tbuckley/cabot-search huggingface dataset:
Association Between Specific Mutations in<i>KRAS</i>Codon 12 and Colorectal Liver Metastasis
Authors: Georgios Antonios Margonis, Yuhree Kim, Gaya Spolverato, Aslam Ejaz, Rohan Gupta, David Cosgrove, Robert Anders, Georgios Karagkounis, Michael A. Choti, Timothy M. Pawlik
Journal: JAMA Surgery (2015)

Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined.To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM.This retrospective single-center study was conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13.Resection of CRLM.Overall survival (OS) and recurrence-free survival.A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P = .82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P = .02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95% CI, 1.05-2.27; P = .03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95% CI, 0.83-2.62; P = .19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95% CI, 1.00-3.17; P = .05) and G12S (HR, 3.33; 95% CI, 1.22-9.10; P = .02) were associated with worse OS compared with patients with wtKRAS (both P < .05). Among patients who recurred, G12V (HR, 2.96; 95% CI, 1.32-6.61; P = .01), G12C (HR, 6.74; 95% CI, 2.05-22.2; P = .002), and G12S mutations (HR, 4.91; 95% CI, 1.52-15.8; P = .01) were associated with worse OS (both P < .05).G12V and G12S mutations of codon 12 were independent prognostic factors of worse OS. Among patients who recurred after resection of CRLM, G12V, G12C, and G12S mutations were associated with worse OS. Information on specific KRAS mutations may help individualize therapeutic and surveillance strategies for patients with resected CRLM.
Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects
Authors: Jeffrey M. Isner, Peter R. Vale, James F. Symes, Douglas W. Losordo
Journal: Circulation Research (2001)

Clinical trials of cardiovascular gene therapy, whether using viral (53%) or nonviral (47%) vectors, have thus far disclosed no evidence indicative of inflammatory or other complications, including death, directly attributable to the vector used. Indeed, despite the fact that initial trials of cardiovascular gene therapy targeted patients with end-stage vascular disease, including critical limb ischemia and refractory myocardial ischemia, the mortality for patients enrolled in clinical trials of cardiovascular gene therapy reported to date compares favorably with mortality for similar groups of patients in contemporary controlled studies of medical or interventional therapies. The most common morbidity reported after cardiovascular gene transfer is lower extremity edema; in contrast to data involving genetically engineered mice, however, evidence of life- or limb-threatening edema has not been described in any patients, including patients after gene transfer for myocardial ischemia. Concerns regarding the potential for angiogenic cytokines to promote the progression of atherosclerosis are not supported by angiographic follow-up of patients with coronary or peripheral vascular disease. The levels and duration of gene expression investigated for therapeutic angiogenesis transfer have been unassociated with hemangioma formation. Likewise, there is little evidence from either preclinical or clinical studies to support the notion that the administration of angiogenic growth factors, per se, is sufficient to stimulate the growth of neoplasms. Patients enrolled in clinical studies of angiogenic cytokines, including patients with diabetes and a previous history of retinopathy, have disclosed no evidence to suggest that ocular pathology is a risk of angiogenic growth factor gene transfer.
International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function
Authors: Helen R. Kirby, Janet J. Maguire, William H. Colledge, Anthony P. Davenport
Journal: Pharmacological Reviews (2010)

