tbuckley/cabot-search huggingface dataset:
High-Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer Disease
Authors: Paul S Aisen, Lon S Schneider, Mary Sano, Ramon Diaz-Arrastia, Christopher H van Dyck, Myron F Weiner, Teodoro Bottiglieri, Shelia Jin, Karen T Stokes, Ronald G Thomas, Leon J Thal
Journal: JAMA (2008)

Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months.Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.clinicaltrials.gov Identifier: NCT00056225.
The significance of low PU.1 expression in patients with acute promyelocytic leukemia
Authors: Xuehua Zhu, Hui Zhang, Maoxiang Qian, Xujie Zhao, Wentao Yang, Ping Wang, Ji Zhang, Kankan Wang
Journal: Journal of Hematology & Oncology (2012)

Although the importance of the hematopoietic transcription factor PU.1 in acute myeloid leukemia (AML) has been demonstrated, the expression of PU.1 in acute promyelocytic leukemia (APL) patient samples awaits further investigation. The current study used APL patient samples to assess the expression pattern of PU.1 in the initiation and progression of APL.We used real-time RT-PCR to compare PU.1 expression between de novo APL patient samples and normal blood specimens, and the results indicated that PU.1 expression was significantly lower in newly diagnosed APL patient samples as compared to normal hematopoietic cells. Further evidence showed a significant inverse correlation between the expression level of PML-RARα and that of PU.1. In addition, we analyzed the correlation between PML-RARα and PU.1 expression in a large population of AML patients retrieved from the expression profiles. The results showed that PU.1 expression was lower in patients with APL than other AML subtypes and there was also a trend towards increasing PU.1 expression from AML-M0 to AML-M5, with the exception of AML-M3 (APL). These observations suggested that PU.1 expression was reduced by PML-RARα in APL patients. Furthermore, we measured PU.1 expression in APL-initiating cells isolated from de novo APL patients by side population cell analysis and found that suppression of PU.1 expression occurred concurrently with PML-RARα expression, indicating the pivotal role of PU.1 in APL initiation.Our findings provide evidence that low PU.1 expression in APL patients is required for disease initiation and progression.
Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis
Authors: Vincenzo Mazzaferro, Raffaele Romito, Marcello Schiavo, Luigi Mariani, Tiziana Camerini, Sherrie Bhoori, Lorenzo Capussotti, Fulvio Calise, Riccardo Pellicci, Giulio Belli, Alessandro Tagger, Massimo Colombo, Ferruccio Bonino, Pietro Majno, Josep M. Llovet
Journal: Hepatology (2006)

Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (&lt;2 years) or late (&gt;2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)-related cirrhosis. A predetermined group of 150 HCV RNA–positive patients undergoing resection of early- to intermediate-stage HCC was stratified into 80 HCV-pure (hepatitis B anticore antibody [anti-HBc]–negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti-HBc–positive) groups, then randomized to IFN-α (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence-free survival (RFS); secondary end points were disease-specific and overall survival. Intention-to-treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life-threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow-up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN-treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence ( P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV-pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09–0.9; P = .04). In conclusion , IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients receiving effective treatment.
Rho Kinases in Autoimmune Diseases
Authors: Alessandra B. Pernis, Edd Ricker, Chien-Huan Weng, Cristina Rozo, Woelsung Yi
Journal: Annual Review of Medicine (2016)

The Rho kinases, or ROCKs, are a family of serine-threonine kinases that serve as key downstream effectors for Rho GTPases. The ROCKs are increasingly recognized as critical coordinators of a tissue response to injury due to their ability to modulate a wide range of biological processes. Dysregulated ROCK activity has been implicated in several human pathophysiological conditions ranging from cardiovascular and renal disorders to fibrotic diseases. In recent years, an important role for the ROCKs in the regulation of immune responses is also being uncovered. We provide an overview of the role of the ROCKs in immune cells and discuss studies that highlight the emerging involvement of this family of kinases in the pathogenesis of autoimmune diseases. Given the potential promise of the ROCKs as therapeutic targets, we also outline the approaches that could be employed to inhibit the ROCKs in autoimmune disorders.
Evidence-Based Public Health: A Fundamental Concept for Public Health Practice
Authors: Ross C. Brownson, Jonathan E. Fielding, Christopher M. Maylahn
Journal: Annual Review of Public Health (2009)

