tbuckley/cabot-search huggingface dataset:
Extracardiac Progenitor Cells Repopulate Most Major Cell Types in the Transplanted Human Heart
Authors: Elina Minami, Michael A. Laflamme, Jeffrey E. Saffitz, Charles E. Murry
Journal: Circulation (2005)

Background— Extracardiac progenitor cells are capable of repopulating cardiomyocytes at very low levels in the human heart after injury. Here, we explored the extent of endothelial, smooth muscle, and Schwann cell chimerism in patients with sex-mismatched (female-to-male) heart transplants. Methods and Results— Autopsy specimens from 5 patients and endomyocardial biopsies from 7 patients were used for this study. Endothelial, vascular smooth muscle, and Schwann cells were stained with antibodies against CD31 or Ulex europaeus lectin, smooth muscle α-actin, and S-100, respectively, and the Y chromosome was identified with in situ hybridization. Biopsy specimens from 1, 4, 6, and 12 months and 5 and 10 years after heart transplantation were evaluated. Y-positive cells were counted by conventional bright-field microscopy and confirmed by confocal microscopy. Endothelial cells showed the highest degree of chimerism, averaging 24.3±8.2% from extracardiac sources. Schwann cells showed the next highest chimerism, averaging 11.2±2.1%; vascular smooth muscle cells averaged 3.4±1.8%. All 3 cell types showed substantially higher chimerism than we previously observed for cardiomyocytes (0.04±0.05%). Endothelial chimerism was much higher in the microcirculation than in larger vessels. Analysis of serial endomyocardial biopsies revealed that high levels of endothelial chimerism occurred as early as 1 month after transplantation (22±6.6%) with no significant increases even up to 10 years after cardiac transplantation. Conclusions— Extracardiac progenitor cells are capable of repopulating most major cell types in the heart, but they do so with varying frequency. The signals for endothelial progenitor recruitment occur early and could relate to injury during allograft harvest or transplantation. The high degree of endothelial chimerism may have immune implications such as for myocardial rejection or graft vasculopathy.
The Rho Family Guanine Nucleotide Exchange Factor Vav-2 Regulates the Development of Cell-Mediated Cytotoxicity
Authors: Daniel D. Billadeau, Stacy M. Mackie, Renee A. Schoon, Paul J. Leibson
Journal: The Journal of Experimental Medicine (2000)

Previous pharmacologic and genetic studies have demonstrated a critical role for the low molecular weight GTP-binding protein RhoA in the regulation of cell-mediated killing by cytotoxic lymphocytes. However, a specific Rho family guanine nucleotide exchange factor (GEF) that activates this critical regulator of cellular cytotoxicity has not been identified. In this study, we provide evidence that the Rho family GEF, Vav-2, is present in cytotoxic lymphocytes, and becomes tyrosine phosphorylated after the cross-linking of activating receptors on cytotoxic lymphocytes and during the generation of cell-mediated killing. In addition, we show that overexpression of Vav-2 in cytotoxic lymphocytes enhances cellular cytotoxicity, and this enhancement requires a functional Dbl homology and Src homology 2 domain. Interestingly, the pleckstrin homology domain of Vav-2 was found to be required for enhancement of killing through some, but not all activating receptors on cytotoxic lymphocytes. Lastly, although Vav and Vav-2 share significant structural homology, only Vav is able to enhance nuclear factor of activated T cells–activator protein 1–mediated gene transcription downstream of the T cell receptor. These data demonstrate that Vav-2, a Rho family GEF, differs from Vav in the control of certain lymphocyte functions and participates in the control of cell-mediated killing by cytotoxic lymphocytes.
Nasopharyngeal Cancer: Molecular Landscape
Authors: Jeff P. Bruce, Kenneth Yip, Scott V. Bratman, Emma Ito, Fei-Fei Liu
Journal: Journal of Clinical Oncology (2015)

Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy arising from the superior aspect of the pharyngeal mucosal space, associated with latent Epstein-Barr virus infection in most cases. The capacity to characterize cancer genomes in unprecedented detail is now providing insights into the genesis and molecular underpinnings of this disease. Herein, we provide an overview of the molecular aberrations that likely drive nasopharyngeal tumor development and progression. The contributions of major Epstein-Barr virus-encoded factors, including proteins, small RNAs, and microRNAs, along with their interactions with pathways regulating cell proliferation and survival are highlighted. We review recent analyses that clearly define the role of genetic and epigenetic variations affecting the human genome in NPC. These findings point to the impact of DNA methylation and histone modifications on gene expression programs that promote this malignancy. The molecular interactions that allow NPC cells to evade immune recognition and elimination, which is crucial for the survival of cells expressing potentially immunogenic viral proteins, are also described. Finally, the potential utility of detecting host and viral factors for the diagnosis and prognosis of NPC is discussed. Altogether, the studies summarized herein have greatly expanded our knowledge of the molecular biology of NPC, yet much remains to be uncovered. Emerging techniques for using and analyzing well-annotated biospecimens from patients with NPC will ultimately lead to a greater level of understanding, and enable improvements in precision therapies and clinical outcomes.
Counterpoint: Evidence-Based Prevention of Type 2 Diabetes: The Power of Lifestyle Management
Authors: Jaakko Tuomilehto
Journal: Diabetes Care (2007)

The need to prevent type 2 diabetes was recognized as early as the 1920s (1), but surprisingly little was done to apply preventive measures against this disease in subsequent decades (2,3). One of the main problems was the lack of evidence based on well-conducted studies. There were several clinical trials, but they were usually grossly underpowered, had flaws in design and conduct, and most used antidiabetes drugs as the intervention (3). Luckily, firm positive results from several randomized controlled trials (4–10) using lifestyle intervention have become available during recent years. Also, several properly designed and conducted trials using antidiabetes drugs in individuals at high risk, i.e., with intermediate hyperglycemia, have reported favorable results (8,10–14). The bottom line is that these recent trials have unequivocally demonstrated that it is possible to reduce the rate of progression to type 2 diabetes in high-risk individuals with intermediate hyperglycemia.

The Swedish Malmo feasibility study (5) used increased physical exercise and weight control as major intervention strategies to prevent or delay type 2 diabetes in men with impaired glucose tolerance (IGT). Men who received intervention had less than half the risk of developing diabetes in 6 years compared with those who decided not to participate in the diet-exercise program.

In the Chinese Da Qing Study (6), people with IGT were randomized by clinic into one of the four groups: exercise only, diet only, diet plus exercise, and a control group. The cumulative incidence of type 2 diabetes during 6 years was significantly lower in the three intervention groups compared with the control group (41% in the exercise group, 44% in the diet group, 46% in the diet plus exercise group, and 68% in the control group) and remained significant even after adjusting for differences in baseline BMI …
RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice
Authors: Sang-Soo Kim, Dan Peer, Priti Kumar, Sandesh Subramanya, Huaquan Wu, Deshratan Asthana, Katsuyoshi Habiro, Yong-Guang Yang, N Manjunath, Motomu Shimaoka, Premlata Shankar
Journal: Molecular Therapy (2009)

