tbuckley/cabot-search huggingface dataset:
Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression
Authors: Viviana Vallacchi, Elisabetta Vergani, Chiara Camisaschi, Paola Deho, Antonello D. Cabras, Marialuisa Sensi, Loris De Cecco, Niccolò Bassani, Federico Ambrogi, Antonino Carbone, Federica Crippa, Barbara Vergani, Paola Frati, Flavio Arienti, Roberto Patuzzo, Antonello Villa, Elia Biganzoli, Silvana Canevari, Mario Santinami, Chiara Castelli, Licia Rivoltini, Monica Rodolfo
Journal: Cancer Research (2014)

Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30(+) lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30(+) lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4(+)Foxp3(+) or PD1(+) subpopulations and CD4(-)CD8(-) T cells. CD30(+) T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30(+) lymphocytes at those sites associate positively with melanoma progression.
Role of lysosomal cathepsin activities in cell hypertrophy induced by NH4Cl in cultured renal proximal tubule cells.
Authors: H Ling, S Vamvakas, M Gekle, L Schaefer, M Teschner, R M Schaefer, A Heidland
Journal: Journal of the American Society of Nephrology (1996)

An increase of renal ammoniagenesis has been implicated in renal hypertrophy associated with various clinical disorders such as metabolic acidosis, diabetic nephropathy, and renal insufficiency. In vivo and in vitro studies have shown that ammonia promotes hypertrophy in tubular epithelial cells. To elucidate its role on protein turnover, the effects of NH4Cl on the activities of cathepsins B, H, and L+B, as well as on protein synthesis and degradation in LLC-PK1 cells, were investigated. The results show that NH4Cl (20 mM) induced cell hypertrophy, as defined by an increase in both cell protein content and cell volume (+25.5 +/- 1.3 and +10.4 +/- 0.1% after 48 h). This hypertrophy was associated with the suppression of the activities of cathepsins B and L+B (-57.0 +/- 0.9 and -54.5 +/- 1.5% after 48 h) and a reduction of protein degradation rate (-59.7 +/- 4.1% after 48 h), but without enhanced protein synthesis. The findings were further supported with an additional experiment, showing that the protein synthesis inhibitor cycloheximide (10 microM) did not blunt NH4Cl-induced cell hypertrophy. Moreover, NH4Cl (20 mM) resulted in a persistent elevation of the lysosomal pH, whereas the rise in the cytosolic pH was only transient. This alkalinization in lysosomes may be causatively involved in the impairment of the activities of cathepsins B and L+B. In conclusion, the suppression of the activities of cathepsins B and L+B and the subsequent reduction of protein breakdown due to intralysosomal alkalinization contribute to NH4Cl-induced hypertrophy in LLC-PK1 cells.
Northwick Park Infection Consultation Service Part I. The aims and operation of the service and the general distribution of infection identified by the service between September 1987 and July 1990
Authors: E.G.L. Wilkins, M.M. Hickey, S. Khoo, A.D. Hale, S. Umasankar, P. Thomas, N. Bhatti, J. Dave, D. Seal, E. Larson, R. Wall, Hillas Smith
Journal: Journal of Infection (1991)
TWEAK is a positive regulator of cardiomyocyte proliferation
Authors: Tatyana Novoyatleva, Florian Diehl, Machteld J. van Amerongen, Chinmoy Patra, Fulvia Ferrazzi, Riccardo Bellazzi, Felix B. Engel
Journal: Cardiovascular Research (2009)

