tbuckley/cabot-search huggingface dataset:
Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation
Authors: C Rigamonti, M F Donato, M Fraquelli, F Agnelli, G Ronchi, G Casazza, G Rossi, M Colombo
Journal: Gut (2008)

Transient elastography (TE) allows non-invasive evaluation of the severity of liver disease in patients with chronic hepatitis C. This procedure, however, warrants further validation in the setting of liver transplantation (LT), including patients under follow-up for recurrent hepatitis C.Tertiary referral hospital.95 patients (75 males) transplanted for end-stage liver disease due to hepatitis C virus.Paired liver biopsy (LB) and TE were carried out 6-156 (median, 35) months after LT. 40 patients with recurrent hepatitis C sequentially evaluated 6-21 months apart.Clinical, laboratory and graft histological features influencing TE results.Median TE values were 7.6 kPa in the 90 patients with a successful TE examination, being 5.6 kPa in the 30 patients with Ishak fibrosis score (S) of 0-1, 7.6 kPa in the 38 with S2-3; 16.7 kPa in the 22 with S4-6, (p < 0.0001). Areas under the ROC curves were 0.85 (95% CI, 0.76 to 0.92) for S > or = 3, 0.90 (95% CI, 0.82 to 0.95) for S > or = 4 with 7.9 and 11.9 kPa optimal TE cut-off (81% and 82% sensitivity, 88% and 94% negative predictive value, respectively). Fibrosis, necroinflammatory activity and higher than 200 IU/l gamma-glutamyl transpeptidase levels independently influenced TE results. During post-LT follow-up, TE results changed in parallel with grading (r = 0.63) and staging (r = 0.71), showing 86% sensitivity and 92% specificity in predicting staging increases.TE accurately predicts fibrosis progression in LT patients with recurrent hepatitis C, suggesting that protocol LB might be avoided in patients with improved or stable TE values during follow-up.
Ultrastructure and Regulation of Lateralized Connexin43 in the Failing Heart
Authors: Geoffrey G. Hesketh, Manish H. Shah, Victoria L. Halperin, Carol A. Cooke, Fadi G. Akar, Timothy E. Yen, David A. Kass, Carolyn E. Machamer, Jennifer E. Van Eyk, Gordon F. Tomaselli
Journal: Circulation Research (2010)

Rationale : Gap junctions mediate cell-to-cell electric coupling of cardiomyocytes. The primary gap junction protein in the working myocardium, connexin43 (Cx43), exhibits increased localization at the lateral membranes of cardiomyocytes in a variety of heart diseases, although the precise location and function of this population is unknown. Objective : To define the subcellular location of lateralized gap junctions at the light and electron microscopic level, and further characterize the biochemical regulation of gap junction turnover. Methods and Results : By electron microscopy, we characterized gap junctions formed between cardiomyocyte lateral membranes in failing canine ventricular myocardium. These gap junctions were varied in structure and appeared to be extensively internalizing. Internalized gap junctions were incorporated into multilamellar membrane structures, with features characteristic of autophagosomes. Intracellular Cx43 extensively colocalized with the autophagosome marker GFP-LC3 when both proteins were exogenously expressed in HeLa cells, and endogenous Cx43 colocalized with GFP-LC3 in neonatal rat ventricular myocytes. Furthermore, a distinct phosphorylated form of Cx43, as well as the autophagosome-targeted form of LC3 (microtubule-associated protein light chain 3) targeted to lipid rafts in cardiac tissue, and both were increased in heart failure. Conclusions : Our data demonstrate a previously unrecognized pathway of gap junction internalization and degradation in the heart and identify a cellular pathway with potential therapeutic implications.
Short-Term Efficacy of Methylphenidate: A Randomized, Double-Blind, Placebo-Controlled Trial Among Survivors of Childhood Cancer
Authors: Raymond K. Mulhern, Raja B. Khan, Stuart Kaplan, Susan Helton, Robbin Christensen, Melanie Bonner, Ronald Brown, Xiaoping Xiong, Sengjie Wu, Sridharan Gururangan, Wilburn E. Reddick
Journal: Journal of Clinical Oncology (2004)

