tbuckley/cabot-search huggingface dataset:
Pityriasis rotunda: A new cutaneous marker of hepatocellular carcinoma?
Authors: Harold O. Conn, Abby Van Voorhees, Sidney N. Klaus
Journal: Hepatology (1987)

Although paraneoplastic phenomena occur frequently in patients with hepatocellular carcinoma, cutaneous changes have rarely been reported. During the past two years, ten South African blacks with hepatocellular carcinoma and pityriasis rotunda have been seen in a single hospital. The rash affected the trunk, especially the lower back and buttocks. The lesions ranged in size from 1.5 to 25 cm and were always multiple. They had a characteristic circular or arcuate configuration with scaling and varying degrees of hyperpigmentation. Pityriasis rotunda may prove to be a useful cutaneous marker of hepatocellular carcinoma in South African blacks.
Effect of Diabetes Mellitus on Formation of Coronary Collateral Vessels
Authors: Adnan Abacı, Abdurrahman Oğuzhan, Sinan Kahraman, Namık Kemal Eryol, Şükrü Ünal, Hüseyin Arınç, Ali Ergin
Journal: Circulation (1999)

Although myocardial ischemia is known to be significantly related to the development of coronary collateral vessels (CCVs), there is considerable variation between patients with ischemic heart disease in the presence of collateral development. The nature of this variability is not well known. Likewise, it remains unclear whether diabetes mellitus (DM) has any effect on CCVs. The aim of this study was to evaluate the effect of DM on CCVs.Of the patients who underwent coronary angiography during the interval between March 1, 1993, and June 20, 1998, in our institution, 306 were diabetic. Those patients in whom coronary angiography is normal or severity of coronary artery stenosis is thought not to be sufficient for the development of CCVs (<75%) were excluded from the study. A total of 205 patients (mean age, 59+/-8 years) met the criteria for the DM group. For case-control matching, 205 consecutive nondiabetic patients (mean age, 58+/-9 years) who had >/=1 diseased vessel with >75% stenosis were included in the control group. The CCVs were graded according to the Rentrop scoring system, and the collateral score was calculated by summing the Rentrop numbers of every patient. There was no statistical difference between patients with and without DM in clinical baseline characteristics. The mean number of diseased vessels in the DM group (1.58+/-0.68) was higher than that in the nondiabetic group (1.42+/-0.65, P=0.005). The mean collateral score was 2.41+/-2.20 in the DM group and 2.60+/-2.39 in the control group. After confounding variables were controlled for, the collateral score in the diabetic group was significantly different from that in the nondiabetic group (P=0.034).Our findings suggest that CCV development is poorer in patients with than in patients without DM. Thus, we can speculate that DM is an important factor affecting CCV development.
Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3β Impairs Degradation of Prolactin Receptor
Authors: Alexander Plotnikov, Ying Li, Thai H. Tran, Weigang Tang, Juan P. Palazzo, Hallgeir Rui, Serge Y. Fuchs
Journal: Cancer Research (2008)

Abstract Prolactin receptors (PRLr) expressed in a majority of breast cancer are activated by prolactin and growth hormone. The PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which, when phosphorylated, recruits the βTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that constitutive oncogenic signaling downstream of ErbB2 and Ras stabilizes PRLr via inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) on Ser9. Importantly, inactivation of GSK3β correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3β is a bona fide PRLr kinase that phosphorylates PRLr on Ser349 and is required for the recognition of PRLr by βTrcp, as well as for PRLr ubiquitination and degradation. [Cancer Res 2008;68(5):1354–61]
Volume and time dependence of respiratory system mechanics in normal anaesthetized paralysed humans
Authors: E D'Angelo, M Tavola, J Milic-Emili
Journal: European Respiratory Journal (2000)

