tbuckley/cabot-search huggingface dataset:
Long-term outcome of human leukocyte antigen mismatching in liver transplantation: Results of the national institute of diabetes and digestive and kidney diseases liver transplantation database
Authors: Vijayan Balan, Kris Ruppert, Jake A. Demetris, Tatiana Ledneva, Rene J. Duquesnoy, Katherine M. Detre, Yuling L. Wei, Jorge Rakela, Daniel F. Schafer, John P. Roberts, James E. Everhart, Russell H. Wiesner
Journal: Hepatology (2008)

Abstract A perfect or nearly perfect human leukocyte antigen (HLA) match has been associated with better immediate and long-term survival of diseased donor kidney transplants. However, the effect of HLA matching for hepatic allografts remains poorly defined. Using data from the National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, we investigated the association between HLA mismatches and hepatic allograft survival, disease recurrence, and immunosuppression interactions. A, B, and DR loci were used to calculate total mismatch scores of 0 (no mismatches in any loci) to 6 (mismatches in all loci). Seven hundred ninety-nine adults (male, 55%; female, 45%) underwent 883 liver transplants. The 10-year graft survival according to total mismatch score was as follows: 0-2, 60%; 3-4, 54%; and 5-6, 57%. There was a negative effect of mismatching at the A locus on patient survival, with shorter survival for patients with 1 or 2 mismatches compared with 0 mismatches [ P = 0.05, hazard ratio (HR) = 1.6]. Patients on tacrolimus with 1 or 2 mismatches at B or DR loci appeared to have increased rates of patient and graft survival compared to patients with 0 mismatches, with the appearance of a protective effect of tacrolimus (HR = 0.67). The effect of HLA mismatching was more pronounced on certain disease recurrences. DR-locus mismatch increased recurrence of autoimmune hepatitis ( P = 0.01, HR = 4.2) and primary biliary cirrhosis ( P = 0.04, HR = 2). Mismatch in the A locus was associated with more recurrence of hepatitis C virus ( P = 0.01, HR = 1.6) and primary sclerosing cholangitis ( P = 0.03, HR = 2.9). Conclusion: Mismatching at the A locus decreases patient survival in liver transplant recipients, and mismatching at the DR and A loci affects recurrence of autoimmune liver diseases and hepatitis C, respectively. (Hepatology 2008.)
Johann Weyer and the Witches
Authors: George E. Ehrlich
Journal: New England Journal of Medicine (1960)

THOUGH the belief in witches and the resultant witch-hunts of the sixteenth century represent mass delusion and mass psychosis to modern physicians, four hundred years ago witches were an article of faith for Protestants and Catholics alike and, as such, within the province of the ecclesiastic authorities. Therefore, the attempts of one physician to bring sanity and reason onto the scene were resented as a trespass into alien fields. The physician, a lone voice in a wilderness, was Johann Weyer, the "father of psychiatry."He was born, in 1515 or 1516, in Grave on the Maas, and is thus claimed . . .
Rationing new medicines in the UK
Authors: M. Drummond, A. Mason
Journal: BMJ (2009)

A fair and consistent process is needed for dealing with absence of evidence

In England and Wales the National Institute for Health and Clinical Excellence (NICE) issues guidance on the appropriate use of medicines that is based on an assessment of evidence submitted by the manufacturer. The scope of the assessment depends on whether the appraisal concerned is a single technology appraisal or a multiple technology appraisal. NICE recently terminated four single technology appraisals of cancer drugs because it did not receive submissions from drug companies that met the institute’s specification of evidence.1 As a result, NICE was unable to recommend the use of the products for the clinical indications for which they were licensed, but it stated that, after considering the reasons for the lack of guidance, NHS organisations could still use the drugs. In contrast, the Scottish Medicines Consortium approves medicines only if drug companies submit evidence, so non-submission results in a recommendation not to use the drugs concerned in the Scottish NHS.2