Proliferation of mammalian cardiomyocytes stops during the first weeks after birth, preventing the heart from regenerating after injury. Recently, several studies have indicated that induction of cardiomyocyte proliferation can be utilized to regenerate the mammalian heart. Thus, it is important to identify novel factors that can induce proliferation of cardiomyocytes. Here, we determine the effect of TNF-related weak inducer of apoptosis (TWEAK) on cardiomyocytes, a cytokine known to regulate proliferation in several other cell types. Stimulation of neonatal rat cardiomyocytes with TWEAK resulted in increased DNA synthesis, increased expression of the proliferative markers Cyclin D2 and Ki67, and downregulation of the cell cycle inhibitor p27KIP1. Importantly, TWEAK stimulation resulted also in mitosis (H3P), cytokinesis (Aurora B), and increased cardiomyocyte numbers. Loss of function experiments revealed that re-induction of proliferation was dependent on tumour necrosis factor receptor superfamily member 12A (FN14) signalling. Downstream signalling was mediated through activation of extracellular signal-regulated kinases and phosphatidylinositol 3-kinase as well as inhibition of glycogen synthase kinase-3beta. In contrast to neonatal cardiomyocytes, TWEAK had no effect on adult rat cardiomyocytes due to developmental downregulation of its receptor FN14. However, adenoviral expression of FN14 enabled efficient induction of cell cycle re-entry in adult cardiomyocytes after TWEAK stimulation. Our data establish TWEAK as a positive regulator of cardiomyocyte proliferation.
Characterization of a Candidate Tumor Suppressor Gene Uroplakin 1A in Esophageal Squamous Cell Carcinoma
Authors: Kar Lok Kong, Dora L. Kwong, Li Fu, Tim Hon Man Chan, Leilei Chen, Haibo Liu, Yan Li, Ying-Hui Zhu, Jiong Bi, Yan-Ru Qin, Simon Ying Kit Law, Xin-Yuan Guan
Journal: Cancer Research (2010)

Esophageal squamous cell carcinoma (ESCC) is increasing in incidence, but the knowledge of the genetic underpinnings of this disease remains limited. In this study, we identified the tetraspanin cell surface receptor uroplakin 1A (UPK1A) as a candidate tumor suppressor gene (TSG), and we investigated its function and mechanism in ESCC cells. UPK1A downregulation occurred in 68% of primary ESCCs examined, where it was correlated significantly with promoter hypermethylation (P < 0.05). Ectopic expression of UPK1A in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation in nude mice. Mechanistic investigations suggested that these effects may be mediated by inhibiting nuclear translocation of β-catenin and inactivation of its downstream targets, including cyclin-D1, c-jun, c-myc, and matrix metalloproteinase 7 (MMP7). Cell cycle arrest elicited by UPK1A at the G(1)-S checkpoint was associated with downregulation of cyclin D1 and cyclin-dependent kinase 4, whereas metastasis suppression was associated with reduction of MMP7. These findings were consistent with evidence derived from clinical samples, where UPK1A downregulation was correlated with lymph node metastasis (P = 0.009), stage (P = 0.015), and overall survival (P < 0.0001). Indeed, multivariate cyclooxygenase regression analysis showed that UPK1A was an independent prognostic factor for overall survival. Taken together, our findings define a function for UPK1A as an important TSG in ESCC development.
Effectiveness of a Home Care Nursing Program in the Symptom Management of Patients With Colorectal and Breast Cancer Receiving Oral Chemotherapy: A Randomized, Controlled Trial
Authors: Alex Molassiotis, Sarah Brearley, Mark Saunders, Olive Craven, Andrew Wardley, Carole Farrell, Ric Swindell, Chris Todd, Karen Luker
Journal: Journal of Clinical Oncology (2009)

To assess the effectiveness of a symptom-focused home care program in patients with cancer who were receiving oral chemotherapy in relation to toxicity levels, anxiety, depression, quality of life, and service utilization.A randomized, controlled trial was carried out with 164 patients with a diagnosis of colorectal (n = 110) and breast (n = 54) cancers who were receiving oral capecitabine. Patients were randomly assigned to receive either a home care program by a nurse or standard care for 18 weeks (ie, six cycles of chemotherapy). Toxicity assessments were carried out weekly for the duration of the patients' participation in the trial, and validated self-report tools assessed anxiety, depression, and quality of life.Significant improvements were observed in the home care group in relation to the symptoms of oral mucositis, diarrhea, constipation, nausea, pain, fatigue (first four cycles), and insomnia (all P < .05). This improvement was most significant during the initial two cycles. Unplanned service utilization, particularly the number of inpatient days (57 v 167 days; P = .02), also was lower in the home care group.A symptom-focused home care program was able to assist patients to manage their treatment adverse effects more effectively than standard care. It is imperative that patients receiving oral chemotherapy are supported with such programs, particularly during initial treatment cycles, to improve their treatment and symptom experiences.
Somatic Mosaicism and Cancer: A Micro-Genetic Examination into the Role of the Androgen Receptor Gene in Prostate Cancer
Authors: Carlos Alvarado, Lenore K. Beitel, Kanishka Sircar, Armen Aprikian, Mark Trifiro, Bruce Gottlieb
Journal: Cancer Research (2005)

