tbuckley/cabot-search huggingface dataset:
THE IMPACT OF NATIONAL CANCER ACT
Authors: Frankie Ann Holmes, Ronald S. Walters, Richard L. Theriault, Aman U. Buzdar, Debra K. Frye, Gabriel N. Hortobagyi, Arthur D. Forman, Lesley K. Newton, Martin N. Raber
Journal: JNCI Journal of the National Cancer Institute (1991)

Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m 2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5–13+months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%–76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no altergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).
Nervous system involvement in association with vasculitis and anticardiolipin antibodies in a patient with systemic sclerosis.
Authors: A L Herrick, P Oogarah, T B Brammah, A J Freemont, M I Jayson
Journal: Annals of the Rheumatic Diseases (1994)

Nervous system involvement in association with vasculitis and anticardiolipin antibodies in a patient with systemic sclerosis Although systemic sclerosis (SSc) is a multi- system disease, signs and symptoms of neurological involvement are unusual, and in contrast to the situation in other connective tissue disorders, vasculitis is thought to be rare.We report a 51 year old man with diffuse SSc who developed vasculitis affecting peripheral nerve and muscle, and subse- quently generalised seizures.He first became unwell in 1985, aged 45 years, when he developed fibrosing alveolitis.Subsequently he developed arthralgias, Raynaud's phenomenon, vasculitic lesions of his finger-tips and mild proximal muscle weakness with elevated creatine phosphokinase (CPK).In 1987 sclerodactyly and skin tethering of the anterior abdominal wall were noted, and skin biopsy of both involved and clinically uninvolved skin showed features of SSc with intimal thickening, oedema and a mild inflammatory cell infiltrate.As well as diffuse skin thickening he went on to develop oesophageal dysmotility, heart block requiring a permanent cardiac pacemaker (but no clinical or echocardio- graphic evidence at the time of myocardial disease), intestinal pseudo-obstruction and small bowel overgrowth.His connective tissue disease had therefore evolved into SSc with overlap features of a myositis.There were no symptoms of a sicca syndrome.He was started on treatment with prednisolone and later in 1987 on alpha-interferon with good effect.He was lost to follow up and discontinued alpha-interferon in January 1991.Six months later he was admitted with a marked clinical deterioration: he was unable to stand, was breathless on minimal exertion, and was complaining of epigastric pain, abdominal distension and diarrhoea, as well as severe Raynaud's.Drug treatment comprised prednisolone 15 mg daily.On examination he was cachectic, with basal crepitations.He had proximal muscle wasting and weakness, profound weakness of ankle dorsi-and plantar flexion and impaired sensation below the knees.He went on to develop a fever.White blood count was raised at 35-8 x on August 12,
Effects of wortmannin on insulin- and ischemia-induced stimulation of GLUT4 translocation and FDG uptake in perfused rat hearts
Authors: S Egert
Journal: Cardiovascular Research (1997)

Objective: Myocardial glucose transport is enhanced by hormonal and other stimuli such as ischemia and hypoxia which induce glucose transporter 4 (GLUT4) translocation. Whether insulin and ischemia share a common signaling mechanism is not yet known. This study investigated whether phosphatidylinositol 3-kinase (PI3K), a signaling intermediate of the insulin-responsible pathway, also participates in the ischemia-induced stimulation of glucose. Methods: Isolated Langendorff-perfused Sprague-Dawley rat hearts were subjected to 100 nmol/l insulin or 15 min of no-flow ischemia with/without 1 μmol/l wortmannin, an inhibitor of PI3K. After perfusion, relative subcellular glucose transporter GLUT4 distribution was assessed by membrane fractionation and immunoblotting and compared to controls. Uptake kinetics of the glucose analog [18F]fluoro-deoxyglucose (FDG) were also studied during perfusion of rat hearts. Results: GLUT4 translocation to the plasma membrane (PM) was increased by insulin 1.8-fold and by ischemia 2.4-fold (P<0.05). FDG uptake was increased by insulin 6.0-fold and by ischemia 6.2-fold (P<0.05). Wortmannin 1 μmol/l inhibited insulin-mediated translocation of GLUT4 and increase in FDG uptake completely. However, it did not show any effect on ischemia-stimulated GLUT4 translocation or on ischemia-induced increase in FDG utilization. A significant correlation was found between relative GLUT4 translocation and FDG uptake in hearts of the insulin series (r = 0.9, P<0.05) and of the ischemia series (r = 0.8, P<0.05). Conclusions: Our results demonstrate that wortmannin did not inhibit ischemia-induced stimulation of myocardial glucose transport, supporting the hypothesis of different signaling pathways for ischemia and insulin.
Promoter-like epigenetic signatures in exons displaying cell type-specific splicing
Authors: Joao Curado, Camilla Iannone, Hagen Tilgner, Juan Valcárcel, Roderic Guigó
Journal: Genome biology (2015)

