tbuckley/cabot-search huggingface dataset:
Biosynthesis of 5-aminolevulinic acid and heme from 4,5-dioxovalerate in the rat.
Authors: K A Morton, J P Kushner, J G Straka, B F Burnham
Journal: Journal of Clinical Investigation (1983)

We previously demonstrated an alternate pathway for the biosynthesis of 5-aminolevulinic acid (ALA) in bovine liver mitochondria and of tetrapyrroles in suspensions of rat hepatocytes (1980. J. Biol. Chem. 255: 3742; 1981. Proc. Natl. Acad. Sci. USA. 78: 5335). This pathway involves a transamination reaction that incorporates the intact 5-carbon skeleton of 4,5-dioxovaleric acid (DOVA) into ALA. We investigated this alternate pathway in vivo by the intraperitoneal injection of DOVA into rats. Incorporation of DOVA and [5-14C]DOVA into urinary ALA and hepatic and erythroid heme was quantified and compared with the incorporation of [4-14C]ALA and [2-14C]glycine into heme. Within 3 h of injection of 175 mumol of DOVA, urinary ALA excretion increased 2.4-fold over controls. After injection of [5-14C]DOVA, 0.11% of the radioactivity was recovered as urinary ALA, which quantitatively accounted for the 2.4-fold increase in ALA excretion. After the injection 175 mumol of [5-14C]DOVA, 0.14% of the radioactivity was recovered after 3 h as hepatic heme. The injection of 1.75 mmol of [2-14C]glycine or 175 mumol of [4-14C]ALA resulted in recovery of 0.2 and 3.4%, respectively, of the radioactivity as hepatic heme after 3 h. These doses of radiolabeled DOVA, glycine, and ALA were injected into rats with phenylhydrazine-induced anemia. Recovery of radioactivity after 3 h as splenic (erythroid) heme was 0.35% for DOVA, 0.072% for glycine, and 0.25% for ALA. These studies establish that the intact 5-carbon skeleton of DOVA can be incorporated into ALA and heme in vivo.
A Phase I and Pharmacokinetic Study of Short Infusions of UCN-01 in Patients with Refractory Solid Tumors
Authors: E. Claire Dees, Sharyn D. Baker, Seamus O'Reilly, Michelle A. Rudek, Susan B. Davidson, Cheryl Aylesworth, Kathy Elza-Brown, Michael A. Carducci, Ross C. Donehower
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To define the maximum tolerated dose and the dose-limiting toxicity of the kinase modulator UCN-01 administered as a short (1-3 hours) infusion to patients with refractory solid tumors and to evaluate the pharmacokinetics of this novel agent. Experimental Design: Twenty-four patients (15 men, 9 women; median age, 59 years; Eastern Cooperative Oncology Group Performance Status, 0-2) were treated with UCN-01 in this phase I study. Using an accelerated titration design, six dose levels were evaluated ranging from 3 mg/m2 over 3 hours to 95 mg/m2 over 1 to 3 hours administered every 28 days. Plasma, urine, and saliva samples were collected for pharmacokinetic analysis. Results: Seventy courses were evaluable for toxicity. The most frequent adverse events were grade 1 to 2 nausea, vomiting, hyperglycemia, and hypotension. Hypotension was dose limiting at 95 mg/m2 when UCN-01 was administered over 1 hour. The recommended dose of UCN-01 as a short infusion is 95 mg/m2 over 3 hours for the first course and 47.5 mg/m2 over 3 hours for second and subsequent courses. No objective responses were observed. Mean (SD) pharmacokinetic variable values in nine patients treated at 95 mg/m2 over 3 hours were volume of distribution at steady state, 14 (5.4) L; β half-life, 406 (151) hours; systemic clearance, 0.028 (0.017) L/h; Cmax, 51 (16) μmol/L; and area under the curve, 19,732 (12,195) μmol/L h. Conclusions: UCN-01 is well tolerated when given at doses of 95 mg/m2 over 3 hours every 28 days with second and subsequent courses given at 50 % of the first course dose.
Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I
Authors: Cameron Dezfulian, Sruti Shiva, Aleksey Alekseyenko, Akshay Pendyal, D.G. Beiser, Jeeva P. Munasinghe, Stasia A. Anderson, Christopher F. Chesley, T.L. Vanden Hoek, Mark T. Gladwin
Journal: Circulation (2009)

Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO(2)(-)) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest.
Improved Transplant‐Free Survival in Patients With Systemic Sclerosis–Associated Pulmonary Hypertension and Interstitial Lung Disease
Authors: Elizabeth R. Volkmann, Rajeev Saggar, Dinesh Khanna, Bryant Torres, Arjan Flora, Lynne Yoder, Philip J. Clements, Robert M. Elashoff, David J. Ross, Harsh Agrawal, Nabeel Borazan, Daniel E. Furst, Rajan Saggar
Journal: Arthritis & Rheumatology (2014)

Survival in patients with systemic sclerosis (SSc)-associated pulmonary hypertension (PH) and interstitial lung disease (ILD) is poor. Evidence supporting the efficacy of aggressive pulmonary arterial hypertension (PAH)-targeted therapy in this population is limited. The aim of this study was to investigate transplant-free survival in patients with isolated SSc-related PAH or SSc-related PH-ILD who were treated with aggressive PAH-targeted therapy.SSc patients with right-sided heart catheterization (RHC)-diagnosed precapillary PH (mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤15 mm Hg, and pulmonary vascular resistance ≥240 dynes × second/cm(5) ) were included. Patients were classified as having ILD based on review of high-resolution computed tomography (CT) chest imaging and spirometry. The Kaplan-Meier method was applied and Cox proportional hazards models were constructed to analyze survival and identify predictive variables.Of 99 patients with SSc-related precapillary PH, 28% had SSc-related PAH and 72% had SSc-related PH-ILD. The 1- and 2-year survival estimates were, respectively, 72% and 59% in the SSc-related PH-ILD group versus 82% and 66% in the SSc-related PAH group (P = 0.5). Within 6 months of the diagnostic RHC, 24% of all patients were started on prostanoid therapy; an additional 24% were started on prostanoid therapy after 6 months. In the multivariate model, male sex (hazard ratio [HR] 0.7, P = 0.01) and prostanoid therapy initiation within 6 months of the RHC (HR 1.4, P = 0.01) were the only factors significantly associated with transplant-free survival, after accounting for the presence of ILD and severity of PH.In this study, survival of patients with SSc-related PH-ILD was modestly improved relative to historical series. While these findings may not be generalizable, improved survival may be due partly to aggressive PAH-targeted therapy.
Bortezomib-Induced Apoptosis with Limited Clinical Response Is Accompanied by Inhibition of Canonical but not Alternative Nuclear Factor-κB Subunits in Head and Neck Cancer
Authors: Clint Allen, Kunal Saigal, Liesl Nottingham, Pattatheyil Arun, Zhong Chen, Carter Van Waes
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Nuclear factor-κB (NF-κB)/REL transcription factors promote cancer cell survival and progression. The canonical (NF-κB1/RELA or cREL) and alternate (NF-κB2/RELB) pathways require the proteasome for cytoplasmic-nuclear translocation, prompting the investigation of bortezomib for cancer therapy. However, limited clinical activity of bortezomib has been observed in many epithelial malignancies, suggesting this could result from incomplete inhibition of NF-κB/RELs or other prosurvival signal pathways. Experimental Design: To examine these possibilities, matched biopsies from 24 h posttreatment were obtained from accessible tumors of patients who received low-dose bortezomib (0.6 mg/m2) before reirradiation in a phase I trial for recurrent head and neck squamous cell carcinoma (HNSCC). Effects of bortezomib on apoptosis and proliferation by TUNEL and Ki67 staining were compared with nuclear staining for all five NF-κB subunits, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated signal transducers and activators of transcription 3 (STAT3) in tumor biopsies, and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTP) and DNA binding assay for the five NF-κB subunits in HNSCC cell lines. Results: HNSCC showed increased nuclear staining for all five NF-κB subunits, phosphorylated ERK1/2, and phosphorylated STAT3. Bortezomib treatment significantly enhanced apoptosis with inhibition of nuclear RELA in three of four tumors, but other NF-κB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was observed within 3 months. In HNSCC cell lines, 10−8 mol/L bortezomib inhibited cell density while inhibiting tumor necrosis factor-α–induced and partially inhibiting basal activation of NF-κB1/RELA, but not NF-κB2/RELB. Conclusions: Although low-dose bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-κB or other prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC.
Discoidin Domain Receptor 1 Null Mice Are Protected against Hypertension-Induced Renal Disease
Authors: Martin Flamant, Sandrine Placier, Anita Rodenas, Cyrile Anne Curat, Wolfgang F. Vogel, Christos Chatziantoniou, Jean-Claude Dussaule
Journal: Journal of the American Society of Nephrology (2006)

