tbuckley/cabot-search huggingface dataset:
Valvular Heart Disease Associated with Fenfluramine–Phentermine
Authors: Heidi M. Connolly, Jack L. Crary, Michael D. McGoon, Donald D. Hensrud, Brooks S. Edwards, William D. Edwards, Hartzell V. Schaff
Journal: New England Journal of Medicine (1997)

Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million.
Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia
Authors: F. Lo Coco, D. Diverio, G. Avvisati, W. Arcese, M.C. Petti, G. Meloni, F. Mandelli, P.P. Pandolfi, F. Grignani, P.G. Pelicci, A. Biondi, V. Rossi, G. Masera, T. Barbui, A. Rambaldi
Journal: The Lancet (1992)
Phase II and Biologic Study of Interferon Alfa, Retinoic Acid, and Cisplatin in Advanced Squamous Skin Cancer
Authors: Dong M. Shin, Bonnie S. Glisson, Fadlo R. Khuri, John L. Clifford, Gary Clayman, Steven E. Benner, Arlene A. Forastiere, Lawrence Ginsberg, Diane Liu, J. Jack Lee, Jeffrey Myers, Helmuth Goepfert, Reuben Lotan, Waun Ki Hong, Scott M. Lippman
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The purpose of this study was to test interferon alfa (IFNα), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin. PATIENTS AND METHODS: Patients with advanced skin SCC received IFNα (5 × 106 IU/m2, subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m2, intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9). RESULTS: Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P = .007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFNα in two skin SCC lines. CONCLUSION: The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFNα, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non–cross-resistant biologic effects in vitro, which may account for the combination's clinical activity.
Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer’s disease
Authors: Yuhki Saito, Tsuyoshi Inoue, Gang Zhu, Naoki Kimura, Motohiro Okada, Masaki Nishimura, Nobuyuki Kimura, Shigeo Murayama, Sunao Kaneko, Ryuichi Shigemoto, Keiji Imoto, Toshiharu Suzuki
Journal: Molecular Neurodegeneration (2012)

Abstract Background One of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Aβ generation. However, the molecular linkage between epileptic seizures and Aβ generation in AD remains unclear. Results X11 and X11-like (X11L) gene knockout mice suffered from epileptic seizures, along with a malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Genetic ablation of HCN1 in mice and HCN1 channel blockage in cultured Neuro2a (N2a) cells enhanced Aβ generation. Interestingly, HCN1 levels dramatically decreased in the temporal lobe of cynomolgus monkeys ( Macaca fascicularis ) during aging and were significantly diminished in the temporal lobe of sporadic AD patients. Conclusion Because HCN1 associates with amyloid-β precursor protein (APP) and X11/X11L in the brain, genetic deficiency of X11/X11L may induce aberrant HCN1 distribution along with epilepsy. Moreover, the reduction in HCN1 levels in aged primates may contribute to augmented Aβ generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and Aβ generation, and in the aggravation of sporadic AD.
Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings
Authors: Alvaro Urbano-Ispizua, Ciril Rozman, Pedro Pimentel, Carlos Solano, Javier de la Rubia, Salut Brunet, Jaime Pérez-Oteyza, Christelle Ferrá, Javier Zuazu, Dolores Caballero, Joan Bargay, Alzira Carvalhais, Jose Luis Dı́ez, Ildefonso Espigado, Adrián Alegre, Montserrat Rovira, Fernando Campilho, Jesús Odriozola, Miguel Angel Sanz, Jordi Sierra, Javier Garcı́a-Conde, Emili Montserrat
Journal: Blood (2002)
Pseudoepitheliomatous hyperplasia in cutaneous T-cell lymphoma. A clinical, histopathological and immunohistochemical study with particular interest in epithelial growth factor expression
Authors: None COURVILLE, None WECHSLER, None THOMINE, None VERGIER, None FONCK, None SOUTEYRAND, None BEYLOT-BARRY, None BAGOT, None JOLY
Journal: British Journal of Dermatology (1999)