This situation is one consequence of NICE’s switch to undertaking more single technology appraisals, the main advantage of which is …
Radiological assessment of the knee in children
Authors: S R Harries, E A Jenkins, R G Hull
Journal: BMJ (1994)

that transoesophageal imaging has not been immediately available to provide surgeons with a viable alternative to biplane angiography in acute thoracic surgical emergencies.We therefore concur with D W Hodgkinson and colleagues.4The much less common condition of stable chronic dissection may satisfactorily be imaged by any of the radiological techniques available, including computed tomography, magnetic resonance imaging, transoesophageal echocardio- graphy, and angiography.
Physical Examination of the Joints
Authors: Ben L. Allen
Journal: JAMA (1965)

Written for the novice in arthritic diseases by a group of rheumatologists, this book concisely describes the physicial examination of joints in the arthritic patient. The individual chapters, each dealing with a separate joint, follow a fairly rigid format, discussing in sequence essential anatomy, inspection, palpation, range of motion, and, when applicable, special examinations. The authors devote their analysis almost entirely to detecting inflammatory changes in the joint, considering noninflammatory findings only lightly. The length of each section is determined by the complexity of the joint and its importance in arthritic diseases; for example, the sternoclavicular joint receives 2 pages and the knee 25.  The illustrations are excellent. Numerous photographs demonstrate many of the techniques of examination and dramatically portray joints involved by inflammatory disease. Halftone drawings with the synovial membrane in blue illustrate the anatomy of most of the joints. For many of them, line drawings indicate the range
Serum-stabilized Naked Caspase-3 siRNA Protects Autotransplant Kidneys in a Porcine Model
Authors: Cheng Yang, Tian Zhao, Zitong Zhao, Yichen Jia, Long Li, Yufang Zhang, Mangen Song, Ruiming Rong, Ming Xu, Michael L Nicholson, Tongyu Zhu, Bin Yang
Journal: Molecular Therapy (2014)

The naked small interfering RNA (siRNA) of caspase-3, a key player in ischemia reperfusion injury, was effective in cold preserved and hemoreperfused kidneys, but not autotransplanted kidneys in our porcine models. Here, chemically modified serum stabilized caspase-3 siRNAs were further evaluated. The left kidney was retrieved and infused by University of Wisconsin solution with/without 0.3 mg caspase-3 or negative siRNA into the renal artery for 24-hour cold storage (CS). After an intravenous injection of 0.9 mg siRNA and right-uninephrectomy, the left kidney was autotransplanted for 2 weeks. The effectiveness of caspase-3 siRNA was confirmed by caspase-3 knockdown in the post-CS and/or post-transplant kidneys with reduced apoptosis and inflammation, while the functional caspase-3 siRNA in vivo was proved by detected caspase-3 mRNA degradation intermediates. HMGB1 protein was also decreased in the post-transplanted kidneys; correlated positively with renal IL-1β mRNA, but negatively with serum IL-10 or IL-4. The minimal off-target effects of caspase-3 siRNA were seen with favorable systemic responses. More importantly, renal function, associated with active caspase-3, HMGB1, apoptosis, inflammation, and tubulointerstitial damage, was improved by caspase-3 siRNA. Taken together, the 2-week autotransplanted kidneys were protected when caspase-3 siRNA administrated locally and systemically, which provides important evidence for future clinical trials.
VULNERABLE CORONARY PLAQUES STILL EXIST EVEN IN LOW LDL-C LEVELS: EVIDENCE FROM STUDY WITH SERIAL CT CORONARY ANGIOGRAPHY
Authors: Chikara Fujita, Taro Ichise, Nobuo Ukawa, Shoji Katsuda, Bunji Kaku, Tomio Taguchi, Yutaka Nitta, Tetsuo Konno, Masa-aki Kawashiri, Masakazu Yamagishi
Journal: Journal of the American College of Cardiology (2014)
Abstract 2015: Thrombospondin-1 is a targetable marker of invasive, mesenchymal- like melanoma cells
Authors: Andreas Behren, Aparna Jayachandran, Matthew Anaka, Christopher Hudson, Jonathan Cebon
Journal: Cancer Research (2014)

