tbuckley/cabot-search huggingface dataset:
Pericytes in the Premetastatic Niche
Authors: Ana E. Paiva, Luiza Lousado, Daniel A.P. Guerra, Patrick O. Azevedo, Isadora F.G. Sena, Julia P. Andreotti, Gabryella S.P. Santos, Ricardo Gonçalves, Akiva Mintz, Alexander Birbrair
Journal: Cancer Research (2018)

Abstract The premetastatic niche formed by primary tumor–derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779–86. ©2018 AACR.
Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors
Authors: Tinya Abrams, Anu Connor, Christie Fanton, Steven B. Cohen, Thomas Huber, Kathy Miller, E. Erica Hong, Xiaohong Niu, Janine Kline, Marjorie Ison-Dugenny, Sarah Harris, Dana Walker, Klaus Krauser, Francesco Galimi, Zhen Wang, Majid Ghoddusi, Keith Mansfield, Si Tuen Lee-Hoeflich, Jocelyn Holash, Nancy Pryer, William Kluwe, Seth A. Ettenberg, William R. Sellers, Emma Lees, Paul Kwon, Judith A. Abraham, Siew C. Schleyer
Journal: Clinical Cancer Research (2018)

Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti-c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.Experimental Design: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.Results: LOP628 exhibited potent antiproliferative activity on c-KIT-positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system.Conclusions: The preclinical findings suggest that the c-KIT-directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT-positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297-308. ©2018 AACR.
Reliably Quantifying Bone Metastases in Prostate Cancer—Are We Finally There?
Authors: Fred Saad
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 17098: Racial Differences in the Prognostic Value of Exercise Capacity: An Analysis of 52,515 Consecutive Patients From the FIT Project
Authors: Mouaz Al-Mallah, Jonathan Rubin, Steve Keteyian, Mohsin Alam, Waqas Qureshi, John Schairer, Khurram Nasir, Michael J Blaha
Journal: Circulation (2013)

Background:  The purpose of this study was to investigate whether differences exist in the prognostic value of exercise capacity between African-Americans (AA) and Caucasians (CA) in predicting all cause mortality.   METHODS:  We included 52,515 AA and CA patients without known coronary disease or heart failure who completed a routine clinical exercise test with or without imaging for diagnostic or screening purposes in a clinical non-invasive laboratory between 1991 and 2009. Patients were followed for a mean duration of 11.5 years for all-cause mortality ascertained by a search of social security death index in 4/2013. Cox proportional hazards regression models were used adjusting for age, gender, weight, smoking, history of HTN, DM, HLD, obesity, family history of CV disease, use of aspirin, anti hypertensives, lipid lowering and diabetes medications, reason referred for a stress test and beta blocker use.   RESULTS:  AA patients (n=16,516) were younger (54 vs. 52 years, p   CONCLUSIONS:  Exercise capacity is a strong predictor of all-cause mortality in both AA and CA; however, a significant interaction exists. Using data from the FIT project, African American patients appear to obtain a greater survival benefit from increasing exercise capacity.
Treatment strategy for metastatic colorectal cancer (mCRC) treated with chemotherapy plus biological targeted agent: Is strategy with biological targeted agent based on the primary tumor lesion possible?
Authors: Tamotsu Sagawa, Kyoko Hamaguchi, Naomi Uemura, Fumito Tamura, Koshi Fujikawa, Yasushi Sato, Yasuo Takahashi
Journal: Journal of Clinical Oncology (2018)

