tbuckley/cabot-search huggingface dataset:
Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R
Authors: Ayalew Tefferi, Terra L. Lasho, Mrinal M. Patnaik, Lyla Saeed, Mythri Mudireddy, Dame Idossa, Christy Finke, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat
Journal: American Journal of Hematology (2017)

Abstract A 27‐gene panel was used for next‐generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS‐R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2‐2.5), SETBP1 (HR 4.1, 95% CI 1.6‐10.2) and TP53 (HR 2.2, 95% CI 1.3‐3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5‐10.2), IDH2 (HR 3.7, 95% CI 1.2‐11.4), and CSF3R (HR 6.0, 95% CI 1.6‐22.6) for leukemia‐free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS‐R weakened the significance of TP53 mutations/variants ( P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS‐R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia‐free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS‐R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision‐making in lower risk MDS.
Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies
Authors: Markus B Sikkel, Darrel P Francis, James Howard, Fabiana Gordon, Christina Rowlands, Nicholas S Peters, Alexander R Lyon, Sian E Harding, Kenneth T MacLeod
Journal: Cardiovascular Research (2017)

It is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests).
AB1066 Diagnostic utility of the median/ulnar nerve cross-sectional area ratio in carpal tunnel syndrome
Authors: T Atan, Z Günendi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The most commonly used ultrasonographic measurements for the diagnosis of CTS are measurement of the median nerve cross-sectional area (m-CSA) at different levels of the carpal tunnel.<sup>1</sup> The cross-sectional area of a nerve may differ according to biometric characteristics such as age, sex, height, weight and wrist thickness.<sup>2–4</sup> <h3>Objectives</h3> The aim of this study was to assess the diagnostic utility of the ultrasonographic ratio of m-CSA to ulnar nerve cross-sectional area (u-CSA), the m-CSA/ u-CSA ratio, in carpal tunnel syndrome (CTS). <h3>Methods</h3> Patients (n=50) with positive symptoms and electromyography results of CTS and control subjects (n=50) with negative electromyography results of CTS were evaluated. The most symptomatic hand of each participant were included in the assesment. Ultrasonographic m-CSA and u-CSA measurements were made at the level of the pisiform bone, and m-CSA/u-CSA ratio was calculated. <h3>Results</h3> Using the m-CSA cut-off value of 9.95 mm<sup>2</sup> showed a sensitivity of 92% and a specificity of 42%. Conversely, the cut-off value 13.90 mm<sup>2</sup> showed a sensitivity of 56% and a specificity of 92%. Using the cut-off value 2.96 for the ratio of m-CSA/u-CSA showed a sensitivity of 86% and a specificity of 38% while using the cut-off value 3.71 showed a sensitivity of 52% and a specificity of 90% in the diagnosis of CTS. <h3>Conclusions</h3> The ratio of m-CSA/u-CSA at the level of the pisiform bone did not provide an additional benefit for the diagnosis of CTS. Ultrasonographic m-CSA measured at the same level was found to be more sensitive and specific method. <h3>References</h3> Mondelli M, Flippou G, Gallo A, Frediani B. Diagnostic utility of ultrasonography versus nerve conduction studies in mild carpal tunnel syndrome. Arthritis Rheum. 2008;59:357–66. Bathala L, Kumar P, Kumar K, Shaik A, Visser LH. Normal values of median nerve cross-sectional area obtained by ultrasound along its course in the arm with electrophysiological correlations, in 100 Asian subjects. Muscle Nerve. 2014;49:284–6. Qrimli M, Ebadi H, Breiner A, et al. Reference values for ultrasonograpy of peripheral nerves. Muscle Nerve. 2016;53:538–44. Won SJ, Kim BJ, Park KS, Yoon JS, Choi H. Reference values for nerve ultrasonography in the upper extremity. Muscle Nerve. 2013;47:864–71. <h3>Disclosure of Interest</h3> None declared
Pregnancy in Wilson's disease: Management and outcome
Authors: Jan Pfeiffenberger, Sandra Beinhardt, Daniel N. Gotthardt, Nicola Haag, Clarissa Freissmuth, Ulrike Reuner, Annika Gauss, Wolfgang Stremmel, Michael L. Schilsky, Peter Ferenci, Karl Heinz Weiss
Journal: Hepatology (2017)

Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD‐specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634‐4.982]). Birth defects occurred in 7 of 209 (3%) live births. Conclusion: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy‐naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (H epatology 2018;67:1261‐1269).
The Value of Traditional Ecological Knowledge for the Environmental Health Sciences and Biomedical Research
Authors: Symma Finn, Mose Herne, Dorothy Castille
Journal: Environmental Health Perspectives (2017)