Children surviving acute lymphoblastic leukemia (ALL) and malignant brain tumors (BTs) have a higher incidence of attention and learning problems in school than do their healthy peers. The present study tests the hypothesis that the psychostimulant methylphenidate (MPH) improves cognitive and social functioning among these patients.We report on 83 long-term survivors of ALL and BT identified as having attentional deficits on behavioral testing and parent or teacher report, and problems with academic achievement. The 47 male and 36 female patients ranged from 0.6 to 14.3 years (median, 5.4 years) of age at diagnosis and 6.7 to 17.9 years (median, 11.9 years) of age at participation. The patients (40 ALL, 43 BT) participated in a randomized, double-blind, 3-week home cross-over trial of placebo (bid), low-dose MPH (0.3 mg/kg; maximum dose, 10 mg bid), and moderate-dose MPH (0.6 mg/kg; maximum dose, 20 mg bid). The primary end points were weekly teacher and parent reports on the Conners' Rating Scales and Social Skills Rating System.Compared to placebo, significant improvement with MPH was reported by teachers and parents on the Conners' Rating Scales and by teachers on the Social Skills Rating System. However, no consistent advantage of moderate dose over low dose was observed. Of those participating, 66 (79.5%) of the 83 patients continued on best clinical management.Treatment with MPH can at least temporarily reduce some attentional and social deficits among survivors of childhood ALL and BT. Long-term follow-up will reveal those subsets of patients who are more likely to benefit from MPH.
Heteromers of amyloid precursor protein in cerebrospinal fluid
Authors: Inmaculada Cuchillo-Ibañez, Inmaculada Lopez-Font, Alba Boix-Amorós, Gunnar Brinkmalm, Kaj Blennow, Jose-Luis Molinuevo, Javier Sáez-Valero
Journal: Molecular Neurodegeneration (2015)

Soluble fragments of the amyloid precursor protein (APP) generated by α- and β-secretases, sAPPα and sAPPβ, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer's disease (AD). However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. Our aim is to characterize possible sAPP oligomers that could contribute to the quantification of sAPPα and sAPPβ in CSF by ELISA, as well as to characterize the possible presence of soluble full-length APP (sAPPf). We employed co-immunoprecipitation, native polyacrylamide gel electrophoresis and ultracentrifugation in sucrose density gradients to characterize sAPP oligomers in CSF. We have characterized the presence of sAPPf in CSF from NDC and AD subjects and demonstrated that all forms, including sAPPα and sAPPβ, are capable of assembling into heteromers, which differ from brain APP membrane-dimers. We measured sAPPf, sAPPα and sAPPβ by ELISA in CSF samples from AD (n = 13) and non-disease subjects (NDC, n = 13) before and after immunoprecipitation with antibodies against the C-terminal APP or against sAPPβ. We demonstrated that these sAPP heteromers participate in the quantification of sAPPα and sAPPβ by ELISA. Immunoprecipitation with a C-terminal antibody to remove sAPPf reduced by ~30% the determinations of sAPPα and sAPPβ by ELISA, whereas immunoprecipitation with an APPβ antibody reduced by ~80% the determination of sAPPf and sAPPα. The presence of sAPPf and sAPP heteromers should be taken into consideration when exploring the levels of sAPPα and sAPPβ as potential CSF biomarkers.
Pheochromocytoma
Authors: Rex M. Crago
Journal: JAMA (1967)

A 21-year-old Negro woman with a suprarenal pheochromocytoma on the left side was treated preoperatively with orally administered phenoxybenzamine hydrochloride and propranolol hydrochloride which are, respectively, α- and β-adrenergic blocking agents. The patient had had hypertension for six months prior to admission. Findings from physical examination were not remarkable except that blood pressure when the patient was supine was 180/120 mm Hg and the cardiac rate average 85 beats per minute. A 47 gm tumor was removed from the left suprarenal area at operation. Throughout the operation the cardiac rate generally ranged from 80 to 90 beats per minute. No significant arrhythmias occurred at any time. We suggest that the patient was protected from β-adrenergic mediated cardiac arrhythmias with the use of propranolol. Phenoxybenzamine and propranolol should be given further evaluation in the preoperative treatment of patients with a functioning phenochromocytoma.
The requirement for adherent cells in the Fc fragment-induced proliferative response of murine spleen cells.
Authors: E L Morgan, W O Weigle
Journal: The Journal of Experimental Medicine (1979)