Pseudoepitheliomatous hyperplasia has occasionally been reported in cutaneous T-cell lymphoma (CTCL). This association raises the question of the relationship between epidermal hyperplasia and the lymphomatous infiltrate. Because epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) have been demonstrated to be involved in epidermal proliferation through binding to EGF receptor (EGFr), we tested the hypothesis that these cytokines could be secreted by lymphomatous cells, and induce the overlying pseudoepitheliomatous hyperplasia. The purposes of this study were: (i) to describe the clinical and immunohistological features of pseudoepitheliomatous hyperplasia; (ii) to determine its frequency in a large series of CTCLs; and (iii) to evaluate the expression of EGF, TGF-alpha and EGFr in CTCL with or without pseudoepitheliomatous hyperplasia. Eleven cases of CTCL with pseudoepitheliomatous hyperplasia were collected from a series of 353 cases of cutaneous lymphoma registered from 1990 to 1996. They consisted of eight of 28 (28.5%) CD30+ large T-cell lymphomas and three of 148 (2%) cases of mycosis fungoides. Epidermal expression of EGF, EGFr and TGF-alpha was stronger in CTCL than in control normal human skin. Lymphomatous T cells expressed EGF and TGF-alpha whereas no expression of these cytokines could be detected in cutaneous and nodal B-cell lymphomas, nor in a normal lymph node. In addition, epidermal expression of EGFr was stronger in CTCL with pseudoepitheliomatous hyperplasia than in control cases of CTCL without pseudoepitheliomatous hyperplasia, suggesting that these cytokines, in association with other factors, are probably involved in the epidermal hyperplasia observed in some cases of CTCL.
Preclinical Studies of TW-37, a New Nonpeptidic Small-Molecule Inhibitor of Bcl-2, in Diffuse Large Cell Lymphoma Xenograft Model Reveal Drug Action on Both Bcl-2 and Mcl-1
Authors: Ramzi M. Mohammad, Anton Scott Goustin, Amro Aboukameel, Ben Chen, Sanjeev Banerjee, Guoping Wang, Zaneta Nikolovska-Coleska, Shaomeng Wang, Ayad Al-Katib
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Overexpression of Bcl-2 protein has been observed in more than 80% of B-cell lymphomas, including diffuse large cell lymphoma (DLCL), the most common subtype of non-Hodgkin's lymphoma. We have previously employed the natural product (−)-gossypol to test its therapeutic potential as a small-molecule inhibitor of Bcl-2 for the treatment of B-cell lymphomas. Experimental Design: Recently, we have used a structure-based strategy to design a new class of potent small-molecule inhibitor acting on Bcl-2. One such lead compound is the benzenesulfonyl derivative TW-37, which was designed to target the BH3-binding groove in Bcl-2 where proapoptotic Bcl-2 proteins, such as Bak, Bax, Bid, and Bim bind. Results: In our fluorescence polarization–based binding assays using recombinant Bcl-2, Bcl-XL, and Mcl-1 proteins, TW-37 binds to Bcl-2, Bcl-XL, and Mcl-1 with Ki values of 290, 1,110 and 260 nmol/L, respectively. Hence, TW-37 is a potent inhibitor of Bcl-2 and has &amp;gt;3-fold selectivity over Bcl-XL. In vitro, TW-37 showed significant antiproliferative effect in a de novo chemoresistant WSU-DLCL2 lymphoma cell line and primary cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. Coimmunoprecipitation experiments showed that TW-37 disrupted heterodimer formation between Bax or truncated-Bid and antiapoptotic proteins in the order Mcl-1 &amp;gt; Bcl-2 &amp;gt;&amp;gt; Bcl-XL. As expected, TW-37 caused apoptotic death. Pre-exposure of lymphoma cells to TW-37 significantly enhanced the killing effect of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) regimen. The maximum tolerated dose of TW-37 in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg, ×3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the addition of TW-37 to CHOP resulted in more complete tumor inhibition compared with either CHOP or TW-37 alone. Conclusions: We conclude that the administration of TW-37, as a potent Bcl-2 and Mcl-1 inhibitor, to standard chemotherapy may prove an effective strategy in the treatment of B-cell lymphoma.
Assembly, Transport, and Function of MHC Class II Molecules
Authors: Peter Cresswell
Journal: Annual Review of Immunology (1994)

