tbuckley/cabot-search huggingface dataset:
Treatment with combination of all-trans retinoic acid and taxol induced differentiation and apoptosis in human malignant glioblastoma U87MG cells xenografted in athymic nude mice
Authors: Surajit Karmakar, Arabinda Das, Stephen Tomlinson, Naren L. Banik, Sunil J. Patel, Swapan K. Ray
Journal: Cancer Research (2005)

1067  The diagnosis of glioblastoma, the most malignant and prevalent brain tumor, is considered as a death sentence in humans because all current therapeutic strategies remain so far ineffective in controlling the malignant growth of glioblastoma. Chemotherapy, which is almost always used at some point in the treatment regimen for glioblastoma, has shown little promise. For our current investigation, we used all-trans retinoic acid (ATRA) and taxol (TXL) alone and also in combination for controlling the growth of human malignant glioblastoma U87MG cells xenografted in athymic nude mice. For xenotransplantation of glioblastoma, 6 weeks-old athymic nude mice (Charles Rivers) were subcutaneously (sc) injected with the exponentially growing U87MG (5 million cells/mouse). Animals with 3 weeks-old glioblastoma xenografts were randomly divided into 4 groups: control, ATRA, TXL, and ATRA plus TXL. Animals in control group did not receive any therapy. Each animal in other group received intraperitoneally (ip) a daily dose of ATRA (1.5 μg/kg), or TXL (45 μg/kg), or ATRA (1.5 μg/kg) plus 4 h later TXL (45 μg/kg) for 7 days. Histopathological examination of H&E stained tumor sections showed that control group maintained characteristic growth of glioblastoma, ATRA alone inhibited tumor cell proliferation and caused astrocytic differentiation, TXL alone induced notable amounts of apoptosis, and ATRA plus TXL caused significant amounts of differentiation with apoptosis. In situ immunofluorescent labeling detected increased calpain expression in apoptosis. Also, in situ TUNEL and double immunofluorescent labeling demonstrated cell death with increased calpain expression in tumor sections treated with TXL, or ATRA plus TXL. Western blot analyses showed changes in expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, cytochrome c release from mitochondria, activation of calpain and caspase-3 for degradation of 270 kD α-spectrin at specific sites to generate correspondingly 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, also activation of caspase-12, and increased fragmentation of inhibitor-of-caspase-3-activated-DNase (ICAD) for completion of apoptotic death in tumors treated with TXL, or ATRA plus TXL. Western blot analyses further showed alterations in levels of expression of p65 NFκB, IκBα, JNK, p-JNK, and p-p38 proteins so as to favor the apoptotic process. Taken together, our investigation in animal model revealed that treatment of xenografted glioblastoma with ATRA plus TXL effectively controlled malignant growth. Further studies need to be conducted to see the efficacy of this combination therapy in brain itself using rats with allografted glioblastoma. This investigation was supported in part by the R01 grants from the NCI and NINDS of the NIH (Bethesda, MD), and also a grant from the State of SC.
MA08.08 Implementation of Diagnostic Biomarker Testing in Lung Cancer: Real-World Data in Japan
Authors: Y. Yatabe, Y. Yoshiki, K. Matsumura, K. Togo, H. Kikkawa, E. Masters, L. Iadeluca, L. Becnel, B. Emir, R. Wiltshire, K. Nishio
Journal: Journal of Thoracic Oncology (2021)
Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL
Authors: Nirali N. Shah, Daniel W. Lee, Bonnie Yates, Constance M. Yuan, Haneen Shalabi, Staci Martin, Pamela L. Wolters, Seth M. Steinberg, Eva H. Baker, Cindy P. Delbrook, Maryalice Stetler-Stevenson, Terry J. Fry, David F. Stroncek, Crystal L. Mackall
Journal: Journal of Clinical Oncology (2021)

CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined.We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables.Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8).We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).
Human ESC-derived MSCs enhance fat engraftment by promoting adipocyte reaggregation, secreting CCL2 and mobilizing macrophages
Authors: Roma Borkar, Xiaoyan Wang, Dejin Zheng, Zhengqiang Miao, Zhenwu Zhang, Enqin Li, Yaojiong Wu, Ren-He Xu
Journal: Biomaterials (2021)

Mesenchymal stem cells (MSCs) derived from somatic tissues have been used to promote lipotransfer, a common practice in cosmetic surgery. However, the effect of lipotransfer varies, and the mechanism of action remains vague. To address these questions, we differentiated human embryonic stem cells, a stable and unlimited source, into MSCs (EMSCs). Then we subcutaneously transplanted human fat aspirates together with EMSCs or PBS as a control into the back of nude mice. Within 24 h of transplantation, EMSCs promoted aggregation and encapsulation of injected fat tissues. Afterward, all grafts gradually shrank. However, EMSC-containing grafts were larger, heavier and had fewer dark areas on the surface than the control grafts. Histologically, more live adipocytes, vascular cells, and macrophages and less fibrosis were observed in EMSC-containing grafts than in the controls. Some EMSCs differentiated into vascular cells and adipocytes in the EMSC-containing grafts. RNA sequencing revealed that human RNA was shown to decline rapidly, while mouse RNA increased in the grafts; further, human genes related to extracellular matrix remodeling, adipogenesis, and chemokine (including CCL2) signaling were expressed at higher levels in the EMSC-containing grafts than they were in the controls. CCL2 knockout reduced macrophage migration towards EMSCs in vitro and early macrophage recruitment to the grafts and the pro-engraftment effect of EMSCs in vivo. Treating mice with a macrophage inhibitor abolished the EMSC effects and converted the grafts to heavy masses of cell debris. Together, these data demonstrate that EMSCs promote fat engraftment via enhanced tissue reconstitution and encapsulation of implanted tissues, which was followed by increased angiogenesis and adipocyte survival and reduced fibrosis, in which stimulated CCL2 signaling and mobilized macrophages play pivotal roles.
Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression
Authors: Roberto Bonelli, Brendan R. E. Ansell, Luca Lotta, Thomas Scerri, Traci E. Clemons, Irene Leung, Tunde Peto, Alan C. Bird, Ferenc B. Sallo, Claudia Langenberg, Melanie Bahlo
Journal: Genome Medicine (2021)

Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease.We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes.Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes.Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Abstract 12204: Vessel Level CAC Scores Obtained During Cardiac PET/CT Are Associated With 1-Year Mace and Degree of Stenosis on Coronary Angiography
Authors: Viet T Le, David B Min, Santanu Biswas, Stacey Knight, Daniel Bride, Kent G Meredith, Steve M Mason, C M Minder, Jeffrey L Anderson, Joseph B Muhlestein, Kirk U Knowlton
Journal: Circulation (2018)

Introduction: There is increasing evidence that elevated overall coronary artery calcium (CAC) scores identify symptomatic patients (pts) at risk for major adverse cardiovascular events (MACE). How...
Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes
Authors: Jürgen G. Okun, Patricia M. Rusu, Andrea Y. Chan, Yuqin Wu, Yann W. Yap, Thomas Sharkie, Jonas Schumacher, Kathrin V. Schmidt, Katherine M. Roberts-Thomson, Ryan D. Russell, Annika Zota, Susanne Hille, Andreas Jungmann, Ludovico Maggi, Young Lee, Matthias Blüher, Stephan Herzig, Michelle A. Keske, Mathias Heikenwalder, Oliver J. Müller, Adam J. Rose
Journal: Nature Metabolism (2021)
Myocardin-related transcription factor A regulates integrin beta 2 transcription to promote macrophage infiltration and cardiac hypertrophy in mice
Authors: Li Liu, Qianwen Zhao, Ming Kong, Lei Mao, Yuyu Yang, Yong Xu
Journal: Cardiovascular Research (2021)

Macrophage-mediated inflammatory response represents a key pathophysiological process in a host of cardiovascular diseases including heart failure. Regardless of aetiology, heart failure is invariably preceded by cardiac hypertrophy. In the present study, we investigated the effect of macrophage-specific deletion of myocardin-related transcription factor A (MRTF-A) on cardiac hypertrophy and the underlying mechanism.We report that when subjected to transverse aortic constriction (TAC), macrophage MRTF-A conditional knockout (CKO) mice developed a less severe phenotype of cardiac hypertrophy compared to wild-type (WT) littermates and were partially protected from the loss of heart function. In addition, there was less extensive cardiac fibrosis in the CKO mice than WT mice following the TAC procedure. Further analysis revealed that cardiac inflammation, as assessed by levels of pro-inflammatory cytokines and chemokines, was dampened in CKO mice paralleling reduced infiltration of macrophages in the heart. Mechanistically, MRTF-A deficiency attenuated the expression of integrin beta 2 (ITGB2/CD18) in macrophage thereby disrupting adhesion of macrophages to vascular endothelial cells. MRTF-A was recruited by Sp1 to the ITGB2 promoter and cooperated with Sp1 to activate ITGB2 transcription in macrophages. Administration of a CD18 blocking antibody attenuated TAC-induced cardiac hypertrophy in mice. Interaction between MRTF-A and the histone demethylase KDM3A likely contributed to IGTB2 transcription and consequently adhesion of macrophages to endothelial cells.Our data suggest that MRTF-A may regulate macrophage trafficking and contribute to the pathogenesis of cardiac hypertrophy by activating ITGB2 transcription.
P09.52 Explore-LC: Uniting Existing Real-World Date Sources to Create a Novel Asia-Pacific Wide Research Platform for Non-Small Cell Lung Cancer
Authors: D. Horsburgh, S. Song, J. Kim, K.C. Toh, J. Ng, G. Stratton, D.H. Lee, S. Yoon, K. Park, H.A. Jung, S.M. Lim, D.K. Kim, R. Stirling, J. Kim, D. Patel
Journal: Journal of Thoracic Oncology (2021)
P76.43 Co-occurring genomic alterations and treatment outcomes in patients with EGFR exon 20 insertion positive NSCLC
Authors: G. Bravo Montenegro, A. Vanderwalde, L. Raez, J. Nieva, R. Feldman, A. Herrmann, M. Nagasaka, C. Ikpeazu, H. Mamdani, S. Pai, A. Wozniak, A. Spira, G. Lopes, S. Liu, C. Kim
Journal: Journal of Thoracic Oncology (2021)
P37.03 Analysis of Ddrug-Induced RNA Expression Changes in NSCLC Patient-Derived Explants as a Potential Tool for Personalized Therapy Choice
Authors: D. Kuznetsova, A. Ivantsov, S. Aleksakhina, S. Baskina, A. Kosmin, I. Bizin, M. Maydin, O. Lopushanskaya, S. Orlov, A. Togo, E. Levchenko, E. Imyanitov
Journal: Journal of Thoracic Oncology (2021)
P75.17 Baseline D-Dimer Levels Predict Prognosis in Advanced Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors
Authors: Z. Zhang, X. Li, S. Zhang, F. Yuan, J. Ma, L. Wang, F. Zhang, H. Tao, X. Zhi, X. Ge, Y. Hu, J. Wang
Journal: Journal of Thoracic Oncology (2021)
The effect of seasonal respiratory virus transmission on syndromic surveillance for COVID-19 in Ontario, Canada
Authors: Arjuna S Maharaj, Jennifer Parker, Jessica P Hopkins, Effie Gournis, Isaac I Bogoch, Benjamin Rader, Christina M Astley, Noah Ivers, Jared B Hawkins, Nancy VanStone, Ashleigh R Tuite, David N Fisman, John S Brownstein, Lauren Lapointe-Shaw
Journal: The Lancet Infectious Diseases (2021)
Patterns of Cutaneous and Noncutaneous Immune-Related Adverse Events Among Patients With Advanced Cancer
Authors: Leah L. Thompson, Nira A. Krasnow, Michael S. Chang, Jaewon Yoon, Edward B. Li, Nicole J. Polyakov, Gabriel E. Molina, Jordan T. Said, Kevin Huang, Juhi R. Kuchroo, Andrea N. Hinton, Kerry L. Reynolds, Steven T. Chen
Journal: JAMA Dermatology (2021)

Cutaneous immune-related adverse events (cirAEs) are some of the earliest toxic reactions to emerge following immune-checkpoint inhibitor (ICI) initiation. As an early indicator of robust inflammatory response, cirAEs may be associated with patterns of immune-mediated toxic effects, but associations between these events and noncutaneous immune-related adverse events (irAEs) remain underexplored.To characterize patterns of cirAEs and irAEs across care settings and examine associations between the features of first cirAE, overall irAE risk, and risk of specific irAE subtypes.A retrospective cohort study was conducted at a single academic medical center. The cohort included 358 patients with cancer who initiated anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 ICI therapy between January 1, 2016, and March 8, 2019, and developed 1 or more cirAEs, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and confirmed via manual medical record review. All relevant information documented before March 31, 2020, was included.Anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 therapy.Associations between specific cirAE morphologic classes and patterns of irAEs (occurrence, timeline, organ class, and specific toxic effects). Given the potential that shared underlying factors are associated with the risk of both noncutaneous and cutaneous toxic effects, the presence of observed positive associations between certain cirAE and irAE subtypes was hypothesized.Of the 358 patients, 213 were men (59.5%); median age was 65 years (interquartile range, 55-73 years). Nearly half of the patients (177 [49.4%]) with cirAE also developed a noncutaneous irAE. Most patients (128 [72.3%]) experienced their first cirAE before developing any irAE. Several cirAE morphologic classes were found to be associated with overall, organ-based, and specific irAEs. More specifically, mucositis was found to be associated with overall irAE risk (odds ratio [OR], 5.28; 95% CI, 1.11-24.26; P = .04), gastrointestinal irAEs (OR, 5.70; 95% CI, 1.11-29.40; P = .04), and the specific diagnosis of gastroenterocolitis (OR, 6.80; 95% CI, 1.24-37.39; P = .03). In addition, psoriasis was associated with an increased risk of endocrine irAEs (OR, 4.54; 95% CI, 1.21-17.04; P = .03).In this cohort study, these findings underscore the risk of multisystem toxic effects in patients experiencing cirAEs and highlight potential opportunities for dermatologists in the management of noncutaneous toxic effects.
P75.01 Activity of Brigatinib in Alectinib-Resistant ALK-Positive NSCLC According to ALK Plasma Mutation Status From J-ALTA Trial
Authors: T. Hida, R. Katayama, M. Nishio, T. Yoshida, T. Kumagai, R. Toyozawa, T. Shimokawaji, K. Goto, K. Nakagawa, T. Seto, N. Yamamoto, T. Asato, K. Hiraoka, P. Zhang, Y. Ohe
Journal: Journal of Thoracic Oncology (2021)
The Landscape of the Heritable Cancer Genome
Authors: Viola Fanfani, Luca Citi, Adrian L. Harris, Francesco Pezzella, Giovanni Stracquadanio
Journal: Cancer Research (2021)

Genome-wide association studies (GWAS) have found hundreds of single-nucleotide polymorphisms (SNP) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of the cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. We hypothesized that SNPs located in protein coding genes and nearby regulatory regions could explain a significant proportion of the heritable risk of cancer. To perform gene-level heritability analysis, we developed a new method, called Bayesian Gene Heritability Analysis (BAGHERA), to estimate the heritability explained by all genotyped SNPs and by those located in genic regions using GWAS summary statistics. BAGHERA was specifically designed for low heritability traits such as cancer and provides robust heritability estimates under different genetic architectures. BAGHERA-based analysis of 38 cancers reported in the UK Biobank showed that SNPs explain at least 10% of the heritable risk for 14 of them, including late onset malignancies. We then identified 1,146 genes, called cancer heritability genes (CHG), explaining a significant proportion of cancer heritability. CHGs were involved in hallmark processes controlling the transformation from normal to cancerous cells. Importantly, 60 of them also harbored somatic driver mutations, and 27 are tumor suppressors. Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance. SIGNIFICANCE: This study describes a new statistical method to identify genes associated with cancer heritability in the broader population, creating a map of the heritable cancer genome with gene-level resolution.See related commentary by Bader, p. 2586.
Assessment of Care Handoffs Among Hospitalist Physicians and 30-Day Mortality in Hospitalized Medicare Beneficiaries
Authors: Monica Farid, Yusuke Tsugawa, Anupam B. Jena
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Inpatients treated by hospitalist physicians, who often work contiguous days, experience handoffs at the end of a scheduled shift block. Evidence suggests that transitions of patient care, or handoffs, among physician trainees are associated with adverse patient outcomes. However, little is known about the association between handoffs and patient outcomes among attending physicians, even though similar concerns apply. <h3>Objective</h3> To examine the association between inpatient handoffs of hospitalist physicians and patient mortality among hospitalized Medicare beneficiaries. <h3>Design, Setting, and Participants</h3> This cross-sectional study analyzed a random sample of Medicare beneficiaries who were hospitalized with a general medical condition between January 1, 2011, and December 31, 2016, and treated by a hospitalist. The study compared outcomes of patients with low vs high probability of physician handoff based on date of patient admission relative to the admitting hospitalist's last working day in a scheduled block, hypothesizing that otherwise similar patients admitted toward the end of a physician's shift block would be more likely to be handed off to another physician compared with patients admitted earlier in the shift block. Data analysis was performed from July 1, 2018, to January 12, 2021. <h3>Exposure</h3> High vs low probability of physician handoff. <h3>Main Outcomes and Measures</h3> The main outcome was patient 30-day mortality rate. <h3>Results</h3> A total of 1 074 000 patients (mean [SD] age, 75.9 [13.7] years; 57.4% female; 82.1% White) were studied. Multivariable regression models adjusted for beneficiary clinical and demographic characteristics and hospital fixed effects (a within-hospital analysis, effectively comparing patients treated at the same hospital). Among 597 288 hospitalizations, no overall difference in 30-day mortality was observed between patients admitted in the 2 days prior (days −1 and −2) to the treating hospitalist's last working day (a high handoff probability) compared with days −6 and −7 (a low handoff probability) (adjusted rate, 10.6%; 95% CI, 10.5%-10.7% vs 10.6%; 95% CI, 10.5%-10.7%; adjusted difference, 0.0%; 95% CI, −0.2% to 0.1%). However, in an exploratory analysis, among patients with high illness severity, defined as those in the top quartile of estimated mortality, 30-day mortality was higher for those with high vs low likelihood of physician handoff (adjusted mortality, 27.8%; 95% CI, 27.6%-27.9% vs 26.8%; 95% CI, 26.6%-27.1%; absolute adjusted difference, 1.0%; 95% CI, 0.5%-1.4%). <h3>Conclusions and Relevance</h3> In this national analysis of Medicare beneficiaries hospitalized with a general medical condition and treated by a hospitalist physician, physician handoff was not associated with increased mortality overall.