Abstract Resistance to anti-cancer therapies arising from genetic heterogeneity is well understood. Less well characterised is the resistance to therapy proposed to occur via the plastic changes in melanoma cells generated by the impact of the tumor microenvironment. In melanoma, phenotypic-switching as means of plasticity has been well described and resembles, at least partially, an epithelial-to-mesenchymal transition (EMT). The presence of mesenchymal-like, invasive and slow-proliferating cells in melanoma, a highly aggressive cancer with intrinsic resistance to chemotherapy, is controversial and their potential contribution to therapeutic resistance has yet to be determined. Methods: We examined melanoma cell lines for the presence of mesenchymal-like cells using CM-Dil, a membrane dye evenly distributed to daughter cells with each cell division as a marker of reduced cell division. Functional assays included invasion and motility assays, in vivo mouse xenograft models as well as an in vivo chicken neural crest transplantation assay. Genome-wide gene-expression profiling was performed using Illumina HT12 arrays. Results: Here we show that mesenchymal-like cells are present in cell lines and in xenograft tumors, survive exposure to cytotoxic drugs and are invasive. Importantly, resistance was associated with a gene expression signature characterized by the expression of thrombospondin, TGFBI, genes associated with the extracellular matrix, and acquisition of increased invasiveness. This gene-expression pattern is reminiscent of an epithelial-to-mesenchymal transition in other solid cancers and a similar phenotype was detected after acquired resistance to the BRAF inhibitors PLX4720 and dabrafenib. Moreover, targeting thrombospondin in an in vivo model of melanoma cell plasticity and invasion led to the complete abrogation of the plastic and invasive potential of melanoma cells. Conclusion: The results link therapeutic resistance to the presence of mesenchymal-like and invasive cells, and identify potential targets for novel therapies directed at eradicating this key melanoma subpopulation. Citation Format: Andreas Behren, Aparna Jayachandran, Matthew Anaka, Christopher Hudson, Jonathan Cebon. Thrombospondin-1 is a targetable marker of invasive, mesenchymal- like melanoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2015. doi:10.1158/1538-7445.AM2014-2015
Three-year Results of the Prospective Evaluation of Radial Keratotomy (PERK) Study
Authors: George O. Waring, Michael J. Lynn, William Culbertson, Peter R. Laibson, Richard D. Lindstrom, Marguerite B. McDonald, William D. Myers, Stephen A. Obstbaum, J. James Rowsey, David J. Schanzlin, Marguerite McDonald, Herbert E. Kaufman, Bruce A. Barron, Richard L. Lindstrom, Donald J. Doughman, J. Daniel Nelson, Stephen A. Obstbaum, Penny Asbell, J. James Rowsey, Hal D. Balyeat, David J. Schanzlin, Ronald E. Smith, James J. Salz, William D. Myers, Robert C. Arends, John W. Cowden, Robert L. Stephenson, Paul Fecko, Jerry Roust, Peter R. Laibson, Juan J. Arentsen, Michael A. Naidoff, Elisabeth Cohen, J. James Rowsey, Jay H. Krachmer, Ceretha S. Cartwright, Robert J. Hardy, James P. McCulley, Robert D. Sperduto, Walter J. Stark, Michael J. Lynn, Richard A. Thoft, James V. Aquavella, Jules L. Baum, Robert J. Hardy, Jay H. Krachmer, Robert D. Sperduto, Joel Sugar, James Ware, George O. Waring, Michael J. Lynn
Journal: Ophthalmology (1987)
Serum hepatocyte growth factor levels in liver diseases: Clinical implications
Authors: Goshi Shiota, Jun-Ichi Okano, Hironaka Kawasaki, Tomokazu Kawamoto, Toshikazu Nakamura
Journal: Hepatology (1995)