A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.
Controlled, prospective trial of psychosocial function before and after continuous positive airway pressure therapy
Authors: T.A. McFadyen, C.A. Espie, N. McArdle, N.J. Douglas, H.M. Engleman
Journal: European Respiratory Journal (2001)

The aim of the study was to investigate psychosocial function before and after continuous positive airway pressure (CPAP) therapy, and establish the determinants and consequences of objective CPAP use. In a prospective, parallel-group study, changes in psychosocial scores were compared with conservative management or CPAP therapy for the sleep apnoea/hypopnoea syndrome (SAHS). Patient/partner couples from the top (CPAP treated, n=44) or bottom (conservatively treated, n=25) of a CPAP waiting list rated marital satisfaction (evaluation and nurturing relationship issues, communication and happiness (ENRICH), behavioural questionnaire), health/functional status (Short-Form-36 Health Survey, functional outcomes of sleep questionnaire) and sleepiness (Epworth sleepiness scale). Both groups' ratings at baseline were completed while on conservative therapy. Baseline variables did not differ between groups. At follow-up, all seven summary psychosocial scores were statistically better in CPAP-treated patients, effect sizes (ES) ranging from moderate (0.5 sd: marital satisfaction) to very large (&gt;1.0 sd: patients health, functional status and sleepiness scores). Scores in conservatively-treated patients deteriorated to a small or moderate degree (ES −0.2– −0.7 sd), while those in the CPAP-treated group improved to a larger degree (0.3–1.3 sd). Baseline polysomnographical and psychosocial scores, including marital satisfaction, did not predict objective CPAP use (r&lt;0.3). CPAP use was modestly correlated (r=0.3–0.6) with improvement in all psychosocial areas. Continuous positive airway pressure produced statistically and clinically significant psychosocial improvements, some of large magnitude, in psychosocial function. Determinants of usage were not identified, but benefits and usage were positively correlated.
Secondary Malignant Neoplasms in Hodgkin's Disease
Authors: E. Paul Getaz
Journal: JAMA (1978)