Kisspeptins are members of the Arg-Phe amide family of peptides, which have been identified as endogenous ligands for a G-protein-coupled receptor encoded by a gene originally called <i>GPR54</i> (also known as <i>AXOR12</i> or <i>hOT7T175</i>). After this pairing, the gene has been renamed <i>KISS1R</i>. The International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name for the receptor is the kisspeptin receptor to follow the convention of naming the receptor protein after the endogenous ligand. The endogenous ligand was initially called metastin, after its role as a metastasis suppressor, and is now referred to as kisspeptin-54 (KP-54), a C-terminally amidated 54-amino acid peptide cleaved from the 145-amino acid gene product. Shorter C-terminal cleavage fragments [KP-14, KP-13 and KP-10 (the smallest active fragment)] are also biologically active. Both receptor and peptide are widely expressed in human, rat, and mouse; the receptor sequence shares more than 80% homology in these species. Activation of the kisspeptin receptor by kisspeptin is via coupling to G<sub>q/11</sub> and the phospholipase C pathway, causing Ca<sup>2+</sup> mobilization. Mutations in the <i>KISS1R</i> gene result in hypogonadotropic hypogonadotropism, and targeted disruption of <i>Kiss1r</i> in mice reproduces this phenotype, which led to the discovery of the remarkable ability of the kisspeptin receptor to act as a molecular switch for puberty. In addition to regulating the reproductive axis, the kisspeptin receptor is also implicated in cancer, placentation, diabetes, and the cardiovascular system.
Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells
Authors: Melinda A. Biernacki, Ovidiu Marina, Wandi Zhang, Fenglong Liu, Ingmar Bruns, Ann Cai, Donna Neuberg, Christine M. Canning, Edwin P. Alyea, Robert J. Soiffer, Vladimir Brusic, Jerome Ritz, Catherine J. Wu
Journal: Cancer Research (2010)

Abstract Curative effects of graft-versus-leukemia–based therapies such as donor lymphocyte infusion (DLI) for chronic myelogenous leukemia (CML) may result from immunologic ablation of self-renewing CML progenitor cells. Patients who achieved durable remissions after DLI developed a significant B-cell lymphocytosis after treatment, which did not occur in patients who were unresponsive to DLI. In this study, we identified antigen targets of this B-cell response by probing two immunoproteomic platforms with plasma immunoglobulins from seven CML patients with clinically apparent graft-versus-leukemia responses after DLI. In total, 62 antigens elicited greater reactivity from post-DLI versus pre-DLI plasma. Microarray analysis revealed that &amp;gt;70% of the antigens were expressed in CML CD34+ cells, suggesting that expression in malignant progenitor cells is a feature common to antibody targets of DLI. We confirmed elevated expression of three target antigens (RAB38, TBCE, and DUSP12) in CML that together consistently elicited antibody responses in 18 of 21 of an additional cohort of CML patients with therapeutic responses, but not in normal donors and rarely in non-CML patients. In summary, immunologic targets of curative DLI responses include multiple antigens on CML progenitor cells, identifying them as potential immunogens for vaccination and/or monitoring of immunotherapeutics designed to eliminate myeloid leukemia stem cells. Cancer Res; 70(3); 906–15
Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis
Authors: Claudia A. Couto, Paulo L. Bittencourt, Gilda Porta, Clarice P. Abrantes-Lemos, Flair J. Carrilho, Bianca D. Guardia, Eduardo L.R. Cançado
Journal: Hepatology (2013)

Reactivity and titers of autoantibodies vary during the course of autoimmune hepatitis (AIH), and some autoantibodies have been associated with disease activity and adverse outcomes after treatment. The aim of this study was to assess the autoantibody behavior in AIH and its significance as predictors of biochemical and histological remission. A total of 117 patients with AIH (mean age 18.6 [4-69] years) were evaluated and tested for autoantibodies at disease onset and successively (mean 3.2 [2-6] times) after a mean follow-up evaluation of 70 [20-185] months. Antismooth muscle (ASMA), antiliver kidney microsome type 1 (anti-LKM1), antiliver cytosol type 1 (anti-LC1), antimitochondrial, antinuclear (ANA), and antiactin antibodies (AAA) were determined at disease onset and 379 other times during the follow-up evaluation through indirect immunofluorescence in rodent tissues, HEp-2 cells, and human fibroblasts. Anti-SLA/LP were assessed 45 times in the follow-up evaluation of 19 patients using enzyme-linked immunosorbent assay (ELISA). Upon admission, AIH types 1 and 2 were observed in 95 and 17 patients, respectively. Five subjects had AIH with anti-SLA/LP as the sole markers. Patients initially negative for AAA did not develop these antibodies thereafter. ANA were detected de novo in six and three subjects with AIH types 1 and 2, respectively. After treatment, only ASMA (>1:80) and AAA (>1:40) were significantly associated with biochemical (76.9% and 79.8%) and histological features (100% and 100%) of disease activity (P < 0.001). With the exception of ANA, the autoantibody profile does not markedly vary in the course of AIH. The persistence of high titers of ASMA and/or AAA in patients with AIH is associated with disease activity.
Disease Penetrance of Late-Onset Parkinsonism
Authors: Joanne Trinh, Ilaria Guella, Matthew James Farrer
Journal: JAMA Neurology (2014)

