tbuckley/cabot-search huggingface dataset:
Abstract 18586: GPD1-L Inhibits the Cardiac Sodium Channel Nav1.5 by decreasing SIRTUIN1 Activity
Authors: Christopher M Lewarchik, Prakash C Viswanathan, Mohan Madhusudanan, Laurie J Kerchner, Pranav Shah, Kathleen M Nilles, Asma Navqi, Xiaodong Zhu, Vineet Agrawal, Haider Mehdi, Yong-Rae Kim, Kaikobad Irani, Barry London
Journal: Circulation (2013)

GPD1-L is a cytosolic protein that catalyzes the reduction of dihydroxyacetone phosphate + NADH into glycerol 3-phosphate + NAD+. Mutations in GPD1-L have been linked to Brugada syndrome and sudden infant death syndrome. GPD1-L regulates the cardiac Na+ channel Nav1.5 but the mechanism is not fully understood. We have recently shown that SIRTUIN1 (SIRT1), a NAD+ dependent deacetylase, increases Na+ current (INa) by deacetylating Nav1.5 and increasing cell surface expression. We therefore tested the hypothesis that GPD1-L mutations alter Nav1.5 activity and INa through a SIRT1-dependent mechanism, and that GPD1L’s catalytic function is an essential component of this regulation. Whole cell patch clamp studies in HEK cells demonstrated that a decrease of GPD1-L expression by siRNA knockdown or catalytic function by mutagenesis increases INa, while overexpression of the A280V Brugada syndrome GPD1-L mutation decreased INa. Moreover, catalytic deficient GPD1-L increased and A280V GPD1-L decreased cell surface expression of Nav1.5. Co-immunoprecipitation studies showed that GPD1-L binds to SIRT1 (Figure A). In addition, catalytically inactive GPD1-L increased and A280V GPD1-L decreased SIRT1deacetylase activity (Figure B). In summary, our evidence supports the hypothesis that GPD1-L functions as a negative regulator of the cardiac Na channel Nav1.5 by interacting with SIRT1 and diminishing its activity; the A280V GPD1-L mutation enhances that inhibition, leading to Brugada syndrome.
Assessing quality of life (QL) and patient reported outcomes (PROs) in clinical trials and clinical practice: A study using a hand-held computerized form of the validated LCSS instrument in patients with non-small cell lung cancer (NSCLC)
Authors: P. G. Kuruvilla, H. Krieger, L. Zibdawi, J. Meharchand, H. Solow, N. Leighl, C. Chin, J. A. Stewart, P. J. Hollen, R. J. Gralla
Journal: Journal of Clinical Oncology (2005)

8067 Background: Improving survival, QL, and PROs are key goals in cancer treatment. Valid QL instruments are available; however, low feasibility in treatment settings remains a barrier to QL assessment. The LCSS was converted into a computerized format for inexpensive hand-held devices (pocket pc), providing an immediate graphic report of current scores and change over time. All data are automatically recorded without transcription. This study documents ease of use and psychometrics with this new approach, comparing the LCSS paper form with the electronic (LCSS-QL). The objectives were to: a) determine correlation of the LCSS-QL with the paper version; b) measure completion times; and c) assess acceptability of the LCSS-QL by patients, nurses, and physicians. Methods: Patients were entered at 9 COMET clinics in Ontario. All had: a) stage III or IV NSCLC, b) KPS ≥ 60, 3) no prior chemotherapy, and 4) received initial courses of docetaxel + platinum. 48 patients completed both the paper and electronic forms (pretreatment, and with the next 4 chemotherapy cycles - paper version with every other cycle). Characteristics: 58% men; KPS (median 80%; range 60% - 100%); age (median 71; range 47–81); Stage IV: 73%. Results: The LCSS-QL had excellent acceptance by patients, nurses, and physicians. Patients required a mean of only 2.1 minutes (SD 1.58 min) to complete the LCSS-QL. Reliability coefficients using Cronbach’s alpha were high for the paper (0.83) and electronic (0.88) versions. Correlation coefficients between paper and electronic forms were in near agreement (0.93, 0.92, 0.92 for each of 3 methods used: Pearson r, Intraclass Correlation Coefficient, Lin’s concordance, respectively) for the total score. Conclusions: 1) The high acceptance rate by patients and professionals, the rapid completion time, good feasibility, reliability, and validity confirm that the electronic LCSS is practical for evaluating QL and PRO endpoints in clinical trials and in patient management; and 2) both the paper and electronic LCSS versions provide the same score for quality of life. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis Aventis Aventis Aventis
Symptom distress, interventions, and outcomes of intensive care unit (ICU) cancer patients referred to a palliative care consult team (PCT)
Authors: M. O. Delgado-Guay, H. A. Parsons, J. L. Palmer, Z. Li, E. Bruera
Journal: Journal of Clinical Oncology (2008)

