients.
Impact of Early Parenteral Nutrition on Metabolism and Kidney Injury
Authors: Jan Gunst, Ilse Vanhorebeek, Michaël P. Casaer, Greet Hermans, Pieter J. Wouters, Jasperina Dubois, Kathleen Claes, Miet Schetz, Greet Van den Berghe
Journal: Journal of the American Society of Nephrology (2013)

A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.
Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques
Authors: Y KONG, X HUANG, X OUYANG, J TAN, G FINGERLEROWSON, M BACHER, W MU, L SCHER, L LENG, R BUCALA
Journal: Cardiovascular Research (2004)

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and has been shown to play a role in pathogenesis of atherosclerosis. The aim of this study is to investigate the potential role of MIF in the destabilization of atherosclerotic plaques by stimulation of vascular MMP-1 expression.MIF and matrix metalloproteinase protein-1 (MMP-1) expression in human atherosclerotic plaques were determined by immunohistochemistry. The functional activity of MIF was examined by its ability to induce MMP-1 expression in vascular smooth muscle cells (VSMCs) in vitro.Two-color immunohistochemistry demonstrated that MIF was strongly upregulated in vulnerable, but not in fibrous plaques. Upregulation of vascular MIF was associated with macrophage accumulation (p<0.01), strong expression of vascular MMP-1 (p<0.001), and collagenolysis in vulnerable atheromatous plaques, but not in the fibrous lesions. Co-expression of MIF and MMP-1 in vulnerable atheromatous plaques appeared to contribute to the weakening of fibrous caps and plaque disruption. The role of MIF in vascular MMP-1 expression was demonstrated by the ability of MIF to directly stimulate VSMCs to express MMP-1 mRNA and protein, and to increase MMP-1 activity in a dose- and time-dependent manner, which was blocked by a neutralizing MIF antibody (p<0.001).MIF and MMP-1 are markedly upregulated in vulnerable atheromatous plaques and are associated with the weakening of the fibrous cap. The ability of MIF to induce MMP-1 expression and collagenolytic activity in VSMCs suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.
Claims of Sex Differences
Authors: Nikolaos A. Patsopoulos, Athina Tatsioni, John P. A. Ioannidis
Journal: JAMA (2007)

Many studies try to probe for differences in risks between men and women, and this is a major challenge in the expanding literature of associations between genetic variants and common diseases or traits.To evaluate whether prominently claimed sex differences for genetic effects have sufficient internal and external validity.We searched PubMed through July 6, 2007, for genetic association studies claiming sex-related differences in the articles' titles. Titles and abstracts and, if necessary, the full text of the article were assessed for eligibility.Two hundred fifteen articles were retrieved by the search. We considered eligible all retrieved association studies that claimed different genetic effects across sexes of 1 or more gene variants for any human disease or phenotype. We considered both biallelic and multiallelic markers (including haplotypes) and both binary and continuous phenotypes and traits. We excluded non-English-language studies; studies evaluating only 1 sex; studies in which sex was treated only as an independent predictor of disease; studies that did not address any association of the investigated genetic variant with a disease or trait; studies not involving humans; and studies in which the authors did not claim any sex difference.Two evaluators independently extracted data with a third evaluator arbitrating their discrepancies. Data evaluation included whether analyses were stated to have been specified a priori; whether sex effects were evaluated in the whole study or subgroups thereof; and whether the claims were appropriately documented, insufficiently documented, or spurious. For appropriately and insufficiently documented claims we performed the calculations for gene-sex interaction whenever raw data were available. Finally, we compared the sex-difference claims with the best internal validity against the results of other studies addressing the same interaction.We appraised 432 sex-difference claims in 77 eligible articles. Authors stated that sex comparisons were decided a priori for 286 claims (66.2%), while the entire sample size was used in 210 (48.6%) claims. Appropriate documentation of gene-sex interaction was recorded in 55 claims (12.7%); documentation was insufficient for 303 claims and spurious for the other 74. Data for reanalysis of claims were available for 188 comparisons. Of these, 83 (44.1%) were nominally statistically significant at a P = .05 threshold, and more than half of them (n = 44) had modest P values between .01 and .05. Of 60 claims with seemingly the best internal validity, only 1 was consistently replicated in at least 2 other studies.In this sample of highly prominent claims of sex-related differences in genetic associations, most claims were insufficiently documented or spurious, and claims with documented good internal and external validity were uncommon.
Phagocytosis, an unrecognized property of murine endothelial liver cells
Authors: Anne-Marie Steffan, Jean-Louis Gendrault, Robert S. McCuskey, Patricia A. McCuskey, André Kirn
Journal: Hepatology (1986)