The proliferative response of mouse B lymphocytes induced by Fc fragments was found to be dependent upon an adherent cell population. The adherent cell is esterase positive, irradiation resistant, and not susceptible to lysis by anti-thymus serum and complement. The mechanism(s) by which Fc fragments induce B-cell proliferation could be the result of the interaction of Fc with both B cells and adherent cells or with adherent cells which then release factors that trigger the B cells to proliferate. Spleen cells from the C3H/HeJ mouse were shown to be unable to respond to Fc fragments. The addition of adherent cells from either C3H/St or C3H/HeN mice to adherent cell depleted C3H/HeJ cells enabled them to respond to Fc, indicating the defect was in the adherent cell population.
Reinduction Platform for Children With First Marrow Relapse of Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Elizabeth A. Raetz, Michael J. Borowitz, Meenakshi Devidas, Stephen B. Linda, Stephen P. Hunger, Naomi J. Winick, Bruce M. Camitta, Paul S. Gaynon, William L. Carroll
Journal: Journal of Clinical Oncology (2008)

Purpose Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials. Patients and Methods One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block. Results Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% ± 6% for ER (n = 63) and 96% ± 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% ± 7% of ER (n = 36) versus 51% ± 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% ± 7% versus 58% ± 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections. Conclusion The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome.
Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia
Authors: Guillermo Garcia-Manero, Steven D. Gore, Christopher Cogle, Renee Ward, Tao Shi, Kyle J. MacBeth, Eric Laille, Heidi Giordano, Sarah Sakoian, Elias Jabbour, Hagop Kantarjian, Barry Skikne
Journal: Journal of Clinical Oncology (2011)

Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m 2 ) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.
Specialized Conducting Fibers in the Interatrial Band
Authors: Michael L. Wagner, Ralph Lazzara, Robert M. Weiss, Brian F. Hoffman
Journal: Circulation Research (1966)

The interatrial band (Bachmann's bundle) was studied both in situ, in the adult dog, and in vitro, using excised canine atria. Electrograms recorded from this structure in the intact animal had a double intrinsic deflection during sinus rhythm, and responded to rapid rates of atrial stimulation with alternation in both configuration and cycle length. Potassium infusions which produced atrial arrest with a sinoventricular rhythm did not abolish electrical activity in the interatrial band. Single fibers of the interatrial band, studied in vitro with microelectrodes, had distinctive transmembrane potentials different from those of ordinary atrial muscle fibers. Action potentials were characterized particularly by a high rising velocity (maximum dv/dt), of the same magnitude as that recorded from Purkinje fibers, and a prominent plateau. These fibers were sensitive to acetylcholine and more resistant to potassium arrest than ordinary atrial fibers. Conduction velocity in the interatrial band was consistently higher than in ordinary atrial muscle. Plots of sequential activation time against linear distance showed different conduction velocities in parallel linear paths, with the highest velocity in the path on the crest of the interatrial band. Due to rapid conduction through the interatrial band, simultaneous activation of right and left atrial points was demonstrated. It is concluded: 1) The interatrial band is not a homogeneous structure, but contains two fiber types. 2) In addition to ordinary atrial muscle, specialized conducting fibers are present in the interatrial band. 3) Impulse spread in the interatrial band is not radial or uniform. Rather, it occurs through several linear paths which probably have infrequent cross-connections.
Chronic renal disease
Authors: M. S Parmar
Journal: BMJ (2002)

Early identification and active management of patients with renal impairment in primary care can improve outcomes

The number of patients with end stage renal disease is growing worldwide. About 20-30 patients have some degree of renal dysfunction for each patient who needs renal replacement treatment.1 Diabetes and hypertension are the two most common causes of end stage renal disease and are associated with a high risk of death from cardiovascular disease.

Mortality in patients with end stage renal disease remains 10-20 times higher than that in the general population. The focus in recent years has thus shifted to optimising the care of these patients during the phase of chronic kidney disease, before the onset of end stage renal disease. This review summarises current knowledge about the various stages of chronic renal disease, the risk factors that lead to progression of disease, and their association with common cardiovascular risk factors. It also provides strategies for intervention at an early stage of the disease process, which can readily be implemented in primary care, to improve the overall morbidity and mortality associated with chronic renal disease.

#### Summary points

Significant renal dysfunction might be present even when serum creatinine is normal or only slightly abnormal

Renal function declines progressively once creatinine clearance falls by about 25% of normal, but symptoms are often not apparent until renal failure is advanced

The baseline rate of urinary protein excretion is the best single predictor of disease progression

The prevalence of common cardiovascular risk factors is high in chronic renal disease; early identification and effective control of these risk factors is important to improve outcomes

Cardiovascular disease accounts for 40% of all deaths in chronic renal disease

Potentially reversible causes should be sought when renal function suddenly declines