769 Background: The data from randomized trials suggested that primary tumor location (PTL) could represent a prognostic and predictive factor in mCRC patients, particularly during treatment with anti- EGFR therapy. However, it remains unclear whether anti-EGFR is effective for right- sided primary tumors (RT). Methods: Single-institution, retrospective, case-control study was reviewed. A total of 110 patients with mCRC were enrolled between January 2011 and December 2016. We evaluated the association between PTL and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy (FOLFOX/CapeOX or FOLFIRI/IRIS) plus cetuximab(Cmab) or bevacizumab(Bmab). The impact of PTL for Cmab and Bmab groups was analyzed, respectively. Results: 76 patients presented Left-sided primary tumors (LT) and 34 patients RT. Median PFS, median OS, and ORR were numerically superior in our study patients with LT compared with patients with RT (PFS, L vs R, 13.0 vs 6.8 M, p = 0.0040; OS, 36.2 vs 19.0 M, p = 0.002; ORR, 67.1 vs 44.1 %, p = 0.022951). In the Cmab group, LT were significantly superior to RT in terms of OS (L vs R, 56.3 vs11.3 M, p = 0.0057). Likewise, in the Bmab group, OS showed differences between the LT and RT (L vs R, 27.8 vs 19.7 M, p = 0.0116). In LT, Cmab group were significantly superior to Bmab group in terms of the OS (C vs B, 56.3 vs 27.8 M p = 0.0428). Conversely, in RT, the survival times showed no differences between Cmab and Bmab group (C vs B, 11.3 vs 19.7 M, p = 0.6555). Furthermore, while early tumor shrinkage(ETS) was associated with favorable outcome in patients with RT who treated Cmab, non-ETS represented a less favorable survival (ETS vs non-ETS, NR vs 11.3 M, p = 0.0335). ETS was a predictor for survival benefit acquired from Cmab treatment for patients with RT with wild-type KRAS/RAS tumors. Conclusions: Our study suggests the conclusion that patients with LT with KRAS/RAS wild-type should be preferentially treated with Cmab. By contrast, in RT, chemotherapy plus Bmab may be effective, but optimal treatment has yet to be defined and ETS may be able to predictive of benefit acquired from Cmab.
Diagnosis of melanoma: Importance of comparative analysis and “ugly duckling” sign.
Authors: Jean Jacques Grob, Yanal Wazaefi, Yvane Bruneu, Caroline Gaudy-Marqueste, Sandrine Monestier, Luc Thomas, Marie-Françoise Avril, Raoul Triller, Giovanni Pellacani, Joseph Malvehy, Bernard Fertil
Journal: Journal of Clinical Oncology (2012)

8578 Background: “Ugly duckling” (UD) sign is widely admitted as a major sign for melanoma (MM) detection. UD is based on the concept of intra-individual comparative analysis, which has never been validated. It is assumed that, in a given individual, variability of nevi is limited and represented by a few similarity clusters (SC) grouping all nevi sharing the same pattern, and that a nevus is suspicious when it does not fit with the SCs of this individual (UD). Objective: To validate the concept of UD and SC. Methods: 9 international experts (dermatologists) and 9 novices (untrained individuals) were blindly tested, using digital images of the nevi at clinical and dermoscospic scale successively in 80 patients, (2,089 nevi and 7 MM). Concordance was assessed by kappa statistics for UDs, and B-cubed metrics for SCs. Results: At clinical scale, experts had a better concordance for UDs (kappa= 0.53, [0.33 - 0.87]) and SCs (B-cubed = 0.65, [0.55, 0.73]), than novices (0.31, [0.03, 0.51] and 0.56 [0.49, 0.64], respectively). Experts identified a mean number of 1 UD and 2.7 SCs per patient, and agreed on consensual UD and SCs, whatever their natural propensity to see a high or a low number of UDs and SCs: among the 254 nevi considered as UDs by at least 1 expert, 54 were considered as such by at least 5, and from them, 20 by all 9 experts. The 20 consensual UDs included all the MMs (7/7) (sensitivity for MM: 100%). At dermoscopic scale, concordance tended to be lower for SCs than at clinical scale. Conclusions: We demonstrated the limited variability of nevi patterns in each patient, the consistency in the recognition of UD, and its clinical relevance, supporting evidence that it is useful for experts and to a lesser degree to general population to spot the skin lesions with the highest probability of being MM.
Clinical Implications of Slower Cognitive Growth in the Psychosis Spectrum—Reply
Authors: Josephine Mollon, Stanley Zammit, Abraham Reichenberg
Journal: JAMA Psychiatry (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Abstract IA12: Intra- and intertumoral heterogeneity and response to therapy in mouse models of SCLC
Authors: Jing Shan Lim, Dian Yang, Yan Ting Shue, Monte Winslow, Julien Sage
Journal: Cancer Research (2018)

Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma that accounts for ~15% of all lung cancers and causes over 200,000 deaths worldwide each year. The majority of SCLC patients have metastatic disease at the time of diagnosis; for these patients, the median survival, even with treatment, is 7-12 months, and the 5-year overall survival is &amp;lt;1%. SCLC is managed with first-line chemotherapy–often cisplatin or carboplatin with etoposide. However, the majority of SCLC patients suffer relapse within months of completing initial therapy due to the persistence of a subpopulation of chemotherapy-resistant cells. Treatment options for SCLC have remained virtually unchanged for the past 30 years, and there are no approved targeted therapies in SCLC. To dissect the molecular changes that regulate SCLC progression, it is critical to analyze purified SCLC cells from tumors at known stages of tumorigenesis. This has not been possible previously using either mouse models or human specimens due to the 1) limited access to lung cancers at defined stages of malignant progression, 2) inability to unambiguously isolate SCLC cells away from stromal cells, and 3) difficulty in performing genome-wide analyses on the few cells that can be isolated from metastases in mouse models or patient biopsies. To overcome these obstacles, we have developed mouse models of SCLC including Cre/lox-mediated deletion of key tumor suppressors (p53, Rb, and the Rb family member p130) as well as activation of fluorescent reporters. This triple-knockout (TKO) model recapitulates the genetics, histology, and metastatic ability of human SCLC. Using this mouse model, we have recently identified new levels of intratumoral heterogeneity in SCLC tumors, including the presence of tumor-propagating cells (TPCs) as well as Notch-active non-neuroendocrine tumor cell population that promotes the growth of TPCs in a non-cell autonomous but tumor-intrinsic manner. Using TKO mice, we have also uncovered distinct mechanisms of intertumoral heterogeneity during tumor progression; in particular, we have shown that one group of tumors gains metastatic potential by upregulation of the Nfib transcription factor and extensive changes in their chromatin state, while others become metastatic in absence of Nfib-driven chromatin dynamics. These observations will be discussed in the context of how SCLC tumors respond to chemotherapy and candidate targeted therapies. Citation Format: Jing Shan Lim, Dian Yang, Yan Ting Shue, Monte Winslow, Julien Sage. Intra- and intertumoral heterogeneity and response to therapy in mouse models of SCLC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA12.
A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases
Authors: Gemma Bullich, Andrea Domingo-Gallego, Iván Vargas, Patricia Ruiz, Laura Lorente-Grandoso, Mónica Furlano, Gloria Fraga, Álvaro Madrid, Gema Ariceta, Mar Borregán, Juan Alberto Piñero-Fernández, Lidia Rodríguez-Peña, Maria Juliana Ballesta-Martínez, Isabel Llano-Rivas, Mireia Aguirre Meñica, José Ballarín, David Torrents, Roser Torra, Elisabet Ars
Journal: Kidney International (2018)
Diagnosis and Management of the Antiphospholipid Syndrome
Authors: David Garcia, Doruk Erkan
Journal: New England Journal of Medicine (2018)

Antiphospholipid antibodies can induce endothelial-cell, complement, platelet, neutrophil, and monocyte activation, leading to thrombosis, renal failure, heart valve disease, pregnancy loss, and neurologic complications. Warfarin is the main treatment option.
Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey
Authors: Simon R Harris, Michelle J Cole, Gianfranco Spiteri, Leonor Sánchez-Busó, Daniel Golparian, Susanne Jacobsson, Richard Goater, Khalil Abudahab, Corin A Yeats, Beatrice Bercot, Maria José Borrego, Brendan Crowley, Paola Stefanelli, Francesco Tripodo, Raquel Abad, David M Aanensen, Magnus Unemo, Jacinta Azevedo, Eszter Balla, Christopher Barbara, Thea Bergheim, Maria José Borrego, Viviane Bremer, Susanne Buder, Panayiota Maikanti-Charalambous, Stephanie Chisholm, Susan Cowan, Brendan Crowley, Tania Crucitti, Mercedes Diez, Mária Dudás, Kirstine Eastick, Agathe Goubard, Maria Haller, Guôrún Svanborg Hauksdóttir, Steen Hoffmann, Gwenda Hughes, Derval Igoe, Samo Jeverica, Irena Klavs, Hilde Kløvstad, Peter Kohl, Vasileia Konte, Ineke Linde, Violeta Mavcutko, Jackie Maistre Melillo, Gatis Pakarna, Peter Pavlik, Despo Pieridou, Guy La Ruche, Guôrún Sigmundsdóttir, Soteroulla Soteriou, Angelika Stary, Paola Stefanelli, Barbara Suligoi, Peter Truska, Eva Tzelepi, Magnus Unemo, Birgit Van Benthem, Alje Van Dam, Julio Vazquez, Inga Velicko, Ruth Verbrugge
Journal: The Lancet Infectious Diseases (2018)