Background: Traditional Ecological Knowledge (TEK) is a term, relatively new to Western science, that encompasses a subset of traditional knowledge maintained by Indigenous nations about the relationships between people and the natural environment. The term was first shared by tribal elders in the 1980s to help raise awareness of the importance of TEK. TEK has become a construct that Western scientists have increasingly considered for conducting culturally relevant research with Tribal nations. Objectives: The authors aim to position TEK in relation to other emerging schools of thought, that is, concepts such as the exposome, social determinants of health (SDoH), and citizen science, and to explore TEK's relevance to environmental health research. This article provides examples of successful application of TEK principles in federally funded research when implemented with respect for the underlying cultural context and in partnership with Indigenous communities. Discussion: Rather than treating TEK as an adjunct or element to be quantified or incorporated into Western scientific studies, TEK can instead ground our understanding of the environmental, social, and biomedical determinants of health and improve our understanding of health and disease. This article provides historical and recent examples of how TEK has informed Western scientific research. Conclusions: This article provides recommendations for researchers and federal funders to ensure respect for the contributions of TEK to research and to ensure equity and self-determination for Tribal nations who participate in research. https://doi.org/10.1289/EHP858
Anti-Pegaspargase, Anti-Calaspargase Pegol , and Anti-Polyethelene Glycol Antibody Incidence in High Risk Acute Lymphoblastic Leukemia Patients Receiving Pegaspargase or Calaspargase Pegol and Associated Anaphylactic or Hypersensitivity Reaction Rates: Results from Children's Oncology Group (COG) Study AALL07P4
Authors: Reuven J Schore, Meenakshi Devidas, Archie Bleyer, Gregory Reaman, Claudia Lebedinsky, Hui Zhang, Herwig Koppensteiner, Mignon L. Loh, Elizabeth Raetz, Naomi Winick, William L. Carroll, Stephen P. Hunger, Anne Angiolillo
Journal: Blood (2016)
Variation in Orthologous Shell-Forming Proteins Contribute to Molluscan Shell Diversity
Authors: Daniel J. Jackson, Laurin Reim, Clemens Randow, Nicolas Cerveau, Bernard M. Degnan, Claudia Fleck
Journal: Molecular Biology and Evolution (2017)

Despite the evolutionary success and ancient heritage of the molluscan shell, little is known about the molecular details of its formation, evolutionary origins, or the interactions between the material properties of the shell and its organic constituents. In contrast to this dearth of information, a growing collection of molluscan shell-forming proteomes and transcriptomes suggest they are comprised of both deeply conserved, and lineage specific elements. Analyses of these sequence data sets have suggested that mechanisms such as exon shuffling, gene co-option, and gene family expansion facilitated the rapid evolution of shell-forming proteomes and supported the diversification of this phylum specific structure. In order to further investigate and test these ideas we have examined the molecular features and spatial expression patterns of two shell-forming genes (Lustrin and ML1A2) and coupled these observations with materials properties measurements of shells from a group of closely related gastropods (abalone). We find that the prominent "GS" domain of Lustrin, a domain believed to confer elastomeric properties to the shell, varies significantly in length between the species we investigated. Furthermore, the spatial expression patterns of Lustrin and ML1A2 also vary significantly between species, suggesting that both protein architecture, and the regulation of spatial gene expression patterns, are important drivers of molluscan shell evolution. Variation in these molecular features might relate to certain materials properties of the shells of these species. These insights reveal an important and underappreciated source of variation within shell-forming proteomes that must contribute to the diversity of molluscan shell phenotypes.
Characterization of BRK/Sik tyrosine kinase in oral squamous cells
Authors: Benjamin J. Petro, Mark W. Lingen, Keiko Watanabe
Journal: Cancer Research (2006)