IMPORTANCE Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism.However, the estimated disease penetrance of these mutations varies widely.OBJECTIVE To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism.DATA SOURCES Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13.The end-of-search date was January 31, 2014.STUDY SELECTION Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient.Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study. DATA EXTRACTION AND SYNTHESISThe age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death. MAIN OUTCOMES AND MEASURESComparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals.RESULTS All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001).In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97)and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years).In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58),whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001). CONCLUSIONS AND RELEVANCEParkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.
Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution
Authors: Rosalie Fisher, Stuart Horswell, Andrew Rowan, Maximilian P Salm, Elza C de Bruin, Sakshi Gulati, Nicholas McGranahan, Mark Stares, Marco Gerlinger, Ignacio Varela, Andrew Crockford, Francesco Favero, Virginie Quidville, Fabrice André, Carolina Navas, Eva Grönroos, David Nicol, Steve Hazell, David Hrouda, Tim O’Brien, Nik Matthews, Ben Phillimore, Sharmin Begum, Adam Rabinowitz, Jennifer Biggs, Paul A Bates, Neil Q McDonald, Gordon Stamp, Bradley Spencer-Dene, James J Hsieh, Jianing Xu, Lisa Pickering, Martin Gore, James Larkin, Charles Swanton
Journal: Genome biology (2014)

Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.
Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis.
Authors: L Feng, W W Tang, D J Loskutoff, C B Wilson
Journal: Journal of the American Society of Nephrology (1993)

Glomerular plasminogen activator inhibitor-1 (PAI-1) steady-state mRNA and bioactivity were increased after the induction of an augmented form of antiglomerular basement membrane (GBM) antibody glomerulonephritis. PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17. PAI-1 mRNA expression correlated with glomerular PAI-1 bioactivity as determined by a functional tissue type plasminogen activator (t-PA) binding assay. Glomerular PAI-1 bioactivity, not detected in controls, increased to 1.4 +/- 0.3 ng/mg of glomerular lysate at 6 h and then decreased to 0.7 +/- 0.1 ng/mg of glomerular lysate by Day 6. The mRNA of the plasminogen activators (urokinase plasminogen activator), t-PA) either remained unchanged or declined through Day 1, with a slight increase in t-PA mRNA at Day 6. Interleukin-1 beta mRNA expression was maximal at 6 h, declining by Day 3. Transforming growth factor beta 1 (TGF-beta 1) mRNA began to increase at Day 1, was maximal at Day 6, and fell only slightly by Day 17. Epidermal growth factor mRNA decreased. The increase in PAI-1 mRNA and bioactivity, possibly induced early by the interleukin-1 beta response and perhaps later by the TGF-beta 1 response, was associated with striking glomerular capillary lumen fibrin accumulations on Day 1, which decreased and appeared to recanalize as the PAI-1 mRNA and bioactivity fell. The glomerular lesion continued to have some fibrin deposits even on Day 17 and, in addition, had changes of thickened GBM, suggestive of the early stages of diffuse glomerulosclerosis. The latter had a temporal relationship with the persisting increase in TGF-beta 1 and PAI-1 mRNA levels. These observations suggest the possibility that inhibition of enzymes capable of remodeling excessive extracellular matrix production may have contributed to the thickened GBM.
Roth’s Spots
Authors: Eytan Z. Blumenthal, Ehud Zamir
Journal: Circulation (1999)

s spots (named for Moritz Roth, Swiss physician, 1849 -1914) are traditionally considered a manifestation of subacute bacterial endocarditis.However, the differential diagnosis of retinal hemorrhages with a central white spot, also referred to as a hemorrhagic cotton-wool spot, includes such entities as anemia, leukemia, retinal phlebitis, Candida albicans infection, vascular diseases, collagen diseases, bacterial sepsis, viral pneumonia, and kala azar, just to name a few, as shown in the figures. 1 Which is the subacute endocarditis-related "true" Roth spot?
Poliomyelitis: Four Simultaneous Cases
Authors: G. O. Barber
Journal: BMJ (1938)