20520 Background: A significant proportion of cancer deaths occur in the in ICU. Advanced cancer patients (pts) admitted to ICU and their family member experience severe distress. The impact of PCT in the ICU pts is not known. Purpose: To characterize symptom distress and outcomes in ICU pts referred to a PCT in a cancer center. Methods: A retrospective review of the PCT consults was done in pts admitted to ICU between 07/2006 and 10/2007. Demographic data, comorbidities, PCT findings, interventions, and outcomes were collected. Results: 88 ICU pts seen among 1637 PCT consults (5%). Median age (range) was 60 years (22–87), 46% female. Primary was hematological (22%), gastrointestinal (22%), lung (20%), breast (9%), and others (26%). 76% had metastatic disease and 44% had chemotherapy ≤4 weeks prior evaluation. 19 pts (21%) were on mechanical ventilation (MV) and 24 pts (27%) on BIPAP. Findings: delirium (81%), dyspnea (82%), pain (84%), fatigue (95%), anxiety (65%), sedation (78%), depression (45%), insomnia (69%), nausea (33%), cachexia (44%), and constipation (60%). Main interventions: participation in DNR conversion (70%), withdrawal of MV (17%), BIPAP (29%), dialysis (11%), and TPN (8%), start/rotate opioid (99%), steroids (70%), antiemetics (79%), bowel regimen (72%), antipsychotic (76%), and counseling (100%). Improvement was observed in: pain 67 (90%), nausea 34 (91%), dyspnea 60 (90%), anxiety 51 (80%), depression 19 (48%), delirium 31 (44%), constipation 44 (83%) and family distress 88(100%). 53 (60%) pts remained in ICU and 35 (40%) were transferred to palliative care unit (PCU). 51/88 ICU pts died during admission (58%), vs 130/1549 (8%) non ICU PTC consults pts (p<0.0001). 28/53 (53%) died in ICU vs total medical ICU deaths 318/1383 (23%) p< 0.0001). 23/35 pts transferred to PCU (66%) died in PCU vs 212/629 (34 %) admitted to PCU from other services (p<0.0001). 37 pts (42%) were discharged alive (14 pts to home with hospice, 11 pts to an inpatient hospice unit, and 10 pts to home with clinic follow up and 2 pts to a nursing facility. Conclusions: ICU referrals to the PCT have severe distress. PCT interventions resulted in symptom improvement. Mortality was high but 47% of pts followed in ICU and 34% of pts transferred to PCU were discharged alive. No significant financial relationships to disclose.
Tracking Body Mass Index From Childhood to Adulthood for Subclinical Cardiovascular Diseases at Adulthood
Authors: Yinkun Yan, Dongqing Hou, Yajun Liang, Xiaoyuan Zhao, Yuehua Hu, Junting Liu, Hong Cheng, Ping Yang, Xinying Shan, Bo Xi, Jie Mi
Journal: Journal of the American College of Cardiology (2016)
Cancer-related TTP: Role of plasma exchange
Authors: M. H. Farhat, B. de Souza, A. Hanbali
Journal: Journal of Clinical Oncology (2009)

