tbuckley/cabot-search huggingface dataset:
CrosstalkNet: A Visualization Tool for Differential Co-expression Networks and Communities
Authors: Venkata Manem, George Alexandru Adam, Tina Gruosso, Mathieu Gigoux, Nicholas Bertos, Morag Park, Benjamin Haibe-Kains
Journal: Cancer Research (2018)

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene-expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and to obtain insights into the biological processes that govern cross-talk between different tumor compartments.Significance: This web application enables researchers to mine complex networks and to decipher novel biological processes in tumor epithelial-stroma cross-talk as well as in other studies of intercompartmental interactions. Cancer Res; 78(8); 2140-3. ©2018 AACR.
A New Left Ventricular Assist Device — Better, but Still Not Ideal
Authors: Mark H. Drazner
Journal: New England Journal of Medicine (2018)

The development of continuous-flow left ventricular assist devices (LVADs), specifically the HeartMate II1 and the HeartWare HVAD,2 was a major advance in the treatment of advanced heart failure. However, complications of continuous-flow LVADs, some of which are thought to be a consequence of their effect in reducing arterial pulsatility, occur far too commonly. More than 60% of patients who receive a continuous-flow LVAD have bleeding, infection, device malfunction, stroke, or death within the first year.3 The HeartMate 3 is a new LVAD that was approved by the Food and Drug Administration for clinical use in August 2017. Its new design . . .
Sequencing of Tumor DNA to Guide Cancer Risk Assessment and Therapy
Authors: David H. Spencer, Timothy J. Ley
Journal: JAMA (2018)

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Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status.
Authors: Julien Taieb, Hampig Raphael Kourie, Jean-François Emile, Karine Le Malicot, Ralyath Balogoun, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Claire Mulot, Olivier Bouche, Thomas Aparicio, Pierre Michel, Josef Thaler, John A. Bridgewater, Eric Van Cutsem, Géraldine Perkins, Ramon Salazar, Come Lepage, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2017)