The purpose of the present investigation was to assess the effect of large tidal volumes and mean lung volumes on the viscoelastic properties of the respiratory system in normal humans; and to verify if in this case the results could be satisfactorily described by a simple linear viscoelastic model of the respiratory system. Twenty-eight subjects (7 females), aged 14-28 yrs, were studied before orthopaedic surgery on the lower limbs. None were obese, or had clinical evidence of cardiopulmonary disease. The interrupter conductance and the viscoelastic constants of the respiratory system were assessed using the rapid end-inspiratory airway occlusion method during mechanical ventilation with tidal volumes up to 3 L and applied end-expiratory pressures up to 23 cmH2O. It was found that the interrupter conductance increased linearly with lung volume over a larger range than used previously; and the viscoelastic resistance and time constant did not change over the entire range of tidal volumes and end-expiratory pressures studied. In conclusion, in normal anaesthetized, paralysed subjects a simple linear viscoelastic model satisfactorily described the viscoelastic behaviour of the respiratory system over the whole range of volume studied.
Impaired Macrophage Migration Inhibitory Factor–AMP-Activated Protein Kinase Activation and Ischemic Recovery in the Senescent Heart
Authors: Heng Ma, Jingying Wang, D. Paul Thomas, Chao Tong, Lin Leng, Wenkui Wang, Melanie Merk, Swen Zierow, Jürgen Bernhagen, Jun Ren, Richard Bucala, Ji Li
Journal: Circulation (2010)

Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway.Ischemic AMPK activation was impaired in aged compared with young murine hearts. The expression and secretion of the AMPK upstream regulator, macrophage migration inhibitory factor (MIF), were lower in aged compared with young adult hearts. Additionally, the levels of hypoxia-inducible factor 1alpha, a known transcriptional activator of MIF, were reduced in aged compared with young hearts. Ischemia-induced AMPK activation in MIF knockout mice was blunted, leading to greater contractile dysfunction in MIF-deficient than in wild-type hearts. Furthermore, intramyocardial injection of adenovirus encoding MIF in aged mice increased MIF expression and ischemic AMPK activation and reduced infarct size.An impaired MIF-AMPK activation response in senescence thus may be attributed to an aging-associated defect in hypoxia-inducible factor 1alpha, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1alpha activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients.
The Oral Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Increases Circulating Endothelial Progenitor Cells in Patients With Type 2 Diabetes
Authors: Gian Paolo Fadini, Elisa Boscaro, Mattia Albiero, Lisa Menegazzo, Vera Frison, Saula de Kreutzenberg, Carlo Agostini, Antonio Tiengo, Angelo Avogaro
Journal: Diabetes Care (2010)

OBJECTIVE Vasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1α (SDF-1α) and are reduced in type 2 diabetes. Because SDF-1α is a substrate of dipeptidyl-peptidase-4 (DPP-4), we investigated whether the DPP-4 inhibitor sitagliptin modulates EPC levels in type 2 diabetic patients. RESEARCH DESIGN AND METHODS This was a controlled, nonrandomized clinical trial comparing 4-week sitagliptin (n = 16) versus no additional treatment (n = 16) in addition to metformin and/or secretagogues in type 2 diabetic patients. We determined circulating EPC levels and plasma concentrations of SDF-1α, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and nitrites/nitrates. RESULTS There was no difference in clinical baseline data between the sitagliptin and control arms. After 4 weeks, as compared with control subjects, patients receiving sitagliptin showed a significant increase in EPCs and SDF-1α and a decrease in MCP-1. CONCLUSIONS Sitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1α. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications.
Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells.
Authors: A C Fluckiger, I Durand, J Banchereau
Journal: The Journal of Experimental Medicine (1994)

