tbuckley/cabot-search huggingface dataset:
Steps Toward Safe Cell Therapy Using Induced Pluripotent Stem Cells
Authors: Hideyuki Okano, Masaya Nakamura, Kenji Yoshida, Yohei Okada, Osahiko Tsuji, Satoshi Nori, Eiji Ikeda, Shinya Yamanaka, Kyoko Miura
Journal: Circulation Research (2013)

The enthusiasm for producing patient-specific human embryonic stem cells using somatic nuclear transfer has somewhat abated in recent years because of ethical, technical, and political concerns. However, the interest in generating induced pluripotent stem cells (iPSCs), in which pluripotency can be obtained by transcription factor transduction of various somatic cells, has rapidly increased. Human iPSCs are anticipated to open enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine and stem cell modeling of human disease. On the other hand, recent reports have emphasized the pitfalls of iPSC technology, including the potential for genetic and epigenetic abnormalities, tumorigenicity, and immunogenicity of transplanted cells. These constitute serious safety-related concerns for iPSC-based cell therapy. However, preclinical data supporting the safety and efficacy of iPSCs are also accumulating. In this Review, recent achievements and future tasks for safe iPSC-based cell therapy are summarized, using regenerative medicine for repair strategies in the damaged central nervous system (CNS) as a model. Insights on safety and preclinical use of iPSCs in cardiovascular repair model are also discussed.
The blood-borne miRNA signature of lung cancer patients is independent of histology but influenced by metastases
Authors: Petra Leidinger, Christina Backes, Michael Blatt, Andreas Keller, Hanno Huwer, Philipp Lepper, Robert Bals, Eckart Meese
Journal: Molecular Cancer (2014)

In our previous studies we reported a panel of 24 miRNAs that allowed discrimination between blood of lung tumor patients independent of the histological subtype and blood of healthy controls with an accuracy of 95.4% [94.9%-95.9%]. Here, we now separately analyzed the miRNA expression in blood of non-small cell lung cancer (NSCLC), including squamous cell lung cancer and adenocarcinoma, and small cell lung cancer (SCLC) patients.In total, we examined the expression levels of 1,205 miRNAs in blood samples from 20 patients from each of the three histological groups and determined differentially expressed miRNAs between histological subtypes and metastatic and non-metastatic lung cancer. We further determined the overlap of miRNAs expressed in each subgroup with the 24-miRNA signature of lung tumor patients.Based on a raw p-value < 0.05, only 18 blood-borne miRNAs were differentially expressed between patients with adenocarcinoma and with squamous cell lung carcinoma, 11 miRNAs between adenocarcinoma and SCLC, and 2 between squamous cell lung carcinoma and SCLC. Likewise, the comparison based on a fold change of 1.5 did not reveal major differences of the blood-borne miRNA expression pattern between NSCLC and SCLC. In addition, we found a large overlap between the blood-borne miRNAs detected in the three histological subgroups and the previously described 24-miRNA signature that separates lung cancer patients form controls. We identified several miRNAs that allowed differentiating between metastatic and non-metastatic tumors both in blood of patients with adenocarcinoma and in blood of patients with SCLC.There is a common miRNA expression pattern in blood of lung cancer patients that does not allow a reliable further subtyping into NSCLC or SCLC, or into adenocarcinoma and squamous cell lung cancer. The previously described 24-miRNA signature for lung cancer appears not primarily dependent on histological subtypes. However, metastatic adenocarcinoma and SCLC can be predicted with 75% accuracy.
National cross sectional study of views on sexual violence and risk of HIV infection and AIDS among South African school pupils
Authors: Neil Andersson, Ari Ho-Foster, Judith Matthis, Nobantu Marokoane, Vincent Mashiane, Sharmila Mhatre, Steve Mitchell, Tamara Mokoena, Lorenzo Monasta, Ncumisa Ngxowa, Manuel Pascual Salcedo, Heidi Sonnekus
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To investigate the views of school pupils on sexual violence and on the risk of HIV infection and AIDS and their experiences of sexual violence. <b>Design</b> National cross sectional study. <b>Setting</b> 5162 classes in 1418 South African schools. <b>Participants</b> 269 705 school pupils aged 10-19 years in grades 6-11. <b>Main outcome measure</b> Answers to questions about sexual violence and about the risk of HIV infection and AIDS. <b>Results</b> Misconceptions about sexual violence were common among both sexes, but more females held views that would put them at high risk of HIV infection. One third of the respondents thought they might be HIV positive. This was associated with misconceptions about sexual violence and about the risk of HIV infection and AIDS. Around 11% of males and 4% of females claimed to have forced someone else to have sex; 66% of these males and 71% of these females had themselves been forced to have sex. A history of forced sex was a powerful determinant of views on sexual violence and risk of HIV infection. <b>Conclusions</b> The views of South African youth on sexual violence and on the risk of HIV infection and AIDS were compatible with acceptance of sexual coercion and "adaptive" attitudes to survival in a violent society. Views differed little between the sexes.
Tris (Dibenzylideneacetone) Dipalladium, a<i>N</i>-Myristoyltransferase-1 Inhibitor, Is Effective against Melanoma Growth<i>In vitro</i>and<i>In vivo</i>
Authors: Sulochana S. Bhandarkar, Jacqueline Bromberg, Carol Carrillo, Ponniah Selvakumar, Rajendra K. Sharma, Betsy N. Perry, Baskaran Govindarajan, Levi Fried, Allie Sohn, Kalpana Reddy, Jack L. Arbiser
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA. Experimental Design: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed. Results: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma. Conclusion: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.
A NEW INSIGHT FOR MONITORING TRAINING IN SPRINTING
Authors: P Jiménez-Reyes, M Molina-Reina, J González-Hernández, Juan González-Badillo
Journal: British Journal of Sports Medicine (2013)

