tbuckley/cabot-search huggingface dataset:
Association between CNVs of BMI-related gene and survival status of LUAD and LUSC patients.
Authors: Haifeng Luo
Journal: Journal of Clinical Oncology (2021)

e20524 Background: In recent decades, many GWAS studies help to discover the gene related to BMI or obesity. FTO, BDNF, LEPR, MC4R, SH2B1, GNPDA2, INSIG2, KCTD15, LEP, MTCH2, NEGR1, NPC1, PCSK1, POMC, TMEM18 and UCP2 are 16 genes showing most significant association with BMI. Those genes impact BMI by either alternating sex hormone metabolism, influencing insulin and insulin-like growth factor, or mediating inflammatory and adipokines. Those pathways impact cancer cells also. Here we report the association between copy number variables (CNV) of those genes and outcome of lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). Methods: 522 individuals in LUAD dataset of TCGA and 504 individuals in LUSC dataset of TCGA are included in this study. CNVs of each gene are main predictors, the survival time is the main outcome in the study, and gender, tumor stage, smoking status are chosen to adjust model. Multivariable Cox models are generated for LUAD patients and LUSC patients respectively. To control false discovery rate (FDR), Benjamini-Hochberg procedure is employed. Results: For LUAD patients, tumor stages impact survival status significantly, but age, gender and smoking status don’t impact survival time significantly. At the same time, CNV of TMEM18 has hazard ratio of 0.0353 (95% CI: 0.0032, 0.3910), which means the gain of genetic materials on the position of TMEM18 gene will protect patients to die after diagnosis of LUAD, and the effect is extremely large. The p-value of 0.006 is less than 0.00625, which is derived with Benjamini-Hochberg procedure with false discovery rate of 0.1. For LUSC patients, only serious tumor stages, tumor stage III and tumor stage IV, impact survival status significantly, and old age will cause patients die earlier significantly. Neither gender nor smoking status don’t impact survival status significantly. When adjusting age, gender, smoking status, and tumor stage, gain of genetic materials on the position of NEGR1 gene does increase the risk of death significantly, and the hazard ratio of CNV of NEGR1 is 9.920 (95% CI: 1.237, 79.552). The p-value of 0.031 is large than 0.00625, which is derived with Benjamini-Hochberg procedure with fase discovery rate of 0.1. Conclusion: Copy number variable of TMEM18 gene impact outcome of LUAD patients significantly. The gain of TMEM18 genetic materials protects patients to die, meanwhile the loss of TMEM18 genetic materials cause patients to have shorter overall survival time. TMEM18 affect the central nervous system to imbalance energy metabolism in previous murine models, and here we found TMEM18 has significant impact on survival status of LUAD patients, so the transmembrane protein gene TMEM18 may be a key factor to outcome of LUAD.
Phase 1/2 study of the novel SUMOylation inhibitor TAK-981 in adult patients (pts) with advanced or metastatic solid tumors or relapsed/refractory (RR) hematologic malignancies.
Authors: Arkadiusz Z. Dudek, Dejan Juric, Afshin Dowlati, Erlene Kuizon Seymour, Jordi Rodon Ahnert, Bingxia Wang, Dennis Huszar, Allison J. Berger, Sharon Friedlander, Alejandro Gomez-Pinillos, Igor Proscurshim, Anthony J. Olszanski
Journal: Journal of Clinical Oncology (2021)

TPS2667 Background: SUMOylation, a posttranslational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in regulating type I interferon (IFN-I)-dependent innate response and functions to constrain the innate immune response, which can impair tumor immune surveillance. TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme subunit 2 (SAE2). Inhibition of SAE2 by TAK-981 disrupts SUMOylation, thereby allowing innate immune system activation. In ex vivo assays, TAK-981 increased phagocytic activity of monocyte-derived macrophages, increased natural killer cell cytotoxicity, and induced markers of dendritic cell activation and maturation via IFN-I signaling. In syngeneic mouse models, TAK-981 resulted in antitumor activity, including complete remissions, and a sustained, protective antitumor immune response. Methods: This first-in-human study of single-agent TAK-981 comprises two parts. Phase 1 primary objectives are to determine safety