Recent studies have established that interleukin (IL)-10 induces growth and most notably differentiation of normal human B lymphocytes. We studied here the effects of IL-10 on the proliferation and survival of B-chronic lymphocytic leukemia (B-CLL) cells. IL-10 was found to inhibit 54-96% of the spontaneous tritiated thymidine incorporation observed in 3 of 12 B-CLL samples. Furthermore, IL-10 decreased the viable cell recovery of all five B-CLL samples tested, irrespective of whether cells were spontaneously synthesizing DNA or not. After 1 wk, B-CLL populations cultured with IL-10 were lost while those cultured without IL-10 survived. Flow cytometric analysis, DNA gel electrophoresis, and Giemsa staining all revealed that IL-10 induced B-CLL cells to die from apoptosis. This IL-10-mediated apoptosis was dose dependent and specific as it could be inhibited by a neutralizing anti-IL-10 antibody. B-CLL cells undergoing apoptosis in response to IL-10 showed decreased Bcl-2 protein levels. Addition of IL-2, IL-4, interferon gamma, and anti-CD40 monoclonal antibody prevented the IL-10-mediated apoptosis of B-CLL cells. None of the malignant B cell populations obtained from eight non-Hodgkin's lymphomas and three hairy cell leukemias underwent apoptosis after IL-10 treatment, thus suggesting that the apoptotic effect of IL-10 is specific for B-CLL cells. Thus, IL-10 inhibits the DNA synthesis and most notably the survival of B-CLL cells, findings that call for considering IL-10 in the immunotherapy of chemoresistant B-CLL.
Personality Traits and Striatal Dopamine Synthesis Capacity in Healthy Subjects
Authors: Aki Laakso, Esa Wallius, Jaana Kajander, Jörgen Bergman, Olli Eskola, Olof Solin, Tuula Ilonen, Raimo K R Salokangas, Erkka Syvälahti, Jarmo Hietala
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Neuroimaging and genetic studies suggest that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). The authors studied whether presynaptic dopamine function is also associated with personality traits. METHOD: Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [18F]fluorodopa in 33 healthy adults, and personality traits were assessed with the Karolinska Scales of Personality. Associations were studied by using a linear regression model controlling for the effects of age and gender on both variables. RESULTS: High scores on two of the anxiety-related personality scales, somatic anxiety and muscular tension, and on one aggressivity-related scale, irritability, were significantly associated with low [18F]fluorodopa uptake in the caudate. No statistically significant associations were observed between [18F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior (impulsiveness and monotony avoidance). CONCLUSIONS: The results suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects. Together with previous studies, they also indicate differential involvement of various components of the dopaminergic system in normal and pathological personality traits.
PROPERTIES OF GUINEA PIG 7S ANTIBODIES
Authors: Kurt J. Bloch, François M. Kourilsky, Zoltan Ovary, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1963)

Guinea pig 7Sgamma(2) antibodies were demonstrated to fix complement in the presence of antigen and to sensitize antigen-coated, tanned erythrocytes for lysis in the presence of complement; guinea pig 7Sgamma(1) antibodies did not participate in these reactions. Gamma-2 antibodies were more efficient in provoking hemorrhagic necrosis in reverse passive Arthus reactions than equal amounts of non-complement-fixing gamma-1 antibodies. Unlike anaphylaxis in the guinea pig, both guinea pig 7Sgamma(1) and 7Sgamma(2) antibodies provoked passive cutaneous anaphylactic reactions in the rat. Efficient hemolytic activity attributable to 7S guinea pig anti-sheep erythrocyte antibodies migrated faster than the peak of complement-fixing activity, but slower than the peak of PCA activity in starch block electrophoresis. It is uncertain whether this activity is a function of a third type of antibody produced in response to the particulate property of the antigen or whether it is due to the antigenic heterogeneity of the erythrocyte cell membrane.
Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium and Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity (N08CB/Alliance)
Authors: Charles L. Loprinzi, Rui Qin, Shaker R. Dakhil, Louis Fehrenbacher, Kathleen A. Flynn, Pamela Atherton, Drew Seisler, Rubina Qamar, Grant C. Lewis, Axel Grothey
Journal: Journal of Clinical Oncology (2013)

Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity. This trial was designed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity.In all, 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous calcium/magnesium before and after oxaliplatin, a placebo before and after, or calcium/magnesium before and placebo after. The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 tool.There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy, including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale. In addition, calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy.This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity.
Postoperative Radiotherapy for Pathologic N2 Non–Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: A Review of the National Cancer Data Base
Authors: Cliff G. Robinson, Aalok P. Patel, Jeffrey D. Bradley, Todd DeWees, Saiama N. Waqar, Daniel Morgensztern, Maria Q. Baggstrom, Ramaswamy Govindan, Jennifer M. Bell, Tracey J. Guthrie, Graham A. Colditz, Traves D. Crabtree, Daniel Kreisel, Alexander S. Krupnick, G. Alexander Patterson, Bryan F. Meyers, Varun Puri
Journal: Journal of Clinical Oncology (2015)