Intermittent exercise with short bouts (30–500 m) of high intensity exercise (90–100% of running intensity) separated by different recovery periods (3–15 minutes) are habitually used by sprinters during training sessions (Gorostiaga et al . JSCR 2010;24:1138–1149). Repetition of sprints may induce neuromuscular fatigue (NMF). The aim of the present study was to quantify the extent of NMF while performing sprint workouts (SW) by analysing the acute metabolic and mechanical response to different SW. Nine high level sprinters (age 23±4 y, body mass 73.7±4.6 kg, height 177.6±5.9 cm; body fat 9.6±2.9%) performed eight SW separated by a week. SW with different number of repetitions (R) for each subject in short distance travelled (DT) [(x)RxDT] and SW with same number of R in long DT [3xDT]. Mechanical responses (i.e. height performance in CMJ and speed loss) and metabolic responses (i.e. blood lactate and ammonia concentrations) were measured pre-exercise, during exercise each repetition performed and post-exercise. CMJ height loss pre-post session were significant for all sprint workouts and competitions analysed and highly correlated to metabolic responses (r=0.86–0.98). These losses were between 9% for 40 m and 26% for 500 m. The fatigue, measured as CMJ height loss, increases with DT, and is strongly correlated to lactate (r=0.93) and ammonia (r=0.98). The metabolic stress developed during the effort can be estimated by controlling CMJ because of the high correlation between CMJ and blood lactate and ammonia concentrations (Jiménez-Reyes et al . MSSE 2012;44(5):582). The high correlations found between mechanical (speed and CMJ height losses) and metabolic (lactate and ammonia) measures of fatigue highlight the utility and validity of using CMJ to monitor training load in different sprint workouts and quantify objectively NMF during SW and competitions.
Toward Optimization of Postremission Therapy for Residual Disease–Positive Patients With Acute Myeloid Leukemia
Authors: Luca Maurillo, Francesco Buccisano, Maria Ilaria Del Principe, Giovanni Del Poeta, Alessandra Spagnoli, Paola Panetta, Emanuele Ammatuna, Benedetta Neri, Licia Ottaviani, Chiara Sarlo, Daniela Venditti, Micol Quaresima, Raffaella Cerretti, Manuela Rizzo, Paolo de Fabritiis, Francesco Lo Coco, William Arcese, Sergio Amadori, Adriano Venditti
Journal: Journal of Clinical Oncology (2008)

