tbuckley/cabot-search huggingface dataset:
Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma
Authors: Kangsheng Tu, Wei Yang, Chao Li, Xin Zheng, Zhongtang Lu, Cheng Guo, Yingmin Yao, Qingguang Liu
Journal: Molecular Cancer (2014)

The E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear. The Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo. In this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo. These results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.
Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression
Authors: A.K.M. Ghulam Muhammad, Marianela Candolfi, Gwendalyn D. King, Kader Yagiz, David Foulad, Yohei Mineharu, Kurt M. Kroeger, Katherine A. Treuer, W. Stephen Nichols, Nicholas S. Sanderson, Jieping Yang, Maksim Khayznikov, Nico Van Rooijen, Pedro R. Lowenstein, Maria G. Castro
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme. Experimental Design: We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1–thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir. Results: This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme–specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8+ T cells. Circulating anti-glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naïve rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells. Conclusions: Treatment with Ad-Flt3L + Ad-TK triggered systemic anti–glioblastoma multiforme cellular and humoral immune responses, and anti–glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial. (Clin Cancer Res 2009;15(19):6113–27)
The RAG Proteins and V(D)J Recombination: Complexes, Ends, and Transposition
Authors: Sebastian D. Fugmann, Alfred Ian Lee, Penny E. Shockett, Isabelle J. Villey, David G. Schatz
Journal: Annual Review of Immunology (2000)

V(D)J recombination proceeds through a series of protein:DNA complexes mediated in part by the RAG1 and RAG2 proteins. These proteins are responsible for sequence-specific DNA recognition and DNA cleavage, and they appear to perform multiple postcleavage roles in the reaction as well. Here we review the interaction of the RAG proteins with DNA, the chemistry of the cleavage reaction, and the higher order complexes in which these events take place. We also discuss postcleavage functions of the RAG proteins, including recent evidence indicating that they initiate the process of coding end processing by nicking hairpin DNA termini. Finally, we discuss the evolutionary and functional implications of the finding that RAG1 and RAG2 constitute a transposase, and we consider RAG protein biochemistry in the context of several bacterial transposition systems. This suggests a model of the RAG protein active site in which two divalent metal ions serve alternating and opposite roles as activators of attacking hydroxyl groups and stabilizers of oxyanion leaving groups.
Recombinant <i>Mycobacterium bovis</i> Bacillus Calmette-Guérin Secreting Merozoite Surface Protein 1 (MSP1) Induces Protection against Rodent Malaria Parasite Infection Depending on MSP1-stimulated Interferon γ and Parasite-specific Antibodies
Authors: Sohkichi Matsumoto, Hideharu Yukitake, Hiroji Kanbara, Takeshi Yamada
Journal: The Journal of Experimental Medicine (1998)

The merozoite surface protein 1 (MSP1) has emerged as a leading malaria vaccine candidate at the erythrocytic stage. Recombinant bacillus Calmette-Guérin (rBCG), which expressed a COOH-terminal 15-kD fragment of MSP1 of Plasmodium yoelii (MSP1-15) as a fusion protein with a secretory protein of Mycobacterium kansasii, was constructed. Immunization of mice with this rBCG induced a higher degree of protection against blood-stage parasite infection than with recombinant MSP1-15 in the RIBI adjuvant (RIBI ImmunoChem Research, Inc., Hamilton, MT) or incomplete Freund's adjuvant systems. We studied the mechanism of protection induced by MSP1-15, and found that interferon (IFN)-γ had a major role in protection in all adjuvant systems we examined. Mice that produced low amounts of MSP1-15 stimulated IFN-γ and could not control parasite infection. The antibody against MSP1-15 did not play a major role in protection in this system. After parasite infection, immunoglobulin G2a antibodies, which had been produced by IFN-γ stimulation, were induced and subsequently played an important role in eradicating parasites. Thus, both cellular and humoral immune responses were essential for protection from malaria disease. These data revealed that BCG is a powerful adjuvant to induce such a protective immune response against malaria parasites.
The changing face of respiratory physiology: 20 years of progress within the ERS: Clinical Physiology and Integrative Biology Assembly contribution to the celebration of 20 years of the ERS
Authors: P. Calverley, G. Miserocchi, L. Puente Maestu, A. Aliverti, W. De Backer, S. Andreas, M. Humbert
Journal: European Respiratory Journal (2010)

Respiratory physiology, the study of the function of the respiratory system in health and disease, was one of the core disciplines in respiratory medicine throughout the second half of the 20th Century. Moreover, clinical and basic physiologists were central to the creation of the European Respiratory Society (ERS) 20 yrs ago. Despite concerns that all the “interesting” questions in physiology had been answered, the last 20 yrs have shown that applying physiological principles to respiratory disease not only leads to new insights into how the lungs work when stressed, but has also identified new areas where the diagnosis and treatment of previously intractable or unrecognised physiological disorders has transformed the lives of large numbers of people.