e13527 Background: Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disease classically described by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic manifestations and renal dysfunction. It is considered a hematologic emergency for which, the treatment of choice is plasma exchange therapy. However, its diagnosis and treatment can be particularly challenging in the setting of disseminated malignancy, as the misdiagnosis of TTP in a patient with cancer-associated thrombotic microangiopathy (TMA) will lead to ineffective use of plasma exchange and delay the timely delivery of chemotherapy. Moreover, patients with disseminated malignancy respond less often to plasma exchange and have a higher mortality rate. Methods: Three patients with disseminated malignancy who presented as TTP are discussed. Two of the three patients were given plasma exchange and had fatal outcomes, while the third patient received chemotherapy as the initial therapy and survived hospitalization. The three patients had prolonged PT with normal aPTT; LDH levels (&gt;1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Results: TMA associated with disseminated malignancy remains a challenging and underdiagnosed condition with very poor prognosis. Plasma exchange has no clinical use is potentially even life-threatening especially when it delays the administration of the appropriate chemotherapy which is the ultimate treatment for the underlying malignancy that resulted in TMA. We propose that the following criteria be used for diagnostic consideration of disseminated malignancy-associated TMA: evidence of hemolysis; leukoerythroblastic picture on the peripheral blood; coagulopathy consisting of elevated d-dimer, prolonged PT with normal aPTT; extreme elevations in the LDH levels (&gt;1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Such patients should be immediately considered for a bone marrow biopsy as chemotherapy should be initiated as soon as possible. Conclusions: See Table. [Table: see text] No significant financial relationships to disclose.
Austri, a Large Randomized Study in Adolescents and Adults with Asthma, Assessing the Safety and Efficacy of Salmeterol in Combination with Fluticasone Propionate Compared to Fluticasone Propionate Alone
Authors: David A. Stempel, Ibrahim Raphiou, Kenneth Kral, Anne Yeakey, Kathy Buaron, Amanda Emmett, Charlene M. Prazma, Steve Pascoe
Journal: Journal of Allergy and Clinical Immunology (2016)
Molecular subtyping and improved treatment of neurodevelopmental disease
Authors: Holly A. F. Stessman, Tychele N. Turner, Evan E. Eichler
Journal: Genome Medicine (2016)

The next-generation sequencing revolution has substantially increased our understanding of the mutated genes that underlie complex neurodevelopmental disease. Exome sequencing has enabled us to estimate the number of genes involved in the etiology of neurodevelopmental disease, whereas targeted sequencing approaches have provided the means for quick and cost-effective sequencing of thousands of patient samples to assess the significance of individual genes. By leveraging such technologies and clinical exome sequencing, a genotype-first approach has emerged in which patients with a common genotype are first identified and then clinically reassessed as a group. This approach has proven a powerful methodology for refining disease subtypes. We propose that the molecular characterization of these genetic subtypes has important implications for diagnostics and also for future drug development. Classifying patients into subgroups with a common genetic etiology and applying treatments tailored to the specific molecular defect they carry is likely to improve management of neurodevelopmental disease in the future.
Phase I/II study of everolimus in patients with advanced hepatocellular carcinoma (HCC).
Authors: L. S. Blaszkowsky, T. A. Abrams, R. A. Miksad, H. Zheng, J. A. Meyerhardt, D. Schrag, E. L. Kwak, C. Fuchs, D. P. Ryan, A. X. Zhu
Journal: Journal of Clinical Oncology (2010)