Abstract Recent evidence has shown that the androgen receptor (AR) plays a major role in all prostate cancer stages, including both androgen-dependent and -independent tumors. A large number of studies have examined the possible effects of a functional polymorphism in the AR gene, a variable-length CAG repeat, on the development of prostate cancer, but the results to date have been inconclusive. We have considered the fact that the tissue heterogeneity present in almost all prostate cancer tumors has rarely been regarded as an indicator of AR genetic heterogeneity. To determine if genetic heterogeneity exists and is a significant event in prostate cancer development, we have examined prostate cancer tumors for somatic shortening of the AR gene CAG repeat. All 72 laser capture microdissected samples from archival prostate cancer tissues, as well as samples from freshly prepared prostate cancer tissues, showed some genetic heterogeneity (somatic mosaicism) for AR CAG repeat length. Cancerous tissues showed a much greater degree of genetic heterogeneity than adjacent benign tissues, as well as a very significant shortening of their CAG repeat lengths. However, CAG repeat length heterogeneity was not observed in normal prostate tissues. It is hypothesized that somatic mosaicism of the AR CAG repeat in prostate cancer tumors may be found to be an important genetic event in precancerous tissue, which may subsequently lead to the development of prostate cancer.
Testimonial to Dr. Berncastle
Authors: C. W. Steel
Journal: BMJ (1848)

<h3>Abstract</h3> Crowded environments affect the pharmacokinetics of drug molecules. Here, we investigate how three macromolecular protein crowders, bovine serum albumin, hen egg-white lysozyme and myoglobin, influence the translational diffusion rates and interactions of four low molecular-weight drugs, fluorescein, doxorubicin, glycogen synthase kinase-3 inhibitor SB216763 and quinacrine. Using Fluorescence Recovery After Photo-bleaching in Line mode (Line FRAP), Brownian dynamics simulations and molecular docking, we find that the diffusive behavior of the small molecules is highly affected by self-aggregation, interactions with the proteins, and surface adhesion. Fluorescein diffusion is decreased by protein crowders due to their interactions. On the other hand, for doxorubicin, the presence of protein crowders increases diffusion by reducing surface interactions. SB216763 shows a third scenario, where BSA, but not myoglobin or lysozyme, reduces self-aggregation, resulting in faster diffusion. Quinacrine was the only small molecule whose diffusion was not affected by the presence of protein crowders. The mechanistic insights gained here into the effects of interactions of small molecules with proteins and surfaces on the translational diffusion of small molecules can assist in optimizing the design of compounds for higher mobility and lower occlusion in complex macromolecular environments. <h3>Significance statement</h3> The activity of small molecules is directly related to their active concentration. This, in turn, relates to their molar concentration and their activity coefficient. Any deviations from ideal behavior affects the small molecule activity. This is particularly important for drugs, where we seek to optimize their molar activity. Here, we follow the diffusional activity of four small molecule drugs in various solutions, with and without protein crowders. The study, which involves experimental measurements and theoretical simulations, shows that 3 of the 4 drugs do not diffuse normally, either due to aggregation, protein binding or surface adhesion. We show the mechanisms driving the abnormal diffusion, and how it can be reduced. Lessons learned from this study can be implemented into drug design.
A STUDY OF THE LOW BLOOD PRESSURES ASSOCIATED WITH ANAPHYLACTIC AND PEPTONE SHOCK AND EXPERIMENTAL FAT EMBOLISM, WITH SPECIAL. REFERENCE TO SURGICAL SHOCK
Authors: J. P. Simonds
Journal: The Journal of Experimental Medicine (1918)