Although recent studies have shown that hepatocyte growth factor (HGF) is a potent mitogen in vivo, the significance of serum HGF in liver diseases remains unclear. To clarify clinical significance of serum HGF in liver diseases, serum HGF was measured in 127 patients with liver diseases and in 200 healthy individuals, using a highly sensitive immunoradiometric assay (IRMA). This assay is specific for HGF and is sensitive enough to detect 0.1 ng/mL of HGF. Mean values for serum HGF in acute hepatitis (AH), chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), primary biliary cirrhosis (PBC), fulminant hepatic failure (FHF), and normal controls were 0.45, 0.40, 1.05, 1.06, 0.44, 16.40, and 0.27 ng/mL, respectively. Serum HGF levels in these diseases were significantly increased compared with those in the controls (P < .001), and exhibited a positive correlation with total bilirubin, indocyanine green (ICG) test (R15), asparate aminotransferase (AST), and a negative correlation with albumin and prothrombin time (P < .001). Cirrhotic patients with modified Child class C had higher levels of serum HGF than those graded as modified Child class A or B (P < .001). In CH, serum HGF levels were significantly related to the histological activity index (HAI) score (P < .002). Seven patients with HCC who underwent transcatheter arterial embolization (TAE) exhibited a gradual increase in serum HGF levels up to day 4 after treatment; these higher levels were maintained until day 7, although AST reached a peak on day 2 and then decreased gradually.(ABSTRACT TRUNCATED AT 250 WORDS)
Impact of NIDDM on Mortality and Causes of Death in Pima Indians
Authors: Maurice L Sievers, Robert G Nelson, William C Knowler, Peter H Bennett
Journal: Diabetes Care (1992)

To compare overall and cause-specific death rates for diabetic and nondiabetic Pima Indians.This community-based study determined overall and cause-specific death rates in persons with and without NIDDM in the Pima population. Underlying causes of death for the 10-yr period from 1975 to 1984 were derived from review of death certificates and medical records. Diabetes diagnoses were based on an ongoing diabetes study initiated by the National Institutes of Health in 1965.Of the 512 deaths, 241 were in Pima Indians with NIDDM; 203 (84%) of the deaths in diabetic subjects were attributed to natural causes (46 diabetic nephropathy, 35 IHD, 29 infections, 20 malignant neoplasms, 20 alcoholic liver disease, 18 stroke, 35 other causes). For natural causes, the overall age-sex-adjusted death rate in diabetic subjects was 1.7 times (95% CI 1.4-2.2) that in nondiabetic subjects. Longer duration of diabetes was significantly related to mortality, an association that was stronger in women than in men. Rates of death from diabetic nephropathy, IHD, and infections (but not stroke) were each significantly related to longer diabetes duration. Together, diabetic nephropathy and IHD accounted for 90% of the excess death rate among diabetic, compared with nondiabetic, Pimas.In Pima Indians, NIDDM has a significant adverse effect on death rates that is directly related to diabetes duration, especially for deaths from diabetic nephropathy, IHD, or infections. Among the Pima, diabetic nephropathy is the leading cause of death, and IHD ranks second--a variation from other populations (in which IHD ranks first), probably partly attributable to a much younger age of onset of diabetes among the Pima than in the U.S. white population.
Na/H antiporter mRNA expression in single nephron segments of rat kidney cortex.
Authors: R Krapf, M Solioz
Journal: Journal of Clinical Investigation (1991)