and tolerability, and to select a recommended phase 2 dose (RP2D); secondary objectives are to assess preliminary antitumor activity, characterize pharmacokinetics (PK), and explore pharmacodynamic (PD) biomarkers. This phase will enroll ̃70 pts with untreatable locally advanced or metastatic solid tumors or RR lymphoma. The phase 2 primary objective is to evaluate preliminary efficacy at the RP2D in ̃132 pts with non-squamous non-small cell lung cancer, cervical cancer, microsatellite-stable colorectal cancer, or CD20+ RR diffuse large B-cell lymphoma or follicular lymphoma. Pts receive TAK-981 via a 1-hour intravenous infusion on days 1, 4, 8, and 11 in 21-day cycles until unacceptable toxicity, pt withdrawal, or death. Dose escalation is proceeding from 3 mg, guided by an adaptive 3+3 design combined with Bayesian logistic regression modelling with overdose control, plus consideration of other safety, clinical, PK, and PD data. The RP2D will be based on the maximum tolerated dose (MTD) or on a biologically effective dose (BED) that is ≤MTD. The BED is defined as a dose at which there is evidence of drug-target engagement and inhibition of SUMOylation, plus: induction of cytokines/chemokines and/or IFN-I signature in tumor or blood; evidence of increased T cell infiltration in tumor; or antitumor activity. PK/PD modeling in the BED range is ongoing and will be used in RP2D determination. Clinical trial information: NCT03648372.
Modular cell-assembled adipose matrix-derived bead foams as a mesenchymal stromal cell delivery platform for soft tissue regeneration
Authors: Pascal Morissette Martin, John T. Walker, Kellie J. Kim, Courtney R. Brooks, Fiona E. Serack, Anna Kornmuller, Laura Juignet, Amanda M. Hamilton, P. Joy Dunmore-Buyze, Maria Drangova, John A. Ronald, Lauren E. Flynn
Journal: Biomaterials (2021)
Study on relationship between chemokines and immune activation phenotype of breast cancer.
Authors: Yanru Wang, Senming Wang, Yingqiang Li, Guorong Lai
Journal: Journal of Clinical Oncology (2021)

e12564 Background: Breast cancer is one of the most common malignant tumors in women. The incidence rate and mortality rate are increasing year by year. Studies have shown that chemokines may act as an important driver in the immune microenvironment of breast cancer. Understanding the potential immunobiological driving effect in breast cancer is important for the early diagnosis of breast cancer, which is helpful to determine the immunotherapy strategy for patients. Methods: Gene expression data of 1050 cases of breast cancer were downloaded from TCGA database. Cluster analysis was applied to investigate the level of immunity of the observations using ssGESA software. The observations were divided into three groups according to their immune score. The expression of CXCL9, CXCL10, CCL4 and CCL5 chemokines were checked for the three groups using PHEATMAP software. The differential expression analysis for the three groups was performed using Edger software. The enrichment analysis was conducted using clusterprofiler software. Results: Cluster analysis showed that the observations could be divided into three subgroups according to their immunity score, and the heatmap proved that expression level of CXCL9, CXCL10, CCL4 and CCL5 chemokines of the subgroup with high immune score were apparently higher than that of the other two subgroups. The differential expression analysis revealed that the expressions of T cell exhaustion genes were markedly different between high-level group and low-level group. A total of 402 differentially expressed genes were identified, among which 380 were up-regulated in high-level group, comparing to low-level group, and 22 were down-regulated in high-level group, comparing to low-level group. Enrichment analysis indicated they were enriched in T cell-related pathway, such as th17, th1, th3 cell differentiation and so on. Conclusions: Our study showed that the expression of four chemokines were obviously different between the groups with high immune score and low immune score. Observations with high expression of four chemokines had more active levels of immune infiltration. Differentially expressed genes were enriched in T cell-related pathway. These four chemokines could be potential biomarkers for breast cancer patients through their unique immune characteristics.