<h3>To the Editor.—</h3> We were interested in the article "Secondary Malignant Neoplasms in Patients With Hodgkin's Disease" by Neufeld et al (239:2470, 1978), as we have recently reviewed secondary malignant neoplasms in our Hodgkin's disease population seen between the years 1910 and 1960 at Roswell Park Memorial Institute. There were 520 patients of whom 289 received irradiation only and 205 received additional chemotherapy at some time during their clinical course. There were 18 secondary malignant neoplasms of which five occurred within one year of the diagnosis of Hodgkin's disease and were, therefore, classified as synchronous. Of the metachronous tumors there were carcinomas of the cervix (three), thyroid (two), breast (two), prostate (two), skin (one), and colon (one). There was one case each of chronic lymphocytic leukemia and chronic myeloid leukemia (CML, which was Philadelphia-chromosome-positive). In addition, one patient had a retinoblastoma before the diagnosis of Hodgkin's disease. Latent periods of
Mice deficient for the glycoprotein show subtle abnormalities in myelin
Authors: Dirk Montag, Karl Peter Giese, Udo Bartsch, Rudolf Martini, Yolande Lang, Horst Blüthmann, Jeevajothie Karthigasan, Daniel A. Kirschner, Eva S. Wintergerst, Klaus-Armin Nave, Jürgen Zielasek, Klaus V. Toyka, Hans-Peter Lipp, Melitta Schachner
Journal: Neuron (1994)
Depressive Symptoms and 24-Hour Urinary Norepinephrine Excretion Levels in Patients With Coronary Disease: Findings From the Heart and Soul Study
Authors: Christian Otte, Thomas C. Neylan, Sharon S. Pipkin, Warren S. Browner, Mary A. Whooley
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Depressive symptoms are associated with an increased risk of cardiac events in patients with heart disease. Elevated catecholamine levels may contribute to this association, but whether depressive symptoms are associated with catecholamine levels in patients with heart disease is unknown. METHOD: The authors examined the association between depressive symptoms (defined by a Patient Health Questionnaire score ≥10) and 24-hour urinary norepinephrine, epinephrine, and dopamine excretion levels in 598 subjects with coronary disease. RESULTS: A total of 106 participants (18%) had depressive symptoms. Participants with depressive symptoms had greater mean norepinephrine excretion levels than those without depressive symptoms (65 μg/day versus 59 μg/day, with adjustment for age, sex, body mass index, smoking, urinary creatinine levels, comorbid illnesses, medication use, and cardiac function). In logistic regression analyses, participants with depressive symptoms were more likely than those without depressive symptoms to have norepinephrine excretion levels in the highest quartile and above the normal range. Depressive symptoms were not associated with dopamine or epinephrine excretion levels. CONCLUSIONS: In patients with coronary disease, depressive symptoms are associated with elevated norepinephrine excretion levels. Future longitudinal studies are needed to determine whether elevations in norepinephrine contribute to adverse cardiac outcomes in patients with depressive symptoms.
Combined Inhibition of Wee1 and PARP1/2 for Radiosensitization in Pancreatic Cancer
Authors: David Karnak, Carl G. Engelke, Leslie A. Parsels, Tasneem Kausar, Dongping Wei, Jordan R. Robertson, Katherine B. Marsh, Mary A. Davis, Lili Zhao, Jonathan Maybaum, Theodore S. Lawrence, Meredith A. Morgan
Journal: Clinical Cancer Research (2014)

Abstract Purpose: While the addition of radiation to chemotherapy improves survival in patients with locally advanced pancreatic cancer, more effective therapies are urgently needed. Thus, we investigated the radiosensitizing efficacy of the novel drug combination of Wee1 and PARP1/2 inhibitors (AZD1775 and olaparib, respectively) in pancreatic cancer. Experimental Design: Radiosensitization of AsPC-1 or MiaPaCa-2 human pancreatic cancer cells was assessed by clonogenic survival and tumor growth assays. Mechanistically, the effects of AZD1775, olaparib, and radiation on cell cycle, DNA damage (γH2AX), and homologous recombination repair (HRR) were determined. Results: Treatment of AsPC-1 and MiaPaCa-2 cells with either AZD1775 or olaparib caused modest radiosensitization, whereas treatment with the combination significantly increased radiosensitization. Radiosensitization by the combination of AZD1775 and olaparib was associated with G2 checkpoint abrogation and persistent DNA damage. In addition, AZD1775 inhibited HRR activity and prevented radiation-induced Rad51 focus formation. Finally, in vivo, in MiaPaCa-2–derived xenografts, olaparib did not radiosensitize, whereas AZD1775 produced moderate, yet significant, radiosensitization (P &amp;lt; 0.05). Importantly, the combination of AZD1775 and olaparib produced highly significant radiosensitization (P &amp;lt; 0.0001) evidenced by a 13-day delay in tumor volume doubling (vs. radiation alone) and complete eradication of 20% of tumors. Conclusions: Taken together, these results demonstrate the efficacy of combined inhibition of Wee1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that Wee1 inhibition sensitizes cells to PARP inhibitor–mediated radiosensitization through inhibition of HRR and abrogation of the G2 checkpoint, ultimately resulting in unrepaired, lethal DNA damage and radiosensitization. Clin Cancer Res; 20(19); 5085–96. ©2014 AACR.
The innate immune function of airway epithelial cells in inflammatory lung disease
Authors: Pieter S. Hiemstra, Paul B. McCray, Robert Bals
Journal: European Respiratory Journal (2015)