Purpose To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non–small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. Patients and Methods Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. Results Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). Conclusion For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone.
Antagonistic antibody prevents toll-like receptor 2–driven lethal shock-like syndromes
Authors: Guangxun Meng, Mark Rutz, Matthias Schiemann, Jochen Metzger, Alina Grabiec, Ralf Schwandner, Peter B. Luppa, Frank Ebel, Dirk H. Busch, Stefan Bauer, Hermann Wagner, Carsten J. Kirschning
Journal: Journal of Clinical Investigation (2004)

Hyperactivation of immune cells by bacterial products through toll-like receptors (TLRs) is thought of as a causative mechanism of septic shock pathology. Infections with Gram-negative or Gram-positive bacteria provide TLR2-specific agonists and are the major cause of severe sepsis. In order to intervene in TLR2-driven toxemia, we raised mAb’s against the extracellular domain of TLR2. Surface plasmon resonance analysis showed direct and specific interaction of TLR2 and immunostimulatory lipopeptide, which was blocked by T2.5 in a dose-dependent manner. Application of mAb T2.5 inhibited cell activation in experimental murine models of infection. T2.5 also antagonized TLR2-specific activation of primary human macrophages. TLR2 surface expression by murine macrophages was surprisingly weak, while both intra- and extracellular expression increased upon systemic microbial challenge. Systemic application of T2.5 upon lipopeptide challenge inhibited release of inflammatory mediators such as TNF-α and prevented lethal shock-like syndrome in mice. Twenty milligrams per kilogram of T2.5 was sufficient to protect mice, and administration of 40 mg/kg of T2.5 was protective even 3 hours after the start of otherwise lethal challenge with Bacillus subtilis. These results indicate that epitope-specific binding of exogenous ligands precedes specific TLR signaling and suggest therapeutic application of a neutralizing anti-TLR2 antibody in acute infection.
A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast Cancer
Authors: Christos Hatzis
Journal: JAMA (2011)

<h3>Context</h3>Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.<h3>Objective</h3>To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.<h3>Design, Setting, and Patients</h3>Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)–negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline–based regimens (then endocrine therapy if estrogen receptor [ER]–positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.<h3>Main Outcome Measures</h3>Distant relapse–free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).<h3>Results</h3>Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.<h3>Conclusion</h3>A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.
Leishmania Donovani. Hamster macrophage interactions in vitro: cell entry, intracellular survival, and multiplication of amastigotes
Authors: K-P Chang, DM Dwyer
Journal: The Journal of Experimental Medicine (1978)

An in vitro system was developed for studying host-parasite cellular interactions in visceral leishmaniasis with amastigotes isolated from infected spleens of hamsters and their peritoneal macrophages maintained by an improved method. The culture system supports the growth of Leishmania donovani amastigotes with different parasite/macrophage ratios for up to 2 wk, yielding results more consistent and reproducible than previously possible. Results indicated that the forms of the amastigotes (with or without adherent host membranes) and the state of the macrophages (with or without stimulation in vivo by thioglycollate or in vitro by aging) had no effect on the growth rate of the parasites, which, however, seems to vary with the macrophage subpopulations. An electron microscope study suggests that amastigotes are ingested through phagocytosis by the macrophages and become lodged in loose phagosomes. Additional evidence with quantitative data is presented to support the earlier findings that phagosome-lysosome fusion occurs after the interiorization of the parasites and that they not only survive but multiply in these vacuoles. During the postinfection periods, reorientation of amastigotes in vacuolar space results in the appearance of three types of parasitophorous vacuoles (parasites in loose vacuoles, in tight-fitting vacuoles or abutting in part against the inner lining of vacuoles). The last category may be the predominant type giving rise to the variations observed. Exogenously introduced dense marker accumulated in these parasitophorous vacuoles of the macrophages infected for several days indicating a continuous accessibility of amastigotes to the ambient mestruum via phagosome-lysosome vacuolar system of the host cells. This finding may have significant implications in parasite nutrition, host immunity, and chemotherapy of leishmaniasis.