tbuckley/cabot-search huggingface dataset:
Efficacy outcomes with bevacizumab added to chemotherapy (bev+CT) compared with chemotherapy alone (CT) in left- and right-sided tumors in metastatic colorectal cancer (mCRC).
Authors: Fotios Loupakis, Herbert I. Hurwitz, Leonard Saltz, Dirk Arnold, Axel Grothey, Quynh Lan Nguyen, Stuart Osborne, Linda Yau, Jonathan Talbot, Stefanie Srock, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

726 Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]
Diurnal proteomics and biomarker discovery in indolent versus aggressive chronic lymphocytic leukemia (CLL) patients: A proof of principle pilot study.
Authors: Georg A. Bjarnason, Tami Martino, Jieran Li, Jian Chen, Moyez Dharsee, Cathy Wang, Peter Kupchak, Kenneth R. Evans, David Spaner
Journal: Journal of Clinical Oncology (2014)

e22220 Background: In rodents, 10-20% of the genome has a 24-hour (h) rhythm in RNA expression. In a microarray study on RNA extracted from CLL cells sampled every 4 hours over 24 hours (6 samples) from 3 male and 6 female CLL patients (pts), we found gender differences in rhythmic RNA expression. We hypothesized that this might have clinical implication for biomarker discovery with some important biomarkers only found at certain times of day and with gender differences. Methods: Sampling for CLL cells and plasma was performed again at 6 time points in male (M) and female (F) CLL patients with indolent (10 pts, 5 M, 5 F) and aggressive CLL (10 pts, 5 M, 5 F). Each 8-plex iTRAQ block for mass spectrometry (MS) based relative quantification comprised all time points for a single patient and a universal control.More than 300 proteins were identified at a 95% confidence level in each iTRAQ experiment, with 74 showing differences in expression between aggressive and indolent pts and 44 proteins showing a significant 24-h rhythm. These putative targets, combined with a set of proteins identified from the literature, were used to generate targets for pilot confirmatory MRM studies in plasma samples drawn at the same time as the CLL cell samples. For each peptide target, mixed model analyses with repeated measures were employed, with the normalized peak area being modeled as a quadratic function of time of collection, and separate quadratic functions in time for males and for females with aggressive CLL, and for males and for females with indolent CLL. Results: A subset of iTRAQ- and literature-derived proteins were shown to differentiate indolent vs. high grade CLL in a manner dependent on both gender and time of sampling. Some proteins would only work as biomarkers in males but not females and vice versa. The timing of sampling significantly impacted on the ability of some proteins to differentiate indolent vs. aggressive CLL pts. Conclusions: Gender differences in rhythmic protein expression may have clinical implications for novel biomarker discovery.
“Normal” Creatinine Levels Predict Persistent Kidney Injury and Waitlist Mortality in Outpatients With Cirrhosis
Authors: Giuseppe Cullaro, Meyeon Park, Jennifer C. Lai
Journal: Hepatology (2018)

Acute kidney injury (AKI) is a critical determinant of outcomes in hospitalized patients with cirrhosis, but little is known of the impact of AKI in the outpatient setting. We analyzed 385 adult outpatients with cirrhosis listed for liver transplant at a single center; excluded were those with severe hepatic encephalopathy, with hepatocellular carcinoma, or on hemodialysis. Baseline serum creatinine (bCr) was defined as the lowest value recorded, peak Cr as the highest value, ΔCr as peak Cr minus bCr, AKI as a rise in serum Cr (sCr) by ≥0.3 mg/dL from bCr, persistent kidney injury as elevation of sCR by ≥0.3 mg/dL from bCr on each subsequent clinical assessment. Among 385 outpatients with cirrhosis, bCr was ≤0.70, 0.70‐0.97, and ≥0.97 mg/dL in 28%, 38%, and 34%, respectively. At a median follow‐up of 16 (range 8‐28) months, 143 (37%) had one or more AKI episode, which increased significantly by bCr group (24% versus 37% versus 48%, P = 0.001). Of these 143 with AKI, 13% developed persistent kidney injury. A multivariable Cox regression analysis highlighted that bCr (hazard ratio [HR], 2.96) and ΔCr (HR, 2.05) were the only factors independently associated with the development of persistent kidney injury ( P &lt; 0.001). The likelihood of death/delisting increased by bCr group (14% versus 19% versus 28%, P = 0.03). A competing risk analysis demonstrated that each 1 mg/dL increase in bCr was independently associated with a 62% higher risk of death/delisting when accounting for transplantation and adjusting for confounders. Conclusion: AKI is not only common in outpatients with cirrhosis but even “clinically normal” bCr levels significantly impact the risk of persistent kidney injury and waitlist mortality, supporting the need for a lower clinical threshold to initiate monitoring of renal function and implementation of kidney‐protective strategies.
Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes
Authors: Natalia Rodriguez-Muela, Andrey Parkhitko, Tobias Grass, Rebecca M. Gibbs, Erika M. Norabuena, Norbert Perrimon, Rajat Singh, Lee L. Rubin
Journal: Journal of Clinical Investigation (2018)