MHC class II molecules assemble in the endoplasmic reticulum in a chaperone-mediated fashion to form a nine-chain structure consisting of three alpha beta dimers associated with an invariant chain trimer. This complex is transported through the Golgi apparatus and into the endosomal system. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. Current evidence argues that the segregation of the class II-invariant chain complex from the constitutive pathway of membrane protein transport occurs in the trans-Golgi network. However, class II-invariant chain complexes that reach the cell surface are also rapidly internalized into endosomes. Within the endosomal system, probably in a late endosome/pre-lysosome, the invariant chain is degraded, releasing alpha beta dimers that bind peptides predominantly derived from endocytosed proteins. Evidence suggests that many of these peptides are actually generated in lysosomes. The precise mechanisms involved in forming class II-peptide complexes are unclear, although the existence of antigen-processing mutants argues that additional gene products, at least one of which is encoded in the MHC, are involved. After binding peptides, class II molecules are transported by an unknown route to the cell surface, where their primary function of presenting antigenic peptides to CD4 + T cells is carried out.
Review of NICE's recommendations, 1999-2005
Authors: James Raftery
Journal: BMJ (2006)

The creation of the National Institute for Clinical Excellence (NICE) in 1999 put the English NHS in a leading role in setting healthcare priorities.1 Although Australia, New Zealand, and Canada have systems that judge the cost effectiveness of drugs,2–4 they do not assess other health technologies. Bodies similar to NICE are reportedly being established in other countries, notably Germany5 and France.6 By April 2005, NICE had published 86 guidances on the use of health technologies and 39 guidelines on the treatment of diseases. It has received several generally favourable reviews from independent agencies including the House of Commons Health Committee,7 the World Health Organization,8 and independent academics.9

NICE appraises the clinical and cost effectiveness of health technologies referred to it by the Department of Health. This is different from a scientific assessment and synthesis of the evidence, which is subcontracted to independent academic groups. The two NICE committees appraise this often incomplete evidence. The committees rely on the judgments of their members, who comprise clinicians, health scientists, managers, and patient representatives.

NICE's recommendations are issued in the form of mandatory guidance to the NHS.10 It started controversially by recommending against the use of zanamavir, an antiviral drug for flu. However, reviews of the guidances issued in the first years show that few recommendations can be classified as simply yes or no.11–14

Despite suggestions to the contrary,11 13 15 NICE has repeatedly stated that it does not have a threshold at which cost effectiveness becomes unacceptable. However, it has clarified that when the cost per quality adjusted life year (QALY) is above £20 000 (€29 000; $37 000), “Judgements about the acceptability of the technology as an acceptable use of NHS resources are more likely to make …
DNMT1–MicroRNA126 Epigenetic Circuit Contributes to Esophageal Squamous Cell Carcinoma Growth via ADAM9–EGFR–AKT Signaling
Authors: Ronghua Liu, Jie Gu, Pei Jiang, Yijie Zheng, Xiaoming Liu, Xuechao Jiang, Enyu Huang, Shudao Xiong, Fengkai Xu, Guangwei Liu, Di Ge, Yiwei Chu
Journal: Clinical Cancer Research (2014)