RNA interference (RNAi)–mediated knockdown of gene expression offers a novel treatment strategy for human immunodeficiency virus (HIV) infection. However, the major hurdle for clinical use is a practical strategy for small interfering RNA (siRNA) delivery to the multiple immune cell types important in viral pathogenesis. We have developed a novel immunoliposome method targeting the lymphocyte function–associated antigen-1 (LFA-1) integrin expressed on all leukocytes and evaluated it for systemic delivery of siRNA in a humanized mouse model. We show that in vivo administration of the LFA-1 integrin–targeted and stabilized nanoparticles (LFA-1 I-tsNPs) results in selective uptake of siRNA by T cells and macrophages, the prime targets of HIV. Further, in vivo administration of anti-CCR5 siRNA/LFA-1 I-tsNPs resulted in leukocyte-specific gene silencing that was sustained for 10 days. Finally, humanized mice challenged with HIV after anti-CCR5 siRNA treatment showed enhanced resistance to infection as assessed by the reduction in plasma viral load and disease-associated CD4 T-cell loss. This study demonstrates the potential in vivo applicability of LFA-1-directed siRNA delivery as anti-HIV prophylaxis. RNA interference (RNAi)–mediated knockdown of gene expression offers a novel treatment strategy for human immunodeficiency virus (HIV) infection. However, the major hurdle for clinical use is a practical strategy for small interfering RNA (siRNA) delivery to the multiple immune cell types important in viral pathogenesis. We have developed a novel immunoliposome method targeting the lymphocyte function–associated antigen-1 (LFA-1) integrin expressed on all leukocytes and evaluated it for systemic delivery of siRNA in a humanized mouse model. We show that in vivo administration of the LFA-1 integrin–targeted and stabilized nanoparticles (LFA-1 I-tsNPs) results in selective uptake of siRNA by T cells and macrophages, the prime targets of HIV. Further, in vivo administration of anti-CCR5 siRNA/LFA-1 I-tsNPs resulted in leukocyte-specific gene silencing that was sustained for 10 days. Finally, humanized mice challenged with HIV after anti-CCR5 siRNA treatment showed enhanced resistance to infection as assessed by the reduction in plasma viral load and disease-associated CD4 T-cell loss. This study demonstrates the potential in vivo applicability of LFA-1-directed siRNA delivery as anti-HIV prophylaxis.
Population structure of the Japanese eel, Anguilla japonica.
Authors: T K Sang, H Y Chang, C T Chen, C F Hui
Journal: Molecular Biology and Evolution (1994)

Mitochondrial DNA (mtDNA) sequences that include (a) a part of the cytochrome b gene, (b) two tRNA genes, and (c) a part of the noncoding D-loop region of 31 Anguilla japonica (Japanese eel) and 1 A. marmorata collected from Taiwan, Japan, and mainland China were determined to evaluate the population structure of Japanese eel. Among 30 genotypes identified from the 31 Japanese eel mtDNAs sequenced, there are 58 variable sites, predominantly clustered at the D-loop region. The phylogenetic tree constructed by the unweighted pair-group method with arithmetic mean shows neither significant genealogical branches nor geographic clusters. Furthermore, the sequence-statistics test reveals little, if any, significant genetic differentiation. These results indicate that the 31 Japanese eels might come from a single population. Analysis of sequence variation in mtDNA by using the relationship between the number of segregating sites and the average number of nucleotide differences under the neutral mutation hypothesis reveals that neutral mutation acts as a major factor influencing the evolutionary divergence of the Japanese eel mitochondrial genome sequenced, especially in the noncoding region.
A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model
Authors: Craig H. Moskowitz, Stephen D. Nimer, Andrew D. Zelenetz, Tania Trippett, Eric E. Hedrick, Daniel A. Filippa, Diane Louie, Maria Gonzales, Janine Walits, Nancy Coady-Lyons, Jing Qin, Richard Frank, Joseph R. Bertino, Andre Goy, Ariela Noy, James P. O'Brien, David Straus, Carol S. Portlock, Joachim Yahalom
Journal: Blood (2001)
Strengthening Medical Device Postmarket Safety Surveillance
Authors: Joseph S. Ross
Journal: JAMA Internal Medicine (2015)

Zian H. Tseng, MD, MAS; Robert M. Hayward, MD; Nina M. Clark, BS; Christopher G. Mulvanny, MS; Benjamin J. Colburn, BA, BS; Philip C. Ursell, MD; Jeffrey E. Olgin, MD; Amy P. Hart, MD; Ellen Moffatt, MD
Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein
Authors: Kevin C O'Connor, Katherine A McLaughlin, Philip L De Jager, Tanuja Chitnis, Estelle Bettelli, Chenqi Xu, William H Robinson, Sunil V Cherry, Amit Bar-Or, Brenda Banwell, Hikoaki Fukaura, Toshiyuki Fukazawa, Silvia Tenembaum, Susan J Wong, Norma P Tavakoli, Zhannat Idrissova, Vissia Viglietta, Kevin Rostasy, Daniela Pohl, Russell C Dale, Mark Freedman, Lawrence Steinman, Guy J Buckle, Vijay K Kuchroo, David A Hafler, Kai W Wucherpfennig
Journal: Nature Medicine (2007)
Long-term time-course of nocturnal breathing disorders in heart failure patients
Authors: G. D. Pinna, R. Maestri, A. Mortara, P. Johnson, D. Andrews, P. Ponikowski, T. Witkowski, M. T. La Rovere, P. Sleight
Journal: European Respiratory Journal (2009)