ACUTE ANTERIOR POLIOMYELITIS MEICABLJOTUSNAL is thought to be possible, provided that complications do iot arise during labour.The selection of cases for trial and the management of labour are of first importance.A suggested routine is described.The decision as to the management of future confinements may be based upon the experience gained from a trial labour.
Inhibition of Wnt-1 Signaling Induces Apoptosis in β-Catenin-Deficient Mesothelioma Cells
Authors: Liang You, Biao He, Kazutsugu Uematsu, Zhidong Xu, Julien Mazieres, Amie Lee, Frank McCormick, David M. Jablons
Journal: Cancer Research (2004)

Abstract It is known that Wnt-1 signaling inhibits apoptosis by activating β-catenin/tcf-mediated transcription. Here, we show that blocking Wnt-1 signaling in β-catenin-deficient mesothelioma cell lines H28 and MS-1 induces apoptotic cell death. Both Wnt-1 small interfering RNA (siRNA) and Dishevelled siRNA induced significant apoptosis in these cell lines. A small molecule inhibitor of c-Jun NH2-terminal kinase inhibited the apoptotic cell killing induced by either Wnt-1 siRNA or Dishevelled siRNA in these cells. Our data suggest that β-catenin-independent noncanonical pathway(s), i.e., Wnt/JNK pathway, may play a role in the apoptotic inhibition caused by Wnt-1 signaling.
Why everyone over 65 deserves influenza vaccine
Authors: C. Diguiseppi
Journal: BMJ (1996)

Why everyone over 65 deserves influenza vaccine Government recommendations should reflect the evidence In a recent issue of Effectiveness Matters, the NHS Centre for Reviews and Dissemination recommends annual influenza vaccination of everyone aged over 65.1 However, the Department of Health recommends vaccination only of individuals at high medical risk or who are institutionalised.2Each year in Britain, there are thousands of hospital admissions and deaths due to influenza infection, most in peo- ple aged over 65.' Confronted with this disease burden and
Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension
Authors: F Blumberg
Journal: Cardiovascular Research (2002)

Objective: The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension. Methods: To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F1α (6-keto-PGF1α), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O2) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day). Results: Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF1α plasma levels rose from 8.2±0.8 to 12.2±2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF1α levels (each P<0.05 vs. hypoxia). Conclusion: Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.
Subclass restriction of murine antibodies. III. Antigens that stimulate IgG3 in mice stimulate IgG2c in rats.
Authors: G P Der Balian, J Slack, B L Clevinger, H Bazin, J M Davie
Journal: The Journal of Experimental Medicine (1980)

The IgG subclass distribution of rat antibodies to 13 different antigens was measured. Antibodies to protein and hapten-protein conjugates were predominantly IgG2a. Antigens labeled thymus-independent type 1, based upon responses in mice, stimulated both IgG2b and IgG2c antibodies, but little IgG2a. Polysaccharide and hapten-polysaccharide antigens (thymus-independent type 2) as well as phosphocholine-keyhole limpet hemocyanin, stimulated predominantly IgG2c antibodies. A division of antigens into essentially the same categories has been made on the basis of subclass restriction in mice. Antigens that stimulate IgG2c in rats stimulate IgG3 in mice. Thus, by comparing subclass preference with a variety of antigens, functional analogues among subclasses in different species can be identified.
Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane®) in combination with gemcitabine in patients with metastatic breast cancer (N0531)
Authors: V. Roy, B.R. LaPlant, G.G. Gross, C.L. Bane, F.M. Palmieri
Journal: Annals of Oncology (2008)