Purpose Despite the identification of several baseline prognostic indicators, the outcome of patients with acute myeloid leukemia (AML) is generally heterogeneous. The effects of autologous (AuSCT) or allogeneic stem-cell transplantation (SCT) are still under evaluation. Minimal residual disease (MRD) states may be essential for assigning patients to therapy-dependent risk categories. Patients and Methods By multiparametric flow cytometry, we assessed the levels of MRD in 142 patients with AML who achieved complete remission after intensive chemotherapy. Results A level of 3.5 × 10 −4 residual leukemia cells (RLCs) after consolidation therapy was established to identify MRD-negative and MRD-positive cases, with 5-year relapse-free survival (RFS) rates of 60% and 16%, respectively (P &lt; .0001) and overall survival (OS) rates of 62% and 23%, respectively (P = .0001). Of patients (n = 77) who underwent a transplantation procedure (56 AuSCT and 21 SCT procedures); 42 patients (55%) were MRD positive (28 patients who underwent AuSCT and 14 patients who underwent SCT) and 35 patients (45%) were MRD negative (28 patients who underwent AuSCT and seven who underwent SCT). MRD-negative patients had a favorable prognosis, with only eight (22%) of 35 patients experiencing relapse, whereas 29 (69%) of 42 MRD-positive patients experienced relapse (P &lt; .0001). In this high-risk group of 42 patients, we observed that 23 (82%) of 28 of those who underwent AuSCT experienced relapse, whereas six (43%) of 14 who underwent SCT experienced relapse (P = .014). Patients who underwent SCT also had a higher likelihood of RFS (47% v 14%). Conclusion A threshold of 3.5 × 10 −4 RLCs postconsolidation is critical for predicting disease outcome. MRD-negative patients have a good outcome regardless of the type of transplant they receive. In the MRD-positive group, AuSCT does not improve prognosis and SCT represents the primary option.
The Cytogenetic Relationship between Primary and Recurrent Meningiomas Points to the Need for New Treatment Strategies in Cases at High Risk of Relapse
Authors: Ana Belén Espinosa, María Dolores Tabernero, Angel Maíllo, José María Sayagués, Juana Ciudad, Marta Merino, Maria Carmen Alguero, Anne Marie Lubombo, Pablo Sousa, Angel Santos-Briz, Alberto Orfao
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recurrence is the major factor influencing the clinical outcome of meningioma patients although the exact relationship between primary and recurrent tumors still needs to be clarified. The aim of the present study is to analyze the cytogenetic relationship between primary and subsequent recurrent meningiomas developed within the same individual. Experimental Design: Multicolor interphase fluorescence in situ hybridization was done for the identification of numerical abnormalities of 12 chromosomes in single-cell suspensions from 59 tumor samples corresponding to 25 recurrent meningioma patients. In 47 of these tumors, the distribution of different tumor cell clones was also analyzed in paraffin-embedded tissue sections. In parallel, 132 nonrecurrent cases were also studied. Results: Most recurrent meningiomas showed complex cytogenetic aberrations associated with two or more tumor cell clones in the first tumor analyzed. Interestingly, in most individuals (74%), exactly the same tumor cell clones identified in the initial lesion were also detected in the subsequent recurrent tumor samples. In the recurrent tumor samples of the remaining cases (26%), we observed tumor cell clones related to those detected in the initial lesion but which had acquired one or more additional chromosome aberrations associated with either the emergence of new clones with more complex karyotypes or the disappearance of the most representative clones from the primary lesions. Multivariate analysis of prognostic factors showed that the Maillo et al. prognostic score, based on age of patient, tumor grade, and monosomy 14, together with tumor size was the best combination of independent variables for predicting tumor recurrence at diagnosis. Conclusion: Overall, our results indicate that the development of recurrent meningiomas after complete tumor resection is usually due to regrowth of the primary tumor and rarely to the emergence of an unrelated meningioma, underlining the need for alternative treatment strategies in cases at high risk of relapse, particularly those with a high Maillo et al. prognostic score and larger tumors.
Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums
Authors: Kodi S. Ravichandran
Journal: The Journal of Experimental Medicine (2010)

Everyday we turnover billions of cells. The quick, efficient, and immunologically silent disposal of the dying cells requires a coordinated orchestration of multiple steps, through which phagocytes selectively recognize and engulf apoptotic cells. Recent studies have suggested an important role for soluble mediators released by apoptotic cells that attract phagocytes (“find-me” signals). New information has also emerged on multiple receptors that can recognize phosphatidylserine, the key “eat-me” signal exposed on the surface of apoptotic cells. This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge.
Supranormal Expiratory Airflow after Bilateral Lung Transplantation Is Associated with Improved Survival
Authors: Michael Eberlein, Solbert Permutt, Robert H Brown, Allison Brooker, Mayy F Chahla, Servet Bolukbas, Steven D Nathan, David B Pearse, Jonathan B Orens, Roy G Brower
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern).characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival.we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) > 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern.the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009).the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients.
HORMONE REPLACEMENT THERAPY, HEART DISEASE, AND OTHER CONSIDERATIONS
Authors: Elizabeth Barrett-Connor, Deborah Grady
Journal: Annual Review of Public Health (1998)

