tbuckley/cabot-search huggingface dataset:
Abstract LB214: Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype
Authors: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Joseph Friedburg, Richard L. Eckert
Journal: Cancer Research (2021)

Abstract Mesothelioma is a fatal asbestos-caused cancer of the mesothelial cells that arises in the pleural and peritoneal cavities in response to asbestos exposure. ACTL6A is an important protein subunit of the SWI/SNF epigenetic regulatory complex but also has independent pro-cancer actions. It is frequently overexpressed in cancer and drives the malignant phenotype; however, it has not been studied in mesothelioma. In the present report, we show that ACTL6A drives mesothelioma cell proliferation, invasion and migration, and that these activities are markedly reduced in ACTL6A knockdown/knockout cells. Moreover, ACTL6A loss is associated with a significant increase in level of the p21Cip1 cyclin-dependent kinase inhibitor. ACTL6A binding to the proximal Sp1 and distal p53 sites on the p21Cip1 gene promoter is associated with reduced p21Cip1 promoter activity, and mRNA and protein level. Similar regulation was observed in cells derived from plural and peritoneal mesothelioma. Moreover, inhibiting the p21Cip1 increase in ACTL6A knockout cells reverses the reduction in cancer phenotype, suggesting the p21Cip1 is an authentic downstream mediator of ACTL6A action. These studies suggest that ACTL6A suppression of p21Cip1 expression contributes to the mesothelioma cell aggressive cancer phenotype and that inhibition of ACTL6A function may be a suitable mesothelioma cancer treatment strategy. Citation Format: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Joseph Friedburg, Richard L. Eckert. Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype [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 LB214.
Abstract 2932: Dysregulated metastatic capacity of ovarian cancer spheroids in response to physiologically relevant media conditions
Authors: Joseph Grieco, Stephanie Edwards Compton, James Smyth, Eva Schmelz
Journal: Cancer Research (2021)

Abstract Ovarian cancer is the deadliest gynecological cancer in women, with a survival rate of less than 30% when the cancer has spread throughout the peritoneal cavity. Aggregation of cancer cells increases their viability and metastatic potential; however, there are limited studies that correlate these functional changes to specific phenotypic alterations. In this study, we investigated how changes in media composition affects the metastatic potential of ovarian cancer cells. This was conducted by using aggregated ovarian cancer cells incubated in different media conditions supplemented with different levels of glucose, glutamine and serum. Additionally, we identified the adherence capacity through examining secretions and expression of extracellular matrix proteins as well as mitochondrial localization and quality control protein content that could support the viability of these aggregates. We determined that spheroid formation requires more glutamine and limited serum and glucose to allow for successful aggregation. Additionally, this media composition supports a more proliferative phenotype that closely resembles the high glucose controls. Low glucose and hypoxia also limit the ability of spheroids to adhere due to limited expression and secretion of collagen type I and fibronectin proteins. Further, we find that mitochondrial localization is promptly more affiliated with the adherence site of spheroids incubated in high glucose, high oxygen media in comparison to low glucose, hypoxic spheroids where mitochondrial localization is heavily dispersed. Finally, we find that mitophagy and mitobiogenesis are codependent in regulating mitochondrial content to support viability in cancer spheroids in peritoneal media conditions. Altogether, these data indicate that ovarian cancer spheroids adapt to non-permissive conditions through limiting their adherence capacity and upregulating mitochondrial quality control functions to support viability during dissemination. Citation Format: Joseph Grieco, Stephanie Edwards Compton, James Smyth, Eva Schmelz. Dysregulated metastatic capacity of ovarian cancer spheroids in response to physiologically relevant media conditions [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 2932.
Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression
Authors: L. C. Stetson, Dheepa Balasubramanian, Susan Pereira Ribeiro, Tammy Stefan, Kalpana Gupta, Xuan Xu, Slim Fourati, Anne Roe, Zachary Jackson, Robert Schauner, Ashish Sharma, Banumathi Tamilselvan, Samuel Li, Marcos de Lima, Tae Hyun Hwang, Robert Balderas, Yogen Saunthararajah, Jaroslaw Maciejewski, Thomas LaFramboise, Jill S. Barnholtz-Sloan, Rafick-Pierre Sekaly, David N. Wald
Journal: Leukemia (2021)
Tumor rejection in<i>Cblb</i><sup>−/−</sup>mice depends on IL-9 and Th9 cells
Authors: Oliver Schanz, Isabelle Cornez, Sowmya Parampalli Yajnanarayana, Friederike Sophie David, Sebastian Peer, Thomas Gruber, Peter Krawitz, Peter Brossart, Annkristin Heine, Jenny Landsberg, Gottfried Baier, Dominik Wolf
Journal: Journal for ImmunoTherapy of Cancer (2021)

Casitas B lymphoma-b (Cbl-b) is a central negative regulator of cytotoxic T and natural killer (NK) cells and functions as an intracellular checkpoint in cancer. In particular, Th9 cells support mast cell activation, promote dendritic cell recruitment, enhance the cytolytic function of cytotoxic T lymphocytes and NK cells, and directly kill tumor cells, thereby contributing to tumor immunity. However, the role of Cbl-b in the differentiation and antitumor function of Th9 cells is not sufficiently resolved. Using Cblb -/- mice, we investigated the effect of knocking out Cblb on the differentiation process and function of different T helper cell subsets, focusing on regulatory T cell (Treg) and Th9 cells. We applied single-cell RNA (scRNA) sequencing of in vitro differentiated Th9 cells to understand how Cbl-b shapes the transcriptome and regulates the differentiation and function of Th9 cells. We transferred tumor-model antigen-specific Cblb -/- Th9 cells into melanoma-bearing mice and assessed tumor control in vivo. In addition, we blocked interleukin (IL)-9 in melanoma cell-exposed Cblb -/- mice to investigate the role of IL-9 in tumor immunity. Here, we provide experimental evidence that Cbl-b acts as a rheostat favoring Tregs at the expense of Th9 cell differentiation. Cblb -/- Th9 cells exert superior antitumor activity leading to improved melanoma control in vivo. Accordingly, blocking IL-9 in melanoma cell-exposed Cblb -/- mice reversed their tumor rejection phenotype. Furthermore, scRNA sequencing of in vitro differentiated Th9 cells from naïve T cells isolated from wildtype and Cblb -/- animals revealed a transcriptomic basis for increased Th9 cell differentiation. We established IL-9 and Th9 cells as key antitumor executers in Cblb -/- animals. This knowledge may be helpful for the future improvement of adoptive T cell therapies in cancer.
Abstract 920: Harnessing multiple mechanisms of action to target Nectin-4 as anti-tumor therapeutics
Authors: Yi Pei, Thomas Pohl, Ahmed Hassan, Anna Przybyla, Raymond Yu, Huarui Lu, Fangqiang Tang, Kevin Chen, Wei Jin, Krizia Dominguez, Haichun Huang, Ming Lei, Zhong Liu, Han Li
Journal: Cancer Research (2021)

Abstract Nectin-4 belongs to an immunoglobulin superfamily (IgSF) of cell adhesion molecules that mediate cell-cell adhesion through homophilic or heterophilic interactions. In addition to the role in cell-cell adhesion, the Nectin family plays important role in regulating a diverse range of physiologic cellular activities, in viral entry, and in immune modulation. Nectin-4 has been reported to be upregulated in various epithelial cell cancers, such as breast cancer, lung cancer, and bladder cancer. The therapeutic value of Nectin-4 as an anti-tumor target has been demonstrated by a recently approved antibody-drug conjugate (ADC), Enfortumab vedotin. To fully exploit the potential of Nectin-4 as an anti-tumor target, we discovered a panel of monoclonal antibodies. These antibodies not only bind specifically to human Nectin-4 with high affinity, but also show differentiating characteristics including cell internalization, blockage of interaction with Nectin-1, blockage of interaction with TIGIT, and ADC-independent cytotoxicity. Our results suggest that in addition to ADC, other mechanisms targeting Nectin-4 can be utilized for therapeutics, such as immunomodulation and antibody- or immune cell-mediated tumor cell killing. Citation Format: Yi Pei, Thomas Pohl, Ahmed Hassan, Anna Przybyla, Raymond Yu, Huarui Lu, Fangqiang Tang, Kevin Chen, Wei Jin, Krizia Dominguez, Haichun Huang, Ming Lei, Zhong Liu, Han Li. Harnessing multiple mechanisms of action to target Nectin-4 as anti-tumor therapeutics [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 920.
Abstract 308: Therapeutic implications of silver nanoparticles in the management of skin cancer
Authors: Shaloam R. Dasari, Paul B. Tchounwou, Clement G. Yedjou, Robert T. Brodell, Allison Cruse
Journal: Cancer Research (2021)

