tbuckley/cabot-search huggingface dataset:
An expanding intracerebral haematoma
Authors: Peter Birkeland, Lisbeth Høgedal, Frantz Poulsen
Journal: BMJ (2015)

A 44 year old man presented to the emergency department with a sudden onset headache.He had no medical history of note and took no drugs.Urgent computed tomography of the head was performed (fig 1).A repeat scan (eight minutes later) was performed after administration of intravenous contrast (OptiRay) (fig 2).Upon return from the radiology department, he developed left sided hemiplegia.His blood pressure was 179/90 mm Hg.After another 46 minutes, computed tomography (fig 3) with angiography (not shown) was performed; no abnormal vessels were seen.Blood tests did not show an underlying coagulopathy.He subsequently deteriorated to localising to pain and making incomprehensible sounds to pain without opening his eyes (Glasgow coma score 8).His pupils remained equal and reactive to light.
Abstract #4690: Preclinical characterization of the HSP90 inhibitor XL888 in melanoma models
Authors: Monique Nicoll
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

HSP90 is a component of a molecular chaperone complex that promotes the conformational maturation and stabilization of many tumor-promoting oncoproteins, including mutant BRAF and AKT. Inhibition of HSP90 results in the destabilization and proteosomal degradation of its client proteins, resulting in potent anti-tumor activity in a broad range of cancer models. XL888 is a selective ATP-competitive inhibitor of HSP90 with a distinct binding mode relative to 17-AAG and other small molecule inhibitors. In preclinical models, XL888 has potent anti-proliferative activity against a diverse panel of 118 tumor cell lines, with a median IC50 of 8.8 nM (range 0.1-1426 nM). From this broad panel, melanoma cell lines emerge as highly sensitive to XL888. As malignant melanoma is frequently characterized by elevated MAPK pathway signaling through gain of function mutations in NRAS or BRAF, and elevated AKT pathway signaling through loss of PTEN, we investigated XL888 effects on both signaling pathways. Western blot analysis reveals that treatment of a panel of melanoma cell lines with XL888 results in marked reduction of the HSP90 client proteins CRAF, BRAF(V600E), and AKT with a corresponding decrease in the level of phospho-ERK and phospho-S6 levels (IC50 values range from 16-122 nM). In vivo, XL888 inhibits the growth of multiple xenograft tumor models in athymic nude mice, including the melanoma model A375, at well tolerated oral doses and schedules. In conclusion, in vitro and in vivo preclinical data demonstrate that XL888 simultaneously attenuates signaling from both MAPK and AKT pathways in melanoma cell lines and supports clinical investigation of XL888 for the treatment of malignant melanoma where these pathways are dysregulated. XL888 is currently in Phase I clinical evaluation in cancer patients.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4690.
Cardiovascular Magnetic Resonance for Risk Stratification of Arrhythmia in Hypertrophic Cardiomyopathy⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Saman Nazarian, João A.C. Lima
Journal: Journal of the American College of Cardiology (2008)
Misdiagnosed pulmonary TB: Influencing factors and diagnostic chances in TB hospital
Authors: Zhanna Laushkina, Pavel Filimonov
Journal: European Respiratory Journal (2012)

Differential diagnosis of pulmonary TB is still difficult. We found the tendency to overdiagnosis of pulmonary TB in TB hospital.   Purpose  of the study was to analyze causes of diagnostic errors and improve the quality of in-hospital management of patients supposed to having of pulmonary TB.   Methods:  Noncomparative retrospective study, subject of interest were medical records of 136 most difficult cases, in which previously established diagnosis of pulmonary TB was rejected. The chances for establishment of true diagnosis and influencing factors were estimated.   Results:  1. Diseases, most often initially misdiagnosed as tuberculosis, were pneumonia (52 %), lung cancer (20 %). 2. The period from the disease manifestation up to establishment of final diagnosis was 84 ± 72.8 (mean±SD) days. 3. Clinicoradiological signs in these cases were more characteristic for TB, than for other pulmonary diseases. 4. Factors found to be associated with false-positive diagnosis is: “limited pulmonary opacity” (OR 1.75, p=0.003), pulmonary dissemination (OR 1.75, p=0.05), detection of low level acid-fast bacilli in sputum (OR 2.0, p=0.04), nonspecific inflammatory findings detected by flexible bronchoscopy (OR 2.2, p=0.000), age more than 40 years (OR 1.75, p=0.01), inconspicuous disease onset (OR 1.9, p=0.01), COPD (OR 1.8, p=0.04), inadequate antibacterial therapy before hospitalization.   Conclusion:  Application of contemporary methodologies of diagnostic tests interpretation, use of rapid TB diagnostic is highly needed.
MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer
Authors: David A. Armstrong, Benjamin B. Green, John D. Seigne, Alan R. Schned, Carmen J. Marsit
Journal: Molecular Cancer (2015)

MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media. Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR-4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b-3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06). MicroRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma. This study demonstrated varying relationships between miRNA detected in biological media from the same patient, and serves to inform the potential of urine-based microRNAs as biomarkers for bladder cancer and potentially other malignancies.
Genomics of Immune Diseases and New Therapies
Authors: Michael Lenardo, Bernice Lo, Carrie L. Lucas
Journal: Annual Review of Immunology (2016)

Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics.
Postconsolidation Maintenance and Monitoring in Patients With Acute Promyelocytic Leukemia
Authors: Chezi Ganzel, Dan Douer, Martin S. Tallman
Journal: Journal of the National Comprehensive Cancer Network (2013)

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). Its exclusivity is reflected by both the clinical course and the management of patients. This article discusses 2 aspects of the unique management of patients with APL: the role of maintenance therapy and polymerase chain reaction (PCR) monitoring. Despite common practice, the efficacy of maintenance therapy in APL is still debated, and the introduction of arsenic trioxide into frontline protocols makes this debate even more challenging. This article also attempts to clarify details regarding the type and duration of maintenance treatment. The presence of residual leukemic cells, seen using PCR analysis of the PML/RARα fusion gene product, in patients who have experienced a complete response has been shown to have a high correlation with subsequent relapse. This fact led to the broad use of PCR monitoring techniques in patients with APL. Practicing clinicians face several questions with regard to monitoring, such as what is the best technique for monitoring patients with APL, who can benefit the most from these tests, what are the best time points, and for how long is monitoring recommended. These questions are addressed in this article.
Beer, wine and lifestyle: a cross-sectional study of the Belgian military population
Authors: Patrick Mullie, Peter Clarys
Journal: Military Medical Research (2015)

A reduction in mortality associated with wine drinking compared to beer drinking has been suggested in the past. A recent meta-analysis could not confirm the observed differential effect. Other characteristics not related to specific components of beer and wine must play a role in the relationship between wine and mortality, thereby explaining the differential protective results. A military population was selected to investigate the lifestyle differences between beer and wine drinkers. A food-frequency questionnaire was used to register alcohol and food consumption, together with questionnaires for health-related and lifestyle characteristics. Three dietary patterns were characterized by the Healthy Eating Index 2010, the Mediterranean Diet Score and a pattern obtained by principal component analysis. In the multivariate analysis, beer consumption decreased with increasing age, military rank, physical activity and dietary pattern scores. Beer consumption increased with total energy intake and with smoking. Wine consumption was associated with a healthier lifestyle compared with beer consumption. Those differences must be taken into account when relating types of alcoholic beverage consumption with health-related outcomes.
Possible beneficial interaction between statins and combination anglotensin receptor blocker (ARB) and ACE inhibitor treatment in patients with myocardial infarction: A post hoc analysis of the VALsartan in acute myocardial iNfarcTion trial (VALIANT)
Authors: JJ McMurray, KS Pieper, H White, Frans Van de Werf, K Swedberg, AJ Dalby, L Kober, AP Maggioni, SD Solomon, H Drexler, RM Califf, MA Pfeffer
Journal: Circulation (2005)
Management of myocardial infarction: looking beyond efficacy∗∗Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Madhu K Natarajan, Shamir Mehta, Salim Yusuf
Journal: Journal of the American College of Cardiology (2000)
Metabolomics Reveals a Key Role for Fumarate in Mediating the Effects of NADPH Oxidase 4 in Diabetic Kidney Disease
Authors: Young-Hyun You, Tammy Quach, Rintaro Saito, Jessica Pham, Kumar Sharma
Journal: Journal of the American Society of Nephrology (2015)