1. In peptone shock there is a marked, precipitate fall in arterial pressure. At the same time there is a fall in venous pressure. 2. In experimental fat embolism, (a) the fall in blood pressure is always gradual; (b) approximately 1 cc. of oil for each pound of body weight must be injected before a lasting fall in arterial pressure is produced; (c) it makes only a slight difference whether this amount is injected in small doses at a time or in relatively large quantities; and (d) when the arterial pressure falls, but not till then, the venous pressure rises. 3. In peptone shock, dyspnea, by its suction and force-pump action upon the reservoir of stagnating blood in the liver, brings more blood to the heart and causes a rise in arterial pressure. By repeatedly inducing short periods of dyspnea at frequent intervals, permanently beneficial results are obtained and the life of the animal can be saved. 4. In experimental fat embolism, dyspnea will cause a rise in blood pressure. But permanently beneficial results have not been obtained by this method. If dyspnea is found to bring permanent improvement in surgical shock, it is indirect evidence that this condition is not due to fat embolism. Respiratory suction is probably not responsible for the rise in blood pressure in experimental fat embolism. It seems more likely that the dyspnea in some way facilitates the passage of blood through the embarrassed pulmonary circulation. Artificial respiration with a bellows will also frequently cause a rise in blood pressure in experimental fat embolism. 5. In peptone shock the respiration is usually not affected, although there is some evidence that the respiratory center may be in a state of increased irritability. In experimental fat embolism, in some animals a violent dyspnea develops spontaneously. This is usually accompanied by edema of the lungs. In other instances, an apnea occurs, even before the blood pressure has begun to decline.
Rothmund–Thomson syndrome and osteosarcoma
Authors: M.R. JUDGE, A. KILBY, J.I. HARPER
Journal: British Journal of Dermatology (1993)

A 10-year-old girl with Rothmund-Thomson syndrome developed a fibular osteosarcoma. Standard chemotherapy produced intolerable toxicity, necessitating a modification of therapy. Initial DNA repair studies on skin fibroblasts were abnormal, but repeat studies failed to reproduce the defects.
Preventing Diabetes in American Indian Communities
Authors: William C. Knowler, Ronald T. Ackermann
Journal: Diabetes Care (2013)

Diabetes incidence can be reduced by lifestyle interventions aimed at weight loss, diet change, and increased physical activity, according to several randomized clinical trials (RCTs) (1–5). Similarly, diabetes incidence rates were reduced in RCTs of metformin, acarbose, troglitazone, rosiglitazone, and pioglitazone (1,4,6–9). These RCTs enrolled nondiabetic adults who were at high risk of developing type 2 diabetes by virtue of having one of more of these characteristics: overweight or obesity, elevated fasting glucose, and impaired glucose tolerance in an oral glucose tolerance test. These lifestyle or drug interventions reduced diabetes incidence rates substantially, with risk reductions ranging from about 25–75%. Diabetes incidence was reduced by 58% during the 2.8-year initial phase of the largest such lifestyle intervention trial, the U.S. Diabetes Prevention Program (DPP) (1). This occurred among all the major race/ethnic groups in the DPP, including American Indians.

Because of this dramatic result and the disproportionate burden of type 2 diabetes among American Indians, the U.S. Congress appropriated funds to implement lifestyle interventions patterned on the DPP starting in 2006 in 36 American Indian or Alaska Native communities. The resulting Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) demonstration project is described in this issue (10). The SDPI-DP was designed to deliver prevention services to a population in need, rather than as another RCT, because RCTs had already shown the efficacy of lifestyle intervention to prevent or delay diabetes in high risk persons. Furthermore, the segments of the U.S. population most affected by type 2 diabetes, especially American Indians who have contributed so much to diabetes research (11), deserve to benefit from the results of diabetes research.