This editorial reflects this diversity of interest, but is only a snapshot of some of the exciting possibilities that a physiological approach to respiratory disease has made possible.

By the late 1980s the key principles underpinning lung mechanics and gas exchange within the lung had been established and applied to most, but not all, problems. One orphan area was the understanding of the mechanisms controlling lung extravascular water volume. Although the lungs are functionally exposed to conditions causing an increase in microvascular filtration, such as capillary recruitment, increase in cardiac output and hypoxia, a common condition in cardiopulmonary disorders, the extracellular matrix normally limits extravascular water volume to <10% (interstitial oedema) 1. Matrix proteoglycans ensure low permeability of capillary endothelium and a fairly rigid interstitial matrix due to their assembly as link molecules within the matrix and among cells 1. However, a sustained condition of interstitial oedema, as well as lung overdistension, produces severe pulmonary complications, such as acute respiratory distress syndrome, which causes disruption of the extracellular matrix leading to an increase in microvascular permeability and unopposed fluid extravasation 1, 2. …
Pulmonary gas transfer in children and adolescents born extremely preterm
Authors: Emma Satrell, Ola Røksund, Einar Thorsen, Thomas Halvorsen
Journal: European Respiratory Journal (2012)

In extremely preterm-born infants, gas exchange takes place in developmentally fetal lungs, disturbing normal acinar growth and differentiation, potentially with long term negative consequences for lung function. The aim was to compare alveolar function in children and adolescents born extremely preterm and at term by measuring diffusing capacity of the lung for carbon monoxide ( D LCO ). Since this procedure may be challenging for subjects with shortcomings often seen after extremely preterm birth, we also assessed the reproducibility of the method. D LCO and D LCO adjusted for lung volume ( K CO ) were measured twice within 2 weeks in two population-based cohorts born at gestational age ≤28 weeks or with birth weight ≤1000 g, aged 10.6 years (n = 35) and 17.7 years (n = 46), and in 81 term-born controls individually matched for sex, age and place of birth. Reproducibility of D LCO measurements was in the same range for preterm and term-born children and young adults, and coefficients of variation were below 10% for all subgroups. K CO was significantly reduced with 7.9% and 7.2% for the oldest and youngest preterm birth cohorts, respectively. Reproducibility of D LCO in children and young adults born extremely preterm was adequate. D LCO and K CO were modestly reduced, supporting recent reports suggesting continuing alveolar growth throughout childhood.
The Association of MicroRNA Expression with Prognosis and Progression in Early-Stage, Non–Small Cell Lung Adenocarcinoma: A Retrospective Analysis of Three Cohorts
Authors: Motonobu Saito, Aaron J. Schetter, Steen Mollerup, Takashi Kohno, Vidar Skaug, Elise D. Bowman, Ewy A. Mathé, Seiichi Takenoshita, Jun Yokota, Aage Haugen, Curtis C. Harris
Journal: Clinical Cancer Research (2011)

There is increasing evidence that altered microRNA expression is associated with tumor progression and survival in cancer patients. We tested if the expression of specific microRNAs was associated with prognosis and disease progression in early-stage lung adenocarcinoma.
Minimal residual disease monitoring in <i>t</i>(8;21) acute myeloid leukemia based on <i>RUNX1‐RUNX1T1</i> fusion quantification on genomic DNA
Authors: Nicolas Duployez, Olivier Nibourel, Alice Marceau‐Renaut, Christophe Willekens, Nathalie Helevaut, Aurélie Caillault, Céline Villenet, Karine Celli‐Lebras, Nicolas Boissel, Eric Jourdan, Hervé Dombret, Martin Figeac, Claude Preudhomme, Aline Renneville
Journal: American Journal of Hematology (2014)

Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing. RUNX1-RUNX1T1 DNA quantification was performed by real-time quantitative PCR using patient-specific primers and probe. MRD levels were evaluated in 71 follow-up samples from 16 patients, with a median of four samples [range 2-7] per patient. RUNX1 breakpoints were located in intron 5 in all cases. RUNX1T1 breakpoints were located in intron 1b in 15 cases and in intron 1a in two cases. RUNX1-RUNX1T1 MRD levels measured on DNA and RNA were strongly correlated (r = 0.8, P < 0.0001). Discordant MRD results were observed in 10/71 (14%) of the samples: in three samples from two patients who relapsed, RUNX1-RUNX1T1 was detectable only on DNA, while RUNX1-RUNX1T1 was detectable only on RNA in seven samples. MRD monitoring on genomic DNA is feasible, but with sensitivity variations depending on the patient breakpoint sequence and the qPCR assay efficiency. Although interpretation of the results is easier because it is closely related to the number of leukemic cells, this method greatly increases time, cost and complexity, which limits its interest in routine practice.
Sleep Apnea in Patients on Conventional Thrice-Weekly Hemodialysis
Authors: Mark L. Unruh, Mark H. Sanders, Susan Redline, Beth M. Piraino, Jason G. Umans, Terese C. Hammond, Imran Sharief, Naresh M. Punjabi, Anne B. Newman
Journal: Journal of the American Society of Nephrology (2006)

Sleep-disordered breathing (SDB) has been noted commonly in hemodialysis (HD) patients, but it is not known whether this is related directly to the treatment of kidney failure with HD or to the higher prevalence of obesity and older age. Forty-six HD patients were compared with 137 participants from the Sleep Heart Health Study (SHHS) who were matched for age, gender, body mass index (BMI), and race. Home unattended polysomnography was performed and scored using similar protocols. The study sample was 62.7 ± 10.1 yr, was predominantly male (72%) and white (63%), and had an average BMI of 28 ± 5.3 kg/m2. The HD sample had a higher systolic BP (137 versus 121 mmHg; P < 0.01) and a higher prevalence of diabetes (33 versus 9%; P < 0.01) and cardiovascular disease (33 versus 13%; P < 0.01) compared with the SHHS sample. The HD group had significantly less sleep time (320 versus 379 min; P < 0.0001) but similar sleep efficiency. HD patients had a higher frequency of arousals per hour (25.1 versus 17.1; P < 0.0001) and apnea-hypopneas per hour (27.2 versus 15.2; P < 0.0001) and greater percentage of the total sleep time below an oxygen saturation of 90% (7.2 versus 1.8; P < 0.0001). HD patients were more likely to have severe SDB (>30 respiratory events per hour) compared with the SHHS sample (odds ratio 4.07; 95% confidence interval 1.83 to 9.07). There was a strong association of HD with severe SDB and nocturnal hypoxemia independent of age, BMI, and the higher prevalence of chronic disease. The potential mechanisms for the higher likelihood of SDB in the HD population must be identified to provide specific prevention and therapy.
Justice Policy Reform for High-Risk Juveniles: Using Science to Achieve Large-Scale Crime Reduction
Authors: Jennifer L. Skeem, Elizabeth Scott, Edward P. Mulvey
Journal: Annual Review of Clinical Psychology (2014)

After a distinctly punitive era, a period of remarkable reform in juvenile crime regulation has begun. Practical urgency has fueled interest in both crime reduction and research on the prediction and malleability of criminal behavior. In this rapidly changing context, high-risk juveniles—the small proportion of the population where crime becomes concentrated—present a conundrum. Research indicates that these are precisely the individuals to treat intensively to maximize crime reduction, but there are both real and imagined barriers to doing so. Mitigation principles (during early adolescence, ages 10–13) and institutional placement or criminal court processing (during mid-late adolescence, ages 14–18) can prevent these juveniles from receiving interventions that would best protect public safety. In this review, we synthesize relevant research to help resolve this challenge in a manner that is consistent with the law's core principles. In our view, early adolescence offers unique opportunities for risk reduction that could (with modifications) be realized in the juvenile justice system in cooperation with other social institutions.
Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial
Authors: Gregg W Stone, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z Peruga, Bruce R Brodie, Dariusz Dudek, Ran Kornowski, Franz Hartmann, Bernard J Gersh, Stuart J Pocock, George Dangas, S Chiu Wong, Martin Fahy, Helen Parise, Roxana Mehran
Journal: The Lancet (2011)
Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy
Authors: Shuichi Okada, Nobuo Okazaki, Haruhiko Nose, Masayoshi Yoshimori, Kazunori Aoki
Journal: Hepatology (1992)