Abstract Skin cancer (SC) is the most common carcinoma affecting 3 million people annually in the United Sates and millions of people worldwide. It is classified as melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC). NMSC represents approximately 80% of NMSC and includes squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). MSC, however, has a higher mortality rate than SC because of its ability to metastasize. SC is a major health problem in the United States with significant morbidity and mortality in the Caucasian population. Treatment options for SC include cryotherapy, excisional surgery, Mohs surgery, curettage and electrodessication, radiation therapy, photodynamic therapy, immunotherapy, and chemotherapy. Treatments are chosen based on the type of skin cancer and the potential for side effects. Novel targeted therapies are being used with increased frequency for large tumors and for metastatic disease. The objective of this review is to highlight new chemotherapeutic agents that utilize silver nanoparticles in the management of SC. A scoping literature search on PubMed, Google Scholar, and Cancer Registry websites revealed that traditional chemotherapeutic drugs have little effect against SC after the cancer has metastasized. Following a discussion of SC biology, epidemiology, and treatment options, this review focuses on the mechanisms of advanced technologies that use silver nanoparticles in SC treatment regimens. Citation Format: Shaloam R. Dasari, Paul B. Tchounwou, Clement G. Yedjou, Robert T. Brodell, Allison Cruse. Therapeutic implications of silver nanoparticles in the management of skin cancer [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 308.
Northern Ireland’s disintegrating secondary care services: more “reform” is not the solution
Authors: Nick Mann
Journal: BMJ (2021)

Smyth cites “long overdue structural reform” as a factor in the disintegration of Northern Ireland’s secondary care services.1 For decades, “reform” has been proposed as the solution to a serially underfunded NHS and social care system.

The NHS has endured these reforms while waiting lists have inexorably …
Association of single nucleotide polymorphisms in angiogenesis genes with expression of VEGF and VEGFR-2 in breast carcinoma.
Authors: Bradley Hancock, Milan Radovich, Sunil Badve, Mangesh Thorat, Faouzi Azzouz, Bryan Schneider
Journal: Cancer Research (2008)