Pre-mRNA splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation. However, the extent and mechanisms behind this interplay remain poorly understood. We use transcriptomic and epigenomic data generated by the ENCODE project to investigate the association between chromatin structure and alternative splicing. We find a strong and significant positive association between H3K9ac, H3K27ac, H3K4me3, epigenetic marks characteristic of active promoters, and exon inclusion in a small but well-defined class of exons, representing approximately 4 % of all regulated exons. These exons are systematically maintained at comparatively low levels of inclusion across cell types, but their inclusion is significantly enhanced in particular cell types when in physical proximity to active promoters. Histone modifications and other chromatin features that activate transcription can be co-opted to participate in the regulation of the splicing of exons that are in physical proximity to promoter regions.
Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women
Authors: Peter Würtz, Mika Tiainen, Ville-Petteri Mäkinen, Antti J. Kangas, Pasi Soininen, Juha Saltevo, Sirkka Keinänen-Kiukaanniemi, Pekka Mäntyselkä, Terho Lehtimäki, Markku Laakso, Antti Jula, Mika Kähönen, Mauno Vanhala, Mika Ala-Korpela
Journal: Diabetes Care (2012)

OBJECTIVE Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level. RESEARCH DESIGN AND METHODS Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors. RESULTS Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P &amp;lt; 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P &amp;lt; 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003–0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose. CONCLUSIONS Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.
Acoustic correlates and perceptual cues in speech
Authors: James R. Sawusch
Journal: Behavioral and Brain Sciences (1998)

Locus equations are supposed to capture a perceptual invariant of place of articulation in consonants. Synthetic speech data show that human classification deviates systematically from the predictions of locus equations. The few studies that have contrasted predictions from competing theories yield mixed results, indicating that no current theory adequately characterizes the perceptual mapping from sound to phonetic symbol.
Increased serum levels of soluble vascular cell adhesion molecule 1 and E-selectin in patients with localized scleroderma
Authors: Kenichi Yamane, Hironobu Ihn, Masahide Kubo, Norihito Yazawa, Kanako Kikuchi, Yoshinao Soma, Kunihiko Tamaki
Journal: Journal of the American Academy of Dermatology (2000)
Plasma Stromal Cell–Derived Factor-1: Host Derived Marker Predictive of Distant Metastasis in Breast Cancer
Authors: Saima Hassan, Andrea Baccarelli, Ombretta Salvucci, Mark Basik
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Homing of breast cancer cells to metastatic sites may be regulated by the production of stromal cell–derived factor (SDF)-1 by specific target organs, which attracts CXCR4-expressing breast cancer cells. We investigated the value of SDF-1 as a predictive blood marker of distant metastasis in breast cancer, together with a common polymorphism of SDF-1, SDF-1-3′A. Experimental Design: Plasma samples were collected prospectively for 270 consecutive primary breast cancer patients with a median follow-up of 3.3 years. Plasma SDF-1 levels were measured using an ELISA, and the polymorphism was identified via PCR-RFLP analysis. Results: Plasma SDF-1 levels were divided into two groups, low and high, based on the median SDF-1 value of 2,661 pg/mL. Patients with low SDF-1 showed an increased risk of developing distant metastasis (relative risk, 1.94; P = 0.02) and poorer breast cancer–specific survival [adjusted hazard ratio (AHR), 3.92; P = 0.007]. Patients with both low plasma SDF-1 levels and the SDF-1-3′A polymorphism showed a poorer breast cancer–specific survival (AHR, 3.98; P = 0.001) and distant disease-free survival (AHR, 2.88; P = 0.003). In a separate cohort of 22 breast cancer patients, we found no significant difference in SDF-1 levels before and posttumor resection. Conclusion: We found that low plasma SDF-1 is an independent host-derived predictive marker of distant metastasis in breast cancer. The prognostic value of the combination of a low plasma SDF-1 level and the SDF-1-3′A polymorphism identifies a cohort of patients with an intrinsic susceptibility for poorer survival.
Bleeding Peptic Ulcer: An Audit of Conservative Management
Authors: X Mueller, J M Rothenbuehler, A Amery, F Harder
Journal: Journal of the Royal Society of Medicine (1994)