A total of 71 consecutive patients with unresectable hepatocellular carcinoma were analyzed retrospectively to determine the significant prognostic factors. All the patients received systemic chemotherapy in a phase 2 study from 1980 to 1990, with no other anticancer treatment. Median survival time and 1–yr and 2–yr survival rates were 5.6 mo, 23% and 5%, respectively. By the univariate analysis, a performance status of 0-1 and tumor size less than 50% of the liver cross–sectional area were shown to be the factors most significantly favoring a better prognosis. By the multivariate analysis using the Cox proportional hazards model, a performance status of 0-1 (p &lt; 0.001), absence of tumor thrombus in the main portal trunk (p = 0.003) and age less than 60 yr (p = 0.036) were independent favorable prognostic factors. A prognostic index was calculated from these three factors according to the following equation: 1.8109 × (0 = performance status of 0-1 and 1 = performance status of 2-3) + 0.9322 × (0 = tumor thrombus absent in the main portal trunk and 1 = present) + 0.6996 × (0 = age &lt; 60 yr and 1 = age ± 60 yr). This index was used to classify the patients into three groups with a good, intermediate and poor prognosis. The median survival times for these three groups were 9.8, 3.8 and 1.9 mo, respectively (p &lt; 0.01). The results of this study may be useful in the design and analysis of future clinical trials of systemic therapy for hepatocellular carcinoma. (Hepatology 1992;16:112-117.)
Thrombopoietin Gene Transfer–Mediated Enhancement of Angiogenic Responses to Acute Ischemia
Authors: Hideki Amano, Neil R. Hackett, Shahin Rafii, Ronald G. Crystal
Journal: Circulation Research (2005)

The development of new blood vessels is a complex process, likely requiring the synergy of multiple angiogenic mediators. This study focuses on the proximal angiogenic response using the platelet as a complex carrier of critical mediators of angiogenesis. Platelet levels are controlled by circulating levels of thrombopoietin (TPO) functioning to activate megakaryocyte differentiation and platelet release through the c-mpl receptor. We hypothesized that TPO gene transfer should enhance correction of experimental ischemia by providing increased levels of platelets and hence platelet-derived mediators of angiogenesis. To evaluate this hypothesis, we dissected the role of the TPO-c-mpl-megakaryocyte-platelet pathway in the angiogenic response using a model of acute hindlimb ischemia of wild-type, TPO(-/-), and c-mpl(-/-) mice. The data demonstrate that infusion of platelets will enhance the angiogenic response in wild-type mice and that the endogenous angiogenic response is blunted in TPO(-/-) and c-mpl(-/-) mice. Consistent with this observation, adenovirus (Ad)-mediated transfer of TPO (AdTPO) enhanced the correction of ischemia in wild-type and TPO(-/-), but not c-mpl(-/-), mice. Local versus systemic administration of AdTPO showed that the effect of TPO gene transfer was systemic, not local, and it could be replaced by gene transfer of VEGF, one of the many mediators of angiogenesis carried by the platelets, even in the absence of components in the TPO-c-mpl-megakaryocyte-platelet pathway.
Illnesses of the Spirit Among the Serer of Senegal
Authors: MORTON BEISER, WINTHROP A. BURR, JEAN-LOUIS RAVEL, HENRI COLLOMB
Journal: American Journal of Psychiatry (1973)

This report is part of an extensive survey of the Serer tribe in West Africa; the purpose is to assess clinical characteristics and prevalence of psychiatric disorder. Using key-informant interviewing, the authors identified three "illnesses of the spirit" as corresponding in many ways to Western notions of mental illness. Case material is presented that provides impressionistic evidence of the universality of some mental disorders.
QUANTITATION OF TRANSPLANTATION IMMUNITY
Authors: John S. Najarian, Joseph D. Feldman
Journal: The Journal of Experimental Medicine (1965)

A technique for in vivo quantitation of transplantation immunity has been presented. Known numbers of H(3)-thymidine-labeled lymphoid cells were injected intravenously into isologous or homologous recipients. The total radioactivity in host spleens was counted at different time intervals. The rate of isotope disappearance from the spleen was exponential to 0.5 per cent of the dose or less. In isologous recipients, the calculated half-life of labeled cells was 82 hours; in homologous recipients it was 40 hours; and in presensitized homologous hosts it was 18 hours. The technique is a highly reproducible, precise, and sensitive measure of transplantation immunity.