CD123 Expression Patterns and Potential of IMGN632, a CD123-Targeted Antibody Drug Conjugate, in Acute Lymphoblastic Leukemia
Authors: Evgeniya Angelova, Charlene Audette, Yelena Kovtun, Naval Daver, Sa A. Wang, Sherry Pierce, Sergej Naumovich Konoplev, Jeffrey L. Jorgensen, Marina Konopleva, Patrick A. Zweidler-McKay, Hagop M. Kantarjian, Elias J. Jabbour, Joseph David Khoury
Journal: Blood (2017)
EPCT-17. DEVELOPING EYA PHOSPHATASE INHIBITORS WITH ON-TARGET EFFECTS IN SHH-MEDULLOBLASTOMA
Authors: Grace H. Hwang, David A Scott, Rosalind A Segal
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma, one of the most frequent malignant pediatric brain tumors, encompasses four molecularly and clinically distinct cancers. Sonic hedgehog (SHH)-subtype medulloblastoma constitutes about 30% of medulloblastomas, and therapies targeting the SHH pathway can lead to new highly selective treatment. The haloacid dehalogenase (HAD) phosphatase Eyes Absent 1 (EYA1) is critically involved in the development and progression of SHH-medulloblastoma: Eya1 is highly expressed in SHH-medulloblastomas, and single cell sequencing indicates that Eya1 is a consistent feature that can be detected in every individual cancer cell. Inhibition of EYA1 interrupts SHH pathway signaling. During normal development, EYA1 promotes symmetric division of cerebellar granule cell precursors (GCPs), the cells of origin for SHH-subtype medulloblastoma, and reduced levels of EYA1 decrease medulloblastoma mortality rates in mouse models. Therefore, targeting EYA1 may be a novel therapeutic avenue for these pediatric cancers. Benzarone derivatives have been suggested as allosteric EYA-inhibitors, and benzarone provides a promising platform for chemical derivatives. Here, we develop 60 novel benzarone derivatives and assess their efficacy in inhibiting SHH-medulloblastoma growth through the inhibition of EYA1. Several of the new compounds inhibit EYA1 phosphotyrosine phosphatase activity in a cell-based assay, interrupt SHH pathway, and prevent SHH-medulloblastoma growth in vitro. Our results show that these novel benzarone derivatives are a new promising avenue for developing therapeutics for pediatric SHH-medulloblastoma via inhibition of EYA phosphatases.
First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland
Authors: C. R. Simpson, T. Shi, E. Vasileiou, S. V. Katikireddi, S. Kerr, E. Moore, C. McCowan, U. Agrawal, S. A. Shah, L. D. Ritchie, J. Murray, J. Pan, D. T. Bradley, S. J. Stock, R. Wood, A. Chuter, J. Beggs, H. R. Stagg, M. Joy, R. S. M. Tsang, S. de Lusignan, R. Hobbs, R. A. Lyons, F. Torabi, S. Bedston, M. O’Leary, A. Akbari, J. McMenamin, C. Robertson, A. Sheikh
Journal: Nature Medicine (2021)

Abstract Reports of ChAdOx1 vaccine–associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0–27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41–13.83), with an estimated incidence of 1.13 (0.62–1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29–3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12–1.34) 0–27 d after vaccination, with an SCCS RR of 0.97 (0.93–1.02). For hemorrhagic events 0–27 d after vaccination, the aRR was 1.48 (1.12–1.96), with an SCCS RR of 0.95 (0.82–1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.
Molecular characteristic of proximal and distal esophagogastric junction adenocarcinomas.
Authors: Lin Xu, Bin Shang, Mingming Bi, Wei Zhong, Yu Zhao, Zhou Wang, Mian Xu, Xiaoliang Shi, Lin Zhang, Gang Chen
Journal: Journal of Clinical Oncology (2021)

e16077 Background: Esophagogastric junction adenocarcinomas (EGJA) are devastating diseases with increasing incidence. The 8th Edition TNM staging of American Joint Committeeon Cancer and Union for International Cancer Control defined that the epicenter of EGJA within 2 cm of the cardia (hereinafter referred to proximal EGJA) is staged according to the staging standard of esophageal cancer, while that more than 2 cm distal from the EGJA (hereinafter referred to distal EGJA) is staged according to the staging standard of stomach cancer. However, the rationality of the new definition in clinical practice is still controversial. Methods: A randomized retrospective study was conducted. Targeted next-generation sequencing of 450 cancer-related genes was performed, by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China, for genomic alteration identification. Results: A total of 198 EGJ patients were included in this study with a median age of 63 years (ranged from 39 to 88 years). Among them, 140 were distal EGJA and 58 were proximal EGJA. Genomic alterations with a high mutation frequency in EGJ include There is no significant difference in the frequencies of these genes between proximal EGJA and distal EGJA. Mutation frequencies of FGFR2 and ZEN217 in distal EGJ were significantly higher than those in proximal EGJA (15.8% vs 5.0%, P = 0.02 and 7.0% vs 0.7%, P = 0.03, respectively). Multivariate regression analysis showed that tumor stage and lymph nodes number were the main factors positively associated with the poor prognosis. However, we found that there was no significant difference in OS between proximal and distal (P = 0.139). Furthermore, our results showed that LRP2 and SPTA1 mutations were significantly associated with better OS of the EGJA patients. Conclusions: In conclusion, with the identification of the mutation landscape of EGJA, the FRFR2 and ZNF127 genes mutations were potential biomarkers to distinguish distal EGJA from proximal EGJA, whereas the LRP2 and SPTA1 gene mutations were potential biomarkers for prognosis prediction in EGJA.