▪ Abstract Multiple observational studies suggest a marked reduction in risk of coronary heart disease (CHD) associated with postmenopausal estrogen use. A new meta-analysis presented here extends these results to estrogen plus progestin regimens. Although the findings from observational studies are strong and consistent, and there are several plausible mechanisms by which estrogen might reduce risk for CHD, most of the known biases would tend to exaggerate estrogen's benefit. Further, estrogen therapy clearly increases risk for endometrial hyperplasia and cancer, venous thromboembolic events and gallbladder disease, and long-term use probably also increases the risk of breast cancer. Therefore, until findings from randomized trials confirm and quantitate the benefit of estrogen therapy for prevention of CHD, we believe it should not be recommended to all postmenopausal women.
Leucocyte endothelial cell adhesion in indomethacin induced intestinal inflammation is correlated with faecal pH
Authors: H Arndt, K-D Palitzsch, J Schölmerich
Journal: Gut (1998)

Recent studies indicate that faecal pH is acidified in patients with inflammatory bowel disease compared with healthy controls. In healthy volunteers, stool pH, faecal flora, and bile acid concentration could be affected by means of elemental diets.To assess the role of variations of faecal pH on leucocyte endothelial cell adhesion in indomethacin induced long lasting ileitis in rats.Indomethacin (7.5 mg/kg subcutaneously) was injected twice, 24 hours apart. Rats were either fed with the identical diet before and 10 days after the induction of inflammation until the experiment, or the diet was changed at the time of induction. Ten postcapillary mesenteric venules (30 microns diameter) per animal were observed using intravital microscopy. Macroscopic visible intestinal ulceration was scored and faecal pH of different sections of the small bowel was determined.Small intestinal faecal pH was 8.5 in controls and 8.0 in indomethacin treated animals. Indomethacin significantly changed microcirculatory parameters: there was a 2.3-fold increase in leucocyte adherence, a 3.2-fold increase in leucocyte emigration, and a 20% reduction in shear rate. Application of various diets or diet combinations resulted in variations in faecal pH ranging from 7.8 to 8.8 which were inversely correlated with macroscopic ulcerations (r = -0.67). Leucocyte adherence was attenuated with increased pH and augmented with decreased pH (r = -0.55). Venular wall shear rate was positively correlated with faecal pH (r = 0.48) while leucocyte emigration showed no correlation. Leucocyte rolling velocity was not significantly altered. Normalisation of faecal pH by different alkalising drugs induced a significant decrease in leucocyte adherence in standard fed, indomethacin treated rats.Faecal pH is lowered in the indomethacin model of long lasting ileitis in rats, which is similar to human inflammatory bowel disease. Alkalisation of faecal pH due to different diets or alkalising drugs reduces indomethacin induced leucocyte endothelial cell adhesion and macroscopic intestinal damage. These results may provide a rationale for the therapeutic effect of enteral diets in Crohn's disease.
Antiviral Therapy and Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence—Reply
Authors: Chun-Ying Wu, Yao-Chun Hsu
Journal: JAMA (2013)

To the Editor: Although using antiviral therapy to suppress hepatitis B virus (HBV) replication after curative resection of hepatocellular carcinoma (HCC) is thought to potentially reduce the rate of HCC recurrence, studies regarding the efficacy of nucleoside analogues in this clinical setting are limited and thus controversial. In the study by Dr Wu and colleagues, the authors used the Taiwan National Health Insurance Research Database for analysis and reported that the use of a nucleoside analogue was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection. Their results support the use of antiviral therapy in the tertiary prevention of HCC. However, several issues need be clarified before extrapolating their results to other eligible patients with HBV-related HCC after curative treatment. First, curative surgical resection is usually defined by an adequate free resection margin on the resected hepatic specimen, plus no clinical or radiological evidence of tumor recurrence within 12 months after resection. However, the pathological details of surgical specimens are not included in the Taiwan database. Therefore, possible misclassification of patients with HCC as curative resection in this study may confound early or late HCC recurrence after surgery, as mentioned in the Editorial by Lok. Second, reimbursement for nucleoside analogue use in Taiwan is granted only to patients in high-risk populations and requires patients to be followed up for at least 6 months before enrollment or to have hepatic decompensation. Therefore, baseline liver disease status, remnant liver function, adherence to follow-up, and health care received may have been different between treated and untreated patients. Although the authors used complex statistical methods to adjust for possible confounding factors, these inherent differences cannot be adjusted for in their analyses. Third, according to the regulations of the Taiwan program, all treated patients need to refill anti-HBV agents monthly, suggesting the follow-up interval between the 2 groups after surgical resection may also be different. The trends in cumulative incidence rates of HCC recurrence and overall mortality were different between treated and untreated patients, even in the first year. This finding contradicts previous studies that found high viral loads and hepatic inflammatory activities to be associated with late HCC recurrence. Because the time from viral infection to tumor development is long, the markedly reduced rates of HCC recurrence and overall mortality within 1 year of curative resection are not anticipated, and there may be other possible mechanisms to explain these unusual observations.