Traditional methods for molecular epidemiology of Neisseria gonorrhoeae are suboptimal. Whole-genome sequencing (WGS) offers ideal resolution to describe population dynamics and to predict and infer transmission of antimicrobial resistance, and can enhance infection control through linkage with epidemiological data. We used WGS, in conjunction with linked epidemiological and phenotypic data, to describe the gonococcal population in 20 European countries. We aimed to detail changes in phenotypic antimicrobial resistance levels (and the reasons for these changes) and strain distribution (with a focus on antimicrobial resistance strains in risk groups), and to predict antimicrobial resistance from WGS data.
Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Padmanee Sharma, Luc Dirix, Filip Yves Francine Leon De Vos, James Patrick Allison, Lore Decoster, Renata Zaucha, Joon Oh Park, Ari M. Vanderwalde, Ritesh S. Kataria, Salvatore Ferro, Gargi Patel, Yong (Ben) Ben, Do-Youn Oh
Journal: Journal of Clinical Oncology (2018)

470 Background: Clinical activity and tolerability of the anti-CTLA-4 antibody, tremelimumab, has yet to be established in metastatic pancreatic ductal adenocarcinoma (mPDAC). In a Phase 2, multicenter, open label study (NCT02527434), tremelimumab was evaluated in pts with advanced solid tumors. We report a planned analysis of the safety and efficacy of tremelimumab monotherapy in a cohort of pts with mPDAC. Methods: Eligible pts were adults with histologically or cytologically confirmed mPDAC with tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Pts received tremelimumab 750 mg IV Q4W for 7 doses, followed by 750 mg Q12W for 2 doses, for up to a total of 12 mo (total 9 doses in 12 mo) or until disease progression or unacceptable toxicity. Pts were radiographically assessed Q6 wks relative to first dose. The primary endpoints were safety (evaluated by CTCAE v4.0) and objective response rate (ORR) by investigator assessments (evaluated by RECIST v1.1). Results: As of April 5, 2017, 20 mPDAC pts had received treatment and were evaluable for efficacy analysis. Median treatment duration was 1.8 mo. There were no observed objective responses (ORR 0%; 95% CI, 0.0, 16.8%). Of 20 pts, 2 were not evaluable and 18 had progressive disease (PD). Based on the full analysis set (N = 20), progression occurred in target lesions in 14 (70%), non-target lesions in 7 (35%), and new lesions in 13 (65%) pts (not mutually exclusive categories). At the time of progression, 11 (61%) pts were on treatment and 7 (39%) had discontinued treatment. Median overall survival was 4 mo (95% CI 2.83 - 5.42). Two (10%) pts were still in follow up at 12 mo after treatment initiation. Treatment-related AEs (trAEs) occurred in 14 pts (70%); grade ≥3 trAEs occurred in 6 pts (30%). Three pts (15%) discontinued therapy due to trAEs. There were no treatment-related deaths. Conclusions: Tremelimumab monotherapy did not appear to be active in mPDAC pts who had tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Clinical trial information: NCT02527434.
Derepression of co-silenced tumor suppressor genes by nanoparticle-loaded circular ssDNA reduces tumor malignancy
Authors: Jing Meng, Shuang Chen, Jing-xia Han, Qiang Tan, Xiao-rui Wang, Hong-zhi Wang, Wei-long Zhong, Yuan Qin, Kai-liang Qiao, Chao Zhang, Wan-feng Gao, Yue-yang Lei, Hui-juan Liu, Yan-rong Liu, Hong-gang Zhou, Tao Sun, Cheng Yang
Journal: Science Translational Medicine (2018)

Circular ssDNA can sequester inhibitory microRNAs to restore tumor suppressor gene function, thereby inhibiting tumor progression.
MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset
Authors: Götz Thomalla, Claus Z. Simonsen, Florent Boutitie, Grethe Andersen, Yves Berthezene, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Franz Fazekas, Jens Fiehler, Ian Ford, Ivana Galinovic, Susanne Gellissen, Amir Golsari, Johannes Gregori, Matthias Günther, Jorge Guibernau, Karl Georg Häusler, Michael Hennerici, André Kemmling, Jacob Marstrand, Boris Modrau, Lars Neeb, Natalia Perez de la Ossa, Josep Puig, Peter Ringleb, Pascal Roy, Enno Scheel, Wouter Schonewille, Joaquin Serena, Stefan Sunaert, Kersten Villringer, Anke Wouters, Vincent Thijs, Martin Ebinger, Matthias Endres, Jochen B. Fiebach, Robin Lemmens, Keith W. Muir, Norbert Nighoghossian, Salvador Pedraza, Christian Gerloff
Journal: New England Journal of Medicine (2018)

Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.