tbuckley/cabot-search huggingface dataset:
Sequenceserver: A Modern Graphical User Interface for Custom BLAST Databases
Authors: Anurag Priyam, Ben J Woodcroft, Vivek Rai, Ismail Moghul, Alekhya Munagala, Filip Ter, Hiten Chowdhary, Iwo Pieniak, Lawrence J Maynard, Mark Anthony Gibbins, HongKee Moon, Austin Davis-Richardson, Mahmut Uludag, Nathan S Watson-Haigh, Richard Challis, Hiroyuki Nakamura, Emeline Favreau, Esteban A Gómez, Tomás Pluskal, Guy Leonard, Wolfgang Rumpf, Yannick Wurm
Journal: Molecular Biology and Evolution (2019)

Abstract Comparing newly obtained and previously known nucleotide and amino-acid sequences underpins modern biological research. BLAST is a well-established tool for such comparisons but is challenging to use on new data sets. We combined a user-centric design philosophy with sustainable software development approaches to create Sequenceserver, a tool for running BLAST and visually inspecting BLAST results for biological interpretation. Sequenceserver uses simple algorithms to prevent potential analysis errors and provides flexible text-based and visual outputs to support researcher productivity. Our software can be rapidly installed for use by individuals or on shared servers.
Abstract #433: Novel mutations in the K-Ras oncogene: implications for personalised medicine in the treatment of colorectal cancer
Authors: Rebecca Bounds, Helga Wolf, Simone Weidlich, Norman Pratt, Francis Carey, Robert Steele, Gillian Smith, C. Roland Wolf
Journal: Cancer Research (2009)

Ras mutations are found in up to one third of human tumors, making Ras genes some of the most frequently mutated oncogenes in human cancer. The Kirsten-Ras (K-Ras) gene is most frequently mutated in colorectal tumors, where activating mutations have previously been described at the \#8220;hotspot\#8221; codons 12, 13 and 61. We have used a combination of \#8220;WAVE\#8482;\#8221; denaturing HPLC analysis and direct sequencing to confirm the presence of hotspot mutations at codons 12 (21.5 %) and 13 (5.6 %) and to identify additional novel K-Ras mutations at codons 19 (  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 433.
A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation
Authors: Melanie S. Vacchio, Thomas Ciucci, Yayi Gao, Masashi Watanabe, Mariah Balmaceno-Criss, Mitchell T. McGinty, Allan Huang, Qi Xiao, Cameron McConkey, Yongmei Zhao, Jyoti Shetty, Bao Tran, Marion Pepper, Golnaz Vahedi, Marc K. Jenkins, Dorian B. McGavern, Rémy Bosselut
Journal: Immunity (2019)
Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length
Authors: Bridget DiPrisco, Ajay Kumar, Bhanu Kalra, Gopal V. Savjani, Zoe Michael, Olivia Farr, Aimilia Eirini Papathanasiou, Helen Christou, Christos Mantzoros
Journal: Metabolism (2019)
Aldo-keto reductase family 1 b10 regulates acetyl-coa carboxylase-α stability and fatty acid synthesis
Authors: Ruilan Yan, Jun Ma, Xuyu Zu, Ji-Ming Cheng, Krishna Rao, Duan-Fang Liao, Deliang Cao
Journal: Cancer Research (2008)

2733  Recent studies have demonstrated that aldo-keto reductase family 1 B10 (AKR1B10), a novel protein overexpressed in human hepatocellular carcinoma and non-small cell lung carcinoma, may facilitate cancer cell growth by detoxifying intracellular reactive carbonyls. This study presents a novel function of AKR1B10 in tumorigenic mammary epithelial cells (RAO-3), regulating fatty acid synthesis. In RAO-3 cells, Sephacryl-S 300 gel filtration and DEAE-Sepharose ion exchange chromatography demonstrated that AKR1B10 exists in two distinct forms, monomers (~40 kDa) bound to DEAE- Sepharose column and protein complexes (~300 kDa) remaining in flow-through. Co-immunoprecipitation with AKR1B10 antibody and protein mass spectrometry analysis identified that AKR1B10 associates with acetyl-CoA carboxylase-α (ACCA), a rate-limiting enzyme of de novo fatty acid synthesis. This association between AKR1B10 and ACCA proteins was further confirmed by the co-immunoprecipitation with ACCA antibody and pull-down assays with recombinant AKR1B10 protein. Intracellular fluorescent studies showed that AKR1B10 and ACCA proteins co-localize in the cytoplasm of RAO-3 cells. More interestingly, siRNA-mediated AKR1B10 knockdown increased ACCA degradation through ubiquitination- proteasome pathway and resulted in more than 50% decrease of fatty acid synthesis in RAO-3 cells. These data suggest that AKR1B10 is a novel regulator of the biosynthesis of fatty acid, an essential component of the cell membrane, in breast cancer cells.
Development of screening tools for the identification of small molecule inhibitors of HIF-1α/HIF-1β protein-protein interaction
Authors: Eun Jung Park, Dehe Kong, Robert Fisher, Robert H. Shoemaker, Giovanni Melillo
Journal: Cancer Research (2005)

1708  Transcription factors are attractive targets for development of novel therapeutics. Selective inhibitors of transcription factors might be obtained by inhibiting protein-protein interaction, a crucial step in dimerization. However, protein-protein interaction is generally considered a difficult target for development of therapeutics. Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, and glucose metabolism. HIF-1 is a heterodimeric protein complex composed of two members of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) domain family, HIF-1α and HIF-1β (or ARNT). In contrast to the constitutively expressed HIF-1β subunit, HIF-1α is an oxygen labile protein, which is degraded through hydroxylation and ubiquitination in normoxia. However, HIF-1α becomes stabilized in response to hypoxia or iron chelators, dimerizes with HIF-1β and binds the hypoxia response element (HRE), thereby activating the expression of numerous hypoxia-response genes. In an attempt to develop screening tools for the identification of small molecule inhibitors of HIF-1α/β heterodimer formation, we have expressed several fragments of the N-terminal domain of HIF-1α and HIF-1β fused to the His or Flag tags, respectively. Several N-terminal fragments of HIF-1α and HIF-1β were expressed containing either the bHLH, PAS-A and PAS-B domains. An ELISA has been developed by immobilizing HIF-1β-Flag protein on anti-flag M2 monoclonal antibodies coated 96-well plates and by detecting binding of HIF-1α-His tag using anti-His-HRP conjugate. In addition, we have used the mammalian two-hybrid system to generate cell lines (293-PAS-A) expressing the luciferase reporter gene upon binding of the pasA domains of HIF-1α and HIF-1β. Expression of luciferase in 293-PAS-A cells was inhibited in a competitive fashion by co-transfection of a protein containing the N-terminal region of HIF-1α. The tools described above were utilized to screen several libraries available at NCI. No active compounds were identified by screening the NCI diversity set using proteins containing the bHLH domains. Several compounds were identified in a primary screen using proteins containing the PAS-A domains of HIF-1α/β and studies are ongoing to validate these active leads. Results of ongoing screening activities using the PAS-A domain of HIF-1α/β as target for the identification of small molecule inhibitors will be presented.
PTH-129 The incidence of remaining effective peristaltic activity in patients diagnosed with absent contractility of the oesophagus
Authors: I Miah, G Sui, T Wong, J Jafari
Journal: Gut (2017)

Introduction  The oesophageal absent contractility diagnosis is a major motility disorder according to the Chicago Classification (CC) [1] that is based on failing to produce peristalsis with distal contractile integration (DCI) of ≥100 mmHgscm.  Aim  To challenge the oesophagus with multiple water swallows (MWS) and solid bolus swallows (SBS) and examine for remaining effective peristaltic activity  Method  Patients selected for study underwent high-resolution manometry (HRM) testing using Sierra Scientific Instruments complementary system (36-channel solid-state catheter and Manoscan 360 data recording device). Patients diagnosed with absent contractility according to CC (version 3) between September 2014 and December 2016 underwent MWS and SBS assessment for remaining peristaltic activity. Effective peristalsis were accepted when normal values of contractile front velocity and distal latency during swallows were met (i.e.≤6.25 cm/s and >4.2s respectively) in addition to demonstrating post-MWS peristalsis with DCI ≥100 mmHgscm [1] and/or SBS with sandwich meal generating peristalsis with DCI ≥405 mmHgscm (DCI values for SBS in normal population between 5%–95% are 404.6–5845.6mmHgscm [2]). The transition zone (TZ) measured during peristaltic activity was at 20 mmHg isobaric contouring.  Results  Number of patients diagnosed with absent contractility was 47 (M:F=19:28, mean age 52 years[18–75 years]),17/47 patients (36.2% of the total cases) produced effective peristaltic activity with MWS and/or SBS.  Seven of the 47 patients (14.9%) demonstrated effective peristalsis with MWS with maximum DCI of 686.3mmHgscm and smallest TZ of 1.9 cm. Of which, MWS generated peristalsis with normal DCI (534–686.3mmHgscm) in 3 of the 7 patients (6.4% of the total cases) and 4 of the 7 patients who produced effective peristalsis to MWS response did not produce peristaltic activity with SBS (8.5% of the total cases).  43/47 patients performed SBS and 13 of the 43 patients (30.2%) produced normal peristalsis in total of 35 swallows (highest DCI=1750 mmHgscm, smallest TZ=0 cm). 10/43 patients (23.3%) produced normal peristalsis during SBS but did not respond to MWS.  Conclusion  More than 1/3 of patients with absent contractility have remaining peristaltic activity on MWS and/or SBS which may have profound impact to oesophageal acid clearance and treatment strategy.  References  . Kahrilas PJ, et al. The Chicago Classification of Esophageal Motility Disorders, v3.0 Neurogastroenterol Motil 2015;27(2):160–174.  . Sweis RTet al. Normal values and inter-observer agreement for liquid and solid bolus swallows in upright and supine positions as assessed by esophageal high-resolution manometry. Neurogastroenterol Motil2011;23(6):509–516.  Disclosure of Interest  None Declared
Benchmarking software tools for detecting and quantifying selection in evolve and resequencing studies
Authors: Christos Vlachos, Claire Burny, Marta Pelizzola, Rui Borges, Andreas Futschik, Robert Kofler, Christian Schlötterer
Journal: Genome biology (2019)

The combination of experimental evolution with whole-genome resequencing of pooled individuals, also called evolve and resequence (E&R) is a powerful approach to study the selection processes and to infer the architecture of adaptive variation. Given the large potential of this method, a range of software tools were developed to identify selected SNPs and to measure their selection coefficients. In this benchmarking study, we compare 15 test statistics implemented in 10 software tools using three different scenarios. We demonstrate that the power of the methods differs among the scenarios, but some consistently outperform others. LRT-1, CLEAR, and the CMH test perform best despite LRT-1 and the CMH test not requiring time series data. CLEAR provides the most accurate estimates of selection coefficients. This benchmark study will not only facilitate the analysis of already existing data, but also affect the design of future data collections.
Early B Cell Factor 1 (EBF1) Regulates Glomerular Development by Controlling Mesangial Maturation and Consequently COX-2 Expression
Authors: Tracy Nelson, Heino Velazquez, Nancy Troiano, Jackie A. Fretz
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The specific mechanisms regulating formation of the glomerular tuft during renal development are largely unknown. A previous study showed the transcription factor Early B cell factor 1 (EBF1) is essential for formation of the glomerular tuft. However, the cell types driving glomerular developmental defects in mice lacking EBF1 were not identified. The authors show that deletion of EBF1 from the glomerular mesangium results in impaired glomerular development, whereas deletion of EBF1 from podocytes does not cause developmental abnormalities. They show that EBF1 in the mesangial cells directs glomerular capillary branching through NFAT activation, and consequently COX-2 expression. This is the first evidence that COX-2 inhibition specifically from the mesangial cells impairs renal development, and furthers our understanding of this essential stage of nephrogenesis. Background We recently showed the transcription factor Early B cell factor 1 (EBF1) is essential for the last stages of metanephric development, and that mice globally deficient in EBF1 display impaired maturation of peripheral glomeruli. EBF1 is present within multiple glomerular cell types, including the glomerular mesangium and podocytes. Methods To identify which cell type is driving the glomerular developmental defects in the global EBF1 knockout mice, we deleted EBF1 from the mesangium/pericytes (Foxd1-cre) or podocytes (Podocin-cre) in mice. Results Deletion of EBF1 from Foxd1 lineage cells resulted in hypoplastic kidneys, poorly differentiated peripheral glomeruli, and decreased proximal tubular mass in the outer cortex. Renal insufficiency was apparent at P21 when proteinuria presents, fibrosis of both the glomeruli and interstitium rapidly progresses, microthrombi appear, and hematuria develops. Approximately half of the Foxd1 + , Ebf1 fl/fl mice die before they are 3 months old. Mice with podocyte-targeted deletion of EBF1 exhibited no developmental abnormalities. Mice with Ebf1 deficiency in Foxd1 lineage cells shared characteristics with Ptgs2 /COX-2–insufficient models, and mechanistic investigation revealed impaired calcineurin/NFATc1 activation and decreased COX-2 expression. Deletion of COX-2 from the interstitial/mesangial lineage displayed a less severe phenotype than EBF1 deficiency in mice. Overexpressing COX-2 in the EBF1-deficient mice, however, partially restored glomerular development. Conclusions The results suggest that EBF1 regulates metanephric development at the last stages of glomerular maturation through its actions in the stromal progenitor (Foxd1 + ) lineage where it mediates proper regulation of calcineurin/NFAT signaling and COX-2 expression.
Histological Evidence for Impaired Myocardial Perfusion Reserve in Severe Aortic Stenosis
Authors: Masliza Mahmod, Kenneth Chan, Betty Raman, Joseph Westaby, Sairia Dass, Mario Petrou, Rana Sayeed, Houman Ashrafian, Saul G. Myerson, Theodoros D. Karamitsos, Mary N. Sheppard, Stefan Neubauer
Journal: JACC. Cardiovascular imaging (2019)
Benefits of neoadjuvant chemotherapy in ovarian, primary peritoneal, or fallopian tube carcinoma.
Authors: Alaina J. Brown, Marilyn Huang, Charlotte C. Sun, Tarrik M. Zaid, Nyla Balakrishnan, Hemendra Mhadgut, Karen H. Lu, Shannon Neville Westin, Diane C. Bodurka
Journal: Journal of Clinical Oncology (2013)

5580 Background: NCCN guidelines recommend consideration of neoadjuvant chemotherapy (NACT) for poor surgical candidates with bulky stage III or IV ovarian, fallopian tube, or primary peritoneal cancer. However, new convincing evidence favoring NACT instead of primary tumor reductive surgery (PTRS) has resulted in shifting practices among gynecologic oncologists. This study compares operative and post-operative outcomes between patients receiving NACT and those undergoing PTRS. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Statistical analyses included Wilcoxon Mann-Whitney, Chi square and Fisher’s exact test. Results: Of 163 patients, 109 (67%) received NACT and 54 (33%) underwent PTRS. The majority in both groups was Caucasian (82%) and had ovarian cancer (85%). The median age of all patients was 62 years. There was no difference in median age between groups. High-grade serous histology was most common. In the PTRS group, 72% were stage IIIC. During cytoreductive surgery, NACT cases had significantly shorter total operative and anesthesia time compared to PTRS cases (p = 0.005). NACT patients had significantly less blood loss (p=0.002) than PTRS patients. Based on available data, there was no difference in intraoperative transfusion rate (p = 0.098). However, PTRS cases had a higher rate of postoperative transfusion compared to NACT cases (p = 0.043). There was no difference in the proportion of optimal surgical cytoreduction between groups (p = 0.422). Available data demonstrated that PTRS patients had significantly more complications and intensive care unit (ICU) admissions compared to those receiving NACT (p = 0.024, p = 0.002 respectively). Conclusions: NACT offers advantages regarding operative and anesthesia time, blood loss, postoperative complications, and ICU admissions. NACT may offer a valuable alternative to PTRS. Further studies are warranted to better define the role of NACT in the upfront treatment of advanced ovarian cancer.
Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus
Authors: Erwan Atcheson, Wenqin Li, Carly M. Bliss, Senthil Chinnakannan, Kathrin Heim, Hannah Sharpe, Claire Hutchings, Isabelle Dietrich, Dung Nguyen, Amit Kapoor, Michael A. Jarvis, Paul Klenerman, Eleanor Barnes, Peter Simmonds
Journal: Hepatology (2019)

Background and Aims The lack of immunocompetent small animal models for hepatitis C virus (HCV) has greatly hindered the development of effective vaccines. Using rodent hepacivirus (RHV), a homolog of HCV that shares many characteristics of HCV infection, we report the development and application of an RHV outbred rat model for HCV vaccine development. Approach and Results Simian adenovirus (ChAdOx1) encoding a genetic immune enhancer (truncated shark class II invariant chain) fused to the nonstructural (NS) proteins NS3‐NS5B from RHV (ChAd‐NS) was used to vaccinate Sprague‐Dawley rats, resulting in high levels of cluster of differentiation 8–positive (CD8 + ) T‐cell responses. Following RHV challenge (using 10 or 100 times the minimum infectious dose), 42% of vaccinated rats cleared infection within 6‐8 weeks, while all mock vaccinated controls became infected with high‐level viremia postchallenge. A single, 7‐fold higher dose of ChAd‐NS increased efficacy to 67%. Boosting with ChAd‐NS or with a plasmid encoding the same NS3‐NS5B antigens increased efficacy to 100% and 83%, respectively. A ChAdOx1 vector encoding structural antigens (ChAd‐S) was also constructed. ChAd‐S alone showed no efficacy. Strikingly, when combined with ChAd‐NS, ChAD‐S produced 83% efficacy. Protection was associated with a strong CD8 + interferon gamma–positive recall response against NS4. Next‐generation sequencing of a putative RHV escape mutant in a vaccinated rat identified mutations in both identified immunodominant CD8 + T‐cell epitopes. Conclusions A simian adenovirus vector vaccine strategy is effective at inducing complete protective immunity in the rat RHV model. The RHV Sprague‐Dawley rat challenge model enables comparative testing of vaccine platforms and antigens and identification of correlates of protection and thereby provides a small animal experimental framework to guide the development of an effective vaccine for HCV in humans.
The psychological projective test Wartegg-Zeichentest: A contribution to the knowledge of patient with cancer—The experience of two Italian centers.
Authors: Chiara Maria La Spina, Giordano D. Beretta, Sergio Stinco, Giovanni Luca Ceresoli, Piermario Salvini, Cristina Ripa, Maria Grazia Sauta, Michela Squadroni, Agnese Rossi, Carlo Barone
Journal: Journal of Clinical Oncology (2013)

e20650 Background: There is growing recognition that psychological implications are important in the comprehensive care of cancer patients (pts); the personality conformation may be an useful and constructive tool ground in order to promote psychic adaptation to cancer, improve communication with patient and keep a good level of quality of life. Methods: A personality projective test, the Wartegg-Zeichentest (WZT), was administered to cancer pts at the start of chemotherapy, in two Italian Oncology Departments from February 2010 to August 2012. During treatment, quality of life level with the Edmonton Symptom Assessment Scale (ESAS) and the possible presence of psychological disorder with the Psychological Distress Inventary (PDI) were also evaluated. Each patient followed a psychological support program. Results: Overall, 106 pts were enrolled. 47 (44%) received adjuvant chemotherapy, while palliative treatment was delivered in the remaining 59 (56%) cases. 39 (37%) pts showed ESAS values related to a poor quality of life, and PDI scores showed the presence of moderate-severe psychological disorders in 38 (35%) pts. Considering both test (ESAS e PDI), 24% of subjects had poor quality of life and moderate to severe psychological disorders. In this subgroup, 81% of pts showed a WZT profile characterized by depressive tendencies, liabilities, inhibition and passiveness behaviour. There was a significant correlation between ESAS and WZT (p&lt;0.001), and between PDI and WZT (p&lt;0.001). WZT had a predictive role in disclosing susceptibility to psychological disorders and treatment compliance. Conclusions: Cancer diagnosis affects perception of reality and discloses in some pts a personality profile characterized by depression, demoralization, inhibition and passiveness behaviour. This group of pts may be more keen to develop physic and psychological distress following cancer diagnosis and treatment. Early evaluation by WZT may be a useful instrument in preventing patient distress, as well in promoting the adaptation process to illness and maintaining a better level of quality of life.
The effects of topical antibiotics on eradication and acquisition of third-generation cephalosporin and carbapenem-resistant Gram-negative bacteria in ICU patients; a post hoc analysis from a multicentre cluster-randomized trial
Authors: N.L. Plantinga, B.H.J. Wittekamp, C. Brun-Buisson, M.J.M. Bonten, B.S. Cooper, P. Coll, J. Lopez-Contreras, J. Mancebo, M.P. Wise, M.P.G. Morgan, P. Depuydt, J. Boelens, T. Dugernier, V. Verbelen, P.G. Jorens, W. Verbrugghe, S. Malhotra-Kumar, P. Damas, C. Meex, K. Leleu, A.M. van den Abeele, F. Esteves, A.F.G.P. de Matos, A. Torres, S.F. Méndez, A.V. Gomez, V. Tomic, F. Sifrer, E.V. Tello, J.R. Ramos, I. Aragao, C. Santos, R.H.M. Sperning, P. Coppadoro, G. Nardi
Journal: Clinical Microbiology and Infection (2019)