Renal cortical tubules consist of polarized epithelial cells where Na/H antiport activity has been demonstrated on the apical and/or basolateral membrane. Apical Na/H antiport activity plays an important role in transcellular bicarbonate (HCO3-) reabsorption, whereas basolateral Na/H antiport activity could be involved in transcellular HCO3- secretion as well as cell volume and pH control. To determine whether this heterogeneity in both localization and function is due to the existence of more than one Na/H antiporter, we studied the tissue distribution of Na/H antiporter mRNA by use of reverse transcription (RT) and polymerase chain reaction (PCR) in isolated nephron segments from rat renal cortex. The primers used were directed against the rat renal cortical Na/H antiporter cDNA which is homologous to the human growth factor-activatable Na/H antiporter. RT/PCR of beta-actin mRNA were performed as positive controls. Na/H antiporter mRNA expression in the proximal tubule was not detectable in S1 and S2 segments from superficial and most midcortical nephrons, which exhibit exclusively luminal Na/H antiport activity. It was expressed in S1 and S2 segments from juxtamedullary nephrons which have also basolateral Na/H antiport activity. Beta-actin mRNA was expressed uniformly in all segments of the proximal tubule. Na/H antiporter mRNA was also expressed in cortical thick ascending limb and cortical collecting duct, segments with basolateral Na/H antiport activity as well as in the glomeruli. In conclusion, at least two different Na/H antiporters exist in the renal cortex, i.e., the proximal tubule. The close correlation between functional localization of basolateral Na/H antiport activity and mRNA expression suggests that the rat kidney Na/H antiporter DNA homologous to the human growth factor activatable Na/H antiporter encodes a basolateral exchanger. The observed expression in a minority of midcortical proximal tubules could reflect a certain heterogeneity in these nephron segments.
Association of KRAS p.G13D Mutation With Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab
Authors: Wendy De Roock, Derek J. Jonker, Federica Di Nicolantonio, Andrea Sartore-Bianchi, Dongsheng Tu, Salvatore Siena, Simona Lamba, Sabrina Arena, Milo Frattini, Hubert Piessevaux, Eric Van Cutsem, Chris J. O’Callaghan, Shirin Khambata-Ford, John R. Zalcberg, John Simes, Christos S. Karapetis, Alberto Bardelli, Sabine Tejpar
Journal: JAMA (2010)

Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab.To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations.We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received off-study treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab.The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival.In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n = 32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P = .005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P = .004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P = .003). In vitro and mouse model analysis showed that although p.G12V-mutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells.In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.
Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis
Authors: Patrick S. C. Leung, Lorenzo Rossaro, Paul A. Davis, Ogyi Park, Atsushi Tanaka, Kentaro Kikuchi, Hiroshi Miyakawa, Gary L. Norman, William Lee, Eric M. Gershwin
Journal: Hepatology (2007)

In our previous work, including analysis of more than 10,000 sera from control patients and patients with a variety of liver diseases, we have demonstrated that with the use of recombinant autoantigens, antimitochondrial autoantibodies (AMAs) are only found in primary biliary cirrhosis (PBC) and that a positive AMA is virtually pathognomonic of either PBC or future development of PBC. Although the mechanisms leading to the generation of AMA are enigmatic, we have postulated that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. This thesis suggests that a severe liver oxidant injury would lead to AMA production. We analyzed 217 serum samples from 69 patients with acute liver failure (ALF) collected up to 24 months post-ALF, compared with controls, for titer and reactivity with the E2 subunits of pyruvate dehydrogenase, branched chain 2-oxo-acid dehydrogenase, and 2-oxo-glutarate dehydrogenase. AMAs were detected in 28/69 (40.6%) ALF patients with reactivity found against all of the major mitochondrial autoantigens. In addition, and as further controls, sera were analyzed for autoantibodies to gp210, Sp100, centromere, chromatin, soluble liver antigen, tissue transglutaminase, and deaminated gliadin peptides; the most frequently detected nonmitochondrial autoantibody was against tissue transglutaminase (57.1% of ALF patients). Conclusion: The strikingly high frequency of AMAs in ALF supports the thesis that oxidative stress-induced liver damage may lead to AMA induction. The rapid disappearance of AMAs in these patients provides further support for the contention that PBC pathogenesis requires additional factors, including genetic susceptibility.