tbuckley/cabot-search huggingface dataset:
Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma.
Authors: J M Karjalainen, J K Kellokoski, M J Eskelinen, E M Alhava, V M Kosma
Journal: Journal of Clinical Oncology (1998)

PURPOSE The transcription factor, activator protein (AP)-2, a 52-kd DNA-binding protein, is suggested to inhibit tumor growth through the activation of p21. To test this hypothesis, we analyzed AP-2 and p21 protein expressions in stage I cutaneous malignant melanomas to clarify their significance with regard to tumor progression and survival. PATIENTS AND METHODS A consecutive series of 369 clinical stage I cutaneous malignant melanoma patients were investigated using immunohistochemistry. The detected expression levels were correlated with each other, with clinicopathologic data, and with melanoma survival. RESULTS The loss of AP-2 expression was significantly associated with low p21 expression (P=.007), high tumor thickness (P=.001), high Clark's level (P=.046), high tumor-node-metastasis (TNM) category (P=.006), recurrent disease (P=.001), and male sex (P=.03). Tumor thickness, Clark's level, TNM category, bleeding, AP-2 index, and sex were all important predictors of both recurrence-free survival (RFS) and overall survival (OS) of melanoma in this order. In Cox's multivariate analysis, high tumor thickness (P=.0001), low AP-2 index (P=.0153), and bleeding (P=.0143) predicted poor RFS. Poor OS was predicted by high tumor thickness (P=.0008) and bleeding (P=.0092). CONCLUSION The loss of AP-2 expression seems to be associated with malignant transformation and tumor progression in cutaneous malignant melanoma. This tumor-suppressive action of AP-2 may be mediated through p21 regulation. Furthermore, decreased AP-2 expression is independently associated with elevated risk of subsequent metastatic behavior of stage I cutaneous malignant melanoma.
DNA Hydroxymethylation Profiling Reveals That WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia
Authors: Raajit K. Rampal, Altuna Alkalin, Jozef Madzo, Aparna Vasanthakumar, Elodie Pronier, Jay P. Patel, Yushan Li, Jihae Ahn, Omar Abdel-Wahab, Alan H. Shih, Chao Lu, Patrick Ward, Jennifer J Tsai, Todd Hricik, Jacob Tallman, Valeria Tosello, Xinyang Zhao, Danette Daniels, Qing Dai, Luisa Ciminio, Iannis Aifantis, Chuan He, François Fuks, Martin S. Tallman, Adolfo A. Ferrando, Stephen Nimer, Elisabeth Paietta, Craig B. Thompson, Jonathan D. Licht, Christopher E Mason, Lucy A Godley, Ari M Melnick, Maria E Figueroa, Ross L Levine
Journal: Blood (2014)
Treatment of Hypertension
Authors: Lawrence E. Ramsay
Journal: JAMA (1978)

<h3>To the Editor.—</h3> Members of the Hypertension Detection and Followup Program Cooperative Group report that approximately 77% of persons found to be hypertensive at screening attended a clinic for a further blood pressure (BP) check, and that approximately 82% of those in whom hypertension was confirmed were still attending the clinic one year later (239:1507, 1978). The members conclude that the program has achieved good participation rates. The meaning of these figures should be considered more critically. The response to the initial screening process was 89%, and it seems reasonable to assume that 11/100 hypertensive patients in the original communities were not detected. Of the 89 detected, 20 (23%) did not attend the clinic, leaving 69 patients. A further 12 patients (18% of 69) were apparently lost to follow-up after one year, leaving 57 patients attending. Thus, the program, which involved vigorous and intensive publicity, persistent individual contact, considerable effort
Subcutaneous alemtuzumab in patients with refractory/relapsed B-CLL after a fludarabine-based regimen
Authors: R. Bezares, G. Stemmelin, D. Argentieri, E. Lanari, E. Guy-Garay, R. Campestri, M. Bartomioli, J. García, S. Giralt, G. Milone
Journal: Journal of Clinical Oncology (2006)