Some important aspects of clinical manifestations of nocturnal breathing disorders in heart failure (HF) patients are still unknown. We questioned whether the severity of these disorders, first, is stable over time; secondly, shows any systematic trend; and, thirdly, can be predicted over time by a single baseline measurement. We studied 79 stable, optimally treated, moderate-to-severe HF patients who performed a monthly cardiorespiratory recording during 1-yr follow-up. According to their behaviour over time, nocturnal breathing disorders were classified as persistent, absent or occasional. During follow-up, clinically relevant breathing disorders were persistent in approximately 50% of the patients, absent in <20% and occasional in approximately 30%. Increasing/decreasing trends were rarely observed. The positive and negative predictive value of baseline measurement for persistent behaviour over time ranged, respectively, from 71% to 91% and from 91% to 95%, depending on different levels of severity of breathing disorders. A large portion of HF patients experience persistent clinically significant nocturnal breathing disorders over long periods of time. Breathing disorders occur irregularly in about one-third of the patients and are negligible in a minority of them. Rarely do they show a steady increase or decrease over time. A single baseline recording predicts a persistent behaviour with moderate-to-high accuracy.
N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape
Authors: De-Min Yu, Xin-Hua Li, Vannary Mom, Zhong-Hua Lu, Xiang-Wei Liao, Yue Han, Christian Pichoud, Qi-Ming Gong, Dong-hua Zhang, Yan Zhang, Paul Deny, Fabien Zoulim, Xin-Xin Zhang
Journal: Journal of Hepatology (2013)
Effects of a <scp>d</scp>-Xylose Preload With or Without Sitagliptin on Gastric Emptying, Glucagon-Like Peptide-1, and Postprandial Glycemia in Type 2 Diabetes
Authors: Tongzhi Wu, Michelle J. Bound, Beiyi R. Zhao, Scott D. Standfield, Max Bellon, Karen L. Jones, Michael Horowitz, Christopher K. Rayner
Journal: Diabetes Care (2013)

OBJECTIVE Macronutrient “preloads” can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy d-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g d-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with 13C-octanoate. Blood was sampled at intervals. Gastric emptying was determined. RESULTS Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P &amp;lt; 0.01 for each) and were lowest after SX (P &amp;lt; 0.05 for each), while overall blood glucose was lower after SX than PC (P &amp;lt; 0.05). The postprandial insulin-to-glucose ratio was attenuated (P &amp;lt; 0.05) and gastric emptying was slower (P &amp;lt; 0.01) after d-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after d-xylose than control only before the meal (P &amp;lt; 0.05) but were sustained postprandially when combined with sitagliptin (P &amp;lt; 0.05). CONCLUSIONS In type 2 diabetes, acute administration of a d-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.
Significance of circulating endothelial progenitor cells in hepatocellular carcinoma
Authors: Joanna W. Y. Ho, Roberta W. C. Pang, Cecilia Lau, Chris K. Sun, Wan Ching Yu, Sheung Tat Fan, Ronnie T. P. Poon
Journal: Hepatology (2006)