One hundred and twenty-six of 157 consecutive patients (80%) admitted for a bleeding peptic ulcer were treated conservatively and retrospectively analysed. There were 52% duodenal, 41% gastric and 7% combined ulcers. The initial shock index (pulse/systolic blood pressure) was in excess of one in 10%. For 22% of the patients no transfusion was required but 10% had more than 6 units of blood during their hospital stay. Forty-nine per cent were on nonsteroidal anti-inflammatory drugs and 83% had at least one coexisting systemic disease. Six patients (5%) had a further haemorrhage, four of whom died. A total of 10 patients (8%) died. Five of them were related to the peptic ulcer disease but also had terminal or multiple systemic diseases precluding any surgery. Their poor short-term prognosis shows how difficult it will be to effectively reduce the mortality in this particular group of conservatively treated patients, even with the recent advent of endoscopic haemostasis, and stresses the importance of carefully identifying high risk patients in trials mounted to improve on the current mortality figures.
Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway
Authors: Tatsuhiro Shibata, Shigeru Saito, Akiko Kokubu, Takafumi Suzuki, Masayuki Yamamoto, Setsuo Hirohashi
Journal: Cancer Research (2010)

Abstract In multicellular organisms, adaptive responses to oxidative stress are regulated by NF-E2–related factor 2 (NRF2), a master transcription factor of antioxidant genes and phase II detoxifying enzymes. Aberrant activation of NRF2 by either loss-of-function mutations in the Keap1 gene or gain-of-function mutations in the Nrf2 gene occurs in a wide range of human cancers, but details of the biological consequences of NRF2 activation in the cancer cells remain unclear. Here, we report that mutant NRF2 induces epithelial cell proliferation, anchorage-independent growth, and tumorigenicity and metastasis in vivo. Genome-wide gene expression profiling revealed that mutant NRF2 affects diverse molecular pathways including the mammalian target of rapamycin (mTOR) pathway. Mutant NRF2 upregulates RagD, a small G-protein activator of the mTOR pathway, which was also overexpressed in primary lung cancer. Consistently, Nrf2-mutated lung cancer cells were sensitive to mTOR pathway inhibitors (rapamycin and NVP-BEZ235) in both in vitro and an in vivo xenograft model. The gene expression signature associated with mutant NRF2 was a marker of poor prognosis in patients with carcinoma of the head and neck region and lung. These results show that oncogenic Nrf2 mutation induces dependence on the mTOR pathway during carcinogenesis. Our findings offer a rationale to target NRF2 as an anticancer strategy, and they suggest NRF2 activation as a novel biomarker for personalized molecular therapies or prognostic assessment. Cancer Res; 70(22); 9095–105. ©2010 AACR.
Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction
Authors: Chieko Yokoyama, Tomoko Yabuki, Manabu Shimonishi, Masayuki Wada, Toshihisa Hatae, Susumu Ohkawara, Junji Takeda, Taroh Kinoshita, Masaru Okabe, Tadashi Tanabe
Journal: Circulation (2002)

Prostacyclin (PGI2) is a short-lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells. To study the role of PGI2 in the vascular system in vivo, PGI2-deficient (PGID) mice were established by genetic disruption of the PGI2 synthase gene.PGI2 synthase-null mice were generated by replacing the exons of PGI2 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene. In these mice, PGI2 levels in the plasma, kidneys, and lungs were reduced, whereas thromboxane and prostaglandin E2 levels became elevated. Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild-type mice (P<0.05). They developed progressive morphological abnormalities in the kidneys, accompanied by atrophy, surface irregularity, fibrosis, cyst, arterial sclerosis, and hypertrophy of vessel walls. Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice. Importantly, these phenotypes have not been reported in PGI2 receptor-deficient mice.PGI2 deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis, especially in mouse kidneys. The findings demonstrated in vivo that PGI2 is important in the homeostasis of blood vessels. Our established PGID mice are useful for studies on the initiation and development of vascular diseases, such as ischemic renal disorders with arterial sclerosis and infarction, and also for studies on the novel signaling pathway of PGI2.
Caffeine Ingestion Is Associated With Reductions in Glucose Uptake Independent of Obesity and Type 2 Diabetes Before and After Exercise Training
Authors: SoJung Lee, Robert Hudson, Katherine Kilpatrick, Terry E. Graham, Robert Ross
Journal: Diabetes Care (2005)