6600 Background: Alemtuzumab is the only immunotherapy that is effective as a single agent in patients with B-CLL who are refractory to, or who have relapsed after, fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. We report the first interim analysis of a new, less intensive schedule of alemtuzumab SC to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg bid during the second and third weeks, and 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg tid. Results: Patients (N = 36) with refractory (19%) or relapsed (81%) B-CLL had a median age of 67 years (range, 43–86 years), 28 were male, 61%/39% had Binet stage B/C disease, and 2 had B-cell prolymphocytic transformation. The median number of prior therapies was 1 (range, 1–4). The median duration of treatment was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 412 mg (range, 150–1,080 mg). Thirty-two patients were evaluable for response. The overall response rate of 93%: complete response (CR), 34%; unconfirmed CR, 6%; partial response (PR), 53%. Two patients (7%) did not respond to therapy. Of the 7 refractory patients, 5 had a PR, 1 did not respond, and 1 was not yet evaluable. Median overall survival was 10 months, which correlated with response and pretreatment status. Minimal residual disease (MRD) was measured by flow cytometry in 5 patients who achieved a CR: 3 patients had &lt;0.5% of CD5/CD19/CD23+ cells, 1 patient had &lt;5% of CLL cells, and 1 patient had &lt;10% CLL cells. According to WHO toxicity criteria, 5 patients experienced grade 3/4 infection; 2 patients had grade 3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusions: Results of this interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy. No significant financial relationships to disclose.
Class II HLA interactions modulate genetic risk for multiple sclerosis
Authors: Loukas Moutsianas, Luke Jostins, Ashley H Beecham, Alexander T Dilthey, Dionysia K Xifara, Maria Ban, Tejas S Shah, Nikolaos A Patsopoulos, Lars Alfredsson, Carl A Anderson, Katherine E Attfield, Sergio E Baranzini, Jeffrey Barrett, Thomas M C Binder, David Booth, Dorothea Buck, Elisabeth G Celius, Chris Cotsapas, Sandra D'Alfonso, Calliope A Dendrou, Peter Donnelly, Bénédicte Dubois, Bertrand Fontaine, Lars Fugger, An Goris, Pierre-Antoine Gourraud, Christiane Graetz, Bernhard Hemmer, Jan Hillert, Ingrid Kockum, Stephen Leslie, Christina M Lill, Filippo Martinelli-Boneschi, Jorge R Oksenberg, Tomas Olsson, Annette Oturai, Janna Saarela, Helle Bach Søndergaard, Anne Spurkland, Bruce Taylor, Juliane Winkelmann, Frauke Zipp, Jonathan L Haines, Margaret A Pericak-Vance, Chris C A Spencer, Graeme Stewart, David A Hafler, Adrian J Ivinson, Hanne F Harbo, Stephen L Hauser, Philip L De Jager, Alastair Compston, Jacob L McCauley, Stephen Sawcer, Gil McVean
Journal: Nature Genetics (2015)
Prognostic Of IgD Myeloma In The Era Of Novel Agents
Authors: Luca Inchiappa, Charles Herbaux, Stéphanie Guidez, Guillemette Fouquet, David Beauvais, Zoé Van de Wyngaert, Helene Demarquette, Sarah Bonnet, Bénédicte Hivert, Mathieu Wemeau, Nathalie Cambier, Christian Rose, Maxime Bemba, Jean Michel Pignon, Thierry Facon, Bruno Royer, Murielle Roussel, Denis Caillot, Marc Wetterwald, Xavier Leleu
Journal: Blood (2013)
Synergistic effect of IL-1alpha, IFN-gamma, and TNF-alpha on RANTES production by human renal tubular epithelial cells in vitro.
Authors: J G Deckers, F J Van Der Woude, S W Van Der Kooij, M R Daha
Journal: Journal of the American Society of Nephrology (1998)

