tbuckley/cabot-search huggingface dataset:
The economic value of targeting aging
Authors: Andrew J. Scott, Martin Ellison, David A. Sinclair
Journal: Nature Aging (2021)

Developments in life expectancy and the growing emphasis on biological and 'healthy' aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate specific diseases? Here we analyze existing data to evaluate the economic value of increases in life expectancy, improvements in health and treatments that target aging. We show that a compression of morbidity that improves health is more valuable than further increases in life expectancy, and that targeting aging offers potentially larger economic gains than eradicating individual diseases. We show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion. Ultimately, the more progress that is made in improving how we age, the greater the value of further improvements.
Diagnostic accuracy of mpMRI-US fusion and micro-ultrasound guided biopsies for clinically significant prostate cancer detection
Authors: D. Maffei, M. Paciotti, P.P. Avolio, N. Frego, V. Fasulo, P. Diana, R. Contieri, A. Uleri, M. Lazzeri, R. Hurle, A.R. Saita, P. Casale, G.F. Guazzoni, N.M. Buffi, G. Lughezzani
Journal: European Urology (2021)
Abstract PL03-03: Inherited susceptibility to cancer: From family reunions to the front line of precision healthcare
Authors: Olufunmilayo I. Olopade
Journal: Cancer Research (2021)

Abstract Cancer genomics has shed much light on tumorigenesis, leading to improved diagnoses and treatments. The marriage of Big Data and genetics research has produced groundbreaking, epidemiologic studies of large swaths of the world's population showing the links between cancer(s) and inherited risk. This work has led to breakthroughs in our understanding of pathogenic mutations, such as in BRCA1 and BRCA2 genes—strong predictors of breast and ovarian cancer risk and possibly the strongest known predictors of aggressive prostate cancer risk. Inherited and sporadic forms of cancer often share common mutational events, with implications for diagnosis, prognosis, treatment and prevention. Our work and that of others demonstrate the significant burden of early onset ER negative breast cancer as well as high rates of pathogenic BRCA1, BRCA2 and PALB2 mutations among young women diagnosed with breast cancer. Our more recent work on the BRCA1 pseudogene identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and anti-tumor responses through regulation of antiviral gene expression. Genome-Wide Association Studies (GWAS) have also identified single nucleotide polymorphisms (SNPS) associated with increased breast cancer risk, including SNP rs13074711 identified from GWAS in women of African Ancestry with breast cancer, which regulates TNFSF10/TRAIL expression in ER negative breastcancer cells. Germline genetics influence somatic mutations and the evolutionary trajectory and life history of individual cancer genomes in diverse populations. Deeper understanding of the nature of this influence will allow us to explore innovative interventions to accelerate progress in precision health care and promote health equity. Citation Format: Olufunmilayo I. Olopade. Inherited susceptibility to cancer: From family reunions to the front line of precision healthcare [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 PL03-03.
Abstract 1924: Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors
Authors: Qiang Li, Douglas D. Fang, Zhe Li, Dajun Yang, Fengqi Cao, Yifan Zhai
Journal: Cancer Research (2021)

Abstract TNF-related apoptosis-inducing ligand (TRAIL) receptor (DR4 or DR5) agonists are promising agents for cancer therapy because they induce apoptosis selectively in cancer cells. However, their clinical effect is hampered by either primary or acquired resistance in cancer cells. Second mitochondria-derived activator of caspase (Smac) mimetics that antagonize the IAPs potently sensitize cancer cells to TRAIL-induced apoptosis in a caspase-8-dependent manner. We evaluated antitumor effects of small-molecule IAP antagonist APG-1387combined with an agonist mouse mAb directed against TRAIL death receptor type 5 (DR5) termed CTB-006 in the preclinical setting. Both agents are in phase I/II clinical development for patients with solid tumors. In vitro the combination treatment showed synergy in a dose-dependent manner across various cancer cell lines, as evidenced by synergistic antiproliferative activity and enhanced induction of caspase-3 cleavage. Potential synergistic in vivo antitumor activity of the combination was then assessed in human triple negative breast cancer (TNBC) xenograft models in mice. Specifically, in MDA-MB-231 and 2LMP TNBC xenograft models, either APG-1387 or CTB-006 single agent exhibited limited antitumor activity, with T/C (%) values of &amp;gt;35% (T, tumor volume in the treatment group; C, tumor volume in the vehicle control group). Only one tumor showed partial regression (PR) by DR5 treatment. Addition of APG-1387 potentiated this effect, with the combination treatment leading to T/C values of 3% to 15%, and complete regression, PR, or stable disease in all treated tumors. In summary, our results suggest great potential of combination therapy with APG-1387 and CTB-006 for solid tumor therapy and deserves further clinical investigation. Citation Format: Qiang Li, Douglas D. Fang, Zhe Li, Dajun Yang, Fengqi Cao, Yifan Zhai. Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors [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 1924.
Tumor budding correlates with discohesive growth pattern, tumor invasiveness and is associated with worse survival of pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC)
Authors: M. Eckstein, C. Kimmel, J. Bruendl, F. Weber, S. Denzinger, M. Gierth, M. Burger, A. Hartmann, W. Otto, J. Breyer
Journal: European Urology (2021)
Differences in outcome of percutaneous coronary intervention between Indigenous and non-Indigenous people in Victoria, Australia: a multicentre, prospective, observational, cohort study
Authors: Luke P Dawson, Luke Burchill, Jessica O'Brien, Diem Dinh, Stephen J Duffy, Dion Stub, Angela Brennan, David Clark, Ernesto Oqueli, Chin Hiew, Melanie Freeman, Christopher M Reid, Andrew E Ajani
Journal: The Lancet Global Health (2021)

Background Data on the patient characteristics and health outcomes of Indigenous Australians having revascularisation for treatment of coronary artery disease are scarce.The aim of this study was to assess differences in patient characteristics, presentations, and outcomes among Indigenous and non-Indigenous Australians having percutaneous coronary intervention (PCI) in urban and larger regional centres in Victoria, Australia. MethodsIn this multicentre, prospective, observational cohort study, data were prospectively collected from six government-funded tertiary hospitals in the state of Victoria, Australia.The Melbourne Interventional Group PCI registry was used to identify patients having PCI at Victorian metropolitan and large regional hospitals between Jan 1, 2005, and Dec 31, 2018.The primary outcome was long-term mortality.Secondary outcomes were 30 day mortality and 30 day major adverse cardiovascular events (MACE), defined as a composite endpoint of death, myocardial infarction, and target-vessel revascularisation.Regression analyses, adjusted for clinically relevant covariates and geographical and socioeconomic indices, were used to establish the influence of Indigenous status on these study outcomes.Findings 41 146 patient procedures were entered into the registry, of whom 179 (0•4%) were recorded as identifying as Indigenous Australian, 39 855 (96•9%) were not Indigenous Australian, and 1112 (2•7%) had incomplete data regarding ethnicity and were excluded.Compared with their non-Indigenous counterparts, Indigenous patients were younger, more often women, and more likely to have comorbidities.Indigenous Australians were also more likely to live in a regional community and areas of socioeconomic disadvantage.Procedural success and complication rates were similar for Indigenous and non-Indigenous patients having PCI.At 30 day follow-up, Indigenous Australians were more likely to be taking optimal medical therapy, although overall follow-up rates were lower and prevalence of persistent smoking was higher.Multivariable analysis showed that Indigenous status was independently associated with increased risk of long-term mortality (hazard ratio 2•49, 95% CI 1•79-3•48; p<0•0001), 30 day mortality (odds ratio 2•78, 95% CI 1•09-7•12; p=0•033), and 30-day MACE (odds ratio 1•87, 95% CI 1•03-3•39; p=0•039).Interpretation Indigenous Australians having PCI in urban and larger regional centres are at increased risk of mortality and adverse cardiac events.Clinically effective and culturally safe care pathways are urgently needed to improve health outcomes among Indigenous Australians who are having PCI.
The US Preventive Services Task Force Recommendation Statement About Screening Asymptomatic Adults for Carotid Stenosis
Authors: Michiel H. F. Poorthuis, Gert J. de Borst
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
Abstract 3035: Identifying potential druggable targets for synovial sarcoma using comparative RNA-seq analysis
Authors: Yvonne A. Vasquez, Jacob Pfeil, Letitia Mueller, Holly Beale, Alfred G. Lyle, Lauren Sanders, Katrina Learned, Ellen Kephart, Anouk van den Bout, Allison Cheney, Sahar Hosseinzadeh, Isabel Bjork, Sofie R. Salama, Olena Vaske
Journal: Cancer Research (2021)

Abstract Synovial sarcoma (SS) is an aggressive soft-tissue malignancy, accounting for 10% of all soft-tissue sarcomas. These tumors can occur at any age but most often affect young adults and adolescents, developing deep in the distal extremities. The prognosis of SS tumors is poor, with a 5-year survival rate of 36-76%, a high rate of metastasis and few treatments. The purpose of this study was to identify novel overexpressed oncogenes that could serve as druggable targets for treating synovial sarcoma patients. We compared the RNA-Seq expression profiles of a cohort of 36 synovial sarcomas to our compendium of RNA-Seq expression data from 12,236 tumor samples (treehousegenomics.ucsc.edu) from pediatric and adult cancer patients. In comparing gene expression in the synovial sarcoma cohort samples against the compendium samples, gene expression outliers were defined as having expression above the gene-specific outlier threshold as defined by the Tukey's outlier method. Among the overexpression outliers, pathway enrichment analysis was used to identify common and druggable pathways, with implications for potential therapeutics for patients with SS. Our analysis identified the overexpression of members of the Sonic Hedgehog pathway in the majority of synovial sarcoma samples. For example, GLI1 expression exceeded the outlier threshold in 35 out of 36 samples. This pathway can be targeted by available small molecule inhibitors. Ongoing work focuses on evaluating the role of Sonic Hedgehog signaling in the pathogenesis of SS using pharmacological inhibition, CRISPRi studies in cell line models of the disease and nanopore sequencing. We currently have 4 patient-derived synovial sarcoma cell lines (HSSY-II, SYO-1, YAMATO, and ASKA) that we can grow in both adherent conditions and in 3D cell culture as sarcospheres. We detected the expression of the SYT-SSX fusion transcript in each of the cell lines by RT-PCR to confirm the cell lines maintained expression of the pathogenic fusion. This work has implications for using comparative tumor RNA-seq derived gene expression data for nominating novel druggable targets specific to synovial sarcoma tumors. Citation Format: Yvonne A. Vasquez, Jacob Pfeil, Letitia Mueller, Holly Beale, Alfred G. Lyle, Lauren Sanders, Katrina Learned, Ellen Kephart, Anouk van den Bout, Allison Cheney, Sahar Hosseinzadeh, Isabel Bjork, Sofie R. Salama, Olena Vaske. Identifying potential druggable targets for synovial sarcoma using comparative RNA-seq analysis [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 3035.
Abstract 1346: Direct targeting of MAPK/ERK signaling pathway is a novel therapeutic approach for high-risk neuroblastoma
Authors: Rameswari Chilamakuri, Bharti Sharma, Danielle C. Rouse, Saurabh Agarwal
Journal: Cancer Research (2021)

Abstract Neuroblastoma is a highly heterogenous pediatric tumor that develops during the early embryonic stages, and accounts for almost 15% of pediatric cancer related deaths. Despite advanced and intensive therapeutic approaches that combine surgery, radiation, and chemotherapy, high-risk neuroblastoma (NB) patients' long-term survival is still less than 50%. Tumor metastasis, relapse, drug-resistance, and treatment related toxicities mandate the development of novel therapeutic approaches to treat NB patients. MAPK/ERK pathway plays an important oncogenic role in different types of cancers, including NB. Activation of the MAPK/ERK pathway is known to induce cancer cell proliferation, progression, metabolism, and resistance to drug-induced apoptosis. In the present study, we investigated the effect of a small-molecule MEK inhibitor that targets MEK1 and MEK2 to block MAPK/ERK pathway in NB. Cytotoxicity assays using Cell-Titer One solution in different MYCN-amplified (NGP, LAN-5, CHLA-255-MYCN) and MYCN-non-amplified (SH-SY5Y, SK-N-AS, CHLA-255) NB cell lines show that MEK inhibitor significantly reduce the NB cell proliferation in a dose-dependent manner. We further performed clonogenic assays and 3D spheroidal assays to mimic the NB tumor growth, and our results show that MEK inhibitor significantly inhibit NB colony formation, inhibit 3D spheroidal tumor size by inducing cell death in 3D spheroidal tumors, in comparison to controls. Additionally, MEK inhibitor in a dose-dependent manner induces apoptosis and blocks cell cycle progression in NB cells in comparison to control, as determined by Annexin V apoptosis assays and Click-iT EdU cell proliferation assay respectively. Furthermore, gene expression analysis show that MEK inhibitor significantly reduce the mRNA expression of specific MAPK/ERK pathway targets such as MEK1, MEK2, and ERK2. Western blot assays further confirm the efficacy of MEK inhibitor in blocking MAPK/ERK pathway by significantly inhibiting the phosphorylation of key pathway proteins. Taken together, our results highlight that: a) MAPK/ERK pathway is implicated in NB growth, and b) direct targeting of MAPK/ERK signaling pathway by using a novel small molecule MEK inhibitor inhibit NB proliferation and 3D tumor growth. We will further combine this MEK inhibitor with current chemotherapy drugs to develop effective therapeutic approaches for NB patients. Citation Format: Rameswari Chilamakuri, Bharti Sharma, Danielle C. Rouse, Saurabh Agarwal. Direct targeting of MAPK/ERK signaling pathway is a novel therapeutic approach for high-risk neuroblastoma [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 1346.
Abstract 3199: In vitro killing assays for immuno oncology candidates
Authors: Thibaut J. Janss, Juliette Lamy, Johan Arnold, Ellen Boelen, Sofie Pattijn
Journal: Cancer Research (2021)

Abstract The need to better understand the tumor microenvironment (TME) dictates the characterization of the cell types involved, the roles they play and how they respond to treatment. To develop better cancer immunotherapies, in vitro primary immune cell bioassays offer an early assessment of their effects on the various players of the TME. Cytotoxic cells are key players in the anti-tumor immune response. CD8+ T cells, also known as cytotoxic T lymphocytes, recognize and kill cells presenting antigens bound to MHC class I molecules, such as neoantigen present on the tumor cells. Activation of CD8+ T cells requires at least two signals from antigen presenting cells: binding of their T cell receptor (TCR) to the appropriate peptide presented on MHC I and co-stimulation by B7 binding to CD28. However, tumor environment developed different mechanisms to reduce this immune cell killing such as checkpoint inhibitors expression. In that case, the immune system will be dampened. A second type of cytotoxic cells, named Natural killer cells, are an innate immune cell type that plays an important role in anti-cancer immunity. NK cells target cells lacking MHC I expression, including cancer cells that have lost expression of MHC I. NK cells induce apoptosis in cancer cells via release of perforin and granzymes from granules, like CD8+ T cells. But here too, NK cells can be broken down by the tumor cells, notably by the PD1/PDL1 interaction. Increasing their efficacy as a therapeutic strategy has made the development of new therapeutics enhancing their anti-tumor response a priority. Those new therapeutics can have several shapes. The Antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the IgG1 isotypes is one of the mechanisms that can be applied by immunoglobulin-based therapeutics. Another way to increase the killing of cancer cells is to target tumor antigens expressed by those cells using for example bispecific molecules that will enhance on the other side the T cell activation. Using primary immune cells, in vitro bioassays were developed to better screen the potential effect of new therapeutics on immune cell killing activity. Their ability to increase or induce a cytotoxic activity and facilitate the anti-tumor immune response can as a result be assessed early in the drug development process. Citation Format: Thibaut J. Janss, Juliette Lamy, Johan Arnold, Ellen Boelen, Sofie Pattijn. In vitro killing assays for immuno oncology candidates [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 3199.
The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors
Authors: Dean Paes, Melissa Schepers, Ben Rombaut, Daniel van den Hove, Tim Vanmierlo, Jos Prickaerts
Journal: Pharmacological Reviews (2021)

The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects. Interestingly, the PDE4 enzyme family consists of several subtypes and isoforms that can be modified post-translationally or can engage in specific protein-protein interactions to yield a variety of conformational states. Inhibition of specific PDE4 subtypes, isoforms, or conformational states may lead to more precise effects and hence improve the safety profile of PDE4 inhibition. In this review, we provide an overview of the variety of PDE4 isoforms and how their activity and inhibition is influenced by post-translational modifications and interactions with partner proteins. Furthermore, we describe the importance of screening potential PDE4 inhibitors in view of different PDE4 subtypes, isoforms, and conformational states rather than testing compounds directed toward a specific PDE4 catalytic domain. Lastly, potential mechanisms underlying PDE4-mediated adverse effects are outlined. In this review, we illustrate that PDE4 inhibitors retain their therapeutic potential in myriad diseases, but target identification should be more precise to establish selective inhibition of disease-affected PDE4 isoforms while avoiding isoforms involved in adverse effects. <h3>Significance Statement</h3> Although the PDE4 enzyme family is a therapeutic target in an extensive range of disorders, clinical use of PDE4 inhibitors has been hindered because of the adverse side effects. This review elaborately shows that safer and more effective PDE4 targeting is possible by characterizing 1) which PDE4 subtypes and isoforms exist, 2) how PDE4 isoforms can adopt specific conformations upon post-translational modifications and protein-protein interactions, and 3) which PDE4 inhibitors can selectively bind specific PDE4 subtypes, isoforms, and/or conformations.
What is the optimal duration of hormonal treatment during salvage radiotherapy in men with pN1 Prostate Cancer? Results form a large Multi-Institutional series
Authors: N. Fossati, E. Mazzone, R. Karnes, S.A. Boorjian, G. Motterle, A. Bossi, T. Kumar, N. Di Muzio, C. Cozzarini, B. Noris Chiorda, G. Gandaglia, A. Stabile, V. Cucchiara, D.. Robesti, D. Bartkowiak, S. Shariat, G. Goldner, S. Joniau, H. Van Poppel, C. Berghen, G. De Meerleer, F. Montorsi, T. Wiegel, A. Briganti
Journal: European Urology (2021)