This study evaluated the significance of circulating bone marrow-derived endothelial progenitor cells (EPCs) in patients with hepatocellular carcinoma (HCC), a solid tumor with rich neovasculature. Eighty patients with HCC were recruited for the study, and 16 patients with liver cirrhosis and 14 healthy subjects were also included for comparison. Blood samples were taken before treatment. Total mononuclear cells were isolated from peripheral blood, preplated to eliminate mature circulating endothelial cells, and colony-forming units (CFUs) formed by circulating EPCs were counted. To validate the CFU scores, FACS quantification of EPCs using CD133, VEGFR2, and CD34 as markers was performed in 30 cases. Our study showed significantly higher mean CFU scores in patients with HCC compared to patients with cirrhosis and healthy controls (P = .001 and .009, respectively). Furthermore, the CFU scores of patients with HCC positively correlated with levels of serum α-fetoprotein (r = .303, P = .017), plasma VEGF (r = .242, P = .035), and plasma interleukin-8 (IL-8) (r = .258, P = .025). Patients with unresectable HCC had higher CFU scores than patients with resectable tumors (P = .027). Furthermore, for those who underwent curative surgery, higher preoperative CFU scores were observed in patients with recurrence within 1 year compared with those who were disease-free after 1 year (P = .013). In conclusion, higher circulating levels of EPCs are seen in patients with advanced unresectable HCC as compared to patients with resectable HCC or those with liver cirrhosis. Our evidence supports the potential use of circulating level of EPCs as a prognostic marker in patients with HCC. (HEPATOLOGY 2006;44:836–843.)
ROLE OF N-ACETYLTRANSFERASE PHENOTYPES IN BLADDER CARCINOGENESIS: A PHARMACOGENETIC EPIDEMIOLOGICAL APPROACH TO BLADDER CANCER
Authors: RaymondA. Cartwright, HowardJ. Rogers, Denise Barham-Hall, RobinW. Glashan, RaadA. Ahmad, Elizabeth Higgins, MohidA. Kahn
Journal: The Lancet (1982)
Novel Ig V gene features of t(14;18) and t(3;14) de novo diffuse large B-cell lymphoma displaying germinal center-B cell like and non-germinal center-B cell like markers
Authors: F Jardin, S S Sahota, P Ruminy, F Parmentier, J M Picquenot, V Rainville, G Buchonnet, S Lepretre, H Tilly, C Bastard
Journal: Leukemia (2006)
Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection
Authors: Qiang Gao, Shuang-Jian Qiu, Jia Fan, Jian Zhou, Xiao-Ying Wang, Yong-Sheng Xiao, Yang Xu, Yi-Wei Li, Zhao-You Tang
Journal: Journal of Clinical Oncology (2007)

To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection.CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031).Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
Detecting pulmonary involvement in extra-pulmonary tuberculosis using chest radiographs (CXR) and sputum sampling: What happens in practice?
Authors: Suzanne Bartington, Marc Lipman, Joanne Cleverley, Charlotte Cash, Ian Cropley, Susan Hopkins
Journal: European Respiratory Journal (2011)

Background:  CXR plus sputum microscopy & culture (TBC) for  M.tuberculosis  (MTB) can identify co-existing pulmonary TB (PTB) in subjects presenting with extra-pulmonary tuberculosis (EPTB). In practice, EPTB subjects with normal CXR may not have sputum sampling performed, leading to underestimation of pulmonary disease.   Objectives:  To determine the use of CXR & TBC in patients with EPTB & their diagnostic utility to detect co-existent PTB.   Study design:  Retrospective clinical and demographic data for TB patients at our hospital (1.1.06 - 31.12.08) obtained from the London TB Register were linked to hospital microbiology & HIV test data. Baseline CXR (B-CXR) were scored by 2 respiratory radiologists blind to patient diagnosis.   Results:  Of 308 cases (median age 39y, 52.9% female), 155 were notified as EPTB only. 143 (92.3%) had B-CXR, with abnormal (abN) features identified in 67 patients (46.9%): 48 (33.6%) consistent with possible PTB & 9 (6.3%) probable PTB, independent of HIV status. Sputum samples were obtained from 54 patients (37.8%). This was less likely in those with a normal B-CXR (21.4% vs. 56.2% abN, p   Conclusion:  Most EPTB patients had a B-CXR, 40% of which were consistent with possible/probable active PTB. Sputum samples were infrequently obtained, though when performed MTB yield was high. Clinical diagnosis of EPTB using B-CXR review alone may underestimate co-existing PTB. To identify infectious cases & improve TB control, sputum collection & TBC should be performed in all patients.