OBJECTIVE—We investigated the effect of caffeine ingestion on insulin sensitivity in sedentary lean men (n = 8) and obese men with (n = 7) and without (n = 8) type 2 diabetes. We also examined whether chronic exercise influences the relationship between caffeine and insulin sensitivity in these individuals. RESEARCH DESIGN AND METHODS—Subjects underwent two hyperinsulinemic-euglycemic clamp procedures, caffeine (5 mg/kg body wt) and placebo, in a double-blind, randomized manner before and after a 3-month aerobic exercise program. Body composition was measured by magnetic resonance imaging. RESULTS—At baseline, caffeine ingestion was associated with a significant reduction (P &amp;lt; 0.05) in insulin sensitivity by a similar magnitude in the lean (33%), obese (33%), and type 2 diabetic (37%) groups in comparison with placebo. After exercise training, caffeine ingestion was still associated with a reduction (P &amp;lt; 0.05) in insulin sensitivity by a similar magnitude in the lean (23%), obese (26%), and type 2 diabetic (36%) groups in comparison with placebo. Exercise was not associated with a significant increase in insulin sensitivity in either the caffeine or placebo trials, independent of group (P &amp;gt; 0.10). CONCLUSIONS—Caffeine consumption is associated with a substantial reduction in insulin-mediated glucose uptake independent of obesity, type 2 diabetes, and chronic exercise.
Postpartum management of hypertension
Authors: K. Bramham, C. Nelson-Piercy, M. J. Brown, L. C. Chappell
Journal: BMJ (2013)

#### Summary points

Hypertension in the postpartum period affects several groups of women, including those with previous chronic hypertension, gestational hypertension, pre-eclampsia, and eclampsia. In addition, pre-eclampsia may present for the first time in the postnatal period. Although the underlying causes and clinical presentation of these types of hypertension vary, patients can be investigated and treated in a similar manner. This review covers management of postpartum hypertension and its future consequences. Hypertension affects 6-10% of pregnancies,1 but few studies have reported the incidence of postpartum hypertension. This review is relevant to general practitioners, obstetricians, and specialists in secondary care who may see women with postpartum hypertension.

#### Sources and selection criteria

We searched PubMed (June 2012) for relevant articles on postpartum management of hypertension, pre-eclampsia, and eclampsia. The MeSH terms for the search included “postpartum”, “hypertension”, “pre-eclampsia”, and “eclampsia”, in addition to keyword variations. We obtained information from prospective randomised clinical trials, cohort studies, case series, systematic reviews, and meta-analyses. We also searched national and international guidelines for those including advice on postpartum management of hypertension and kidney disease.

Generalised systemic vasodilation occurs during pregnancy; despite a 40-50% increase in cardiac output, mean arterial pressure drops by about 10 mm Hg to reach its lowest value by mid-pregnancy.2 During the last trimester, blood pressure gradually increases to …
Phase I trial of a Toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma
Authors: Youn H. Kim, Michael Girardi, Madeleine Duvic, Timothy Kuzel, Brian K. Link, Lauren Pinter-Brown, Alain H. Rook
Journal: Journal of the American Academy of Dermatology (2010)
Glomerular Podocytopathy in Patients with Systemic Lupus Erythematosus
Authors: Steven W. Kraft, Melvin M. Schwartz, Stephen M. Korbet, Edmund J. Lewis
Journal: Journal of the American Society of Nephrology (2004)

A series of patients with systemic lupus erythematosus (SLE) and proteinuria were studied to determine whether nephrotic-range proteinuria was associated with diffuse epithelial cell foot process effacement in the absence of peripheral glomerular immune aggregate deposition. Biopsies from patients with known or suspected SLE and a histologic diagnosis of (1) normal by light microscopy, (2) mesangial proliferative glomerulonephritis, or (3) focal segmental glomerulosclerosis were studied. Biopsies were excluded when they demonstrated endocapillary proliferation or necrosis by light microscopy or electron-dense glomerular basement membrane deposits by electron microscopy. Patients were required to fulfill four of 11 American Rheumatologic Association criteria for the diagnosis of SLE, and proteinuria could not be associated with nonsteroidal anti-inflammatory drug use. Eighteen biopsies were studied, eight from patients with nephrotic-range proteinuria (>/=3 g/d) and 10 from patients with non-nephrotic proteinuria. The time from diagnosis of SLE to biopsy was shorter for nephrotic patients that for nonnephrotic patients. Seven of eight biopsies from nephrotic patients demonstrated at least 80% foot process effacement, whereas no biopsy from a nonnephrotic patient exhibited >20% effacement. There were no other significant pathologic differences between the nephrotic and nonnephrotic patients. The single common morphologic feature associated with nephrotic proteinuria was diffuse visceral epithelial cell foot process effacement. It is concluded that the development of nephrotic-range proteinuria in patients with SLE without peripheral immune aggregate deposition or endocapillary proliferation on renal biopsy is more likely a manifestation of SLE than the coexistence of idiopathic minimal-change glomerulopathy and SLE.
A DOUBLE BLIND RANDOMIZED STUDY TO EVALUATE THE EFFICACY OF BINDARIT IN PREVENTING CORONARY STENT RESTENOSIS
Authors: Antonio Colombo, Ugo Limbruno, Corrado Lettieri, Ernesto Lioy, Angelo Guglielmotti, Marco Calabresi, Marco Valgimigli, Daniela Pierucci
Journal: Journal of the American College of Cardiology (2012)