Irreversible but modifiable complications (anaemia, cardiovascular disease, metabolic bone disease, malnutrition) …
Use of CD200 blockade inhibitor to enhance glioma immunotherapy
Authors: Elisabet Mesias, Zhengming Xiong, Elizabeth Pluhar, Michael Olin
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Utilizing tumors as a source of vaccine antigens in immunotherapy has demonstrated promising results. However, to date, researchers have failed to overcome the complex interplay between the tumor and its surrounding microenvironment resulting in T cell tolerance. The progression
Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells
Authors: Marina Pisano, Gabriella Pagnan, Maria Antonietta Dettori, Sara Cossu, Irene Caffa, Ilaria Sassu, Laura Emionite, Davide Fabbri, Michele Cilli, Fabio Pastorino, Giuseppe Palmieri, Giovanna Delogu, Mirco Ponzoni, Carla Rozzo
Journal: Molecular Cancer (2010)

Abstract Background Sharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin -related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors. Results In this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin . Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin , but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P &lt; 0.001 and D6 vs curcumin P &lt; 0.01; Neuroblastoma: D6 vs both control and curcumin : P &lt; 0.001 ). Conclusions Our data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors.
Hypermethylation of SNAP91 as an alternative mechanism of epidermal growth factor signalling dysregulation: a genome-wide meta-analysis with validation of colorectal cancers
Authors: Andrew Beggs, Jonathan James, Kai Leong, Germaine Caldwell, Karina Ronlund, Simon Bach, Steen Kølvraa, Dion Morton, Glenn Matthews
Journal: The Lancet (2014)
TL antigen as a transplantation antigen recognized by TL-restricted cytotoxic T cells.
Authors: A Morita, T Takahashi, E Stockert, E Nakayama, T Tsuji, Y Matsudaira, L J Old, Y Obata
Journal: The Journal of Experimental Medicine (1994)

In contrast to broadly expressed classical class I antigens of the major histocompatibility complex, structurally closely related TL antigens are expressed in a highly restricted fashion. Unlike classical class I antigens, TL antigens are not known to be targets of cytotoxic T cells or to mediate graft rejection. Whereas classical class I antigens function as antigen-presenting molecules to T cell receptors (TCR), the role of TL is yet to be defined. To elucidate the function of TL, we have derived transgenic mice expressing TL in most tissues including skin by introducing a TL gene, T3b of C57BL/6 mouse origin, driven by the H-2Kb promoter. By grafting the skin of transgenic mice, we demonstrate that TL can serve as a transplantation antigen and mediate a TCR-alpha/beta+ CD8+ cytotoxic T cell response. This T cell recognition of TL does not require antigen presentation by H-2 molecules. Furthermore, we show that C57BL/6 F1 mice develop CD8+ T cells that are cytotoxic for C57BL/6 TL+ leukemia cells, providing further support for the concept that aberrantly expressed nonmutated proteins such as TL can be recognized as tumor antigens.
The Effect of Urban Air Pollution on Inflammation, Oxidative Stress, Coagulation, and Autonomic Dysfunction in Young Adults
Authors: Kai-Jen Chuang, Chang-Chuan Chan, Ta-Chen Su, Chung-Te Lee, Chin-Sheng Tang
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

The biological mechanisms linking air pollution to cardiovascular events still remain largely unclear.To investigate whether biological mechanisms linking air pollution to cardiovascular events occurred concurrently in human subjects exposed to urban air pollutants.We recruited a panel of 76 young, healthy students from a university in Taipei. Between April and June of 2004 or 2005, three measurements were made in each participant of high-sensitivity C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasminogen activator fibrinogen inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA) in plasma, and heart rate variability (HRV). Gaseous air pollutants were measured at one air-monitoring station inside their campus, and particulate air pollutants were measured at one particulate matter supersite monitoring station 1 km from their campus. We used linear mixed-effects models to associate biological endpoints with individual air pollutants averaged over 1- to 3-day periods before measurements were performed.We found that increases in hs-CRP, 8-OHdG, fibrinogen, and PAI-1, and decreases in HRV indices were associated with increases in levels of particles with aerodynamic diameters less than 10 microm and 2.5 microm, sulfate, nitrate, and ozone (O(3)) in single-pollutant models. The increase in 8-OHdG, fibrinogen, and PAI-1, and the reduction in HRV remained significantly associated with 3-day averaged sulfate and O(3) levels in two-pollutant models. There were moderate correlations (r = -0.3) between blood markers of hs-CRP, fibrinogen, PAI-1, and HRV indices.Urban air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction simultaneously in healthy young humans, with sulfate and O(3) as two major traffic-related pollutants contributing to such effects.