The NADPH oxidase (NOX) isoform NOX4 has been linked with diabetic kidney disease (DKD). However, a mechanistic understanding of the downstream effects of NOX4 remains to be established. We report that podocyte-specific induction of NOX4 in vivo was sufficient to recapitulate the characteristic glomerular changes noted with DKD, including glomerular hypertrophy, mesangial matrix accumulation, glomerular basement membrane thickening, albuminuria, and podocyte dropout. Intervention with a NOX1/NOX4 inhibitor reduced albuminuria, glomerular hypertrophy, and mesangial matrix accumulation in the F1 Akita model of DKD. Metabolomic analyses from these mouse studies revealed that tricarboxylic acid (TCA) cycle-related urinary metabolites were increased in DKD, but fumarate levels were uniquely reduced by the NOX1/NOX4 inhibitor. Expression of fumarate hydratase (FH), which regulates urine fumarate accumulation, was reduced in the diabetic kidney (in mouse and human tissue), and administration of the NOX1/NOX4 inhibitor increased glomerular FH levels in diabetic mice. Induction of Nox4 in vitro and in the podocyte-specific NOX4 transgenic mouse led to reduced FH levels. In vitro, fumarate stimulated endoplasmic reticulum stress, matrix gene expression, and expression of hypoxia-inducible factor-1α (HIF-1α) and TGF-β. Similar upregulation of renal HIF-1α and TGF-β expression was observed in NOX4 transgenic mice and diabetic mice and was attenuated by NOX1/NOX4 inhibition in diabetic mice. In conclusion, NOX4 is a major mediator of diabetes-associated glomerular dysfunction through targeting of renal FH, which increases fumarate levels. Fumarate is therefore a key link connecting metabolic pathways to DKD pathogenesis, and measuring urinary fumarate levels may have application for monitoring renal NOX4 activity.
Domestication selected for deceleration of the circadian clock in cultivated tomato
Authors: Niels A Müller, Cris L Wijnen, Arunkumar Srinivasan, Malgorzata Ryngajllo, Itai Ofner, Tao Lin, Aashish Ranjan, Donnelly West, Julin N Maloof, Neelima R Sinha, Sanwen Huang, Dani Zamir, José M Jiménez-Gómez
Journal: Nature Genetics (2015)
Abstract 20350: Discordant Left Bundle Branch Block is Associated With Left Ventricular Dyssyncrhony at Cardiac Magnetic Resonance Imaging in Patients With Nonischemic Cardiomyopathy
Authors: Alessandro Valleggi, Michele Emdin, Giovanni D Aquaro, Claudio Passino, Giuseppe Vergaro, Andrea Barison, Luigi E Pastormerlo, Luigi Padeletti
Journal: Circulation (2014)

LBBB is frequently linked to left ventricular (LV) dyssynchrony and adverse prognosis in HF. LBBB has been defined as concordant (cLBBB) or discordant (dLBBB), when associated in lead I and V5, V6 with a positive or negative T wave respectively. dLBBB has been associated with a worse clinical and prognostic profile in HF patients. We sought to evaluate association between different patterns of LV dV/dT curves at CMR, LBBB morphology, clinical correlates and prognostic role in patients with nonischemic systolic HF. Methods and Results: One hundred and fifteen consecutive patients with LBBB were submitted between 2004 and 2014 to a complete cardiological evaluation, including CMR with analysis of dV/dT curves of LV contraction, and follow-up for cardiac events. We distinguished two different patterns of global and segmental LV systole: a “narrow” pattern (NP) generated by synchronous contraction of wall segments; a “wide” pattern (WP), when delay in contraction between wall segments resulted in a prolungation of systolic peak with a flat or notched morphology. Fourteen patients presenting with normal LV dimensions and function all had cLBBB and NP, while out of 101 patients with HF, those with dLBBB (65%) presented with shorter QRS duration (p &lt; .01) and higher level of NT-proBNP (p &lt; .001). WP was observed more frequent in dLBBB patients (p &lt; .003) as a mark of greater intraventricular dyssynchrony. According to systolic pattern, those with WP had higher levels of NT-proBNP, lower EF and higher LV volumes than those with NP, whereas no significant difference was found in QRS duration. At multivariate analysis only dLBBB (p=.006) and EF (p=.001) were independent predictors of WP. At Kaplan-Meier analysis, the presence of WP was associated with a worse prognosis considering a composite end-point of cardiac death, hospitalization for HF and ICD shock (p&lt;.005). At Cox analysis only presence of WP (p = .029) and level of NT-proBNP (p= .004) were independent predictors. Conclusions: In nonischemic systolic HF patients with LBBB, presence of a WP at CMR dV/dT curves is associated with dLBBB, identifies greater LV dyssynchrony with possible major benefits from resynchronization therapy and is an independent prognosticator.
Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial.
Authors: T. S. Maughan, R. Adams, C. G. Smith, M. T. Seymour, R. H. Wilson, A. M. Meade, D. Fisher, A. Madi, J. Cheadle, R. S. Kaplan
Journal: Journal of Clinical Oncology (2010)