e14542 Background: The PI3K/Akt/mTOR pathway plays a critical role in HCC pathogenesis. We performed a phase I/II study of everolimus (RAD001), an oral inhibitor of mTOR, in patients (pts) with advanced HCC. Methods: Eligibility criteria included histologically confirmed measurable unresectable or metastatic HCC, 0-2 prior systemic regimens, ECOG PS ≤ 2, CLIP score ≤ 3, and adequate organ function. Pts received everolimus 5 or 10 mg daily by mouth (6 weeks/cycle). Once the optimal biological dose (OBD) was established, the planned two-stage phase II study was implemented. Primary endpoints were the OBD of everolimus (phase I) and progression-free survival (PFS) rate at 24 weeks (phase II). Results: 28 pts enrolled: median age = 65 (range 33-81), M/F = 18/10, ECOG 0/1/2 = 11/16/1, Child A/B = 23/5, CLIP 0/1/2/3 = 1/9/9/9, BCLC B/C = 2/26, prior systemic regimens 0/1/2 = 8/11/9. 11 pts had received prior sorafenib. No dose-limiting toxicity was observed at the 5 or 10 mg dose level in phase I. During phase II, 25 pts received 10 mg everolimus daily. The PFS rate at 24 weeks was 8% (95% CI: 2%- 25%). Median PFS = 3.8 months (95% CI: 2.5-4.6), median TTP = 3.9 months (95% CI: 2.5-5.5), and median OS = 8.4 months (95% CI: 3.9-21.1). One pt (4%) had partial response and 10 (40%) had stable disease (44% disease control rate). The most frequent adverse events (AEs) were: fatigue (52%), hyperglycemia (48%), diarrhea (44%), anemia (44%), leukopenia (40%), thrombocytopenia (40%), SGOT (36%), hyponatremia (36%), anorexia (36%), lymphopenia (32%), stomatitis (28%), and rash (28%). Grade 3-4 AEs were infrequent: lymphopenia (12%), SGOT (12%), hyponatremia (8%), and one pt (4%) each with anemia, SGPT, hyperglycemia, proteinuria, and rash. As the first stage of the phase II study did not meet the predefined primary endpoint, the study was terminated early. Conclusions: Everolimus was well tolerated in patients with advanced HCC, and 10 mg daily was chosen for the phase II study. Most frequent AEs included fatigue, myelosuppression, transaminase elevation, diarrhea, and stomatitis. Although the phase II study was terminated after the first stage, modest antitumor activity was observed with everolimus in HCC including a TTP of 3.9 months and disease control rate of 44%. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alnylam Pharmaceuticals, Amgen, Bayer, Bristol-Myers Squibb, Genentech, Genomic Health, ImClone Systems, Merck, Pfizer, Roche
Portal Vein Chemotherapy for Colorectal Cancer: a Meta-analysis of 4000 Patients in 10 Studies
Journal: JNCI Journal of the National Cancer Institute (1997)

Background : Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. Purpose : We undertook a meta-analysis to assess the effects on recurrence and survival of administering fluorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Methods : Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5–7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co-administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two-sided. Results : Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7% (standard deviation [SD] = 1.2%) ( P = .006). When just the nine hypothesis-testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) ( P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) ( P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. Conclusions: PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.
Abstract 649: Does Chronic Increase of Glucose Uptake Cause Cardiac “glycotoxicity”?
Authors: Jie Yan, Ivan Luptak, Lei Cui, Mohit Jain, Ronglih Liao, Rong Tian
Journal: Circulation (2007)

A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile but its role in the pathogenesis of cardiac diseases is incompletely understood. We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared to wildtype (WT) littermates, the GLUT1-TG mice showed normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. When the hearts were subjected to ischemia-reperfusion, an age-related impairment in functional recovery was observed in WT; cardiac function recovered to 35% vs. 52% of the preischemic level in old (22 months) vs. young (3 months) WT hearts respectively (p&lt;0.05). Ischemic tolerance was markedly enhanced in GLUT1-TG hearts, and importantly, the greater functional recovery in GLUT1-TG hearts was sustained at older age (83% vs. 86% for old and young GLUT1-TG, respectively, p=ns). 31 P NMR spectroscopic measurement showed delayed ATP depletion, reduced acidosis during ischemia and improved recovery of high energy phosphate content in old GLUT1-TG hearts (p&lt;0.05 vs. old WT). These differences were found to be independent of alterations in the activations of Akt and AMPK by ischemia. During reperfusion, glucose oxidation was 3-fold higher while fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared to old WT (p&lt;0.05) suggesting that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts. Thus, these results suggest that a normal heart is capable of adapting to chronic increases in basal glucose entry into cardiomyocytes without developing “glucotoxicity”, and furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.
Histologic and Histochemical Preneoplastic Changes in the Bladder Mucosae of Dogs Given 2-Naphthylamine2
Authors: Jack L. Radomski, Charlene Krischer, Kenneth N. Krischer
Journal: JNCI Journal of the National Cancer Institute (1978)