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.
Comparison of long-term cosmetic outcomes for different treatments of superficial basal cell carcinoma
Authors: Maud H.E. Jansen, Fabienne H.J. Koekelkoren, Patty J. Nelemans, Aimee H.M.M. Arits, Marieke H. Roozeboom, Nicole W.J. Kelleners-Smeets, Klara Mosterd
Journal: Journal of the American Academy of Dermatology (2018)
Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects
Authors: Ken Muramatsu, Hideyuki Ujiie, Ichiro Kobayashi, Wataru Nishie, Kentaro Izumi, Takamasa Ito, Norihiro Yoshimoto, Ken Natsuga, Hiroaki Iwata, Hiroshi Shimizu
Journal: Journal of Allergy and Clinical Immunology (2018)
Controversies and Future Directions of Ocular Biomarkers in Alzheimer Disease
Authors: Sally S. Ong, P. Murali Doraiswamy, Eleonora M. Lad
Journal: JAMA Neurology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Oral Antibiotic Exposure and Kidney Stone Disease
Authors: Gregory E. Tasian, Thomas Jemielita, David S. Goldfarb, Lawrence Copelovitch, Jeffrey S. Gerber, Qufei Wu, Michelle R. Denburg
Journal: Journal of the American Society of Nephrology (2018)

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown. Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case–control study nested within 641 general practices providing electronic health record data for &gt;13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins. Results Exposure to any of five different antibiotic classes 3–12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages ( P &lt;0.001) and 3–6 months before index date ( P &lt;0.001), with all but broad-spectrum penicillins remaining statistically significant 3–5 years from exposure. Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.
MHRA bans valproate prescribing for women not in pregnancy prevention programme
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The Medicines and Healthcare Products Regulatory Agency (MHRA) has banned the antiepileptic drug sodium valproate in the UK in all women of childbearing potential who are not enrolled in a pregnancy prevention programme.

The regulator said that it had made the decision to protect public health and in close collaboration with professional bodies, NHS organisations, and patient and campaign groups.1

Women or girls who are already taking valproate should consult their GP to have their …
Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non–Small Cell Lung Cancer <i>In Vitro</i> and <i>In Vivo</i>
Authors: Sarwat Naz, Anastasia Sowers, Rajani Choudhuri, Maria Wissler, Janet Gamson, Askale Mathias, John A. Cook, James B. Mitchell
Journal: Clinical Cancer Research (2018)

Abstract Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non–small cell lung cancer (NSCLC) cells in vitro and in vivo. Experimental Design: IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer. Effects of abemaciclib and IR combination in vivo were studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. After IR, abemaciclib treatment inhibited DNA damage repair as measured by γH2AX. Mechanistically, abemaciclib inhibited RB phosphorylation, leading to cell-cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pools, causing nutrient stress. In vivo, abemaciclib, when administered in an adjuvant setting for the second week after fractionated IR, further inhibited vasculogenesis and tumor regrowth, with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting the CDK4/6 pathway by abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC. Conclusions: Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker-driven combination therapeutic strategy for patients with NSCLC. Clin Cancer Res; 24(16); 3994–4005. ©2018 AACR.
Hepatic autophagy potentiates ureagenesis and its enhancement protects against acute and chronic hyperammonemia
Authors: L. Soria, G. Allegri, D. Melck, N. Pastore, P. Annunziata, D. Paris, E. Polishchuk, E. Nusco, B. Thöny, A. Motta, J. Häberle, A. Ballabio, N. Brunetti-Pierri
Journal: Journal of Hepatology (2018)
Saroglitazar treatment prevents NASH, eliminates hepatocyte ballooning, and significantly improves serum LFTs, lipids and insulin resistance in DIAMOND(tm) mice compared to pioglitazone benchmark
Authors: R. Caffrey, J. Marioneaux, P. Santhekadur, P. Bedossa, B. Philip, S. Giri, M. Jain, A. Sanyal
Journal: Journal of Hepatology (2018)
Role of alpha-1 antitrypsin genotypes in the progression of adult liver disease
Authors: V. Pereira, R. Gaspar, C. Simões, L. Maia, D. Costa, J. Carvão, A. Oliveira, G. Serrão, V. Jesus, M.C. Sucena, C. Santos, J. Gomes, J. Lages, I. Abreu, S. Freitas, S. Carvalhana, M. Mandorfer, H. Cortez-Pinto, G. Macedo, M. Trauner, R. Liberal, L. Jasmins
Journal: Journal of Hepatology (2018)
Abstract 11516: Non-Ischemic Fibrosis as a Marker of Adverse Right Ventricular Remodeling - A Multimodality Imaging Study
Authors: Jiwon Kim, Nina Kukar, Claudia L Ma, Chaitanya B Medicherla, Omar K Khalique, Parag Goyal, Prashanth Venkatesh, Richard B Devereux, Evelyn Horn, Jonathan W Weinsaft
Journal: Circulation (2015)