The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed.
Beyond an occult kinematics of the mind
Authors: Keith K. Niall
Journal: Behavioral and Brain Sciences (2001)

The evidence for a kinematics of the mind is confounded by uncontrolled properties of pictures. Effects of illumination and of picture-plane geometry may underlie some evidence given for a process of mental rotation. Pictured rotation is confounded by picture similarity, gauged by gray-level correlations. An example is given involving the depicted rotation of Shepard-Metzler solids in depth. [Hecht; Kubovy &amp; Epstein; Shepard; Todorovič]
Is there evidence that walking groups have health benefits? A systematic review and meta-analysis
Authors: Sarah Hanson, Andy Jones
Journal: British Journal of Sports Medicine (2015)

Objective To assess the health benefits of outdoor walking groups. Design Systematic review and meta-analysis of walking group interventions examining differences in commonly used physiological, psychological and well-being outcomes between baseline and intervention end. Data sources Seven electronic databases, clinical trial registers, grey literature and reference lists in English language up to November 2013. Eligibility criteria Adults, group walking outdoors with outcomes directly attributable to the walking intervention. Results Forty-two studies were identified involving 1843 participants. There is evidence that walking groups have wide-ranging health benefits. Meta-analysis showed statistically significant reductions in mean difference for systolic blood pressure −3.72 mm Hg (−5.28 to −2.17) and diastolic blood pressure −3.14 mm Hg (−4.15 to −2.13); resting heart rate −2.88 bpm (−4.13 to −1.64); body fat −1.31% (−2.10 to −0.52), body mass index −0.71 kg/m 2 (−1.19 to −0.23), total cholesterol −0.11 mmol/L (−0.22 to −0.01) and statistically significant mean increases in VO 2 max of 2.66 mL/kg/min (1.67–3.65), the SF-36 (physical functioning) score 6.02 (0.51 to 11.53) and a 6 min walk time of 79.6 m (53.37–105.84). A standardised mean difference showed a reduction in depression scores with an effect size of −0.67 (−0.97 to −0.38). The evidence was less clear for other outcomes such as waist circumference fasting glucose, SF-36 (mental health) and serum lipids such as high-density lipids. There were no notable adverse side effects reported in any of the studies. Conclusions Walking groups are effective and safe with good adherence and wide-ranging health benefits. They could be a promising intervention as an adjunct to other healthcare or as a proactive health-promoting activity.
Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation
Authors: Corey Cutler, Pratik Multani, David Robbins, Haesook T. Kim, Thuy Le, Jonathan Hoggatt, Louis M. Pelus, Caroline Desponts, Yi-Bin Chen, Betsy Rezner, Philippe Armand, John Koreth, Brett Glotzbecker, Vincent T. Ho, Edwin Alyea, Marlisa Isom, Grace Kao, Myriam Armant, Leslie Silberstein, Peirong Hu, Robert J. Soiffer, David T. Scadden, Jerome Ritz, Wolfram Goessling, Trista E. North, John Mendlein, Karen Ballen, Leonard I. Zon, Joseph H. Antin, Daniel D. Shoemaker
Journal: Blood (2013)