3502 Background: In COIN one randomization was between continuous oxaliplatin (Ox) and fluoropyrimidine (Fp) CT and the same CT plus cetuximab (C). The choice of Fp, capecitabine (Cap) or infusional 5-fluouroracil plus leucovorin (FU), was decided prior to randomization. The primary outcome was overall survival (OS) in KRAS wild-type (wt) pts. Further analysis of NRAS, BRAF, MSI and EGFR status has been performed. Methods: Pts had measurable, inoperable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Patients were randomized between (A) continuous OxFp (OxFU q2w or OxCap q3w) and (B) OxFp + weekly C. Results: 1,630 pts were accrued between 03/05 and 05/08 from the UK and Ireland. Pt characteristics: median age 63; 92% had PS 0-1; 66% received OxCap and 34% received OxFU. Tumor samples from 1,316 (81%) pts were available for KRAS analysis. 729 (55%) were KRAS wt. 102 (8%) had BRAF and 50 (4%) had NRAS mutations. 4% had MSI. In the primary analysis cohort there was no evidence of a difference in either OS or progression-free survival (PFS) from addition of C to Ox-based CT (OS: HR = 1.04, 95% CI 0.87-1.23, p = 0.67; PFS: HR = 0.96, 95%CI 0.82-1.12, p = 0.60). A small difference in best overall response (CR/PR at any time on treatment) was observed (57% with OxFp, 64% with OxFp + C, p = 0.049). From pre-specified exploratory analyses of 15 potential predictive covariates, we observed a suggestion of an interaction between the choice of CT (OxFU vs. OxCap) and the effect of adding C on PFS (p=0.07), suggesting a benefit from C in OxFU treated pts, but no evidence of a benefit in OxCap treated pts. Among pts with no KRAS, BRAF or NRAS mutation (N=581; a subset of the primary cohort) we also observed an interaction between the number of metastatic sites at baseline (0/1 vs. > 1) and randomised treatment on OS (p = 0.01) and PFS (p = 0.04), suggesting a benefit from C in pts with 0/1 metastatic sites at baseline. Conclusions: The addition of C to Ox-based CT did not improve OS or PFS in KRAS wt pts. However, we have identified at least two possible predictive covariates. These relationships require further analysis which will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Roche Merck Serono
Hormone replacement therapy (HRT) in women with previously treated primary breast cancer: Update XII
Authors: A. Z. Bluming
Journal: Journal of Clinical Oncology (2006)

10596 Background: To assess the incidence of contralateral or recurrent breast cancer among women prospectively treated with HRT after initial breast cancer diagnosis. Methods: A community-based, prospective, single-arm, pilot study of HRT among 241 women with previously treated primary breast cancer. Results: Median duration of HRT is 83+ months (range 12+–161+). Median interval from initial surgery to initiation of HRT is 52 months (range 2–361 months). Follow-up to date is 100%. Actuarial disease-free survival (DFS), disease-specific survival (DSS), &amp; median duration of HRT by stage are listed in the table. One hundred and fourteen patients have stopped HRT (47%), 57 because of anxiety about taking HRT (24%), 48 because of breast cancer development (20%), 3 because of the development of non-breast cancers, 2 died of nonmalignant disease, 3 because of HRT-associated symptoms, and 1 because of pulmonary emboli without clinical phlebitis. CHRT, as opposed to ERT, was administered to 50% of all patients and 57% of the 48 who subsequently developed breast cancer on study. Actuarial DFS to 20 years for T1N0 patients was 72% versus 63% for comparable T1N0 patients who did not receive HRT. Conclusions: No evidence to date of increased development, recurrence or of breast cancer-related death associated with post diagnosis HRT. [Table: see text] No significant financial relationships to disclose.