Background Non-ischemic mid wall fibrosis (MWF) on cardiac magnetic resonance (CMR) has been linked to poor prognosis in patients with right ventricular (RV) dysfunction, but its link to adverse RV remodeling is unknown. Methods The population comprised patients with RV dysfunction (EF&lt;50%) undergoing CMR and transthoracic echo (TTE) within a 14 day (5±3) interval. Cardiac structure, function, and MWF were assessed on CMR; MWF was defined in accordance with standard criteria (mid wall or epicardial septal fibrosis). Pulmonary artery systolic pressure (PASP) was measured on echo. RV wall stress was calculated via an established formula: RV wall stress=(4π*[0.620] 3 *PASP*RVESV)/(3*RV myocardial volume) Results 118 patients (65% male, 55±18yo) with RV dysfunction were studied, among whom 47% had MWF. Patients with MWF had lower RVEF (34±10 vs. 39±9%; p=0.01) but similar LVEF (40±21 vs 39±18%; p=0.7) and LV volumes (p=NS). RV wall stress was higher with MWF (26±10 vs. 19±9kPa; p&lt;0.001) corresponding to increased RVESV (143±79 vs. 110±36ml; p=0.006), myocardial mass (60±21 vs. 53±17gm; p=0.04), and PASP (52±18 vs. 41±18 mmHg; p=0.001). MWF was associated with increased wall stress among subgroups with isolated RV (p=0.003) and concomitant LV dysfunction (p=0.02). Among RV wall stress components, MWF was independently associated with RV volume (OR=1.17 per 10 ml, [CI 1.04-1.32]; p=0.01) and PASP (OR=1.43 per 10 mmHg, [1.14-1.81]; p=0.002) but not RV mass (OR=0.91 per 10gm, [0.69-1.20]; p=0.5) [model χ 2 =21; p 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p&lt;0.001; Figure). Conclusion MWF strongly relates to increased RV wall stress. Among wall stress components, MWF was independently associated with both RV chamber dilation and afterload, supporting the concept that MWF is a generalized marker of adverse RV chamber remodeling.
Biomarkers in DPYD and TYMS genes related with the toxicity profile and therapeutic outcomes of patients with gastrointestinal tumors treated with fluoropyrimidines.
Authors: Eliude R. Nascimento, Millene A. Bechara, Ney PC Santos, Danielle Feio Da Costa, Williams Fernandes Barra, Juliana Passos Pereira, Amanda Raquel Gomes, Eriksen A.C. Gonçalves, Mayara FERREIRA Mota, Tayssa CL Vilhena, Rubem Almeida Junior, Gicely N.L. Pereira, Natalle S.C. Freitas, Marianne R. Fernandes, Antonio A.C. Modesto
Journal: Journal of Clinical Oncology (2015)