288  Background: There is vast heterogeneity in the tumor expression of angiogenic proteins, namely Vascular Endothelial Growth Factor (VEGF) and its cognate receptor VEGF Receptor-2 (VEGFR-2). Single nucleotide polymorphisms (SNPs) are widely known to be a causative factor in the regulation of the expression of various genes. In this study, we sought to associate whether or not SNPs in the Hypoxia Inducible Factor-1α (HIF-1α), VEGF, VEGFR-1, VEGFR-2, endothelial Nitric Oxide Synthase (eNOS), Neuropilin-1 (NRP-1), or NRP-2 genes influence expression of angiogenic proteins in breast cancer tissues.  Methods: Forty-four cases of breast tumor tissues were obtained from the pathology archives at Indiana University. ER/PR, HER2 status as well as histologic grade were obtained for all specimens. DNA was extracted from tumor blocks, and genotyping was performed for the following SNPs: HIF-1α (P582S, A588T), VEGF (-2578C/A, -1498C/T, -1154 G/A, -634G/C, & 936C/T), VEGFR-1 (-962C/T), VEGFR-2 (V297I & Q472H), eNOS(-786T/C, E298D), NRP-1(F561L, V733I), NRP-2 (K123R). Subsequently, immunohistochemistry (IHC) for VEGF & VEGFR-2 was performed and an H-Score for each sample was determined. T-test and Fisher’s exact test were used to assess associations between polymorphisms and protein expression. IHC for microvessel density as well as mRNA quantification will be assessed.  Results: The VEGF-2578 A/-1498 C/-1154 G/-634 G/+936 C haplotype (freq.= 14%, H-Score=52) resulted in a significantly lower mean VEGFR-2 IHC H-Score when compared to the other two common haplotypes CTGGC (freq.= 28%, H-Score=124, p=.026) and CTGCC (freq.= 21%, H-Score=141, p=.012). No other associations between SNPs and protein expression of VEGF & VEGFR-2 were observed. Associations between genotype, protein expression, & microvessel density with known clinical variables are planned.  Conclusion: Our data support a novel association between the VEGF-2578 A/-1498 C/-1154 G/-634 G/+936 C haplotype and decreased VEGFR-2 expression in breast cancer. Previous reports of these SNPs have not shown association between polymorphic variability in the promoter of the VEGF ligand and its expression of its cognate receptor VEGFR-2. Elucidation of the mechanisms of polymorphic induced cross-talk between VEGF & VEGFR-2 is ongoing.
Imperative versus elective minimally-invasive partial nephrectomy: Results of a multi-institutional collaborative series
Authors: U. Anceschi, R.S. Flammia, A. Brassetti, G. Tuderti, M.C. Ferriero, A. Minervini, A. Mari, A. Grosso, M. Carini, U. Capitanio, A. Larcher, F. Montorsi, R. Autorino, A. Veccia, C. Fiori, D. Amparore, F. Porpiglia, D. Eun, J. Lee, I. Deerwesh, C. Sundaram, J. Steward, M. Gallucci, G. Simone
Journal: European Urology (2021)
Characteristics of Deaths Among Individuals in US Immigration and Customs Enforcement Detention Facilities, 2011-2018
Authors: Molly Grassini, Sophie Terp, Briah Fischer, Sameer Ahmed, Madeline Ross, Niels Frenzen, Elizabeth Burner, Parveen Parmar
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Concerns have been raised that substandard medical care has contributed to deaths in US Immigration and Customs Enforcement (ICE) detention facilities. After each in-custody death, ICE produces detainee death reviews, which describe the circumstances of the death and determine whether ICE Performance-Based National Detention Standards (PBNDS) were violated. <h3>Objective</h3> To describe factors associated with deaths in ICE detention facilities. <h3>Design, Setting, and Participants</h3> This case series used data extracted from detainee death reviews of deaths among individuals detained in ICE facilities for whom these reviews were available from January 2011 to December 2018. <h3>Exposures</h3> All individuals were in the custody of ICE at the time of death. <h3>Main Outcomes and Measures</h3> Data including demographic information, medical histories, recorded medical data, and reported violations of PBNDS were systematically extracted and summarized. <h3>Results</h3> Among 71 individuals who died in an ICE detention facility during the study period, detainee death reviews were available for 55 (77.5%). Most were male (47 [85.5%]), and the mean (SD) age at death was 42.7 (11.5) years. Individuals resided in the US for a mean (SD) of 15.8 (13.2) years before detention and were in ICE custody for a median of 39 days (interquartile range, 9-76 days) before death. Most had low burdens of preexisting disease, with 18 (32.7%) having a Charlson Comorbidity Index score of 0 and 15 (27.3%) having a score of 1 or 2. A total of 47 deaths (85.5%) were attributed to medical causes and 8 (14.5%) to suicide. Markedly abnormal vital signs were documented in the death reviews before 29 of 47 deaths from medical causes (61.7%), and 21 of these 29 deaths (72.4%) were preceded by abnormal vital signs during 2 or more encounters with ICE personnel before death or terminal hospital transfer. Overall, 43 detainee death reviews (78.2%) identified PBNDS violations related to medical care, with a mean (SD) of 3.2 (3.0) deficiencies per detainee death review. <h3>Conclusions and Relevance</h3> In this case series, deaths in ICE detention facilities from 2011 to 2018 occurred primarily among young men with low burdens of preexisting disease. Markedly abnormal vital signs preceded death or hospital transfer for most nonsuicide deaths. The PBNDS were violated in most detainee death reviews. These results suggest that additional oversight and external evaluation of practices related to medical and psychiatric care within ICE facilities are needed.
Adverse events of different chemotherapy regimens in the first-line treatment of patients with advanced or metastatic urothelial cancer: A systematic review and network meta-analysis of randomized controlled trials
Authors: E. Laukhtina, K. Mori, H. Mostafaei, A.S. Merseburger, P. Nyirady, M. Moschini, F. Quhal, B. Pradere, R. Sari Motlagh, V.M. Schuettfort, D. Enikeev, S.F. Shariat
Journal: European Urology (2021)
Pathological role of the prostaglandin E2-specific type E prostanoid receptors in hormone-sensitive and castration-resistant prostate cancer
Authors: K. Ohba, Y. Miyata, J. Harada, T. Matsuda, A. Otsubo, Y. Mukae, K. Mitsunari, T. Matsuo, H. Sakai
Journal: European Urology (2021)
Abstract 1896: The genomic features of Chinese cancer patients harboring HLA LOH
Authors: Jian Zhao, Jie Hu, Xiuqin Zhang, Xuan Gao, Fan Tong, Xiaorui Fu, Yuting Yi, Yanfang Guan, Xuefeng Xia, Jian'an Huang
Journal: Cancer Research (2021)