Impairment of the phagocytic capacities of Kupffer cells, as is found in Frog Virus 3 hepatitis of mice, allows the endothelial liver cells to take up intravenously inoculated latex particles of 1.0 μm diameter. In vitro experiments with cultivated endothelial cells isolated by collagenase perfusion of the liver and purified by centrifugal elutriation demonstrate that uptake occurs via a typical mechanism of phagocytosis involving pseudopodia. Ingestion of latex is inhibited by incubation of the cells at 4°C and by treatment with cytochalasin B, whereas colchicine has no effect. These results demonstrate that: (i) the Kupffer cells are not the only cells of the hepatic sinusoid capable of phagocytosis; and (ii) under conditions where the phagocytosis in Kupffer cells is impaired, the endothelial cells may participate in the clearance of large particles from the blood.
A Randomized Trial of Continuous Subcutaneous Insulin Infusion and Intensive Injection Therapy in Type 1 Diabetes for Patients With Long-Standing Poor Glycemic Control
Authors: J. Hans DeVries, Frank J. Snoek, Piet J. Kostense, Nathalie Masurel, Robert J. Heine
Journal: Diabetes Care (2002)

OBJECTIVE—To assess in a randomized crossover trial the efficacy of continuous subcutaneous insulin infusion in improving glycemic control and health-related quality of life in type 1 diabetic patients with long-standing poor glycemic control. RESEARCH DESIGN AND METHODS—A total of 79 patients in 11 Dutch centers were randomized to 16 weeks of continuous subcutaneous insulin infusion followed by 16 weeks intensive injection therapy or the reverse order. Glycemic control was assessed by HbA1c, self-reported hypoglycemic events, and blood glucose memory meter read outs. Changes in quality of life were assessed by self-report questionnaires administered at baseline and 16 weeks. RESULTS—As the drop-out rate after crossover was high (17 of 79 patients [22%]), we analyzed the trial as a parallel clinical trial, using data of the first half of the crossover phase only. At 16 weeks, mean HbA1c was 0.84% (95% CI −1.31 to −0.36) lower in the continuous subcutaneous insulin infusion group compared with the insulin injection group (P = 0.002). Stability of blood glucose self-measurement values, expressed as SD of the nine-point blood glucose profiles, improved in the insulin pump group by 29.3 ± 41.1 vs. 8.2 ± 36.5% in the injection group (P = 0.039). The number of mild hypoglycemic episodes per patient-week was 0.99 (95% CI 0.11–1.87) higher in the insulin pump group (P = 0.028). Weight gain was similar in both groups. Scores on the Short-Form 36-Item subscales ‘general health’ and ‘mental health’ improved in the continuous subcutaneous insulin infusion group, compared with stable values in the injection group (P = 0.048 and 0.050, respectively). CONCLUSIONS—Continuous subcutaneous insulin infusion improves glycemic control and some aspects of health-related quality of life in patients with a history of long-term poor glycemic control.
Responsiveness of the International Classification of Functioning, Disability and Health (ICF) Core Set for rheumatoid arthritis
Authors: T Uhlig, R Moe, S Reinsberg, T K Kvien, A Cieza, G Stucki
Journal: Annals of the Rheumatic Diseases (2008)

The comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for rheumatoid arthritis (RA) is a selection of 96 categories from the ICF, representing relevant aspects in the functioning of patients with RA.To study the responsiveness of the ICF Core Set for RA in rheumatological practice.A total of 46 patients with RA (72% women, mean (SD) age 53.6 (12.6) years, disease duration 6.3 (8.0) years) were interviewed at baseline and again after 6 months treatment with a disease-modifying antirheumatic drug (DMARD), applying the ICF Core Set for RA with qualifiers for problems on a modified three-point scale (no problem, mild/moderate, severe/complete). Patient-reported outcomes included Modified Health Assessment Questionnaire (MHAQ) and Short-Form 36 (SF-36) health survey, and disease activity was calculated. Responsiveness was measured as change in qualifiers in ICF categories, and was also compared with change in patient-reported outcomes.After 6 months of DMARD treatment, improvement by at least one qualifier was seen in 20% of patients (averaged across all ICF categories), 71% experienced no change and 9% experienced worsening symptoms. Findings were similar across the different aspects of functioning. Mainly moderate effect sizes were seen for 6-month changes in the ICF Core Set for RA, especially in patients with improved health status, with similar effect size for disease activity. The components in the ICF Core Set for RA were only weakly associated with patient-reported outcomes and disease activity.The ICF Core Set for RA demonstrated moderate responsiveness in this real-life setting of patients where minor changes occurred during treatment with DMARDs.