Despite the many accomplishments of public health, a greater attention to evidence-based approaches is warranted. This article reviews the concepts of evidence-based public health (EBPH), on which formal discourse originated about a decade ago. Key components of EBPH include making decisions on the basis of the best available scientific evidence, using data and information systems systematically, applying program-planning frameworks, engaging the community in decision making, conducting sound evaluation, and disseminating what is learned. Three types of evidence have been presented on the causes of diseases and the magnitude of risk factors, the relative impact of specific interventions, and how and under which contextual conditions interventions were implemented. Analytic tools (e.g., systematic reviews, economic evaluation) can be useful in accelerating the uptake of EBPH. Challenges and opportunities (e.g., political issues, training needs) for disseminating EBPH are reviewed. The concepts of EBPH outlined in this article hold promise to better bridge evidence and practice.
Allogeneic hematopoietic stem cell transplantation for myelofibrosis and chronic myelomonocytic leukemia
Authors: Natasha Kekre, Vincent T. Ho
Journal: American Journal of Hematology (2015)

The efficacy of hematopoietic stem cell transplantation (HSCT) is not well established in Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs). Without randomized prospective trials comparing HSCT to non-HSCT options or comparing HSCT regimens, physicians must rely on prognostic scoring systems and clinical experience when making decisions about who and when to transplant patients with Ph- MPNs. These patients are vulnerable to hepatic toxicity and graft failure after HSCT because of their increased likelihood of portal hypertension, massive splenomegaly, and extensive bone marrow fibrosis related to their disease. In this review, we aim to outline the indications and modalities of HSCT as they pertain to the Ph- MPNs and CMML based on the currently available evidence. We will further highlight the challenges of HSCT in these diseases, including but not limited to the incorporation of JAK inhibitors into HSCT for myelofibrosis.
Six-Year Incidence of Proteinuria in Type 1 Diabetic African Americans
Authors: Monique S. Roy, Mahmoud Affouf, Alec Roy
Journal: Diabetes Care (2007)

We sought to report the 6-year incidence of proteinuria and associated risk factors in African Americans with type 1 diabetes.African Americans (n = 483) with type 1 diabetes were reexamined in a 6-year follow-up study. Proteinuria and creatinuria were measured in 4-h timed urine specimens obtained at initial and follow-up visits. Other evaluations included a structured clinical interview, ocular examination, masked grading of seven stereoscopic fundus photographs, blood pressure measurements, blood assays, and administration of the Beck Depression Inventory (BDI).Over the 6-year period, 117 (42.9%) of the 473 patients at risk developed "any" proteinuria, defined as either microalbuminuria (26.0%) or overt (16.9%) proteinuria; 87 (23.5%) progressed from micro- or no albuminuria to overt proteinuria and 39 (8.7%) to end-stage renal disease; and 40 (20.6%) regressed. Peak incidence of any proteinuria occurred for patients who were 10-14 years of age or had 5-10 years of diabetes duration at baseline. Multiple regression analysis showed that baseline albumin excretion rate (AER), systemic hypertension, blood cholesterol, and high BDI depression scores were significant and independent risk factors for incidence of any proteinuria.In African Americans with type 1 diabetes, the 6-year incidence of proteinuria is high, particularly among young patients and those with a relatively short duration of diabetes at baseline. Baseline AER is the strongest predictor for incidence of any proteinuria.
Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia
Authors: E WEIR, A OLSCHEWSKI
Journal: Cardiovascular Research (2006)

Localized alveolar hypoxia causes constriction of the small resistance pulmonary arteries, thus diverting the desaturated, mixed-venous blood to better ventilated areas of the lung. Although modulated by endothelial vasoactive substances, the constrictor response to hypoxia is intrinsic to the smooth muscle cell. Ion channels are important elements in two of the three components of the response. Hypoxia inhibits several potassium channels (voltage-gated and TASK), leading to membrane depolarization and calcium entry through L-type channels. It also causes release of calcium from the sarcoplasmic reticulum, with consequent repletion through store-operated calcium channels. Finally, the effect of the rise in cytosolic calcium is amplified by enhanced calcium sensitivity of the actin/myosin interaction, achieved by the hypoxia-induced increase in Rho-kinase activity. The change in oxygen tension that stimulates these three "executive" components is signaled by a change in the redox status of the smooth muscle cell and probably by downstream changes in G-proteins. Ion channels also play a critical role in the vascular remodeling that results in chronic hypoxic pulmonary hypertension, seen when all the pulmonary vascular bed is hypoxic, at high altitude and in patients with chronic lung diseases. The same inhibition of potassium channels and influx of calcium results in high cytosolic levels of potassium and calcium. These, respectively, lead to inhibition of apoptosis and an increase in cellular proliferation. A better understanding of the pathophysiology of hypoxic pulmonary vasoconstriction and vascular remodeling will enable the design of better treatments for hypoxic and other forms of pulmonary hypertension.
Adjuvant Chemotherapy for High-Risk Operable Breast Cancer
Authors: Aman U. Buzdar
Journal: Journal of Clinical Oncology (2007)