Abstract HLA LOH is an immune escape mechanism subject to microenvironmental selection pressures in tumor evolution. In previous study, the prevalence of HLA LOH in Chinese cancer patients has been characterized. However, the genomic features of patients harboring HLA LOH remains unknown. Methods The sequencing data of 1021 cancer genes from 1504 advanced patients across 11 diverse cancer types was analyzed to investigate the internal relationship between HLA LOH and genomic alteration. Exon 2, exon 3, and bilateral introns of HLA-A/B/C genes were well covered in the 1021-gene panel. HLA LOH was analyzed using the LOHHLA algorithm. Results Consistent with previous study, we found that the occurrence of HLA LOH is related to genomic instability. In colorectal cancer, the HLA LOH ratio of MSS samples was significantly higher than that of MSI-H samples. Among the remaining 10 cancer types, the trend was consistent (Table 1). These results revealed that HLA LOH is a potential immune escape mechanism for MSS patients. In NSCLC and BRCA, HLA LOH is associated with an elevated TMB (p&amp;lt;0.001, p&amp;lt;0,05). The alteration frequency of TP53 and LRP1B in HLA LOH group was significantly higher than that in HLA stable group (p&amp;lt;0.001, p=0.005, respectively). The occurrence of HLA LOH is also related to alterations in several important signaling pathways. The alteration frequencies of RTK/RAS pathway, p53 pathway, Notch pathway, Hippo pathway and Nrf2 pathway in the HLA LOH group were significantly higher than that in HLA stable group. These results are indicating that HLA LOH may mediate tumorigenesis by interfering with normal signaling transduction. Conclusions and Discussion Statistical results revealed that the occurrence of HLA LOH was related to genomic instability, including high TMB level and alterations in oncogenic signaling pathways, which may facilitate tumor formation. Overall, these findings may provide useful information for clinical practice and immunotherapy. The correlation between MSI stage and HLA LOHCancer TypesMSIHLA LOHHLA stablePercent with HLA LOHP valueColorectal cancerMSS617146.2%0.025MSI-H31416.7%Remaining 10 cancer typesMSS48549949.3%0.031MSI-H51525.0% Citation Format: Jian Zhao, Jie Hu, Xiuqin Zhang, Xuan Gao, Fan Tong, Xiaorui Fu, Yuting Yi, Yanfang Guan, Xuefeng Xia, Jian'an Huang. The genomic features of Chinese cancer patients harboring HLA LOH [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 1896.
Mesothelioma Risk Score: A New Prognostic Pretreatment, Clinical-Molecular Algorithm for Malignant Pleural Mesothelioma
Authors: Beow Y. Yeap, Assunta De Rienzo, Ritu R. Gill, Michela E. Oster, Mary N. Dao, Nhien T. Dao, Rachel D. Levy, Kimberly Vermilya, Corinne E. Gustafson, Gavin Ovsak, William G. Richards, Raphael Bueno
Journal: Journal of Thoracic Oncology (2021)