So that the earliest morphologic changes produced in dog bladders by a bladder carcinogen could be detected, 25 mg 2-naphthylamine/kg was given daily to dogs for 1, 6, and 36 weeks. Among early changes observed in some, but not all, dogs at 1 and 6 weeks were a loss of the bladder luminal membrane, hyperplasia of the epithelium, and lymphocytic infiltration of the submucosa. These changes were also present, to a more severe degree, in all dogs at 36 weeks. A more advanced preneoplastic change observed only at 36 weeks was a scalloped appearance of the normally straight basal cell line due to the beginning of nodule formation of the hyperplastic epithelial cells (von Brunn's epithelial nests). Histochemically, the alkaline phosphatase activity was altered from the normally regular, dense staining of the basal cell layer to a weaker, intermittent staining. No tumors were observed. Of the dogs given the same dose of 2-naphthylamine for 26 weeks and then kept for 3 years before being killed, 2 dogs had normal bladders but the other 2 had epithelial carcinomas.
Complementary and alternative medicine: What do oncology healthcare providers think?
Authors: C. S. Tung, C. C. Sun, L. Cohen, M. Frenkel, L. M. Ramondetta, J. A. Smith, P. Parker, D. C. Bodurka
Journal: Journal of Clinical Oncology (2009)

e20614 Background: The use of complementary and alternative medicine (CAM) is growing as the oncology patient (pt) population increases. The purpose of this study was to assess current CAM practice patterns of oncology healthcare providers. Methods: We distributed a 20-page anonymous survey to all physicians (), mid-level practitioners, clinical pharmacists, and dietitians at a comprehensive cancer center. The survey examined factors influencing a provider's inquiry towards pt CAM use, as well as current perception and use of 15 different CAM modalities, such as meditation, acupuncture, chiropractic, and herbal therapy. Descriptive statistics, chi-square, and Student's t-test were used for analysis. Results: 671/1,601 (42%) surveys were returned with s comprising 50% of the responses. 83% of respondents believed CAM has a role in cancer care. Over 70% indicated that massage, meditation/prayer, relaxation techniques, and acupuncture have potential uses, primarily to relieve symptoms not controlled by conventional therapy (tx) (47%) and as psycho-social-spiritual support (47%). Respondents estimated 28% of pts utilize CAM; 25% of respondents and 19% of pts initiated CAM discussions during pt visits. Those in medicine-based fields were more likely to discuss pt CAM use compared to surgical specialities (30% vs. 19%, p&lt;0.01), but there was no significant difference in comfort level to discuss CAM modalities. s were less likely to discuss CAM use compared to all other providers (21% vs. 31%, p&lt;0.01). s were also less comfortable discussing herbs (37% vs. 51%, p&lt;0.01), massage (73% vs. 82%, p&lt;0.05), meditation/prayer (71% vs. 82%, p&lt;0.05), and relaxation tx (67% vs. 77%, p&lt;0.01) compared to all other providers but more comfortable discussing acupuncture (63% vs. 55%, p&lt;0.05). Respondents cited lack of knowledge in CAM as the primary reason for not discussing CAM with pts. Conclusions: Past studies estimate that &gt;50% of patients use at least one form of CAM. Our study suggests that oncology providers critically underestimate the number of patients incorporating CAM into their treatment. Improving provider education on CAM therapies is essential to improve patient-physician communication regarding potential risks and benefits of CAM with traditional cancer therapies. No significant financial relationships to disclose.
The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Studies
Authors: Rupert W. Strauss, Alex Ho, Beatriz Muñoz, Artur V. Cideciyan, José-Alain Sahel, Janet S. Sunness, David G. Birch, Paul S. Bernstein, Michel Michaelides, Elias I. Traboulsi, Eberhart Zrenner, SriniVas Sadda, Ann-Margret Ervin, Sheila West, Hendrik P.N. Scholl
Journal: Ophthalmology (2016)
TT Virus infection in patients with chronic hepatitis C: susceptibility to interferon therapy.
Authors: P. Ciccorossi, A. Ricchiuti, F. Costa, M. Bellini, P. Da Massa Carrara, P. Arpe, F. Maggi, M. L. Vatteroni, M. Bendinelli, G. Maltinti, Santino Marchi
Journal: Hepatology (1999)