In this issue of the Journal of Clinical Oncology, results are reported from the Southwest Oncology Group (SWOG)/Intergroup phase III randomized study of dose-dense chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide compared with four cycles of high-dose chemotherapy (HDCT) with doxorubicin and cyclophosphamide and autologous hematopoietic progenitor cell support. 1 All 536 patients treated in this study had four or more involved axillary lymph nodes.The authors found no evidence that high-dose chemotherapy with autologous stem-cell support was superior to dose-dense chemotherapy.In fact, HDCT was associated with a higher rate of toxic effects and with an insignificant inferior outcome.The past three decades of research into using adjuvant therapies to improve the outcome of patients with high-risk breast cancer has resulted in several approaches that have significantly altered the natural history of the disease and improved our understanding of the biology of breast cancer. 2,3 Breast cancer comprises a group of biologically different diseases, and our knowledge and understanding of these subsets of disease are evolving.To provide our patients with optimal clinical management, we need to be familiar with some of the distinct subsets of breast cancer and different therapeutic approaches.A high proportion of breast cancers are invasive ductal carcinomas, with or without steroid hormone receptors or HER2 overexpression.For the small number of patients with squamous, myoepithelial, or spindle cell histologies, the disease does not express hormone or HER2 receptors and it also does not respond to current adjuvant therapies.Current adjuvant therapy options for patients with hormonereceptor-positive disease include ovarian ablation, ovarian suppression, or antiestrogens for premenopausal patients and antiestrogens 3 or aromatase inhibitors for postmenopausal patients. 3,4 For patients with hormone-receptor-negative disease, endocrine therapies have no favorable impact on the risk of recurrence or the risk of a second primary breast cancer.
Oncogenic Role of <b> <i>eIF-5A2</i> </b> in the Development of Ovarian Cancer
Authors: Xin-Yuan Guan, Jackie M-W. Fung, Ning-Fang Ma, Sze-Hang Lau, Lai-Shan Tai, Dan Xie, Yu Zhang, Liang Hu, Qiu-Liang Wu, Yan Fang, Jonathan S. T. Sham
Journal: Cancer Research (2004)

Abstract Amplification of 3q26 is one of the most frequent chromosomal alterations in many solid tumors, including ovarian, lung, esophageal, prostate, breast, and nasopharyngeal cancers. A candidate oncogene to eukaryotic initiation factor 5A2 (eIF-5A2), a member of eukaryotic initiation factor 5A subfamily, has been isolated from a frequently amplified region at 3q26.2. In this work, the tumorigenic ability of eIF-5A2 was demonstrated by anchorage-independent growth in soft agar and tumor formation in nude mice. Furthermore, antisense DNA against eIF-5A2 could inhibit cell growth in ovarian cancer cell line UACC-1598 with amplification of eIF-5A2 in form of double minutes. Cell growth rate in UACC-1598 was also inhibited when the expression level of EIF-5A2 was decreased by the reduction of the copy number of double minutes. The correlation of EIF-5A2 overexpression and clinical features of ovarian cancer was investigated using tissue microarray, and the result showed that eIF-5A2 overexpression was significantly associated with the advanced stage of ovarian cancer. These findings suggest that eIF-5A2 plays important roles in ovarian pathogenesis.
Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo.
Authors: M L Nierodzik, A Plotkin, F Kajumo, S Karpatkin
Journal: Journal of Clinical Investigation (1991)