MicroRNAs (miRNA) are involved in and are controlled by epigenetic regulation, and thereby form a reciprocal regulatory circuit. Using next-generation sequencing (NGS)-based miRNA profiling, this study aimed to discover esophageal squamous cell carcinoma (ESCC)-specific miRNAs and miRNA-related epigenetic modulations.NGS-based miRNA profiles were generated for four pairs of ESCC tissues and adjacent normal tissues. In situ hybridization was used to assess miRNA expression and its correlation with prognosis. miRNA-related DNA methylations were identified using bisulfite genomic sequencing, and the role of DNA methyltransferase 1 (DNMT1) was investigated using RNA interference. miRNA targets were screened by mRNA sequencing, and functional validation was performed in vitro and in vivo.NGS-based miRNA profiling identified 78 differentially expressed miRNAs in ESCC. Among them, microRNA126-3p (miR-126) was significantly downregulated, and its downregulation correlated with poor ESCC prognosis. Downregulation of miR-126 was due to promoter hypermethylation of its host gene, Egfl7. DNMT1 was aberrantly upregulated in ESCC and responsible for the hypermethylation of Egfl7. Intriguingly, DNMT1 was suppressed by overexpression of miR-126, indicating the existence of a regulatory feedback circuit. ADAM9 was identified as a key target of miR-126. Ectopic expression of miR-126 or silencing of ADAM9 reduced ESCC cell proliferation and migration by inhibiting epidermal growth factor receptor-AKT signaling.Our results indicate that miR-126 is a potential prognostic indicator for ESCC and suggest that a novel "DNMT1-miR-126 epigenetic circuit" is involved in ESCC progression. Consequently, miR-126-based epigenetic modulations may provide a basic rationale for new approaches to antitumor therapeutics.
The Problem Areas in Diabetes Scale: An evaluation of its clinical utility
Authors: Garry W Welch, Alan M Jacobson, William H Polonsky
Journal: Diabetes Care (1997)

OBJECTIVE To evaluate the reliability and concurrent and discriminant validity of the Problem Areas in Diabetes (PAID) scale, a new measure of emotional functioning in diabetes. RESEARCH DESIGN AND METHODS A battery of questionnaires, including the PAID, was completed by 256 volunteer diabetic outpatients. In our analyses, we examined the PAID's internal structure and compared mean IDDM and NIDDM treatment group scores in regression analyses to explore its discriminant validity. We also evaluated concurrent validity from the correlations between the PAID and diabetes-specific measures of coping and health attitudes and HbA1c. RESULTS Principal component analyses identified a large emotional adjustment factor, supporting the use of the total score. Significant sizable correlations were found between the PAID and a range of selected health attitudinal measures. There were significant differences (with small-to-moderate effect sizes) in PAID scores between IDDM and NIDDM patients and between IDDM and NIDDM insulin- and tablet-treated subgroups; no differences were found between NIDDM insulin- and tablet-treated subgroups. CONCLUSIONS The study findings provided support for the construct validity of the PAID, including evidence for discriminant validity from its ability to detect differences between IDDM and NIDDM treatment groups expected to differ in the emotional impact of life with diabetes. Future studies should explore the PAID's performance in nonspecialist treatment settings as well as its responsiveness to clinical change.
Current concepts in Alzheimer’s Disease: molecules, models and translational perspectives
Authors: Bart PF Rutten, Harry WM Steinbusch
Journal: Molecular Neurodegeneration (2013)

The field of neuroscience research in AD has been evolving rapidly over the last few years, and has pinpointed a number of candidate targets for molecules with crucial role in the pathophysiology of AD. Recent developments have furthermore enabled new ways of modeling the disease, while an increasing number of preclinically validated targets is currently being taken one step forward and tested in clinical trials. These recent developments are reviewed in the current Special Issues Series on "Current concepts in Alzheimer's disease research: molecules, models and translational perspectives" in a number of state-of-the-art manuscripts.
High incidence of primary pulmonary hypertension associated with appetite suppressants in Belgium
Authors: M Delcroix, X Kurz, D Walckiers, M Demedts, R Naeije
Journal: European Respiratory Journal (1998)