It …
Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200
Authors: Bruce J. Giantonio, Paul J. Catalano, Neal J. Meropol, Peter J. O'Dwyer, Edith P. Mitchell, Steven R. Alberts, Michael A. Schwartz, Al B. Benson
Journal: Journal of Clinical Oncology (2007)

Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.
Nonsustained Ventricular Tachycardia in the Setting of Acute Myocardial Infarction
Authors: Asim N. Cheema, Kathleen Sheu, Michele Parker, Alan H. Kadish, Jeffrey J. Goldberger
Journal: Circulation (1998)

Background —Nonsustained ventricular tachycardia (NSVT) has significant prognostic implications in the setting of healing and healed myocardial infarction (MI), but only limited information is available on its importance in the setting of acute MI. We evaluated the prognostic significance of NSVT characteristics in the setting of acute MI. Methods and Results —A prospective database was used to identify 112 patients with NSVT within 72 hours of acute MI. A control group was identified matched for age, sex, type of MI, and thrombolytic treatment. Mean age was 64 to 65 years in the 2 groups with 71% to 72% men. Q-wave MI was noted in 52% to 53%, and thrombolytic therapy was administered to 31% to 32% of patients in each group. In-hospital ventricular fibrillation occurred more frequently in the NSVT group (9% versus 0% in the control group; P &lt;0.001), but total in-hospital (10% versus 4%) and follow-up mortality (10% versus 17%) did not differ between the 2 groups. With a Cox regression model, specific NSVT characteristics were predictive of mortality. The strongest predictor was time from presentation to occurrence of NSVT. Shortest RR interval during NSVT was also a univariate predictor of mortality. Multivariate analysis identified time from presentation to occurrence of NSVT as the strongest predictor of mortality ( P &lt;0.0001). The increased relative risk of NSVT was first significant when it occurred 13 hours from presentation and continued to increase as the time from presentation to occurrence of NSVT increased, plateauing at ≈24 hours with a relative risk of 7.5. Conclusions —Contrary to prevailing clinical opinion, NSVT that occurs in the setting of acute MI does have important prognostic significance. Specifically, the currently accepted notion that NSVT that occurs within 48 hours of acute MI has no prognostic significance needs to be adjusted. Although NSVT that occurs within the first several hours of presentation does not have an associated adverse prognosis, NSVT that occurs beyond the first several hours after presentation is associated with significant increases in relative risk.
The CD4+ T-Cell Response of Melanoma Patients to a MAGE-A3 Peptide Vaccine Involves Potential Regulatory T Cells
Authors: Violaine François, Sabrina Ottaviani, Nicolina Renkvist, Julie Stockis, Gerold Schuler, Kris Thielemans, Didier Colau, Marie Marchand, Thierry Boon, Sophie Lucas, Pierre van der Bruggen
Journal: Cancer Research (2009)

Abstract Melanoma patients were injected with various vaccines containing a MAGE-A3 peptide presented by HLA-DP4. Anti–MAGE-A3.DP4 T cells were not detectable in the blood before vaccination, but their frequencies after vaccination ranged from 2 × 10−6 to 2 × 10−3 among the CD4+ blood T lymphocytes of the patients. The CD4+ blood T lymphocytes that stained ex vivo with HLA-DP4 tetramers folded with the MAGE-A3 peptide were selected by flow cytometry and amplified under clonal conditions. About 5% of the CD4+ T-cell clones that recognized the MAGE-A3.DP4 antigen had a CD25+ phenotype in the resting state. These CD25+ clones had a high capacity to suppress the proliferation of another T-cell clone after peptide stimulation in vitro. Most of them had high FOXP3 expression in the resting state and an unmethylated FOXP3 intron 1. They produced active transforming growth factor-β but none of cytokines IFN-γ, interleukin-2 (IL-2), IL-4, IL-5, and IL-10. About 20% of CD25− clones had a significant but lower suppressive activity. Most of the CD25− clonal populations contained cells that expressed FOXP3 in the resting state, but FOXP3 demethylation was not observed. We conclude that MAGE-A3.DP4 vaccination can produce CD4+ T cells that may exert regulatory T-cell function in vivo. [Cancer Res 2009;69(10):4335–45]