HGG-43. INTERROGATING THE ROLE OF PEA3 ONCOGENIC TRANSCRIPTION FACTORS IN PEDIATRIC HIGH-GRADE K27M GLIOMAS
Authors: Hannah Park, Naomi Kobritz, Shaunt Mehdikhani, Joshua Breunig;
Journal: Neuro-Oncology (2021)

Abstract Pediatric high-grade gliomas (HGGs) are an aggressive form of pediatric brain tumors which pose a grim five-year survival with little advancement in therapeutic efficacy, often requiring a multimodal therapeutic combination of chemotherapy, resection, and radiation. We have previously shown that proper function of ETS transcription factors is necessary for gliomagenesis in Ras/MAPK-driven pediatric gliomas. It is our hypothesis that ETS transcription factors are necessary for tumor initiation in HGGs by promoting the necessary glial cell fates in glioma. Further, we hypothesize that functional inhibition of ETS proteins following tumor formation will improve survival and outcome in HGG. Functional inhibition of ETS proteins using a competitive dominant-negative mutant was shown to completely rescue neural stem cell depletion, tumor formation and tumor-free survival in two rodent models of HGGs. Mechanistically, we show evidence that Pea3 factors may induce glial-cell fate by promoting Olig2 expression and activation of glial transcriptional programs. Indeed, transcriptomic analysis of ETS-perturbed HGG tumors revealed that Sox9 and Olig2 transcription factor networks were dependent on proper ETS function. Further, we show evidence that Etv5 can directly interact with promoter regions of glial fate master regulators in human primary glioma cell lines. To empirically determine the effect of Pea3 proteins on tumorigenesis, we have created a novel methodology for inducible gain- and loss-of-function genetic interrogation of these factors in vivo. Our survival results and combined single-cell RNA-sequencing of individual groups show that inhibition of the Pea3 family leads to a marked increase in survival in K27M glioma by regulating key features of glioblasts. All in all, our group provides evidence that the ETS family of transcription factors is necessary for glial specification of tumor cells and induce pro-glial transcriptional programs by activating OPC- and astrocyte-specific genes in K27M-driven tumors.
Herbal treatment with uva ursi extract versus fosfomycin in women with uncomplicated urinary tract infection in primary care: a randomized controlled trial
Authors: Ildikó Gágyor, Eva Hummers, Guido Schmiemann, Tim Friede, Sebastian Pfeiffer, Kambiz Afshar, Jutta Bleidorn
Journal: Clinical Microbiology and Infection (2021)
A micro-organosphere potency assay for adoptive T-cell therapy.
