tbuckley/cabot-search huggingface dataset:
Identification of Novel p53 Target Genes in Ionizing Radiation Response
Authors: Kuang-Yu Jen, Vivian G. Cheung
Journal: Cancer Research (2005)

Abstract The tumor suppressor p53 plays an essential role in cellular adaptation to stress. In response to ionizing radiation, p53 regulates the transcription of genes in a diverse set of pathways including DNA repair, cell cycle arrest, and apoptosis. Previously, we identified by microarray analysis a set of genes that are transcriptionally activated or repressed in response to radiation exposure. In this study, we use computational methods and molecular techniques, including location analysis (ChIP-on-chip assay), to identify ionizing radiation–responsive genes that are directly regulated by p53. Among the 489 ionizing radiation–responsive genes examined, 38 genes were found to be p53 targets. Some of these genes are previously known to be directly regulated by p53 whereas others are novel p53 targets. We further showed that the novel p53 target genes are transcriptionally regulated by p53. The binding of p53 to promoters of target genes correlated with increased transcript levels of these genes in cells with functional p53. However, p53 binding and subsequent transcriptional activation of these target genes were significantly diminished in cells with mutant p53 and in cells from patients with ataxia telangiectasia, which have impaired p53 activation following ionizing radiation exposure. Identification and characterization of ionizing radiation–responsive p53 target genes extend our knowledge of the diverse role that p53 plays in the DNA damage response.
Obstructive sleep apnea-related fatigue and serum testosterone
Authors: Raluca Mihaela Bercea, Traian Mihaescu, Cristian Cojocaru, Bjørn Bjorvatn
Journal: European Respiratory Journal (2013)

Introduction:  Fatigue is a common understudied symptom of obstructive sleep apnea (OSA). It has also been reported as a major symptom associated with low serum testosterone level in non-OSA patients.   Aims and objectives:  The aim of this study was to investigate in adult obese males affected by OSA, the relationship between fatigue and serum testosterone in order to identify among all measured parameters the predictors for OSA-related fatigue.   Methods:  Fifteen OSA patients and fifteen control subjects were enrolled in the study. Testosterone was determined in blood morning samples collected within one hour after awakening. Daytime sleepiness was assessed by the Epworth Sleepiness Scale and fatigue was evaluated with Multidimensional Fatigue Inventory. Statistical analysis included  t -test, correlation, regressions and Kruskal-Wallis test followed by  post-hoc  analysis.   Results:  The results indicated that mean testosterone level was 3.55±0.7 ng/ml in OSA group and 4.26±1.1 ng/ml in controls ( P =0.049). An inverse correlation was found between testosterone and fatigue scores ( P  P >0.05). Among all variables, testosterone was the only independent significant predictor for physical fatigue ( t =-2.56,  P =0.033,  R =0.978,  R 2  =0.958) and reduced activity ( t =-4.41,  P =0.002,  R =0.966,  R 2  =0.934) in the OSA patients.   Conclusions:  The present study showed that OSA-related fatigue was strongly associated with serum testosterone, together with OSA severity.
Aggression, suicide, and serotonin: relationships to CSF amine metabolites
Authors: Gerald L Brown, Michael H. Ebert, Peter F. Goyer, David C. Jimerson, William J. Klein, William E. Bunney, Frederick K. Goodwin
Journal: American Journal of Psychiatry (1982)

In an earlier, separate study, the authors found that human aggression and suicide (a specific aggression-related behavior) were associated with lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. That study focused on subjects with personality disorders without affective illness. In the present study they examine the life history of aggression and history of suicidal behavior in 12 subjects with borderline personality disorders without major affective disorder. Histories of aggressive behaviors and of suicide attempts were significantly associated with each other, and each was significantly associated with lower 5-HIAA levels. Altered serotonin metabolism may be a highly significant contributing factor to these behaviors in whatever diagnostic group they occur.
Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93
Authors: U. Creutzig, J. Ritter, M. Zimmermann, D. Reinhardt, J. Hermann, F. Berthold, G. Henze, H. Jürgens, H. Kabisch, W. Havers, A. Reiter, U. Kluba, F. Niggli, H. Gadner
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.
Medicare and Medicaid at 50 Years
Authors: Drew Altman, William H. Frist
Journal: JAMA (2015)