Interstitial rejection of renal allografts is associated with infiltrating mononuclear cells. Mechanisms leading to this mononuclear cell influx are still not fully resolved. The chemokine RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) is chemotactic for monocytes and T cells. In renal allograft biopsies of patients undergoing rejection, RANTES is found in infiltrating monocytes and T cells, as well as in the tubular epithelium. This study analyzes the production of RANTES in vitro by proximal tubular epithelial cells (PTEC) after stimulation with the inflammatory cytokines interleukin-1alpha, (IL-1alpha), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). Unstimulated PTEC or PTEC stimulated with the cytokines IL-1alpha, IFN-gamma, and TNF-alpha alone did not produce detectable amounts of RANTES. However, a combination of IFN-gamma and either IL-1alpha or TNF-alpha resulted in strong induction of RANTES production up to 2046 +/- 817 pg/ml or 2595 +/- 525 pg/ml per 1 x 10(5) PTEC, respectively. After stimulation with IL-1alpha and TNF-alpha, RANTES production was less prominent than the combination of IFN-gamma with either IL-1alpha or TNF-alpha, and only detectable in 5 of 7 PTEC lines tested. The production of RANTES was both dose- and time-dependent and was inhibited by cycloheximide, indicating that de novo protein synthesis is required. Because the production of RANTES by PTEC is more pronounced in the presence of T cell-derived IFN-gamma (in combination with either IL-1alpha or TNF-alpha), it was hypothesized that RANTES produced by PTEC presumably plays a prominent role in the amplification phase of the immune response rather than in the initiation phase.
Correlation of CXCR4 expression in resected pancreatic adenocarcinoma (PA) with relapse and survival after adjuvant radiochemotherapy (RCT)
Authors: R. Maréchal, P. Demetter, A. Berton, I. Salmon, J. Van Laethem
Journal: Journal of Clinical Oncology (2009)

e22022 Background: The chemoreceptors CXCR4, CXCR7 and the hypoxia inductible factor-1 alpha (HIF-1α) are implicated in PA growth, dissemination and angiogenesis. These protagonists are expected to play a key role in radiotherapy and chemotherapy resistance in PA. Methods: We conducted a retrospective study of patients undergoing curative surgery (R0 resection) for PA between 2001 and 2006 in our institution. All were treated with adjuvant RCT (treatment group). The treatment group was case-matched with resected PA patients who did not receive any adjuvant therapy (control group). FFPE specimens were subjected to immunohistochemical analysis using tissue microarray and monoclonal antibodies against human CXCR4, CXCR7, and HIF-1α. Based on the intensity (I) and the extend (E) of staining, cases were stratified into those with high (E x I&gt;3) or low (E x I ≤ 3) expression of CXCR4, CXCR7 and HIF-1α and results were correlated with disease-free survival (DFS) and overall survival (OS). Results: 31 PA patients (median age: 57years, range: 39–76) were analysed in the treatment group and 30 (median age: 59 years, range: 38–81) in the control group. The two groups were well-matched in terms of age, sex, tumor stage (T1-T2 vs T3-T4), tumor differentiation (poor vs well-moderate), lymph node (LN) status (N0 vs N+), lymphatic and vascular embols. In univariate analysis, CXCR4 expression and LN status were associated with DFS and OS (OS, CXCR4 low/high : HR, 5.43, 95%CI: 2.03–14.49, p=0.001; N0/N+: HR: 4.62, 95% CI, 1.33–13.12, p=0.016; DFS: CXCR4 low / CXCR4 high : HR, 3.01, 95%CI: 1.21–7.46, p=0.018; N0/N+: HR: 3.30, 95% CI, 1.09–9.90, p=0.034) in the treatment group while in the control group LN status was the only variable significantly correlated with DFS and OS. CXCR4 appeared to be the only independant predictor for DFS (CXCR4 low/high : HR, 4.95, 95%CI: 1.68–14.71, p=0.007) and OS (CXCR4 low/high : HR, 4.76, 95%CI: 2.03–14.49, p=0.004) in the treatment group but not in the control group. Conclusions: CXCR4 was an independant predictor for DFS and OS after adjuvant RCT in resected PA patients. This chemoreceptor could be implicated in the resistance of pancreatic cancer cells to RCT and its targeted inhibition deserves clinical evaluation. No significant financial relationships to disclose.
Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms
Authors: Lu Zhang, Huan-wei Ru, Fu-zeng Chen, Chun-yan Jin, Rui-feng Sun, Xiao-yong Fan, Ming Guo, Jun-tao Mai, Wen-xi Xu, Qing-xia Lin, Jun Liu
Journal: Molecular Therapy (2015)

Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development. Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development.
Abstract 20606: NADPH Oxidase 4-dependent Hydrogen Peroxide Production in Human Atrial Fibrillation: Relationship to Hypertension
Authors: Jun Zhang, Antony Y Kim, Ling Gao, Doan Ngo, Rafael J Ramire, Aman Mahajan, Hua Cai
Journal: Circulation (2010)

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia that is associated with increased risk of thromboembolism. Patients with AF often die of stroke caused by thrombi origin...
Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome
Authors: F P Tambaro, G Garcia-Manero, S M O'Brien, S H Faderl, A Ferrajoli, J A Burger, S Pierce, X Wang, K-A Do, H M Kantarjian, M J Keating, W G Wierda
Journal: Leukemia (2015)
Severe Hypoglycemia Requiring Medical Intervention in a Large Cohort of Adults With Diabetes Receiving Care in U.S. Integrated Health Care Delivery Systems: 2005–2011
Authors: Ram D. Pathak, Emily B. Schroeder, Elizabeth R. Seaquist, Chan Zeng, Jennifer Elston Lafata, Abraham Thomas, Jay Desai, Beth Waitzfelder, Gregory A. Nichols, Jean M. Lawrence, Andrew J. Karter, John F. Steiner, Jodi Segal, Patrick J. O’Connor
Journal: Diabetes Care (2015)

Appropriate glycemic control is fundamental to diabetes care, but aggressive glucose targets and intensive therapy may unintentionally increase episodes of hypoglycemia. We quantified the burden of severe hypoglycemia requiring medical intervention in a well-defined population of insured individuals with diabetes receiving care in integrated health care delivery systems across the U.S.This observational cohort study included 917,440 adults with diabetes receiving care during 2005 to 2011 at participating SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) network sites. Severe hypoglycemia rates were based on any occurrence of hypoglycemia-related ICD-9 codes from emergency department or inpatient medical encounters and reported overall and by age, sex, comorbidity status, antecedent A1C level, and medication use.Annual rates of severe hypoglycemia ranged from 1.4 to 1.6 events per 100 person-years. Rates of severe hypoglycemia were higher among those with older age, chronic kidney disease, congestive heart failure, cardiovascular disease, depression, and higher A1C levels, and in users of insulin, insulin secretagogues, or β-blockers (P < 0.001 for all). Changes in severe hypoglycemia occurrence over time were not clinically significant in the cohort as a whole but were observed in subgroups of individuals with chronic kidney disease, congestive heart failure, and cardiovascular disease.Risk of severe hypoglycemia in clinical settings is considerably higher in identifiable patient subgroups than in randomized controlled trials. Strategies that reduce the risk of hypoglycemia in high-risk patients are needed.
New Insights Into the Relationship Between the Skin and Endocrine Disorders
Authors: Rachel V. Reynolds
Journal: JAMA Dermatology (2015)

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Effects of novel heparin-derived compounds on tumor uptake of chemotherapeutics and chemoresponse
Authors: P. Phillips, M. Yalcin, H. Cui, H. H. Abdel-Nabi, M. Sajjad, R. Bernacki, S. Mousa
Journal: Journal of Clinical Oncology (2009)

2537 Thrombotic complications are the second most common cause of mortality in cancer patients and fibrin deposition in the tumor microenvironment might play a key role in tumor progression and inference with tumor chemotherapeutic uptake. Treatments that target these processes may result in improved uptake of chemotherapeutic agents and subsequent inhibition of tumor growth and metastasis. Tissue Factor (TF) is frequently associated with aggressive behavior and poor outcome in tumors. We have previously demonstrated potent anti-tumor efficacy for various mechanisms that interfere with TF/VIIa. The purpose of this study was to investigate the effects of low molecular weight heparins (LMWH) and sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake. Studies: (1) Nude mice xenograft A549 human lung carcinoma: LMWH or S-NACH at 10 mg/kg S.C. daily effectively limited tumor growth. (2) LCC6 human lung tumor xenograft model: Paclitaxel alone or in combination with Tinzaparin or S-NACH on tumor re-growth after discontinuation of treatment: Paclitaxel + S-NACH treatment showed significant (P&lt;0.01) tumor growth suppression and improved survival when compared to Paclitaxel. (3) Biodistribution studies: animals were injected with LMWH S.C. daily for 5 days (10 mg/kg) then injected i.v. with [ 124 -I]-Paclitaxel. LMWH increased [ 124 -I]-Paclitaxel uptake into LCC6 tumors with tumor: muscle ratios several fold greater than that of [ 124- I]-Paclitaxel alone at 24 hrs post injection. This is a highly significant result in the light of the fact that the FDA criterion for a clinically meaningful effect is a 15% increase in uptake. (4) HPLC studies of tumor uptake of Doxorubicin (DOX in mice treated with 10 mg/kg of LMWH or S-NACH for 10 days followed by Doxorubicin (2.5 mg/kg). Both LMWH and S-NACH significantly (P&lt;0.01) increased the uptake of chemotherapeutic agent DOX in MCF7 DOX resistant tumors by 1.5–2 folds but not in heart or lung tissues, confirming the findings obtained with another agent [ 124 -I]-Paclitaxel. Conclusions: LMWH or S-NACH increased chemotherapeutics uptake and hence chemoresponse. Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increase tumor chemo responsiveness and overcoming tumor chemo resistance. No significant financial relationships to disclose.
Angiotensin-converting enzyme gene polymorphism (ACEGP) and cancer cachexia (CC): Is there a link?
Authors: A. A. Vigano, N. Hamel, J. Morais, W. Foulkes, R. Kilgour, R. Bond, B. Trutschnigg, S. Brar, J. Theberge, M. Tremblay
Journal: Journal of Clinical Oncology (2007)

9011 Background: ACEGP greatly influences functional status and is currently the gene most involved in human fitness. The insertion allele (II) (a 287 bp fragment) rather than the deletion allele (DD) for the angiotensin-converting enzyme (ACE) gene is associated with low ACE levels in tissues and enhanced metabolic efficiency, as demonstrated by an improved response to vigorous training in healthy individuals. In addition, lower tissue ACE activity in mice was associated with decreased insulin resistance, greater glucose uptake in the skeletal muscle, and higher glycogen and fat stores. The aim of the study was to gather preliminary data on the potential association between muscle mass and ACEGP in advanced cancer patients (ACP). Methods: Buffy coat serum and plasma was obtained from 55 patients 18 years or older, newly diagnosed with Stage III (inoperable)-IV non-small cell lung cancer and unresectable/ metastatic gastrointestinal cancers seen within the McGill University Health Center. Muscle surface area (MSA-cm 2 ) was calculated from computerized tomography slices at the L3 vertebrae using TOMOVISION SliceOmatic software version 4.3. Muscularity (M-cm 2 /m 2 ) and lean body mass (LBM-kg) were calculated by extrapolation of image analysis used to quantify lean tissue. Results: ANOVA confirmed significant difference (p&lt;0.001) among MSA (II: 134.04±35.23; ID: 122.37±29.74; DD: 115.22±27.55), M (47.72±8.67; 41.65±9.26; 41.80±9.26), and LBM (43.00±11.21; 39.29±9.46; 37.01±8.77). In a multiple linear regression model, the II allele was associated with higher M (p=0.042) and a trend for higher MSA and LBM (p=0.059) independent of age, gender, diagnosis, and treatment received. Conclusions: Our data suggest ACEGP influences muscle mass in ACP. Further investigations in a larger sample of ACP are underway to determine whether ACEGP is an important predisposing factor to CC-associated muscle wasting. No significant financial relationships to disclose.