Authors: Naveen Natesh, Shengli Ding, Golshid Sanati, Shiaowen David Hsu, Scott Joseph Antonia, Xiling Shen
Journal: Journal of Clinical Oncology (2021)

e15027 Background: Lung cancer is the leading cause of death worldwide. Metastatic lung cancer patients often relapse or grow refractory to chemotherapy, radiotherapy, and checkpoint inhibitors. Adoptive T cell therapy (ACT) has been garnering more attention due to longitudinal complete responses. Tumor resections from patients harbor tumor-infiltrating lymphocytes (TILs) which can be cultured ex vivo and assessed for tumor reactivity before infusion. This generally follows a patient lymphodepletion regimen which allows the transferred T cells an optimal environment to proliferate and survive in the patient. TIL ACT can produce complete responses – rarely ever observed using traditional onco-therapy – in metastatic melanoma patients. However, while TILs specific to the neo-antigens expressed by tumor cells can be expanded ex vivo, this observed specificity is low in the clinic. Researchers have attempted to solve this by priming ex vivo expanded T cells with antigen-presenting cells previously pulsed with peptides representative of the neo-antigen repertoire of the matched tumor, but have rarely observed complete responses, likely due to current biomarkers for T cell activity poorly predicting anti-tumor cytotoxicity. To date there has been no acceptable potency assay for manufactured TILs, a requirement by the FDA for approval to use them in the clinic. Thus, the need to assess potency of ex vivo engineered T-cells against matched tumor cells is evident. Methods: We have developed a novel diagnostic immune-oncology (IO) pipeline, which uses a membrane-microfluidic platform to culture patient-derived tumor micro-organospheres (MOs) in extracellular matrix droplets. MOs can be rapidly established following patient tumor sample acquisition through biopsies or resection, and preserve the stromal cell populations in the original tumor microenvironment, as characterized by both flow cytometry and single-cell RNA-seq. An automated imaging assay was further established to robustly quantify the amount of immune-induced apoptosis of tumor cells in the MOs by patient-matched TILs, which is highly specific and yields minimal background. Results: We find that this method is not only amenable to high-throughput microscopy, but the larger surface-area-to-volume ratio of micro-organospheres also allows greater TIL infiltration and interaction with tumor cells. The resulting highly-sensitive assay requires far fewer input immune and tumor cells to achieve robust, clinical grade sensitivity response, making it the first clinically feasible assay for testing personalized TIL potency. Conclusions: The MO IO technology is currently being used for assessing clinical efficacy of manufactured TIL products for an upcoming ACT trial for non-small cell lung cancer patients. This technology also provides a companion to TIL ACT, CAR T therapy, and other immunotherapies, for which the ability to predict clinical potency is generally lacking.
Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study
Authors: Xintong Li, Anna Ostropolets, Rupa Makadia, Azza Shoaibi, Gowtham Rao, Anthony G Sena, Eugenia Martinez-Hernandez, Antonella Delmestri, Katia Verhamme, Peter R Rijnbeek, Talita Duarte-Salles, Marc A Suchard, Patrick B Ryan, George Hripcsak, Daniel Prieto-Alhambra
Journal: BMJ (2021)

Abstract Objective To quantify the background incidence rates of 15 prespecified adverse events of special interest (AESIs) associated with covid-19 vaccines. Design Multinational network cohort study. Setting Electronic health records and health claims data from eight countries: Australia, France, Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. Participants 126 661 070 people observed for at least 365 days before 1 January 2017, 2018, or 2019 from 13 databases. Main outcome measures Events of interests were 15 prespecified AESIs (non-haemorrhagic and haemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell’s palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated intravascular coagulation, encephalomyelitis (including acute disseminated encephalomyelitis), Guillain-Barré syndrome, and transverse myelitis). Incidence rates of AESIs were stratified by age, sex, and database. Rates were pooled across databases using random effects meta-analyses and classified according to the frequency categories of the Council for International Organizations of Medical Sciences. Results Background rates varied greatly between databases. Deep vein thrombosis ranged from 387 (95% confidence interval 370 to 404) per 100 000 person years in UK CPRD GOLD data to 1443 (1416 to 1470) per 100 000 person years in US IBM MarketScan Multi-State Medicaid data among women aged 65 to 74 years. Some AESIs increased with age. For example, myocardial infarction rates in men increased from 28 (27 to 29) per 100 000 person years among those aged 18-34 years to 1400 (1374 to 1427) per 100 000 person years in those older than 85 years in US Optum electronic health record data. Other AESIs were more common in young people. For example, rates of anaphylaxis among boys and men were 78 (75 to 80) per 100 000 person years in those aged 6-17 years and 8 (6 to 10) per 100 000 person years in those older than 85 years in Optum electronic health record data. Meta-analytic estimates of AESI rates were classified according to age and sex. Conclusion This study found large variations in the observed rates of AESIs by age group and sex, showing the need for stratification or standardisation before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases.