tbuckley/cabot-search huggingface dataset:
Abstract 1115: BET bromodomain inhibition synergizes with MEK inhibitors in uveal melanoma
Authors: Grazia Ambrosini, Elgilda Musi, Gary K. Schwartz
Journal: Cancer Research (2021)

Abstract Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Approximately 50% of the patients develop hepatic metastasis and the median survival rate is 12 months. Currently available drugs have shown limited clinical activity in patients with UM and there is an urgent need for new effective therapies. UM is characterized by activating mutations of G protein q/11, mutations in BAP1, and amplification of the oncogene MYC. Epigenetic dysregulation plays a critical role in UM pathogenesis, and we have demonstrated that Gnaq/11 mutant UM cells are addicted to BRD4 activity. BRD4 is a key regulator of transcriptional elongation by recruiting positive transcriptional elongation factor complex (PTEFb) to chromatin and activating RNA polymerase II-dependent transcription. While BET inhibitors have shown potent activity in pre-clinical studies, single-agent BET inhibitors exhibited limited efficacy in advanced UM clinical trials. MAPK signaling in constitutively active in Gnaq/11 mutant UM cells and previous studies have shown that the MAPK pathway mediates resistance to BET inhibition. Therefore, we sought to combine MEK and BET inhibitors in a panel of UM cells. We found synergistic activities with a variety of structurally distinct MEK inhibitors including trametinib and binimetinib in combination with BET inhibitors, such as I-BET and PLX2853. These combinations induced a greater reduction in cell viability and significant apoptosis compared to either monotherapy, in both parental and BET inhibitor-resistant cells. Western blot studies were performed to evaluate the mechanism of the combination treatment with BET and MEK inhibition and demonstrated a marked downregulation of p-ERK, MYC, Bcl-xL and upregulation of BIM with the combination therapy. Similarly, the combination treatment resulted in greater inhibition of tumor growth compared to either BET or MEK inhibition alone in a Gnaq mutant xenograft model. In conclusion, our studies suggest that co-targeting of MEK and BET proteins may be required to maximize the responses of UM cells to BET inhibitors. Clinical trials with the combination of BET and MEK inhibitors are warranted. Citation Format: Grazia Ambrosini, Elgilda Musi, Gary K. Schwartz. BET bromodomain inhibition synergizes with MEK inhibitors in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1115.
Abstract 36: ARAF mutations confer resistance to RAF dimer inhibitors in NRAS and BRAF mutant melanoma
Authors: Shiva Malek
Journal: Cancer Research (2021)

Abstract Belvarafenib, a potent and selective RAF dimer inhibitor, exhibits clinical activity in BRAFV600E and NRAS mutant melanoma patients. Here, through generation of belvarafenib resistant NRAS mutant melanoma cells and through analysis of circulating tumor DNA from patients treated with belvarafenib, we identified novel recurrent mutations in ARAF, within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer and kinase activity dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of RAF dimer inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF driven resistance and suggests a rational combination for clinical use. Taken together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors. Citation Format: Shiva Malek. ARAF mutations confer resistance to RAF dimer inhibitors in NRAS and BRAF mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 36.
Implementation of donation after circulatory death kidney transplantation can safely enlarge the donor pool: A systematic review and meta-analysis
Authors: Elsaline Rijkse, Sebastiaan Ceuppens, Hongchao Qi, Jan N.M. IJzermans, Dennis A. Hesselink, Robert C. Minnee
Journal: International Journal of Surgery (2021)

Donation after circulatory death (DCD) kidney transplantation has been introduced to address organ shortage. However, DCD kidneys are not accepted worldwide due to concerns about inferior quality. To investigate whether these concerns are justified, we performed a systematic review and meta-analysis to investigate DCD graft outcomes compared to donation after brain death (DBD).EMBASE, Medline, Cochrane, Web of Science and Google Scholar were searched from database inception until September 2020. Exclusion criteria were studies reporting on pediatric/dual kidney transplants, multi-organ transplants or studies including normothermic perfusion techniques. The primary outcome was graft survival. Secondary outcomes were primary non-function (PNF), delayed graft function (DGF), 3-months biopsy-proven acute rejection (BPAR), 1-year estimated Glomerular Filtration Rate (eGFR), patient survival, and urologic complications. A random-effects model was used for meta-analysis. Meta-regression analysis was performed in case of high between-study heterogeneity.Fifty-one studies were included, comprising 73,454 DCD and 518,229 DBD recipients. One-year graft loss was increased in DCD recipients (death-censored: risk ratio (RR) 1.10 (95%-confidence interval (CI) 1.04-1.16), all-cause: RR 1.13 (95%-CI 1.08-1.19)). Ten-year graft loss was similar to DBD (death-censored: RR 1.02 (95%-CI 0.92-1.13), all-cause: RR 1.03 (95%-CI 0.94-1.13)). DCD recipients had an increased risk of PNF (RR 1.43 (95%-CI 1.26-1.62)), DGF (RR 2.02 (95%-CI 1.88-2.16)), and 1-year mortality (RR 1.10 (95%-CI 1.01-1.21)). No differences were observed for 3-months BPAR, ureter stenosis/leakage, 1-year eGFR and 10-year mortality.Long-term DCD kidney transplant outcomes are similar to DBD despite a higher risk of PNF, DGF, and a 13% increased risk of graft loss in the first year after transplantation. These results should encourage implementation of DCD programs.
Reverse translation approach generates a signature of penetrating fibrosis in Crohn’s disease that is associated with anti-TNF response
Authors: Shanshan Xiong, Charles E Whitehurst, Li Li, Gyu Seong Heo, Chin-Wen Lai, Umang Jain, Brian D Muegge, Scott T Espenschied, Ryan J Musich, Minhu Chen, Yongjian Liu, Ta-Chiang Liu, Thaddeus S Stappenbeck
Journal: Gut (2021)

Objective Fibrosis is a common feature of Crohn’s disease (CD) which can involve the mesenteric fat. However, the molecular signature of this process remains unclear. Our goal was to define the transcriptional signature of mesenteric fibrosis in CD subjects and to model mesenteric fibrosis in mice to improve our understanding of CD pathogenesis. Design We performed histological and transcriptional analysis of fibrosis in CD samples. We modelled a CD-like fibrosis phenotype by performing repeated colonic biopsies in mice and analysed the model by histology, type I collagen-targeted positron emission tomography (PET) and global gene expression. We generated a gene set list of essential features of mesenteric fibrosis and compared it to mucosal biopsy datasets from inflammatory bowel disease patients to identify a refined gene set that correlated with clinical outcomes. Results Mesenteric fibrosis in CD was interconnected to areas of fibrosis in all layers of the intestine, defined as penetrating fibrosis. We found a transcriptional signature of differentially expressed genes enriched in areas of the mesenteric fat of CD subjects with high levels of fibrosis. Mice subjected to repeated colonic biopsies showed penetrating fibrosis as shown by histology, PET imaging and transcriptional analysis. Finally, we composed a composite 24-gene set list that was linked to inflammatory fibroblasts and correlated with treatment response. Conclusion We linked histopathological and molecular features of CD penetrating fibrosis to a mouse model of repeated biopsy injuries. This experimental system provides an innovative approach for functional investigations of underlying profibrotic mechanisms and therapeutic concepts in CD.
Immune Checkpoint Inhibitor Therapy Toxicities
Authors: Heather S. L. Jim, Hans Knoop, Adam P. Dicker
Journal: JAMA (2021)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
マウスにおける免疫予防および治療腫瘍抑制のためのアジュバントパルスmRNAワクチンナノ粒子【JST・京大機械翻訳】
Authors: Islam Mohammad Ariful, Rice Jamie, Reesor Emma, Zope Harshal, Tao Wei, Lim Michael, Ding Jianxun, Chen Yunhan, Aduluso Dike, R Zetter Bruce, C Farokhzad Omid, Shi Jinjun
Journal: Biomaterials (2021)
A randomized study to investigate the effect of focal zone size on treatment outcomes in patients undergoing extracorporeal shockwave lithotripsy to renal calculi
Authors: C.F.A. Ng, C-H. Yee, W.Y. Kong, S.Y. Lau, K.F. Chiu, Y.C. Teoh, C.W. Chu, K-T. Wong
Journal: European Urology (2021)
Abstract LB113: Regulation of PARP-1 expression in mammary tumor cell lines after treatment with olaparib
Authors: Marina Gobbe Moschetta-Pinheiro, Jucimara Colombo, Murilo de Souza Tuckumantel, Gabriela Karam Rebolho, Debora Aparecida Zuccari
Journal: Cancer Research (2021)

Abstract Introduction: Breast cancer is the most common tumor type among women and has a high mortality rate, which is associated with late detection of the disease and treatment failure due to the acquisition of resistance to protocol treatments. It is known that a variety of antitumor drugs are capable of inducing chemoresistance by activating DNA repair pathways. Among these, the PARPs are involved in the recognition and repair of simple-strand breaks. As a consequence, new drugs such as PARP inhibitors (olaparib), are being investigated as potential therapeutic targets in cancer, as an alternative to evade the resistance of tumor cells to chemotherapeutic agents, such as those in the class of platinum salts. In this context, the aim of this study was to evaluate the PARP expression after olaparib tratament with in mammary tumor cell lines. Materials and Methods: Mammary tumor cell lines MDA-MB-468 and CF41 was cultured in DMEM high glucose culture medium, at 37°C in 5% CO2. Cell viability was measured by MTT assay after treatment with different concentrations of carboplatin. Once stablished the concentration of 10µM for carboplatin and 10µM of olaparib, the protein and gene expression of PARP-1 were detected by immunofluorescence and real time PCR, respectively. Results: There was a significantly decrease of cell viability after treatment with different concentrations of carboplatin in 24 hours. Both PARP-1 protein and gene expression significantly decreased after treatment with carboplatin and olaparib. In some cases, the treatment action was potentiated when performed in combination. Conclusion: Our results suggest the efficacy of olaparib in controlling the mechanism of DNA repair activated by PARPs in human and canine breast cancer cells. Citation Format: Marina Gobbe Moschetta-Pinheiro, Jucimara Colombo, Murilo de Souza Tuckumantel, Gabriela Karam Rebolho, Debora Aparecida Zuccari. Regulation of PARP-1 expression in mammary tumor cell lines after treatment with olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB113.
Abstract 12767: Absence of Coronary Artery Disease by Coronary Angiography is Associated With a Lower Risk of Myocardial Infarction Than in the General Population
Authors: Kevin Kris Warnakula Olesen, Morten Madsen, Christine Gyldenkerne, Pernille Gro Thrane, Troels Thim, Lisette Okkels Jensen, John W Eikelboom, Hans Erik Bøtker, Henrik Toft Sørensen, Michael Maeng
Journal: Circulation (2019)

Introduction: Conflicting information regarding long-term prognosis among patients without obstructive coronary artery disease (CAD) leads to challenges in management after coronary angiography. Hy...
COVID-19 pneumonitis and cystic lung disease, pneumothorax and pneumomediastinum
Authors: Serenydd Everden, Irfan Zaki, Gareth Trevelyan, James Briggs
Journal: Thorax (2021)

One of the puzzling aspects in the visual attention literature is the discrepancy between electrophysiological and fMRI findings: whereas fMRI studies reveal strong attentional modulation in the earliest visual areas, single-unit and local field potential studies yielded mixed results. In addition, it is not clear to what extent spatial attention effects extend from early to high-order visual areas. Here we addressed these issues using electrocorticography recordings in epileptic patients. The patients performed a task that allowed simultaneous manipulation of both spatial and object-based attention. They were presented with composite stimuli, consisting of a small object (face or house) superimposed on a large one, and in separate blocks, were instructed to attend one of the objects. We found a consistent increase in broadband high-frequency (30–90 Hz) power, but not in visual evoked potentials, associated with spatial attention starting with V1/V2 and continuing throughout the visual hierarchy. The magnitude of the attentional modulation was correlated with the spatial selectivity of each electrode and its distance from the occipital pole. Interestingly, the latency of the attentional modulation showed a significant decrease along the visual hierarchy. In addition, electrodes placed over high-order visual areas (e.g., fusiform gyrus) showed both effects of spatial and object-based attention. Overall, our results help to reconcile previous observations of discrepancy between fMRI and electrophysiology. They also imply that spatial attention effects can be found both in early and high-order visual cortical areas, in parallel with their stimulus tuning properties.
Biomedical Applications of Metal 3D Printing
Authors: Luis Fernando Velásquez-García, Yosef Kornbluth
Journal: Annual Review of Biomedical Engineering (2021)

Additive manufacturing's attributes include print customization, low per-unit cost for small- to mid-batch production, seamless interfacing with mainstream medical 3D imaging techniques, and feasibility to create free-form objects in materials that are biocompatible and biodegradable. Consequently, additive manufacturing is apposite for a wide range of biomedical applications including custom biocompatible implants that mimic the mechanical response of bone, biodegradable scaffolds with engineered degradation rate, medical surgical tools, and biomedical instrumentation. This review surveys the materials, 3D printing methods and technologies, and biomedical applications of metal 3D printing, providing a historical perspective while focusing on the state of the art. It then identifies a number of exciting directions of future growth: (a) the improvement of mainstream additive manufacturing methods and associated feedstock; (b) the exploration of mature, less utilized metal 3D printing techniques; (c) the optimization of additively manufactured load-bearing structures via artificial intelligence; and (d) the creation of monolithic, multimaterial, finely featured, multifunctional implants.
Lymph node staging with 18F-PSMA-1007 PET/CT in newly diagnosed prostate cancer using histopathological evaluation as a reference
Authors: R. Hermsen, E.B.C. Wedick, M.J.M. Vinken, L.W.M. Van Kalmthout, H.V.N. Küsters-Vandevelde, C.H.W. Wijers, D.M. Somford, J.P.A. Van Basten
Journal: European Urology (2021)
Assessment of Screening Mammography Recommendations
Authors: Andrea Wolf
Journal: JAMA Internal Medicine (2021)

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 Internal Medicine 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 Internal Medicine journal
Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis
Authors: Ray Y Chen, Xiang Yu, Bronwyn Smith, Xin Liu, Jingcai Gao, Andreas H Diacon, Rodney Dawson, Michele Tameris, Hong Zhu, Yahong Qu, Ruanqing Zhang, Shouguo Pan, Xiaowei Jin, Lisa C Goldfeder, Ying Cai, Kriti Arora, Jing Wang, Joel Vincent, Stephanus T Malherbe, Friedrich Thienemann, Robert J Wilkinson, Gerhard Walzl, Clifton E Barry
Journal: The Lancet Microbe (2021)

Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [
Abstract 125: First report of a full spectrum of de novo induced human breast cancer subtypes generated from oncogene-transduced freshly isolated normal human mammary cells
Authors: Susanna Tan, Sylvain Lefort, Amal El-Naggar, Davide Pellacani, Poul H. Sorensen, Connie Eaves
Journal: Cancer Research (2021)

Abstract Human breast cancers are genetically and biologically heterogeneous with variable responses to current treatments. As an alternative strategy to identify causal and shared mechanisms, we have been exploring the utility of creating de novo models of human breast cancers from freshly isolated, purified subsets of normal human mammary cells that are lentivirally transduced with defined genes of interest and then transplanted subcutaneously in Matrigel into highly immunodeficient adult female Nonobese-diabetic/Rag1-/--IL2Rγc-/- (NRG) mice. In an initial study using this approach, we discovered that forced expression of KRASG12D alone rapidly generates small (growth-arrested), but polyclonal and serially transplantable invasive ductal carcinomas (IDCs) from both normal basal and luminal progenitor subsets of normal human mammary cells. This outcome is neither replaced nor influenced by transduction of the cells with mutant forms of TP53 or PI3KCA (Nguyen et al Nature 2015). More recently, we have found that transduction of these normal human mammary cells with a cDNA encoding a myristylated form of AKT1 (myrAKT1) produces a model of ductal carcinoma in situ (DCIS), whereas forced expression of BMI1, MYC and TP53R273C with KRASG12D (KBMT) rapidly produces large and aggressive tumors within 6 weeks post-transplant, with intermediate outcomes obtained when either MYC or TP53R273C is omitted. Immunohistochemical staining for estrogen, progesterone and epidermal growth factor receptor 2 suggests that the KBMT tumors are triple negative, and that the proportion of proliferating cells in the KBMT tumors is higher than in the tumors induced by just KRASG12D. The latter finding is consistent with the known role of BMI1 as a positive upstream regulator of proliferation via its ability to inhibit expression of p16INK4a, although the relevance of this activity in the KBMT model has yet to be established. At the opposite end of the spectrum, we have also shown that co-induced suppression of Y-Box binding protein-1 (YBX1) expression blocks the in vivo growth of KRASG12D-induced IDCs and its forced increased expression enhances the growth of myrAKT-induced DCIS cells. Taken together, these findings illustrate the advantages of creating and characterizing de novo models of human breast cancers to identify and manipulate pathways that are required for the acquisition of malignant properties. Citation Format: Susanna Tan, Sylvain Lefort, Amal El-Naggar, Davide Pellacani, Poul H. Sorensen, Connie Eaves. First report of a full spectrum of de novo induced human breast cancer subtypes generated from oncogene-transduced freshly isolated normal human mammary cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 125.