Medicare and Medicaid are the nation's 2 largest public health insurance programs, serving the elderly, those with disabilities, and mostly lower-income populations. The 2 programs are the focus of often deep partisan disagreement. Medicare and Medicaid payment policies influence the health care system and Medicare and Medicaid spending influences federal and state budgets. Debate about Medicare and Medicaid policy sometimes influences elections.To review the roles of Medicare and Medicaid in the health system and the challenges the 2 programs face from the perspectives of the general public and beneficiaries, health care professionals and health care institutions, and policy makers.Analysis of publicly available data and private surveys of the public and beneficiaries.Together, Medicare and Medicaid serve 111 million beneficiaries and account for $1 trillion in total spending, generating 43% of hospital revenue and representing 39% of national health spending. The median income for Medicare beneficiaries is $23,500 and the median income for Medicaid beneficiaries is $15,000. Future issues confronting both programs include whether they will remain open-ended entitlements, the degree to which the programs may be privatized, the scope of their cost-sharing structures for beneficiaries, and the roles the programs will play in payment and delivery reform.As the number of beneficiaries and the amount of spending for both Medicare and Medicaid increase, these programs will remain a focus of national attention and policy debate. Beneficiaries, health care professionals, health care organizations, and policy makers often have different interests in Medicare and Medicaid, complicating efforts to make changes to these large programs.
Abstract 19444: The Effect of Daily Feedback on Changes in Dietary Intake and Adherence to Fat and Energy Goals
Authors: Erica J Ambeba, Susan M Sereika, Mindi A Styn, Lei Ye, Yaguang Zheng, Britney N Beatrice, Laura K Maydak, Sushama D Acharya, Lora E Burke
Journal: Circulation (2012)

Introduction: Dietary self-monitoring is essential for successful weight management. Tailored feedback messages delivered in real-time can enhance motivation and improve dietary adherence. This study examined the effect of daily, tailored feedback messages on dietary intake and adherence to energy and fat goals in the SMART Trial, a 24-month behavioral weight loss study. Methods: Participants (N=210) were randomly assigned to self-monitor via a paper diary, personal digital assistant (PDA), or PDA that provided daily feedback messages based on self-monitoring entries. The message library was changed at 12 months to limit desensitization. To assess the effect of feedback, changes in dietary intake and adherence to energy and fat goals were compared between the groups that did (FB, n=70) or did not (NFB, n=140) receive feedback. Dietary intake was assessed every 6 months and modeled as percent change from baseline using linear mixed modeling. Marginal modeling with generalized estimating equations was applied to examine the probability of being adherent to energy and fat goals. Results: Participants (78% White, 84% female) had a mean age of 46.8 years and BMI of 34.0 kg/m 2 . At baseline, mean energy intake was 2090 kcal, and 33.7% of calories were from fat. At 24 months, FB group achieved significantly greater reductions in energy (-23.4% vs. -14.1%, p=.02) and saturated fat intake (-9.3% vs. 3.4%, p=.03) compared to the NFB group. Overall, a higher percent of the FB group was adherent; however, adherence declined at 12 months and then rebounded (see Figure). Conclusions: Receiving daily, tailored feedback messages appeared to enhance reductions in energy and saturated fat intake. The decline and later improvements in adherence in the FB group suggest that the message library may need to be changed more often. Findings suggest that daily feedback can improve dietary and self-monitoring adherence, important strategies in weight management and CVD prevention.
The role of 5-HT2 receptors in the early development of lung fibrosis
Authors: Anna Löfdahl, Martina C. Holst, Lena Thiman, Christina Wenglén, Kristina Rydell-Törmänen, Anna-Karin Larsson Callerfelt, Gunilla Ekström, Gunilla Westergren-Thorsson
Journal: European Respiratory Journal (2014)

In the fibrotic lung, myofibroblasts contribute to a remodeled ECM through deposition of matrix proteins. Serotonin (5-hydroxytryptamine, 5-HT) has been suggested to be associated with the development of fibrosis through e.g. differentiation and activation of myofibroblasts. The pro-fibrotic action is thought to be mediated by 5-HT class 2 (5-HT2) receptors.  The aims of the study were to investigate the role of 5-HT and potential therapeutic effects of selective 5-HT2 receptor antagonists in the development of lung fibrosis.  In human lung fibroblasts, cultured with or without TGF-β1, the effects of 5-HT and small molecule 5-HT2 receptor antagonists (EXT5/EXT9; new compounds in development) were studied. Expression of alpha-smooth muscle actin (α-SMA), evaluated with Western blot and qrt-PCR analysis, was used as readout for myofibroblast differentiation. The total amount of proteoglycans, representing ECM production, was measured by [ 35 S] sulfate labeling in culture medium.  TGF-β1 increased α-SMA production by 69% (±11) and the combination of TGF-β1 + 5-HT increased the α-SMA production by 107% (±18) after 24h. 5-HT2 receptors antagonists reduced the α-SMA production to levels seen without fibrotic stimuli. After treatment with EXT5 or EXT9, the total production of proteoglycans was reduced by 51% (±0.6) and 64% (±18), respectively. Preliminary  in vivo  data supports a reduced matrix production after treatment with 5-HT2 antagonists.  Our findings have given important insight into the pro-fibrotic role of 5-HT and 5-HT2 receptors, influencing myofibroblasts differentiation and proteoglycan production  in vitro ; suggesting 5-HT2 receptors as potential therapeutic targets in early lung fibrosis.
Asthma and respiratory symptoms among elderly and younger adults in relation to home environment in multifamily buildings in Sweden
Authors: Juan Wang, Karin Engvall, Greta Smedje, Dan Norbäck
Journal: European Respiratory Journal (2014)

Aim: To study associations between asthma and respiratory symptoms in Swedish adults and home environment.  Methods: A questionnaire study among occupants in a stratified random sample of multi-family buildings in Sweden. Associations were analysed by logistic regression, controlling for gender, age and smoking, with mutual adjustment.  Results: Among 5775 participants (response rate 46%): 56.5% were females, 12.0% were current smokers, 17.7% had wheeze, 11.7% day breathlessness, 6.0% night breathlessness, 11.5% doctor diagnosed asthma and 7.7% current asthma. Those living in colder climate zone had more wheeze (p=0.027) and night breathlessness (p=0.002). Subjects in buildings constructed during 1961-1975 had more day breathlessness (OR=1.53), compared with those in buildings constructed before 1961. Living in rented apartments was associated with wheeze (OR=1.20) and day breathlessness (OR=1.31). ETS was associated with current asthma (OR=1.53). Reported odour was associated with doctor-diagnosed asthma (OR=1.49) and current asthma (OR=1.52). Building dampness was associated with wheeze (OR=1.42) and day breathlessness (OR=1.57). More window opening time was associated with more day breathlessness (p=0.036) and night breathlessness (p=0.011).The associations between building dampness and symptoms was stronger for younger adults ( 65 years).  Conclusions: Certain construction years (1961-1985), building dampness, ETS, rented apartments and reported odour can be risk factors for asthma. Elderly may react differently to indoor factors as compared to younger adults.
Abstract 1162: Proteomic Characterization of the Secretome of Peripheral Blood-derived Smooth Muscle Progenitors
Authors: David Simper, Ursula Mayr, Ulrike Benbow, Andrew Newby, Qingbo Xu, Manuel Mayr
Journal: Circulation (2007)

Background. Recent studies on circulating progenitor cells of the myeloid lineage have led to a new appreciation of their secretome, as paracrine factors may support tissue regeneration. Methods and Results. Using a mass-spectrometry-based proteomic approach complemented by protein separation using two-dimensional gel electrophoresis, we compared the conditioned medium of plasma-derived smooth muscle progenitors (SPCs) and human aortic smooth muscle cells (SMCs). In total, over 150 individual protein features were identified. The majority of proteins were common to both cell lines, but higher amounts of the interstitial collagenase MMP-1, and of inflammatory cytokines, i.e. IL-8 and MCP-1, were found in the conditioned medium of SMCs compared to SPCs, which was subsequently verified by multiplex cytokine assays. ELISA measurements also confirmed that the concentrations of MMP-1 in the conditioned medium of SMCs exceeded the levels in the supernatant of SPCs. Although MMP-1 activity was partially antagonized in SMCs by a coordinated increase in TIMP-1, MMP-1 activity remained lower in SPCs. As a functional consequence, SMCs shedded more N-cadherin, an established MMP target, from their cell surface and showed a stronger invasive capacity. In contrast, SPCs produced more collagen, fibronectin and biglycan, but less perlecan than SMCs. A proteomic comparison between SPCs and endothelial progenitor cells (EPCs) revealed that the production of extracellular matrix proteins and the attenuated secretion of inflammatory cytokines was a specific characteristic of SPCs. EPCs secreted high levels of cathepsins, predominantly cathepsin D, B, Z and L, which were not detected in the conditioned medium of SPCs. Conclusion. The present study constitutes the first comprehensive assessment of different circulating progenitors of the myeloid lineage demonstrating that apart from their potential physical contribution to lesion formation, SPCs might contribute to plaque stability by limiting inflammatory reactions and contributing to extracellular matrix deposition.
An In Vitro Model of Human Red Blood Cell Production From Hematopoietic Progenitor Cells
Authors: Punam Malik, Timothy C. Fisher, Lora L.W. Barsky, Licheng Zeng, Parvin Izadi, Alan L. Hiti, Kenneth I. Weinberg, Thomas D. Coates, Herbert J. Meiselman, Donald B. Kohn
Journal: Blood (1998)
Clinical and Genetic Characterization Of Patients With C-CBL Mutated Juvenile Myelomonocytic Leukemia By Whole-Exome/Deep Sequencing
Authors: Hideki Muramatsu, Hirotoshi Sakaguchi, Xinan Wang, Kenichi Yoshida, Yusuke Okuno, Masashi Sanada, Yinyan Xu, Sayoko Doisaki, Atsushi Narita, Nozomu Kawashima, Asahito Hama, Yoshiyuki Takahashi, Nao Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Makishima, Jaroslaw P. Maciejewski, Satoru Miyano, Seishi Ogawa, Seiji Kojima
Journal: Blood (2013)
Thermochemotherapy of Liver Metastases
Authors: Kenneth P. Ramming, F. Kristian Storm
Journal: Liver Cancer (1985)

Surgery is the treatment of choice for hepatic metastases. Refinement in surgical technique and postoperative care in the last decade have resulted in satisfactory morbidity and mortality for elective hepatic resections, and surgery remains the only modality with consistent, rewarding two- and five-year cure rates. Unfortunately, because many hepatic metastases impinge on vital structures, or because of multiplicity of lesions, only about 5% to 7% of patients with hepatic metastases are candidates for surgical resection. The results of conventional chemotherapy, particularly in patients with metastases of malignant melanoma or colon cancer, are dismal. Thus a variety of innovative approaches utilizing infusion therapy by a variety of routes and using a variety of devices, often combined with other modalities, has evolved. This report contains our early clinical experience with the treatment of hepatic metastases using hyperthermia and chemotherapy, particularly in metastases of colorectal cancer and malignant melanoma.
Mortality Associated With Medical Therapy Versus Elective Colectomy in Ulcerative Colitis
Authors: Meenakshi Bewtra, Craig W. Newcomb, Qufei Wu, Lang Chen, Fenglong Xie, Jason A. Roy, Cary B. Aarons, Mark T. Osterman, Kimberly A. Forde, Jeffrey R. Curtis, James D. Lewis
Journal: Annals of Internal Medicine (2015)

Background: Ulcerative colitis (UC) can be treated with surgery or medications. Patients often must choose between long-term immunosuppressant therapy or total colectomy. Whether one of these treatment approaches has a mortality benefit is uncertain. Objective: To determine whether patients with advanced UC treated with elective colectomy have improved survival compared with those treated with medical therapy. Design: Retrospective matched cohort study. Setting: Data from all 50 states for Medicaid beneficiaries (2000 to 2005), Medicare beneficiaries (2006 to 2011), and dual-eligible persons (2000 to 2011). Patients: 830 patients with UC pursuing elective colectomy and 7541 matched patients with UC pursuing medical therapy. Measurements: The primary outcome was time to death. Cox proportional hazards models were used to compare the survival of patients with advanced UC treated with elective colectomy or medical therapy. The models controlled for significant comorbid conditions through matched and adjusted analysis. Results: The mortality rates associated with elective surgery and medical therapy were 34 and 54 deaths per 1000 person-years, respectively. Elective colectomy was associated with improved survival compared with long-term medical therapy (adjusted hazard ratio [HR], 0.67 [95% CI, 0.52 to 0.87]), although this result did not remain statistically significant in all sensitivity analyses. Post hoc analysis by age group showed improved survival with surgery in patients aged 50 years or older with advanced UC (HR, 0.60 [CI, 0.45 to 0.79]; P = 0.032 for age-by-treatment interaction). Limitations: Retrospective nonrandomized analysis is subject to residual confounding. The source cohort was derived from different databases throughout the study. Sensitivity and secondary analyses had reduced statistical power. Conclusion: Elective colectomy seemed to be associated with improved survival relative to medical therapy among patients aged 50 years or older with advanced UC. Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality.
High-dose (HD) imatinib in patients (pts) with previously untreated chronic myeloid leukemia (CML) in early chronic phase (CP): preliminary results of a multicenter community based trial
Authors: J. Cortes, F. Giles, A. Salvado, I. Sams, J. Hohneker, M. Albitar, B. Powell, S. Goldberg, H. Kantarjian
Journal: Journal of Clinical Oncology (2005)

6518 Background: A recent single center study suggests that using HD imatinib (800 mg/day) results in significant molecular responses for many patients. We therefore initiated a multicenter community-based single-arm phase II trial of HD imatinib in pts with early CP CML. Methods: Pts were ≥18 years (yrs), in early CP (≤6 months from diagnosis), without prior therapy except for ≤1 month of imatinib or hydroxyurea, and with normal organ function. Pts received imatinib 400 mg twice daily and dose was adjusted for grade ≥3 toxicity; filgrastim was encouraged for pts with grade ≥2 neutropenia. Results: To date, 36 pts have been enrolled in 20 institutions with a median follow-up of 5 months (mos) (0.5–9 mos). The median age is 51 yrs (28–76 yrs). Nineteen patients (53%) had hemoglobin <12 g/dl and 13 (35%) had platelets >450 x109/L. According to the Sokal classification, 14 (39 %), 18 (50%), and 3(8%) were in the low, intermediate and high-risk groups, respectively. Twenty seven pts have had a molecular analysis at 3 mos from the start of therapy and 22 (81%) achieved BCR-ABL/ABL levels <0.05%, with 11 (41%) having undetectable BCR-ABL by Q-PCR. Eleven 11 pts had Q-PCR at 6 mos and 10 (91%) achieved undetectable BCR-ABL. The most common grade ≥3 non-hematologic toxicity was fatigue (n=4, 11%), rash (n=3, 8%), nausea/vomiting (n=2, 6%), and musculoskeletal pain (n=2, 6%). Twelve patients developed grade ≥3 myelosuppression, including neutropenia (n= 5,14%), thrombocytopenia (n=5,14%), and anemia (n=2, 5%). Seventeen 17 (47%) patients required treatment interruptions and 16 of those (44%) have required dose reductions. Neupogen was administered to 8 (22%) pts with 3 (8%) pts for grade ≥3 neutropenia. Most common toxicities for dose reductions were fatigue (6, 17%), nausea/vomiting (9, 25%), and rash (5, 14%). Conclusions: High-dose imatinib is tolerable and effective for pts with newly diagnosed CP-CML in a multicenter setting. Compared to 400 mg daily of imatinib, pts at 800 mg daily achieve substantially higher rates of molecular response with majority having BCR-ABL/ABL ratios under 0.05% at 3 months and up to 41% having undetectable BCR-ABL on Q-PCR. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis