tbuckley/cabot-search huggingface dataset:
Hematopoietic expression of a chimeric murine‐human <scp>CALR</scp> oncoprotein allows the assessment of <scp>anti‐CALR</scp> antibody immunotherapies in vivo
Authors: Sarada Achyutuni, Harini Nivarthi, Andrea Majoros, Eva Hug, Christina Schueller, Ruochen Jia, Cecilia Varga, Michael Schuster, Martin Senekowitsch, Dimitris Tsiantoulas, Anoop Kavirayani, Christoph J Binder, Christoph Bock, Oleh Zagrijtschuk, Robert Kralovics
Journal: American Journal of Hematology (2021)

Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR.
OA01.07 A Phase II Study of the Oral Selective AXL Inhibitor Bemcentinib with Pembrolizumab in Patients with Advanced NSCLC
Authors: M.G. Krebs, Å. Helland, E. Carcereny Costa, E. Arriola Aperribay, M. Dómine Gómez, J. Trigo Pérez, J. Thompson, J. Strauss, A.L. Ortega Granados, E. Felip, E. Schmidt, M. Chisamore, N. Madeleine, A. Rayford, K. Lorens, A. Siddiqui, H. Gabra, J. Nautiyal, D. Micklem, J. Lorens, J. Spicer
Journal: Journal of Thoracic Oncology (2021)
Painting the portrait of athlete health: a call for interconnected health information systems
Authors: Dustin Nabhan, David Taylor, Jonathan T Finnoff
Journal: British Journal of Sports Medicine (2021)

Athlete health promotion programmes depend on accurate and complete sport epidemiology data.1 Many methods are used for health surveillance in elite athletes: research registries, medical records, screening questionnaires for clinical and research use and athlete monitoring systems designed for high performance management teams.2–4 In this clinical commentary, we describe our theory that the true incidence and prevalence of health conditions may be best described by interconnected data systems that aggregate the information from each of these inputs into one live data table. We then introduce a system developed by a National Olympic & Paralympic Committee that is used to help document medical records of individuals for clinical athlete management, while also contributing to knowledge of athlete cohorts for population-based health promotion programmes.

The best predictor of future injury is prior injury; however, systems that categorise an athlete’s previous injury, track new conditions and maintain records of risk factors are not readily available for use in the clinical setting.5 Analysis of existing injury surveillance systems provide examples of common flaws with current systems (eg, inconsistent definitions, poor data hygiene, failure to report …
P76.84 EGFR Status, Risk Factors for Brain Metastases and Overall Survival in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients
Authors: M. Chowdhury, K. Hueniken, S. Schmid, C. Brown, K. Khan, P. Walia, A. Sabouhanian, E. Strom, J. Herman, W. Xu, N. Leighl, P. Bradbury, A. Sacher, F. Shepherd, G. Liu, D. Shultz
Journal: Journal of Thoracic Oncology (2021)
Stomatin-Mediated Inhibition of the Akt Signaling Axis Suppresses Tumor Growth
Authors: Nor Idayu A. Rahman, Akira Sato, Khurelbaatar Tsevelnorov, Akio Shimizu, Masahiro Komeno, Mohammad Khusni Bin Ahmat Amin, Md Rasel Molla, Joanne Ern Chi Soh, Le Kim Chi Nguyen, Akinori Wada, Akihiro Kawauchi, Hisakazu Ogita
Journal: Cancer Research (2021)

The growth and progression of cancers are crucially regulated by the tumor microenvironment where tumor cells and stromal cells are mutually associated. In this study, we found that stomatin expression was markedly upregulated by the interaction between prostate cancer cells and stromal cells. Stomatin suppressed cancer cell proliferation and enhanced apoptosis in vitro and inhibited xenograft tumor growth in vivo. Stomatin inhibited Akt activation, which is mediated by phosphoinositide-dependent protein kinase 1 (PDPK1). PDPK1 protein stability was maintained by its binding to HSP90. Stomatin interacted with PDPK1 and interfered with the PDPK1-HSP90 complex formation, resulting in decreased PDPK1 expression. Knockdown of stomatin in cancer cells elevated Akt activation and promoted cell increase by promoting the interaction between PDPK1 and HSP90. Clinically, stomatin expression levels were significantly decreased in human prostate cancer samples with high Gleason scores, and lower expression of stomatin was associated with higher recurrence of prostate cancer after the operation. Collectively, these findings demonstrate the tumor-suppressive effect of stromal-induced stomatin on cancer cells. SIGNIFICANCE: These findings reveal that interactions with stromal cells induce expression of stomatin in prostate cancer cells, which suppresses tumor growth via attenuation of the Akt signaling axis.
OA01.06 Randomised Phase 2 Study of Nivolumab (N) Versus Nivolumab and Ipilimumab (NI) Combination in EGFR Mutant NSCLC
Authors: G. Lai, J. Alvarez, J.C. Yeo, N.L. Sim, A. Tan, S. Zhou, L. Suteja, T.W. Lim, N. Rohatgi, J. Yeong, A. Takano, K.H.T. Lim, A. Gogna, C.W. Too, K.D. Zhuang, A. Jain, W. Tan, R. Kanesvaran, Q.S. Ng, M. Ang, T. Rajasekaran, L. Wang, C.K. Toh, W. Lim, W.L. Tam, F. Ginhoux, S.H. Tan, A. Skanderup, D. Tan, E. Tan
Journal: Journal of Thoracic Oncology (2021)
Exploiting Tumor Neoantigens to Target Cancer Evolution: Current Challenges and Promising Therapeutic Approaches
Authors: Ravi G. Gupta, Fenge Li, Jason Roszik, Gregory Lizée
Journal: Cancer Discovery (2021)

Immunotherapeutic manipulation of the antitumor immune response offers an attractive strategy to target genomic instability in cancer. A subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neoantigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes originating from nonsynonymous single-nucleotide variants in the coding exome. Here we review emerging approaches for identifying, prioritizing, and immunologically targeting personalized neoantigens using polyvalent cancer vaccines and T-cell receptor gene therapy. SIGNIFICANCE: Several major challenges currently impede the clinical efficacy of neoantigen-directed immunotherapy, such as the relative infrequency of immunogenic neoantigens, suboptimal potency and priming of de novo tumor-specific T cells, and tumor cell-intrinsic and -extrinsic mechanisms of immune evasion. A deeper understanding of these biological barriers could help facilitate the development of effective and durable immunotherapy for any type of cancer, including immunologically "cold" tumors that are otherwise therapeutically resistant.
P04.08 Dynamics of Coagulation Factor XIII Activity After Thoracoscopic Lobectomy for Early-Stage Lung Cancer Patients
Authors: Y. Yamauchi, Y. Saito, S. Shirai, F. Yokote, T. Sakai, H. Dejima, Y. Sakao, M. Kawamura
Journal: Journal of Thoracic Oncology (2021)
Relationship of spiritual constructs to mental health PROs in adolescents with cancer.
Authors: Maureen Lyon, Daniel H. Grossoehme, Justin N. Baker, Sarah Friebert, Yao Cheng, Jody Chrastek, Jessica Thompkins, Matthew Tweddle, Jichuan Wang, Jennifer Needle
Journal: Journal of Clinical Oncology (2019)

136 Background: Global beliefs and goals form a meaning system, which plays a role in adjusting to stressors like cancer. Spirituality (search for the sacred) is a meaning system that can play a role in adolescent coping, and psychosocial adjustment to chronic disease. When malignancies occur during adolescence, there are long-term consequences to adjustment, functioning, and disease self-management. Methods: Data were obtained from 126 adolescents diagnosed with cancer at various stages and 4 sites in a longitudinal pediatric advance care planning intervention trial. Scales used: demographic; 2 spiritual scales (Brief-MMRS and FACIT-Sp v4); and 2 emotional PROMIS items (anxiety and depression). Bivariate relationships were analyzed. Structural equation modeling examined the relationship between spiritual and PROMIS items. Bootstrap with 1000 resamples was applied to due to sample size. Results: Mean age was 16.9 years (range: 14-20), with a mean time since diagnosis of 77 months (range: 1-232); 21% were on active treatment. The majority were female (57%) and white (79%). Most identified as spiritual (89%) and religious (83%). When asked if they believed they will be spiritually healed from cancer by a miracle, 49% reported “yes.” Adolescents viewing cancer as God’s punishment were more likely to have high depression (p = 0.03). Very or moderately spiritual teens were more likely to have high anxiety and high depression (p = 0.02). Meaning/peace (FACIT-Sp subscale) mediated feeling God’s presence on anxiety (β = -3.5; 95% CI: -9.2, -0.48) and depression (β = -4.6; 95%CI: -10.7, -1.1); and mediated religious identification on anxiety (β = -3.1; 95%CI:-6.9, -0.6) and depression (β = -4.1; 95%CI:-9.3,-0.24). Conclusions: Our findings are consistent with adult literature and a single longitudinal study of teens with cancer: spiritual distress (cancer is God’s punishment) is associated with poorer mental health outcomes, and meaning with positive outcomes. Adolescent anxiety and depression were inversely related to feeling God’s presence, and to identifying as religious; this effect was mediated by their sense of meaning/peace. Meaning-making is a modifiable process, opening a novel focus for intervention development. Clinical trial information: NCT02693665.
The Value of Total Knee Replacement in Patients With Knee Osteoarthritis and a Body Mass Index of 40 kg/m<sup>2</sup> or Greater
Authors: Angela T. Chen, Corin I. Bronsther, Elizabeth E. Stanley, A. David Paltiel, James K. Sullivan, Jamie E. Collins, Tuhina Neogi, Jeffrey N. Katz, Elena Losina
Journal: Annals of Internal Medicine (2021)

Background: Total knee replacement (TKR) is an effective and cost-effective strategy for treating end-stage knee osteoarthritis. Greater risk for complications among TKR recipients with a body mass index (BMI) of 40 kg/m2 or greater has raised concerns about the value of TKR in this population. Objective: To assess the value of TKR in recipients with a BMI of 40 kg/m2 or greater using a cost-effectiveness analysis. Design: Osteoarthritis Policy Model to assess long-term clinical benefits, costs, and cost-effectiveness of TKR in patients with a BMI of 40 kg/m2 or greater. Data Sources: Total knee replacement parameters from longitudinal studies and published literature, and costs from Medicare Physician Fee Schedules, the Healthcare Cost and Utilization Project, and published data. Target Population: Recipients of TKR with a BMI of 40 kg/m2 or greater in the United States. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Total knee replacement. Outcome Measures: Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Results of Base-Case Analysis: Total knee replacement increased QALYs by 0.71 year and lifetime medical costs by $25 200 among patients aged 50 to 65 years with a BMI of 40 kg/m2 or greater, resulting in an ICER of $35 200. Total knee replacement in patients older than 65 years with a BMI of 40 kg/m2 or greater increased QALYs by 0.39 year and costs by $21 100, resulting in an ICER of $54 100. Results of Sensitivity Analysis: In TKR recipients with a BMI of 40 kg/m2 or greater and diabetes and cardiovascular disease, ICERs were below $75 000 per QALY. Results were most sensitive to complication rates and preoperative pain levels. In the probabilistic sensitivity analysis, at a $55 000-per-QALY willingness-to-pay threshold, TKR had a 100% and 90% likelihood of being a cost-effective strategy for patients aged 50 to 65 years and patients older than 65 years, respectively. Limitation: Data are derived from several sources. Conclusion: From a cost-effectiveness perspective, TKR offers good value in patients with a BMI of 40 kg/m2 or greater, including those with multiple comorbidities. Primary Funding Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.
Case 8-2021: A 34-Year-Old Woman with Cholangiocarcinoma
Authors: Lipika Goyal, Christopher T. Chen, Theodore T. Pierce, Vikram Deshpande
Journal: New England Journal of Medicine (2021)

A 34-year-old woman was evaluated in the oncology clinic for the management of recurrent, metastatic intrahepatic cholangiocarcinoma. Before evaluation, an extended right hepatectomy had been performed, and the patient had received adjuvant therapy with gemcitabine and cisplatin. When relapse of the cancer occurred, additional management decisions were made.
Abstract 12500: A Phenotype Risk Score for Monogenic Aortopathy is Associated With Dilatation of the Thoracic Aorta and Risk of Adverse Aortic Events
Authors: Zi Ye, Iftikhar J Kullo
Journal: Circulation (2018)

Introduction: Previous studies suggested shared genetic risk between Mendelian and complex diseases. Hypothesis: We hypothesized that a phenotype risk score (PRS) of monogenic aortopathy is associa...
Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19
Authors: Luc Morin, Laurent Savale, Tài Pham, Romain Colle, Samy Figueiredo, Anatole Harrois, Matthieu Gasnier, Anne-Lise Lecoq, Olivier Meyrignac, Nicolas Noel, Elodie Baudry, Marie-France Bellin, Antoine Beurnier, Walid Choucha, Emmanuelle Corruble, Laurent Dortet, Isabelle Hardy-Leger, François Radiguer, Sabine Sportouch, Christiane Verny, Benjamin Wyplosz, Mohamad Zaidan, Laurent Becquemont, David Montani, Xavier Monnet
Journal: JAMA (2021)

Little is known about long-term sequelae of COVID-19.
Abstract #1258: TOR signaling maintains nucleolar architecture and timely exit from mitosis
Authors: Changxian Shen, Mary-Ann Bjornsti
Journal: Cancer Research (2009)

TOR, a conserved PI-3K-related kinase family member, is a central regulator of cell growth and proliferation in response to a range of environmental and intracellular conditions. Dysregulation of the Akt-mTOR pathway has been linked with malignant transformation and tumor progression. Several analogs of rapamycin, a selective inhibitor of TOR, are currently in development in oncology clinical trials. Rapamycin analogs also demonstrate remarkable antitumor activity in combination with conventional cytotoxic drugs, including microtubile poisons such as vincristine, although the molecular basis for these interactions is often unclear. To assess TOR pathway function during mitosis, we used the genetically tractable yeast Saccharomyces cerevisiae as a model system. We found that rapamycin inhibition of the conserved TOR complex 1 (TORC1) delayed progression through mitosis, with a more severe delay in late anaphase. These alterations in cell cycle transit coincided with the prolonged activity of the mitotic Clb2/Cdk1 and the delayed accumulation of the Sic1 Cdk inhibitor. In yeast, most, if not all, Cdk1-induced phosphorylation events are reversed by a conserved protein phosphatase, Cdc14, which is itself controlled by the Cdc14 early anaphase release (FEAR) network and mitosis exit network (MEN). Our findings demonstrate that Cdc14 is spatially regulated by TORC1 signaling. Rapamycin inhibition of TORC1 induces the premature release of Cdc14 from the nucleolus and impairs the activity of the MEN network. The net result is a delayed inactivation of Clb2/Cdk1, which is necessary for the completion of mitosis and cell cycle progression into G1 phase. Surprisingly, rapamycin-induced mislocalization of Cdc14 also coincides with alterations in mitotic spindle orientation and in nucleolar morphology. These data suggest that TORC1 signaling is required to maintain nucleolar integrity, such that the nucleolar retention of Cdc14 can be spatially and temporally coordinated with it\#8217;s activation during mitosis. One prediction of this model is that rapamycin inhibition of TORC1 in cells that lack a functional spindle assembly checkpoint may partially protect cells from the cytotoxic activity of microtubule poisons (such as nocodazole) by delaying cell cycle transit through mitosis. Indeed, this was the case in a mad2 delete strain. Our findings implicate TORC1 signaling as a critical determinant of nucleolar integrity and cell cycle exit from mitosis, which may be exploited in the clinical development of microtubule targeted agents. Supported by NIH CA23099 and ALSAC.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1258.
Intermediate-Term Outcomes of Endoscopic or Open Vein Harvesting for Coronary Artery Bypass Grafting
Authors: Marco A. Zenati, Deepak L. Bhatt, Eileen M. Stock, Brack Hattler, Todd H. Wagner, Faisal G. Bakaeen, Kousick Biswas
Journal: JAMA Network Open (2021)

This randomized clinical trial examines intermediate-term outcomes of endoscopic vs open vein harvesting for coronary artery bypass grafting as part of the Randomized Endo-Vein Graft Perspective (REGROUP) trial.
Lung virome: New potential biomarkers for asthma severity and exacerbation
Authors: Sungmi Choi, Kyoung-Hee Sohn, Jae-Woo Jung, Min-Gyu Kang, Min-Suk Yang, Sujeong Kim, Jeong-Hee Choi, Sang-Heon Cho, Hye-Ryun Kang, Hana Yi
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 1423: The Cardioprotective Effects of Postconditioning Against Acute Myocardial Infarction are Mediated by Adenosine A2A Receptor Activation
Authors: Zequan Yang, Yaqin Xu, Amy R Lankford, Joel Linden, Jakob Vinten-Johansen, Brent A French
Journal: Circulation (2006)

Background: Postconditioning significantly reduces myocardial ischemia/reperfusion injury and infarct size in animals and humans. Pharmacological inhibition studies suggest that endogenous adenosin...
Dermatologic infections in cancer patients treated with checkpoint inhibitors
Authors: Mytrang H. Do, Dulce M. Barrios, Gregory S. Phillips, Michael A. Postow, Allison Betof Warner, Jonathan E. Rosenberg, Sarah J. Noor, Alina Markova, Mario E. Lacouture
Journal: Journal of the American Academy of Dermatology (2021)

The incidence of dermatologic infections in patients receiving checkpoint inhibitors (CPIs) has not been systematically described.Identify the incidence of dermatologic infections in patients who received CPIs.Retrospective review of dermatologic infections in patients who received CPIs between 2005 and 2020 and were evaluated by dermatologists at Memorial Sloan Kettering Cancer Center.Of 2061 patients in the study, 1292 were actively receiving CPIs (≤ 90 days since the last dose) and 769 had previously been on CPIs (> 90 days since the last dose). The dermatologic infection rate was significantly higher in patients with active CPI treatment (17.5%) than in patients not actively being treated (8.2%; P < .0001). In patients on CPIs, 82 (36.2%), 78 (34.5%), and 48 (21.2%) had bacterial, fungal, and viral infections, respectively, and 18 (8.0%) had polymicrobial infections. Anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy was associated with the highest risk of infection (hazard ratio, 2.93; 95% confidence interval, 1.87 to 4.60; P < .001).Retrospective design and sample limited to patients referred to dermatology.Patients actively receiving CPIs are more susceptible to dermatologic infections, with anti-cytotoxic T-lymphocyte-associated antigen-4 monotherapy carrying the highest risk, suggesting that the index of suspicion for infections should be increased in these patients to minimize morbidity and optimize care.
<i>QuickStats:</i> Death Rates* Attributed to Excessive Cold or Hypothermia† Among Persons Aged ≥15 Years, by Urban-Rural Status§ and Age Group — National Vital Statistics System, United States, 2019
Authors: Merianne Spencer
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

yrs 55 74 yrs 75 84 yrs ≥85 yrs Deaths per 100,000 Urban Rural Age group* Crude rate of deaths per 100,000 population; 95% confidence intervals indicated by error bars.† Deaths attributed to excessive cold or hypothermia were identified using the International Classification of Diseases, Tenth Revision multiple cause of death code X31 (Exposure to excessive natural cold) or T68 (Hypothermia).§ Urban-rural status is determined by the Office of Management and Budget's February 2013 delineation of metropolitan statistical areas (MSAs), in which each MSA must have at least one urban area of ≥50,000 inhabitants.Areas with <50,000 inhabitants are grouped into the rural category.In 2019, among persons aged ≥15 years, death rates attributed to excessive cold or hypothermia were higher in rural areas than in urban areas across every age group.Crude rates were lowest among those aged 15-34 years at 0.2 and 0.5 per 100,000 population in urban and rural areas, respectively.Rates increased with age, with the highest rates among those aged ≥85 years at 4.6 in urban areas and 8.6 in rural areas.Differences between urban and rural rates also increased with age.
Harnessing the tunable cavity of nanoceria for enhancing Y-27632-mediated alleviation of ocular hypertension
Authors: Li-Jyuan Luo, Duc Dung Nguyen, Jui-Yang Lai
Journal: Theranostics (2021)

Background: Y-27632 is a potent ophthalmic drug for the treatment of ocular hypertension, a globally prevalent eye disease. However, the sustained delivery of Y-27632 by a therapeutic carrier to lesion sites located in the inner segments of the eye for effectively treating the ocular disorder still remains challenging. Methods: To realize the goal, a strategy based on solvothermal-assisted deposition/infiltration in combination with surface modification is utilized to synthesize hollow mesoporous ceria nanoparticles (HMCNs) with tailorable shell thicknesses and drug release profiles. The shell thickness of HMCNs is rationally exploited for achieving sustained drug release and advanced therapeutic benefits. Results: The shell thickness can regulate release profiles of Y-27632, displaying that thick and thin (~40 nm and ~10 nm) shelled HMCNs reveal burst release characteristics (within 2 days) or limited drug loading content (~10% for the 40 nm thick). As a compromise, the HMCNs with moderate shell thickness (~20 nm) possess the most sustained drug release over a period of 10 days. In a rabbit model of glaucoma, a single instillation of the optimized Y-27632-loaded HMCNs can effectively treat glaucoma for 10 days via simultaneously repairing the defected cornea (recovery of ~93% ATP1A1 mRNA levels), restoring the reduced thickness of outer nuclear layer to normal (~64 µm), and restoring ~86% of the impaired photoreceptor cells. Conclusion: A comprehensive study on the importance of HMCN shell thickness in developing long-acting nano eye drops for the efficient management of glaucoma is proposed. The findings suggest a central role of nanobiomaterial structural engineering in developing the long-life eye drops for pharmacological treatment of intraocular diseases.