Primary pulmonary hypertension is a rare, progressive and incurable disease, which has been associated with the intake of appetite suppressant drugs. The importance of this association was evaluated in Belgium while this country still had no restriction on the prescription of appetite suppressants. Thirty-five patients with primary pulmonary hypertension and 85 matched controls were recruited over 32 months (1992-1994) in Belgium. Exposure to appetite-suppressants was assessed on the basis of hospital records and standardized interview. Twenty-three of the patients had previously taken appetite suppressants, mainly fenfluramines, as compared with only 5 of the controls (66 versus 6%, p<0.0001). Five patients died before the interview, all of them had taken appetite suppressants. In 8 patients the diagnosis of primary pulmonary hypertension was uncertain, 5 of them had taken appetite suppressants. The patients who had been exposed to appetite suppressants tended to be on average more severely ill, and to have a shorter median delay between onset of symptoms and diagnosis. A policy of unrestricted prescription of appetite suppressants may lead to a high incidence of associated primary pulmonary hypertension. Intake of appetite suppressants may accelerate the progression of the disease.
Targeted Deletion of Kv4.2 Eliminates <i>I</i> <sub>to,f</sub> and Results in Electrical and Molecular Remodeling, With No Evidence of Ventricular Hypertrophy or Myocardial Dysfunction
Authors: Weinong Guo, W. Edward Jung, Céline Marionneau, Franck Aimond, Haodong Xu, Kathryn A. Yamada, Thomas L. Schwarz, Sophie Demolombe, Jeanne M. Nerbonne
Journal: Circulation Research (2005)

Previous studies have demonstrated a role for voltage-gated K + (Kv) channel α subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K + current, I to,f , channels. Biochemical studies suggest that mouse ventricular I to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kvβ1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I to,f densities. Interestingly, the phenotypic consequences of manipulating I to,f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2 −/− ) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2 −/− ventricular myocytes revealed that I to,f is eliminated. In addition, the slow transient outward K + current, I to,s , and the Kv1.4 protein (which encodes I to,s ) are upregulated in Kv4.2 −/− ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2 −/− ventricles. Similar to Kv4.3, expression of Kvβ1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2 −/− ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I to,f in Kv4.2 −/− mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I to,f channels but also that the loss of I to,f per se does not have overt pathophysiological consequences.
Characterization of a Germ-Line Deletion, Including the Entire <i>INK4/ARF</i> Locus, in a Melanoma-Neural System Tumor Family: Identification of <i>ANRIL</i>, an Antisense Noncoding RNA Whose Expression Coclusters with <i>ARF</i>
Authors: Eric Pasmant, Ingrid Laurendeau, Delphine Héron, Michel Vidaud, Dominique Vidaud, Ivan Bièche
Journal: Cancer Research (2007)

Abstract We have previously detected a large germ-line deletion, which included the entire p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster, in the largest melanoma-neural system tumor (NST) syndrome family known to date by means of heterozygosity mapping based on microsatellite markers. Here, we used gene dose mapping with sequence-tagged site real-time PCR to locate the deletion end points, which were then precisely characterized by means of long-range PCR and nucleotide sequencing. The deletion was exactly 403,231 bp long and included the entire p15/CDKN2B, p16/CDKN2A, and p14/ARF genes. We then developed a simple and rapid assay to detect the junction fragment and to serve as a direct predictive DNA test for this large French family. We identified a new large antisense noncoding RNA (named ANRIL) within the 403-kb germ-line deletion, with a first exon located in the promoter of the p14/ARF gene and overlapping the two exons of p15/CDKN2B. Expression of ANRIL mainly coclustered with p14/ARF both in physiologic (various normal human tissues) and in pathologic conditions (human breast tumors). This study points to the existence of a new gene within the p15/CDKN2B-p16/CDKN2A-p14/ARF locus putatively involved in melanoma-NST syndrome families and in melanoma-prone families with no identified p16/CDKN2A mutations as well as in somatic tumors. [Cancer Res 2007;67(8):3963–9]