tbuckley/cabot-search huggingface dataset:
Treatment of hepatitis C virus–associated mixed cryoglobulinemia with direct‐acting antiviral agents
Authors: Meghan E. Sise, Allyson K. Bloom, Jessica Wisocky, Ming V. Lin, Jenna L. Gustafson, Andrew L. Lundquist, David Steele, Michael Thiim, Winfred W. Williams, Nikroo Hashemi, Arthur Y. Kim, Ravi Thadhani, Raymond T. Chung
Journal: Hepatology (2015)

Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all‐oral direct‐acting antiviral (DAA) therapy in HCV‐associated MCS (HCV‐MCS) is largely unknown. The authors studied case series of patients with HCV‐MCS who were treated with sofosbuvir‐based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV‐MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7‐2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. Conclusion : SVR12 rates for sofosbuvir‐based DAA regimens in HCV‐MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression. (H epatology 2016;63:408–417)
Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review
Authors: Jonathan D. Schoenfeld, Anand Mahadevan, Scott R. Floyd, Michael A. Dyer, Paul J. Catalano, Brian M. Alexander, David F. McDermott, Irving D. Kaplan
Journal: Journal for ImmunoTherapy of Cancer (2015)

<h3>Background</h3> Ipilimumab improves survival in metastatic melanoma patients. This population frequently develops brain metastases, which have been associated with poor survival and are often treated with radiation. Therefore, outcomes following ipilimumab and radiation are of interest, especially given case reports and animal studies suggest combined treatment may generate abscopal responses outside the radiation field. <h3>Findings</h3> We reviewed sixteen consecutive melanoma patients who received 1 to 8 courses of radiation, with a sum total of 51, systematically evaluating abscopal responses by following the largest extra-cranial lesion. We also reviewed other series of patients treated with cranial radiation and ipilimumab. Our patients received between 1 and 8 courses of cranial radiation. Four patients received radiation concurrently with ipilimumab. Median survival was 14&nbsp;months, and 17&nbsp;months in patients initially treated with SRS. Interestingly, after radiotherapy, there was a 2.8-fold increased likelihood that the rate of extra-cranial index lesion response improved that didn't reach statistical significance (<i>p</i> = 0.07); this was more pronounced when ipilimumab was administered within three months of radiation (<i>p</i> &lt; 0.01). <h3>Conclusion</h3> Our experience and review of recently published series suggest ipilimumab and cranial radiation is well tolerated and can result in prolonged survival. Timing of ipilimumab administration in relation to radiation may impact outcomes. Additionally, our results demonstrate a trend for favorable systemic response following radiotherapy worthy of further evaluation in studies powered to detect potential synergies between radiation and immunotherapy.
Go-CART: an animal-free system for the assessment of CAR T cell function
Authors: Pradip Bajgain, Usanarat Anurathapan, Ayumi Watanabe, John Wilson, Sujita Sukumaran, Norihiro Watanabe, Helen Heslop, Cliona Rooney, Malcolm Brenner, Ann Leen, Juan Vera
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The preclinical development of chimeric antigen receptor (CAR) T cell therapy has been hindered by the inadequacy of current in vitro methods to predict T cell performance (i.e. migration, proliferation and anti-tumor activity), which do not recapitulate in vivo conditions. For
Accelerated Evolution of Enhancer Hotspots in the Mammal Ancestor
Authors: Alisha K. Holloway, Benoit G. Bruneau, Tatyana Sukonnik, John L. Rubenstein, Katherine S. Pollard
Journal: Molecular Biology and Evolution (2015)

Mammals have evolved remarkably different sensory, reproductive, metabolic, and skeletal systems. To explore the genetic basis for these differences, we developed a comparative genomics approach to scan whole-genome multiple sequence alignments to identify regions that evolved rapidly in an ancestral lineage but are conserved within extant species. This pattern suggests that ancestral changes in function were maintained in descendants. After applying this test to therian mammals, we identified 4,797 accelerated regions, many of which are noncoding and located near developmental transcription factors. We then used mouse transgenic reporter assays to test if noncoding accelerated regions are enhancers and to determine how therian-specific substitutions affect their activity in vivo. We discovered enhancers with expression specific to the therian version in brain regions involved in the hormonal control of milk ejection, uterine contractions, blood pressure, temperature, and visual processing. This work underscores the idea that changes in developmental gene expression are important for mammalian evolution, and it pinpoints candidate genes for unique aspects of mammalian biology.
A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC)
Authors: R. J. Amato, P. Harris, M. Dalton, M. Khan, R. Alter, Q. Zhai, J. R. Brady, J. Jac, R. Hauke, S. Srinivas
Journal: Journal of Clinical Oncology (2007)

5026 Background: Sorafenib has demonstrated activity with limited toxicity at a dose of 400 mg bid in MRCC pts. This presents an opportunity to explore a more intensive drug administration. This study allowed individual pt titration designed to evaluate the ability for pts to dose escalate. Response rate (RR), time to progression (TTP) and overall survival (OS) will be assessed. Methods: Eligibility included; pathologic diagnosis of a component of clear cell, progressive measurable MRCC, no more than 1 prior therapy, karnofsky performance status (KPS) = 70%, adequate organ/marrow function and no active CNS involvement. Initial dose 400 mg bid, daily. Dose escalation defined in the table below: Re-evaluation is performed every 8 weeks. RECIST criteria is utilized. Results: 46 patients have been enrolled. 44 are evaluable. 37 male/7 female, median age 50 years (43–79). 19 pts received prior therapy. 39 pts had a KPS of 100%, 5/90%. Sites of disease included; lung, nodal, liver, bone, adrenal, pancreas and kidney. 26 pts 1 metastatic site, 12 /2, 6/3 or more. 22 pts continue to receive sorafenib therapy; 2/800 mg, 7/1,200 mg, and 13/1,600 mg. 8 pts complete response (CR), 14 pts/partial response (PR) and 14 pts stable for 3+ months. Median duration of therapy is 6+ (range 0.2+ - 12+) months. 2 pts have not been reevaluated. Treatment related adverse events to-date; hand/foot syndrome, skin rash, diarrhea, alopecia, fatigue, hypertension, hypophosphatemia, and elevated amylase/lipase. Conclusion: 91% of pts were escalated to 1,200 mg or 1,600 mg per day. Dose escalated sorafenib has promising anti-tumor activity in pts with MRCC as demonstrated by a 52% CR/PR rate. Anti-tumor activity is further suggested by prolonged TTP = 3 months for 33% of pts. Independent radiology review is in progress. Intra-patient dose escalation data in association with anti-tumor activity and toxicity will be presented. [Table: see text] [Table: see text]
Abstract 9466: Recombinant Mitochondrial Transcriptional Factor A Protein Attenuates Pathological Remodeling in Cardiac Myocytes
Authors: Takeo Fujino, Tomomi Ide, Masayoshi Yoshida, Ken Onitsuka, Atsushi Tanaka, Yuko Hata, Takako Takehara, Kazuya Hosokawa, Takafumi Sakamoto, Motohiro Nishida, Kenji Sunagawa
Journal: Circulation (2011)

Introduction: Mitochondrial transcriptional factor A (TFAM), a nucleoid protein of mitochondrial DNA (mtDNA), is essential not only for transcription and replication but also maintenance of mtDNA. We have previously reported that, in failing myocardium, TFAM expression and the myocardial mtDNA copy number were decreased. Moreover, in myocardial infarction, overexpression of TFAM attenuated the decrease in the mtDNA copy number, ameliorated cardiac remodeling, and markedly improved survival. Since exogenously-administrated recombinant TFAM protein has been shown to enter mitochondria in cultured cells, we examined our hypothesis that recombinant TFAM protein administration attenuates pathological remodeling in cardiac myocytes. Methods and Results: We prepared recombinant human TFAM including mitochondrial targeting signal by glutathione s-transferase fusion protein purification protocol. Recombinant TFAM was successfully recruited into mitochondria of rat neonatal cardiac myocytes, whereas TFAM without mitochondrial targeting signal was observed in nucleus. Treatment with TFAM increased the mtDNA copy number dose-dependently (100 nM: 1.8±0.1-folds), whereas it did not change morphology or population of mitochondria (electron microscopy). To elucidate the mechanism of TFAM on signaling pathways in cardiac hypertrophy, we investigated the effects of TFAM on the nuclear factor of activated T cell (NFAT) signaling, which is a major transcriptional factor regulating pathological hypertrophy and remodeling. TFAM totally abolished NFAT nuclear translocation induced by both angiotensin II (41±3% to 2±1%, p&lt;0.01) and endothelin-1 (43±3% to 3±1%, p&lt;0.01), suppressing respective NFAT transcriptional activity and NFAT-dependent gene expression. TFAM inhibited subsequent morphological hypertrophy of cardiac myocytes (angiotensin II: 1686±37 to 1167±20 μ m 2 , p&lt;0.01, and endothelin-1: 1759±44 to 1206±21 μ m 2 , p&lt;0.01). Conclusion: Recombinant TFAM increases the mtDNA copy number, and attenuates angiotensin II and endothelin-1-induced hypertrophy via inhibiting NFAT signaling. Recombinant TFAM would be an attractive, novel therapeutic strategy for cardiac hypertrophy and remodeling.
Resection of a large rectal polyp with the simultaneous combination of snare polypectomy and full-thickness resection device resection
Authors: Andreas Fischer, Richard Knoop, Christine Walker, Robert Thimme, Hans-Jürgen Richter-Schrag
Journal: Endoscopy (2015)

A new device for full-thickness colorectal resection, the so-called full-thickness resection device (FTRD; Ovesco Endoscopy, Tübingen, Germany) has been available since November of 2014. It is the first commercial system based on the over-the-scope clip (OTSC) principle. The FTRD consists of a modified 14 t OTSC mounted on a transparent cap, which has a monofilament polypectomy snare preloaded on its tip. The FTRD can be mounted over a standard colonoscope [1]. Because the volume of the transparent FTRD cap is greater than that of the OTSC cap (3 cm3 vs. 0.9 cm3), full-thickness specimens with a median resection surface of 5 cm2 (range 1.6 cm2 – 12.9 cm2) can be obtained [2].
Transcriptome-wide RNA processing kinetics revealed using extremely short 4tU labeling
Authors: J. David Barrass, Jane E. A. Reid, Yuanhua Huang, Ralph D. Hector, Guido Sanguinetti, Jean D. Beggs, Sander Granneman
Journal: Genome biology (2015)

RNA levels detected at steady state are the consequence of multiple dynamic processes within the cell. In addition to synthesis and decay, transcripts undergo processing. Metabolic tagging with a nucleotide analog is one way of determining the relative contributions of synthesis, decay and conversion processes globally.By improving 4-thiouracil labeling of RNA in Saccharomyces cerevisiae we were able to isolate RNA produced during as little as 1 minute, allowing the detection of nascent pervasive transcription. Nascent RNA labeled for 1.5, 2.5 or 5 minutes was isolated and analyzed by reverse transcriptase-quantitative polymerase chain reaction and RNA sequencing. High kinetic resolution enabled detection and analysis of short-lived non-coding RNAs as well as intron-containing pre-mRNAs in wild-type yeast. From these data we measured the relative stability of pre-mRNA species with different high turnover rates and investigated potential correlations with sequence features.Our analysis of non-coding RNAs reveals a highly significant association between non-coding RNA stability, transcript length and predicted secondary structure. Our quantitative analysis of the kinetics of pre-mRNA splicing in yeast reveals that ribosomal protein transcripts are more efficiently spliced if they contain intron secondary structures that are predicted to be less stable. These data, in combination with previous results, indicate that there is an optimal range of stability of intron secondary structures that allows for rapid splicing.
Use of coloured overlays and lenses are unlikely to help children with dyslexia, study finds
Authors: I. Torjesen
Journal: BMJ (2015)

Vision problems are rare in dyslexic children, and most have perfect eyesight, a large UK population based study has found.

The study’s findings, published in Pediatrics on 25 May,1 reinforced the argument that coloured overlays and lenses are unlikely to help with reading difficulties in children with dyslexia. Around 375 000 UK children have dyslexia, and the use of coloured overlays and lenses by such children is common in educational establishments. Parents can spend hundreds of pounds on them, but their effectiveness remains uncertain.

Studies examining the effectiveness of these reading aids have tended to be poorly designed or inconclusive.2 Professional bodies, including the Royal College …
Abstract 11056: Hospitals Accepting Greater Proportions of High Risk Transfer-In STEMI Patients Do Not Have Higher Risk-Adjusted Hospital Mortality: A Report From the AHA Mission: Lifeline Program
Authors: Michael C Kontos, Tracy Y Wang, Anita Y Chen, Laine Thomas, Eric Bates, Harold Dauerman, Timothy Henry, Stephen V Manoukian, Matthew T Roe, William J French
Journal: Circulation (2014)

Background: Mortality is an important quality measure for acute MI hospital care. There is concern that, despite risk adjustment, PCI receiving hospitals receiving a disproportionate volume of high risk STEMI transfers may have their reported mortality adversely affected. Methods: All STEMI patients from April 2011 to December 2013 in the ACTION Registry®-GWTG™ were included. High risk was defined as pts with either cardiogenic shock or cardiac arrest on admission. Hospitals were divided into tertiles based on the proportion of high risk STEMI patients who were transferred relative to the total number of STEMI patients treated. Adjusting for covariates in the ACTION mortality risk model, the differences in risk-adjusted in-hospital mortality in each tertile were determined before and after excluding high risk STEMI transfer pts. Results: Among 119,680 STEMI pts treated at 539 primary PCI hospitals, 37,028 (31%) pts were transfers, of whom 4,500 (4%) were high risk. The proportion of high risk STEMI transfers ranged from 0-12% across hospitals. Times from initial hospital presentation to PCI were similar across tertiles: Low 107 min; Middle, 100 min; High 106 min. The ACTION mortality risk model, which includes cardiogenic shock but not cardiac arrest, slightly underestimated mortality for high-risk STEMI transfer pts (observed in-hospital mortality rate: 26%, predicted mortality rate: 24%). While differences in observed hospital mortality were present among hospitals with a greater proportion of high-risk transfers, risk-adjusted mortality was unaffected by the inclusion or exclusion of high-risk transfer patients across all tertiles (TABLE). Conclusions: Receiving PCI hospitals accepting greater proportions of high risk STEMI transfer pts did not have a higher risk-adjusted in-hospital mortality when a clinical mortality risk model was used for risk adjustment.
Smoking bans are more effective than taxes at limiting social smoking in young adults, US study shows
Authors: Susan Mayor
Journal: BMJ (2015)

Comprehensive public smoking bans are more effective than taxes on cigarettes for limiting social smoking in young adults, shows a US study,1 but it found that heavy smokers were deterred more by taxes.

The study combined information on US tobacco policies at the state and the local city level with data from the National Longitudinal Survey of Youth 1997 and followed up 4341 young adults aged 19 to 31 yearly from 2004 to 2011. Researchers looked at the effect of tobacco bans and taxes on smoking habits.

Results …
An Experimentally Informed Evolutionary Model Improves Phylogenetic Fit to Divergent Lactamase Homologs
Authors: Jesse D. Bloom
Journal: Molecular Biology and Evolution (2014)

Phylogenetic analyses of molecular data require a quantitative model for how sequences evolve. Traditionally, the details of the site-specific selection that governs sequence evolution are not known a priori, making it challenging to create evolutionary models that adequately capture the heterogeneity of selection at different sites. However, recent advances in high-throughput experiments have made it possible to quantify the effects of all single mutations on gene function. I have previously shown that such high-throughput experiments can be combined with knowledge of underlying mutation rates to create a parameter-free evolutionary model that describes the phylogeny of influenza nucleoprotein far better than commonly used existing models. Here, I extend this work by showing that published experimental data on TEM-1 beta-lactamase (Firnberg E, Labonte JW, Gray JJ, Ostermeier M. 2014. A comprehensive, high-resolution map of a gene’s fitness landscape. Mol Biol Evol. 31:1581–1592) can be combined with a few mutation rate parameters to create an evolutionary model that describes beta-lactamase phylogenies much better than most common existing models. This experimentally informed evolutionary model is superior even for homologs that are substantially diverged (about 35% divergence at the protein level) from the TEM-1 parent that was the subject of the experimental study. These results suggest that experimental measurements can inform phylogenetic evolutionary models that are applicable to homologs that span a substantial range of sequence divergence.
Female genital mutilation
Authors: G. I Meniru, M. O Meniru, U. O Ezeh
Journal: BMJ (1995)

Should be abolished

EDITOR—Is the abolition of female genital mutilation just another feminist issue? Is it racism or cultural insensitivity to stamp out this practice in Britain? Should we continue to avoid doing anything about it on the grounds that it is “a private, difficult, and sensitive” issue? Anyone who does not know the answers to these questions should take another look at the photograph of a female infant being mutilated1 because it answers all questions relating to what the correct stance of the Western world to this practice should be.

Concerted action should be taken to abolish female genital mutilation in Britain, with …
ImmTACs: bi-specific TCR-anti-CD3 fusions for targeted tumour killing
Authors: Zoe Donnellan, Giovanna Bossi, Jane Harper, Joseph Dukes, Nathaniel Liddy, Samantha Paston, Tara Mahon, Peter Molloy, Malkit Sami, Emma Baston, Brian Cameron, Andrew Johnson, Annelise Vuidepot, Namir Hassan, Bent Jakobsen
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Tumour-specific T cells have the potential to eradicate cancer. However anti-tumour immunity is limited by low TCR affinities, MHC downregulation by cancer cells and an immunosuppressive tumour microenvironment. As most tumour-associated antigens are auto-antigens, tumour specific
The applicability and prognostic value of the TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous NK/T-cell lymphoma patients
Authors: Woo Jin Lee, Ye Jin Lee, Chong Hyun Won, Sung Eun Chang, Jee Ho Choi, Mi Woo Lee
Journal: Journal of the American Academy of Dermatology (2015)
Identification of Cyclin‐Dependent Kinase 1 as a Novel Regulator of Type I Interferon Signaling in Systemic Lupus Erythematosus
Authors: Lingling Wu, Yuting Qin, Shiwei Xia, Min Dai, Xiao Han, Yanfang Wu, Xiaoyan Zhang, Jianyang Ma, Yan Wang, Yuanjia Tang, Zheng Liu, Wei Zhu, Bahija Jallal, Yihong Yao, Bo Qu, Nan Shen
Journal: Arthritis & Rheumatology (2015)

Objective Type I interferon (IFN) signaling is regarded as a central pathogenic pathway in systemic lupus erythematosus (SLE). Specific inhibition of this pathway is a core area for the development of new therapies for SLE. This study was undertaken to clarify the pathogenic mechanism involved and to identify new therapeutic targets, using a high‐throughput screening platform to determine novel regulators that contribute to the overactivation of the type I IFN signaling pathway in SLE. Methods A high‐throughput IFN‐stimulated response element (ISRE)–luciferase assay was used to screen for candidate genes that regulate the IFN signaling pathway. Western blotting was used to confirm the regulatory function of CDK1. SYBR Green quantitative reverse transcriptase–polymerase chain reaction was used to detect the expression of individual IFN‐stimulated genes (ISGs). The differential expression of CDK1 and ISGs in SLE patients and healthy controls was analyzed using RNA sequencing data and a microarray. Results The high‐throughput ISRE‐luciferase assay revealed that CDK1 enhanced type I IFN signaling. Consistent with this finding, CDK1 promoted the type I IFN–induced phosphorylation of STAT‐1 and the up‐regulated expression of ISGs. CDK1 expression was elevated in peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens from SLE patients and correlated positively with their IFN scores. A CDK1 inhibitor reduced the expression of ISGs in PBMCs from SLE patients and in renal cells from mice with lupus. Conclusion Our findings indicate that CDK1 is a positive regulator of the IFN signaling pathway. The overexpression of CDK1 might contribute to the abnormally amplified type I IFN signaling in SLE, and the inhibition of CDK1 could be used to down‐regulate type I IFN signaling in SLE.