e12618 Background: Fluoropyrimidines are the main chemotherapy treatment of gastrointestinal tumors, however, around 30% of patients exhibit severe toxicities. Biomarkers are essential for precision medicine, useful for predicting better drugs combination and minimally toxic effective dose. We studied two polymorphisms involved in the metabolic pathway of 5-fluorouracil: DPYD*5 (rs1801159) and TYMS (rs16430), associated with toxicity profile and therapeutic outcome in Brazilian patients with gastrointestinal tumors. Methods: A retrospective, cross-sectional, case-control was performed to evaluate 126 patients treated with fluoropyrimidines. The TaqMan system was used to investigate the polymorphism DPYD*5, while polymorphisms INDEL in TYMS gene were identified by a multiplex PCR. The CTCAE v4.0 were used to evaluate toxicity. Clinical and radiological response were based on medical records. Results: Adverse events occurred in 70.6%, and 21.4% were severe. The average ancestry was 48.7% European, followed by Native Americans (30.5%) and African (21.3%). The frequency of mutation DPYD*5 was 45.2% and TYMSmutation was 63.0%, and 32.8% of patients had mutations in both genes. Allelic mutations investigated present in only one gene or both were not associated with toxicity or therapeutic response. The risk of African ancestry progressing to death during treatment was higher than other ancestries (P = 0.034; OR = 56.6; CI95% = 1.3-23.7), as well as the risk of disease progression (P = 0.006; OR = 197.16; CI95% = 4.4-8.7%). Conclusions: The predictive and prognostic value of mutations DPYD*5 and TYMS (rs16430) for toxicity and therapy outcomes of fluoropyrimidines was not statistically proven in this serie. The risk of disease progression and mortality during treatment with fluoropyrimidines was higher in average African ancestry.
Abstract 19685: Liver Dysfunction as Reflected by MELD (the Model For End Stage Liver Disease) Score Could Better Predict Postoperative Outcome in Patients Undergoing Cardiac Surgery than Child-Turcotte-Pugh Classification
Authors: Mai Murata, Tomoko S Kato, Kenji Kuwaki, Kan Kajimoto, Taira Yamamoto, Atsushi Amano
Journal: Circulation (2015)

Background: Liver dysfunction increases postoperative morbidity and mortality following cardiac surgery. Child-Turcotte-Pugh (CTP) classification had been used in the evaluation of liver function. More recently, the composite model for end stage liver disease (MELD) score has become recognized as a more robust and objective scoring system than CTP classification. However, the predictive power of CTP and MELD scores for postoperative outcome in patients undergoing cardiac surgery has not yet been fully elucidated. Methods and Results: Postoperative outcome and preoperative liver function estimated by the CTP classification or the MELD scores were investigated in 1856 consecutive patients (69.3% male, age 66. 8±12.2 years) undergoing cardiac surgery between 2010 and 2013 at our institution. The proportions of patients in CTP class A, B and C were 91.8% (n=1704), 8.1% (n=151) and 0.05% (n=1); and mean MELD scores in patients in each CTP class were 9.4, 15.5 and 36.7, respectively. A MELD cutoff value of 12 can predict postoperative mortality with a sensitivity and specificity of 78.7 and 63.9%, respectively, with an area under the curve (AUC) from the ROC analysis of 0.75248 (p&lt;0.0001). Child class B/C predicts morality with a sensitivity and specificity of 23.7 and 92.2%. High MELD score (&gt;12) was associated with longer intubation time (33.6±5.1 vs. 12.2±2.7 hours, p&lt;0.0001), longer ICU (4.8±0.3 vs. 2.2±0.2 days, p&lt;0.0001) and total-hospital stay (34.5±1.0 vs. 22.8±0.6 days, p&lt;0.0001) and more incidence of renal replacement therapy requirement (46.0 vs. 4.4%, p&lt;0.0001) than those with low MELD scores (&lt;12). The predictive strength of the MELD, MELD component variables and CTP class (B/C vs. A) were quantitatively compared based on AUC by using the DeLong test, which revealed that MELD score was the strongest predictor for morality (pairwise comparison, all p&lt;0.05). Conclusions: Assessment of liver dysfunction using the MELD scoring system is useful for predicting postoperative morality and morbidity following cardiac surgery. MELD scoring system was a stronger predictor for morality than CTP classification.
Response by Magnussen et al to Letter Regarding Article, “Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)”
Authors: Christina Magnussen, Francisco M. Ojeda, Renate B. Schnabel
Journal: Circulation (2018)
VCAM-1 and soluble CD-163 as novel non-invasive markers of liver fibrosis in patients with autoimmune hepatitis – a prospective study
Authors: M. Janik, B. Kruk, K. Kostrzewa, R.-W. Joanna, F. Lammert, M. Krawczyk, M. Milkiewicz, P. Milkiewicz
Journal: Journal of Hepatology (2018)