78   Oral squamous cell carcinoma (OSCC) is an aggressive epithelial malignancy that is the sixth most common neoplasm in the world today. The mortality rate, which includes patients receiving traditional treatment, remains approximately 50%, and therapies that are targeted specifically to oral epithelial cells are limited. The non-receptor protein tyrosine kinase BRK/Sik (BRK: human breast tumor kinase; PTK) (Sik: mouse src-related intestinal kinase) is an epithelial cell specific kinase which has a tissue specific pattern of expression. BRK appears to play a role in cell proliferation, migration and differentiation in different cell types under different conditions. Thus far, very little is known about BRK expression and function in human oral epithelium. The purpose of this study was to characterize the function of BRK/Sik in normal oral squamous cells and in oral squamous cell carcinoma. To this end, we generated oral squamous cell carcinoma (OSCC) cells that express wildtype (WT), kinase defective (KM), and constitutively active (YF) BRK/Sik using retroviral transduction and studied signal transduction upon addition of EGF. We also performed immunohistochemistry of archival tissues as well as FACS analysis to identify cells that do not express BRK in oral epithelium. In addition, we examined the effect of BRK siRNA on normal oral epithelial cells. The results are as follows: In a time course analysis, WT BRK/Sik in OSCC is phosphorylated within 2 min of adding EGF and this phosphorylation dissipates in 5-10 min. WT and YF BRK/Sik co-immunoprecipitates with tyrosine phosphorylated proteins of 180,125 and 70 kD. However, KM BRK/Sik co-immunoprecipitates with the 125kD protein only. The known substrate of BRK, SAM68, associates with BRK/Sik in 20 min of adding EGF. Immunohistochemistry and FACS data indicate that cells in basal epithelial layers and cells in the mitotic phase of the cell cycle do not express BRK/Sik. In addition, suppression of BRK expression in normal oral squamous cells is associated with an increase in PCNA expression, further indicating that BRK/Sik is involved in suppressing cell proliferation in normal oral epithelium. In conclusion, the results of this study suggest that BRK/Sik functions to suppress cell proliferation in oral epithelial cells, which is contrary to its reported function in other cell types. In addition, BRK/Sik associates with a minimum of three distinct proteins whose identity is not yet established.
カスパーゼ活性化プロドラッグ化学療法のためのドキソルビシン/ヘパリン複合ナノ粒子【Powered by NICT】
Authors: Khaliq Nisar Ul, Sandra Febrina Carolina, Park Dal Yong, Lee Jae Young, Oh Keun Sang, Kim Dongkyu, Byun Youngro, Kim In-San, Kwon Ick Chan, Kim Sang Yoon, Yuk Soon Hong
Journal: Biomaterials (2016)
Virtual and Augmented Reality Systems for Renal Interventions: A Systematic Review
Authors: Felicitas J. Detmer, Julian Hettig, Daniel Schindele, Martin Schostak, Christian Hansen
Journal: IEEE Reviews in Biomedical Engineering (2017)

Purpose: Many virtual and augmented reality systems have been proposed to support renal interventions. This paper reviews such systems employed in the treatment of renal cell carcinoma and renal stones. Methods: A systematic literature search was performed. Inclusion criteria were virtual and augmented reality systems for radical or partial nephrectomy and renal stone treatment, excluding systems solely developed or evaluated for training purposes. Results: In total, 52 research papers were identified and analyzed. Most of the identified literature (87%) deals with systems for renal cell carcinoma treatment. About 44% of the systems have already been employed in clinical practice, but only 20% in studies with ten or more patients. Main challenges remaining for future research include the consideration of organ movement and deformation, human factor issues, and the conduction of large clinical studies. Conclusion: Augmented and virtual reality systems have the potential to improve safety and outcomes of renal interventions. In the last ten years, many technical advances have led to more sophisticated systems, which are already applied in clinical practice. Further research is required to cope with current limitations of virtual and augmented reality assistance in clinical environments.
Identification of Novel Circulating Biomarkers Predicting Rapid Decline in Renal Function in Type 2 Diabetes: The Fremantle Diabetes Study Phase II
Authors: Kirsten E. Peters, Wendy A. Davis, Jun Ito, Kaye Winfield, Thomas Stoll, Scott D. Bringans, Richard J. Lipscombe, Timothy M.E. Davis
Journal: Diabetes Care (2017)

OBJECTIVE To assess the ability of plasma apolipoprotein (apo) A-IV (apoA4), apo C-III, CD5 antigen-like (CD5L), complement C1q subcomponent subunit B (C1QB), complement factor H–related protein 2, and insulin-like growth factor binding protein 3 (IBP3) to predict rapid decline in estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS Mass spectrometry was used to measure baseline biomarkers in 345 community-based patients (mean age 67.0 years, 51.9% males) from the Fremantle Diabetes Study Phase II (FDS2). Multiple logistic regression was used to determine clinical predictors of rapid eGFR decline trajectory defined by semiparametric group-based modeling over a 4-year follow-up period. The incremental benefit of each biomarker was then assessed. Similar analyses were performed for a ≥30% eGFR fall, incident chronic kidney disease (eGFR &amp;lt;60 mL/min/1.73 m2), and eGFR decline of ≥5 mL/min/1.73 m2/year. RESULTS Based on eGFR trajectory analysis, 35 participants (10.1%) were defined as “rapid decliners” (mean decrease 2.9 mL/min/1.73 m2/year). After adjustment for clinical predictors, apoA4, CD5L, and C1QB independently predicted rapid decline (odds ratio 2.40 [95% CI 1.24–4.61], 0.52 [0.29–0.93], and 2.41 [1.14–5.11], respectively) and improved model performance and fit (P &amp;lt; 0.001), discrimination (area under the curve 0.75–0.82, P = 0.039), and reclassification (net reclassification index 0.76 [0.63–0.89]; integrated discrimination improvement 6.3% [2.1–10.4%]). These biomarkers and IBP3 contributed to improved model performance in predicting other indices of rapid eGFR decline. CONCLUSIONS The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes.
胎児脱細胞化心臓の3次元足場は成人と比較した心臓細胞を支持する強化した可能性を示す【Powered by NICT】
Authors: A C Silva, S C Rodrigues, J Caldeira, A M Nunes, V Sampaio-Pinto, T P Resende, M J Oliveira, Barbosa, S Thorsteinsdottir, D S Nascimento, P Pinto-do-O
Journal: Biomaterials (2016)
High prevalence of hepatitis E virus in semen of infertile male and causes testis damage
Authors: Fen Huang, Feiyan Long, Wenhai Yu, Jianwen Situ, Lijie Fu, Zhanlong He, Hao Dong, Chenchen Yang, Yunlong Li, Fan Yang, Daqiao Wei
Journal: Gut (2017)

We read with interest the paper by Todt et al 1 concerning the mutagenesis of Hepatitis E virus (HEV) caused by ribavirin treatment. HEV is a major cause of acute hepatitis worldwide and lacks a specific treatment.1 2 It replicates in many extrahepatic sites (spleen, kidney, brain and muscle3–5), but whether the testis is included is unknown. Active HEV has been detected in body fluids (blood,2 urine4 and milk6), but no report exists for semen.

Thus, HEV prevalence in the semen of infertile males (n=185) sexually abstinent for at least 2 days was investigated by reverse transcriptase-PCR. Ethical approval was obtained from the Institutional Ethics Committee. Unexpectedly, 28.11% (52/185) of the males were HEV RNA positive (HEV RNA+; detectable HEV ORF1 and ORF2 were considered as HEV RNA+, figure 1A) with comparable viral titers to that from urine (see figure S1 in the online supplementary file 1). The prevalence of HEV in semen was higher in infertile males than in serum of pregnant women (1.82%) or the general population (0.58%) in the same city.

### Supplementary file 1

[SP1.pdf] 



Figure 1 
(A) Positive rate of Hepatitis E virus (HEV) RNA in the semen of …
Activity of second line axitinib in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib: Results from SAX Italian real world trial.
Authors: Sabrina Rossetti, Francesco Jacopo Romano, Carmine D'Aniello, Carla Cavaliere, Salvatore Pisconti, Gelsomina Iovane, Massimiliano Berretta, Paolo Marchetti, Anna Crispo, Raffaele Piscitelli, Paolo Muto, Piera Maiolino, Sisto Perdonà, Gerardo Botti, Gaetano Facchini
Journal: Journal of Clinical Oncology (2017)

e16054 Background: Axitinib, a selective tyrosine kinase inhibitor (TKI), is currently approved for the treatment of mRCC after failure of prior treatment with sunitinib or cytokine, according to AXIS trial results. The best sequence hasn’t been established: both axitinib and everolimus (a mTOR inhibitor) are viable therapeutic options, although recently immunotherapy agents entered this setting. This Italian multi-institutional retrospective analysis evaluated outcomes of Axitinib in exclusive sequence after sunitinib in second line treatment of mRCC Methods: Medical records of 148 patients treated with Axitinib from 21 Italian Oncology Centers were retrospectively assessed: PFS, OS, ORR DCR, and safety profile of axitinib were primary endpoints. Results: Median PFS and OS were 7.14 and 15.5 months, respectively. Overall, axitinib at standard schedule of 5 mg bid, was well tolerated, with no grade 4 toxicity event. Most common adverse events were hypertension (26% of the cases), fatigue (50 %), hypothyroidism (18%). At univariate analysis, when patients were stratified by Heng score, mPFS was 5.8, 7.0 and 9.0 months according to poor, intermediate and favourable risk group, respectively. When stratified by median duration of prior sunitinib therapy (≥ 13,1 mo vs &lt; 13,1 mo), there was a statistically significant difference in PFS with 8.8 vs 6.3 months, respectively. Disease control rate (DCR) to previous sunitinib treatment was associated to longer PFS with axitinib ( 8.0 months vs4.0 months). The sequence sunitinib-axitinib was well tolerated, with a mOS of 41 months. At multivariate analysis, prognostic factors for progression were gender (p-value = 0,006), DCR to axitinib (p &lt; 0,0001) and to previous sunitinib (p = 0,041); DCR to axitinib (p = &lt; 0,0001), nephrectomy (p = 0,002) and Heng score (p = 0,025) independently affected overall survival. Conclusions: The preliminary SAX results in the real world population are consistent with available literature. The study confirms that Axitinib is effective and safe in routine clinical practice, and its efficacy seems to be greater in patients who most benefited from first-line sunitinib.