Recent studies have revealed a role for platelets and the platelet-adhesive proteins, fibronectin and von Willebrand factor (vWF) in platelet-tumor cell interaction in vitro and metastasis in vivo. The present report documents the effect of thrombin treatment of platelets on this interaction in vitro and in vivo. In vitro, thrombin at 100-1,000 mU/ml maximally stimulated the adhesion of six different tumor cell lines from three different species two- to fivefold. As little as 1-10 mU/ml was effective. The effect of thrombin was specific (inhibitable by hirudin, dansyl-arginine N-(3-ethyl-1,5 pentanediyl) amide and unreactive with the inactive thrombin analogue N-P-tosyl-L-phenylchloromethylketone-thrombin and D-phenylalanyl-L-propyl-L-arginine chloromethylketone-thrombin (PPACK-thrombin), and required high-affinity thrombin receptors (competition with PPACK-thrombin but not with N-P-tosyl-L-lysine-chloromethyl-ketone-thrombin). Functionally active thrombin was required on the platelet surface. Binding of tumor cells to thrombin-activated platelets was inhibitable by agents known to interfere with the platelet GPIIb-GPIIIa integrin: monoclonal antibody 10E5, tetrapeptide RGDS and gamma chain fibrinogen decapeptide LGGAKQAGDV, as well as polyclonal antibodies against the platelet adhesive ligands, fibronectin and vWF. In vivo, thrombin at 250-500 mU per animal increased murine pulmonary metastases fourfold with CT26 colon carcinoma cells and 68-413-fold with B16 amelanotic melanoma cells. Thus, thrombin amplifies tumor-platelet adhesion in vitro two- to fivefold via occupancy of high-affinity platelet thrombin receptors, and modulation of GPIIb-GPIIIa adhesion via an RGD-dependent mechanism. In vivo, thrombin enhances tumor metastases 4-413-fold with two different tumor cell lines.
Predicting Degree of Benefit From Adjuvant Trastuzumab in NSABP Trial B-31
Authors: Katherine L. Pogue-Geile, Chungyeul Kim, Jong-Hyeon Jeong, Noriko Tanaka, Hanna Bandos, Patrick G. Gavin, Debora Fumagalli, Lynn C. Goldstein, Nour Sneige, Eike Burandt, Yusuke Taniyama, Olga L. Bohn, Ahwon Lee, Seung-Il Kim, Megan L. Reilly, Matthew Y. Remillard, Nicole L. Blackmon, Seong-Rim Kim, Zachary D. Horne, Priya Rastogi, Louis Fehrenbacher, Edward H. Romond, Sandra M. Swain, Eleftherios P. Mamounas, D. Lawrence Wickerham, Charles E. Geyer, Joseph P. Costantino, Norman Wolmark, Soonmyung Paik
Journal: JNCI Journal of the National Cancer Institute (2013)

National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31.Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided.Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001).We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).
Characteristics of patients with antiphospholipid syndrome with major bleeding after oral anticoagulant treatment
Authors: G Castellino
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To study the demographic and clinical characteristics of patients with antiphospholipid syndrome (APS) with serious haemorrhagic complications of anticoagulant treatment in an attempt to establish risk factors for bleeding. <h3>METHODS</h3> Patients with APS who were attending our lupus unit and who presented with severe bleeding while receiving oral anticoagulation were studied retrospectively. Severe bleeding was defined by the need for admission to hospital. Demographic data, clinical features, concomitant diseases and drugs, warfarin doses, duration of anticoagulation, and International Normalised Ratios (INR) at the time of bleeding were collected. <h3>RESULTS</h3> Fifteen patients were included in the study (12 with systemic lupus erythematosus (SLE) plus APS and 3 with primary APS). The median age was 41.7 (range 27–66) and the median duration of the disease was 12.9 years (range 3–22). Duration of anticoagulation was between 10 days and 17 years. The INR at the time of bleeding was under 3 in 4 patients, between 3 and 4 in 5 patients and above 4 in 6 patients. There were 4 episodes of subdural haematoma, 4 episodes of renal haematoma (two after renal biopsy), 2 episodes of ovarian haemorrhage, 2 episodes of rectal haemorrhage, 1 episode of menorrhagia, 1 episode of haemarthrosis, and 1 episode of spinal haematoma. Concomitant drugs were aspirin in 9 patients, antibiotics in 2 patients, and azathioprine in 3 patients. In 6 patients hypertension was present as a concomitant disease. There were no deaths due to bleeding. Anticoagulant treatment was restarted in all patients and 3 of them had a new episode of bleeding. <h3>CONCLUSION</h3> No relation was established between age, duration of oral anticoagulant treatment, and bleeding. Concomitant drugs, mainly aspirin, and high blood pressure were present at the time of bleeding in a large number of patients.