3515 Background: Recent data suggest that the anatomic site of colon primary tumor may be an important factor in the interpretation of molecular markers with clinical outcome in metastatic colon cancer (CC) patients (pts). We assessed here the prognostic value of primary location in fully resected stage III CC pts and its relationship to MSI, RAS and BRAF mutational status. Methods: Pts enrolled in the PETACC-8 trial were analyzed. We categorized tumor site as located proximal (left-sided) or distal (right-sided) to the splenic flexure. The association between tumor location and disease free survival (DFS), survival after relapse (SAR) and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, MSI, BRAF and RASmutation status. The outcome of pts receiving FOLFOX or FOLFOX and cetuximab in the adjuvant setting were also determined according to tumor site. Results: Among the 1869 pts with full molecular data available, 755 (40%) had a right-sided tumor, 164 (10%) were MSI, 942 (50%) were mutated for RAS and 212 (11%) were mutated for BRAF. Right-sided tumor was not prognostic for DFS in the whole population but was associated to a shorter SAR (HR: 1.54 [1.23 - 1.93], p = 0.001) and OS (HR: 1.25 [1.02 - 1.54], p = 0.03). Same results were observed for MSS and for MSI pts. However, when looking at pts mutated for RAS or BRAF(MUT) and those double wild type (DWT) for those mutations, we found that right-sided tumors, when compared to left-sided tumors, was associated with a worst DFS in DWT patients (HR:1.39[1.01-1.92], p = 0.04) and a better DFS in MUT patients (HR:0.77[0.63-0.95], p = 0.01). These results were found independently of the treatment received and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions: In the whole study population of stage III CC pts, though right-sided tumor location influences OS as previously reported, it does not seem to influence DFS but only SAR, when disease becomes metastatic. Interestingly, sidedness seems to influence DFS when splitting the population in MUT or DWT for RAS and BRAF, with a worst DFS for right-sided tumors in DWT and a worst DFS for left-sided tumors in RAS or BRAF mutants. Clinical trial information: 2005-003463-23.
Intravenous versus subcutaneous immunoglobulin – Authors' reply
Authors: Ivo N van Schaik, Orell Mielke, Arman Sabet, Koshy George, Leslie Roberts, Ross Carne, Stefan Blum, Robert Henderson, Philip Van Damme, Jelle Demeestere, Sandrine Larue, Catherine-Andree Pinard D'Amour, Vera Bril, Ari Breiner, Pavel Kunc, Martin Valis, Jana Sussova, Tomas Kalous, Radomir Talab, Michal Bednar, Toomas Toomsoo, Inna Rubanovits, Katrin Gross-Paju, Ulvi Sorro, Mika Saarela, Mari Auranen, Jean Pouget, Shahram Attarian, Gwendal Le Masson, Anne-Cécile Wielanek-Bachelet, Claude Desnuelle, Emilien Delmont, Pierre Clavelou, Dominique Aufauvre, Jens Schmidt, Jana Zschuentssch, Claudia Sommer, Daniela Kramer, Olaf Hoffmann, Carsten Goerlitz, Judith Haas, Marko Chatzopoulos, Min-Suk Yoon, Ralf Gold, Peter Berlit, Andrea Jaspert-Grehl, David Liebetanz, Anna Kutschenko, Martin Stangel, Corinna Trebst, Petra Baum, Florian Then Bergh, Juliane Klehmet, Andreas Meisel, Fabian Klostermann, Johanna Oechtering, Helmar Lehmann, Michael Schroeter, Tim Hagenacker, Daniel Mueller, Anne-Dorte Sperfeld, Florian Bethke, Hans-Peter Hartung, Vivian Drory, Avi Algom, David Yarnitsky, Beth Brianna Murinson, Antonio Di Muzio, Fausta Ciccocioppo, Sandro Sorbi, Sabrina Mata, Angelo Schenone, Marina Grandis, Giuseppe Lauria, Daniele Cazzato, Giovanni Antonini, Stefania Morino, Dario Cocito, Maurizio Zibetti, Takanori Yokota, Takuya Ohkubo, Takashi Kanda, Motoharu Kawai, Kenichi Kaida, Hiroyuki Onoue, Satoshi Kuwabara, Masahiro Mori, Masahiro Iijima, Ken Ohyama, Gen Sobue, Masayuki Baba, Masahiko Tomiyama, Kazutoshi Nishiyama, Tsugio Akutsu, Kazumasa Yokoyama, Kazuaki Kanai, Ivo N. van Schaik, Filip Eftimov, Nicolette. C. Notermans, Nora. A. Visser, Catharina Faber, Janneke. G.J. Hoeijmakers, Ingemar S.J. Merkies, Nan van Geloven, Konrad Rejdak, Urszula Chyrchel-Paszkiewicz, Carlos Casanovas Pons, María Antonia Alberti Aguiló, Josep Gamez, María Figueras, Celedonio Marquez Infante, Sonia Benitez Rivero, Michael Lunn, Jasper Morrow, David Gosal, Timothy Myles Lavin, Isaac Melamed, Alessandro Testori, Senda Ajroud-Driss, Daniela Menichella, Ericka Simpson, Eugene Chi-Ho Lai, Mazen Dimachkie, Richard J. Barohn, Said Beydoun, Harpreet Johl, Dale Lange, Alexander Shtilbans, Suraj Muley, Shafeeq Ladha, Miriam Freimer, John Kissel, Norman Latov, Russell Chin, Eroboghene Ubogu, Sandi Mumfrey, T. Hermanth P. Rao, Paul MacDonald, Khema Sharma, Ginna Gonzalez, Jeffrey Allen, David Walk, Lisa Hobson-Webb, Karissa Gable, Richard A. Lewis, David R. Cornblath, John-Phillip Lawo, Michaela Praus, Billie L. Durn, Orell Mielke
Journal: The Lancet Neurology (2018)
Abstract 14391: Influence of Coronary Plaque Morphologies by Intravascular Ultrasound and Optical Coherence Tomography on the Occurrence of Periprocedural Myocardial Infarction in Patients With Stable Angina Pectoris
Authors: Shigeki Kimura, Hirofumi Otani, Keiichi Hishikari, Tomoyo Sugiyama, Hiroyuki Hikita, Atsushi Takahashi, Mitsuaki Isobe
Journal: Circulation (2013)

Background:  Periprocedural myocardial infarction (PMI) is an important and not uncommon complication observed after percutaneous coronary intervention (PCI) in patients with coronary artery disease. Prediction of PMI before PCI is important. We sought to investigate the predictors of PMI in patients with stable angina pectoris (SAP) by using intravascular imaging modalities.   Methods:  We investigated 128 consecutive SAP lesions which underwent pre-PCI intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The occurrence of PMI was defined by elevation of cardiac troponin T (cTnT) level at 24h after PCI ≥5 times the upper limit of normal range in patients with normal baseline values (cTnT    Results:  PMI was observed in 56 (43.8%) lesions. Lesions with PMI had higher frequencies of OCT-derived thin-cap fibroatheroma (TCFA) (fibrous-cap thickness  180°) (30.4% vs. 6.9%, p 2 ) (55.4% vs. 37.5%, p=0.04), and lesion at right coronary artery (42.9% vs. 20.8%, p=0.007), and longer stent length (24.2±7.2 vs. 21.4±7.5mm, p=0.03) and larger plaque burden (82.5±5.5 % vs. 78.8±9.9%, p=0.009). Multivariate analysis revealed that OCT-TCFA (odds ratio (OR): 4.48, 95% CI: 1.40-14.32, p=0.01), attenuated plaque on IVUS (OR: 7.32, 95% CI: 2.36-22.69, p   Conclusion:  Assessment of plaque morphologies by pre-PCI IVUS and OCT may be useful in the prediction of periprocedural myocardial infarction in SAP patients.
A multicenter phase ib-IIR trial assessing activity of regorafenib in combination with modified gemcitabine-oxaliplatin (mGEMOX) in patients with advanced biliary tract cancer (aBTC).
Authors: Eric Assenat, Fabienne Portales, Marc Ychou
Journal: Journal of Clinical Oncology (2018)

427 Background: News therapeutic options are needed in aBTC systemic treatment. Regorafenib (a multi target tyrosine kinase inhibitor) showed efficacy in several digestive tumors and could be associated with conventional chemotherapy in BTC. The Phase Ib primary objective was to determine the recommended Regorafenib dose combined with mGEMOX. The randomized phase II will assess efficacy of the combination compared to mGEMOX alone. We present here the results of the analysis planned at the end of phase Ib. Methods: Three dose levels (80, 120 and 160mg) of Regorafenib combined with mGEMOX, 3 to 6 patients each, were planned, and up to 12 patients to confirm the recommended dose-level. Patients received Regorafenib from day 1 to 14, and mGEMOX on days 1 and 8 (IV Gemcitabine 900mg/m2 followed with Oxaliplatin 80mg/m2 IV). Results: From 10.2014 to 11.2016, 22 patients were included in two French centers: 6, 3 and 13 patients in levels 1, 2 and 3, respectively. 2 patients (level 3) were not evaluable for recommended dose identification or tolerance and excluded from analysis. Patients were 70% men, of median age 62.5 years (20-74), ECOG PS 0 (60%) or 1 (40%). Primary tumor was localized within (60%) or outside (30%) the liver, or in the gall-bladder (10%). Eight (30%) patients underwent surgery. The Regorafenib relative dose-intensity was 101.8 [89.3-107.1], 100 [96.4-100] and 100% [51.8-103.6] for dose levels 1, 2 and 3, respectively. Regorafenib dose modifications during treatment occurred for 0 (level 1), 0 (level 2), and 3 patients (27%) (level 3). Toxicities were (level 1, 2, 3): grade 3 diarrhea (1, 0, 0), grade 3 asthenia (0, 0, 1), grade 2 hand-foot syndrome (1, 0, 0), grade 3 hypertension (2, 1, 2), grade 3/4 neutropenia (1/0, 1/0, 0/2), grade 3 thrombopenia (1, 0, 1), grade 3 anemia (0, 0, 1). Four DLTs were reported: 1 in level 1 (grade 3 diarrhea) and 3 in level 3 (2 grade 4 neutropenia, 1 grade 3 anemia). Conclusions: Regorafenib shows acceptable toxicity combined with mGEMOX; the DLTs reported were mainly related to conventional chemotherapy. Dose level 3, 160mg/day Regorafenib will be used in ongoing phase IIR assessing efficacy of this combination. Clinical trial information: NCT02386397.
The peopling of the last Green Sahara revealed by high-coverage resequencing of trans-Saharan patrilineages
Authors: Eugenia D’Atanasio, Beniamino Trombetta, Maria Bonito, Andrea Finocchio, Genny Di Vito, Mara Seghizzi, Rita Romano, Gianluca Russo, Giacomo Maria Paganotti, Elizabeth Watson, Alfredo Coppa, Paolo Anagnostou, Jean-Michel Dugoujon, Pedro Moral, Daniele Sellitto, Andrea Novelletto, Fulvio Cruciani
Journal: Genome biology (2018)

Little is known about the peopling of the Sahara during the Holocene climatic optimum, when the desert was replaced by a fertile environment. In order to investigate the role of the last Green Sahara in the peopling of Africa, we deep-sequence the whole non-repetitive portion of the Y chromosome in 104 males selected as representative of haplogroups which are currently found to the north and to the south of the Sahara. We identify 5,966 mutations, from which we extract 142 informative markers then genotyped in about 8,000 subjects from 145 African, Eurasian and African American populations. We find that the coalescence age of the trans-Saharan haplogroups dates back to the last Green Sahara, while most northern African or sub-Saharan clades expanded locally in the subsequent arid phase. Our findings suggest that the Green Sahara promoted human movements and demographic expansions, possibly linked to the adoption of pastoralism. Comparing our results with previously reported genome-wide data, we also find evidence for a sex-biased sub-Saharan contribution to northern Africans, suggesting that historical events such as the trans-Saharan slave trade mainly contributed to the mtDNA and autosomal gene pool, whereas the northern African paternal gene pool was mainly shaped by more ancient events.
Abstract P286: C-Reactive Protein, Inflammation, and Incident Venous Thrombosis: Reasons for Geographic and Racial Differences in Stroke (REGARDS)
Authors: Nels C Olson, Mary Cushman, Leslie A McClure, Suzanne E Judd, Pamela L Lutsey, Russell P Tracy, Aaron R Folsom, Neil A Zakai
Journal: Circulation (2013)

Background:  Inflammation is associated with increased risk of atherothrombosis. While C-reactive protein (CRP), a widely used biomarker of inflammation, is higher in the presence of several risk factors for venous thromboembolism (VTE), the role of CRP in predicting risk of VTE remains controversial. We examined the associations of circulating CRP and other biomarkers of inflammation with incident VTE in a large multi-ethnic population.   Methods:  REGARDS recruited 30,239 participants in their homes across the continental US between 2003-07; by design 55% were female, 41% black, and 56% lived in the southeast. CRP, white blood cell count (WBC), platelet count, and serum albumin were measured in baseline samples of REGARDS. CRP was log-transformed to normalize the distribution; back transformed means are presented. Cox models were used to calculate the association of biomarkers with VTE accounting for VTE risk factors; albumin was modeled per SD lower value.   Results:  There were 268 incident VTE events over 4.6 years of follow-up. Mean CRP was higher, and platelet count and albumin lower, in those with incident VTE compared to those without incident VTE (CRP: 2.8 vs. 2.2 mg/l; platelet count: 238 vs. 225 x10 9  cells/l; and albumin; 4.1 vs. 4.2 g/dl) (all p-values    Conclusion:  Higher CRP and lower albumin are associated with increased risk for VTE, while white cell count and platelet count were not.These data may reflect inherent differences in the biology related to inflammation and VTE, and suggest that CRP and albumin may be risk factors for VTE.
Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody–Drug Conjugates
Authors: Hui Zhao, John Atkinson, Sara Gulesserian, Zhilan Zeng, Jenny Nater, Jimmy Ou, Peng Yang, Karen Morrison, Jeffrey Coleman, Faisal Malik, Pia Challita-Eid, Sher Karki, Hector Aviña, René Hubert, Linnette Capo, Josh Snyder, Sung-Ju Moon, Roland Luethy, Brian A. Mendelsohn, David R. Stover, Fernando Doñate
Journal: Cancer Research (2018)

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. Cancer Res; 78(8); 2115-26. ©2018 AACR.
The pan-cancer, pan-biomarker landscape for precision immuno-oncology.
Authors: Howard L. McLeod, Anders E. Berglund, Jiqiang Yao, Melissa Avedon, Jamie K. Teer
Journal: Journal of Clinical Oncology (2017)

43 Background: Precision medicine has the opportunity to also change medical practice. However, there are many cancer treatments for which there are few tools for individualized selection based on patient-specific attributes. This is especially the case for the immune check point inhibitors, where a subset of patients receive almost unimaginable benefit, there is a significant incidence of severe, life threatening, and persistent autoimmune oriented toxicities, and the financial burden is real for patients. At least 3 distinct predictive immunooncology biomarkers (IOMark) have been proposed. This includes tumor mutation analysis, expression of PD-L1, and tumor-specific t cell subset (Weber Predictor). However, there is little data on the intrapatient relationship of these putative response markers. Methods: Analysis of individual patient IOMark status was determined in TCGA patients that had cancers for which immunotherapy is FDA approved (n = 2039; bladder, colorectal, kidney, lung, melanoma, stomach). Patients were categorized as putative high/low predicted responders for each biomarker [neoantigen burden (whole exome cutpoint = 225), PD-L1 (median), Weber predictor (upper 50% for each of CD8/Ki67/EOMES)]. Results: A high neoantigen burden was detected in 1%-60% of the tumors (median 31%; range kidney to melanoma). There was less variance for high PD-L1 (26%-78%, median 49%; colorectal to lung). The Weber predictor ranged from 2% to 41% (kidney to stomach). A subset of each cancer type were positive for each of the response markers (0% to 12%; median 6%; renal to stomach). There is not a high association between the IOMarks. Conclusions: Immuno-oncology is in need of robust IOMark, to allow more informed patient treatment. Analysis of the currently most promising IOMarks show high variation across tumor types and within tumor types. Only a subset of patients has high response predicted for all 3 IOMarks. The IOMarks are independent and identify distinct patient features.
A Case of Preventable Vision Loss
Authors: Meghan Smith, Elizabeth Hendren, Ophir Vinik
Journal: JAMA Internal Medicine (2018)

This Teachable Moment reports the case of a woman with jaw pain, bitemporal headaches, and scalp tenderness who developed acute right eye partial vision loss, an inferior visual field defect, and a hyperemic optic disc, consistent with ischemic optic neuropathy.
Meta-analysis of airway epithelium gene expression in asthma
Authors: Yi-Hsuan Tsai, Joel S. Parker, Ivana V. Yang, Samir N.P. Kelada
Journal: European Respiratory Journal (2018)

Differential gene expression in the airway epithelium of patients with asthma versus controls has been reported in several studies. However, there is no consensus on which genes are reproducibly affected in asthma. We sought to identify a consensus list of differentially expressed genes (DEGs) using a meta-analysis approach.We identified eight studies with data that met defined inclusion criteria. These studies comprised 355 cases and 193 controls and involved sampling either bronchial or nasal epithelium. We conducted study-level analyses, followed by a meta-analysis. Likewise, we applied a meta-analysis framework to the results of study-level pathway enrichment.We identified 1273 DEGs, 431 of which had not been identified in previous studies. 450 DEGs exhibited large effect sizes and were robust to study population differences in age, sex, race/ethnicity, medication use, smoking status and exacerbations. The magnitude of differential expression of these 450 genes was highly similar in bronchial and nasal airway epithelia. Meta-analysis of pathway enrichment revealed a number of consistently dysregulated biological pathways, including putative transcriptional and post-transcriptional regulators.In total, we identified a set of genes that is consistently dysregulated in asthma, that links to known and novel biological pathways, and that will inform asthma subtype identification.