tbuckley/cabot-search huggingface dataset:
Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours
Authors: Kate Young, Rita T Lawlor, Chanthirika Ragulan, Yatish Patil, Andrea Mafficini, Samantha Bersani, Davide Antonello, David Mansfield, Sara Cingarlini, Luca Landoni, Antonio Pea, Claudio Luchini, Liliana Piredda, Nagarajan Kannan, Gift Nyamundanda, Daniel Morganstein, Ian Chau, Bertram Wiedenmann, Michele Milella, Alan Melcher, David Cunningham, Naureen Starling, Aldo Scarpa, Anguraj Sadanandam
Journal: Gut (2020)

Objective A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease. Design Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence. Results The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%–31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype. Conclusion This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.
Abstract 5343: Experimental targeted alpha-particle therapy against liver metastasis of HER2-positive gastric cancer in mice
Authors: Sumitaka Hasegawa, Huizi Keiko Li
Journal: Cancer Research (2020)

Abstract Gastric cancer (GC) is one of the common cancer type and a leading cause of cancer-related death worldwide. Liver metastasis of gastric cancer (LMGC) is often found in GC patients and a fatal condition that is hard to be cured. HER2 overexpression is detected in a subset of about 10-20% of GC. HER2-targeting antibody trastuzumab has been used clinically for the treatment against advanced GC positive for HER2. Recently, targeted alpha-particle therapy has emerged as a new therapeutic option of cancer. Radionuclide astatine-211 is produced by cyclotron and emits alpha-particle at its decay with about 7 hours-half-life. Alpha-particle beam induces irreparable DNA damages to kill the cells. Here we investigated the therapeutic efficacy and toxicities of At-211-armed trastuzumab in a mouse model of LMGC positive for HER2. Trastuzumab was conjugated with At-211 to produce alpha-emitting antibodies targeting HER2 ([At-211]-trastuzumab). To generate a mouse LMGC model, we injected luciferase-labelled HER2-positive human metastatic NCI-N87 GC cells into splenic vein of severe combined immunodeficiency mice. Bio-distribution data showed that the maximum uptake of [At-211]trastuzumab in the liver metastatic GC tumors was approximately 12% of injected dose per tissue gram at 24 hours after injection. [At-211]trastuzumab was excreted mostly in the urine. For experimental therapeutics, a single dose of systemic injection of [At-211]trastuzumab (1 MBq) significantly reduced a tumor burden in the liver to extend the survival of model mice significantly compared to controls. Transient leukocytopenia was observed in mice received 1 MBq of [At-211]trastuzumab at 5-7 days after injection. No body weight loss was so far found in the mice treated with [At-211]trastuzumab. No Biochemical abnormalities for Liver and kidney function were found. These data suggest that targeted alpha-particle therapy using [At-211]trastuzumab is effective for LMGC. Citation Format: Sumitaka Hasegawa, Huizi Keiko Li. Experimental targeted alpha-particle therapy against liver metastasis of HER2-positive gastric cancer in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5343.
Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes
Authors: Kohjiro Ueki, Takayoshi Sasako, Yukiko Okazaki, Kana Miyake, Masaomi Nangaku, Yasuo Ohashi, Mitsuhiko Noda, Takashi Kadowaki
Journal: Kidney International (2020)

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.
Abstract B60: Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid
Authors: Hsuan Shun Huang, Tang-Yuan Chu
Journal: Clinical Cancer Research (2020)

Abstract The etiology of ovarian high-grade serous ovarian cancers (HGSC) originating from the epithelium of fallopian tube fimbriae is elusive. Based on the incessant ovulation hypothesis, our previous studies found that ROS released during ovulation, collaborated with hemoglobin from retrograde menstruation, caused oxidative damage and DNA breaks to the fimbrial epithelial cells. Repeated exposures of ovulatory follicular fluid could induce tumorigenesis of in Trp53-null mice and transform human fimbrial epithelial cells (FE25) immortalized by E6/E7. In addition to mutagenic ROS, we later identified IGF-axis proteins abundantly present in follicular fluid (FF) are largely responsible for the stemness activation and transformation of FE25 cells. However, FF-IGF signal does not confer other key phenotypes induced by FF, such as mitogenesis and cell migration. In this study, we further clarified the role of HGF, another growth factor abundantly present in FF. Treating FE25 cells with pure HGF and IGF2 could fully recapitulate the anchorage-independent growth (AIG) activity of FF with equal colony number of 55±12 and 60±6, respectively. Inhibitor of HGF cMET receptor, AMG337, greatly reduced the AIG activity to 8±5 colonies. HGF is known to be activated by a cascade of activation by cleavage of its precursor pro-HGF and the precursor (pro-HGFA) of its activating protein HGFA. We found FF contains a high level of these pro-form proteins and a low amount of the cleaved active forms. Interestingly, these pro-form HGF axis proteins are extremely stable in FF. After one-month incubation at 37 degrees Celsius, they could still be activated and exerted AIG of FE25 cells. Once encountering the cell surface, protease cleavage is initiated to activated pro-HGFA to HGFA, which then cleaves pro-HGF to HGF. Via the c-MET/AKT/ERK signaling, the activated HGF confers the mitogenic and transformation activity of FF. In FF, HGF seems to cooperate with IGF2 to sustain a long-term proliferation of fimbrial epithelial cells initiated by ROS-induced mutagenesis and clonally expanded by IGF axis signaling. A reservoir of durable pro-forms of HGFA and HGF are responsible for this sustained transformation activity. Thus, the mutagenic, clonogenic, and sustained mitogenic activities in FF strongly support the incessant ovulation theory with ovulatory carcinogens to be the culprit. Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B60.
Abstract 4458: New HDAC inhibitor (M166) has a synergistic effect with immune checkpoint inhibitor in lung cancer treatment
Authors: Sung Yong Lee, Hyun-Seock Shin, Juwhan Choi
Journal: Cancer Research (2020)

Abstract Recently, Immune checkpoint inhibitor (ICI) has been widely applied to various types of cancer therapies and it is used as a treatment in clinical application. ICI has a higher effect on lung cancer than other cancers; however, the treatment efficiency is only about 25%. Therefore, many research groups are making efforts to improve treatment efficiency with co-treatment therapy using chemical medications and ICIs. We evaluated the efficacy of a new PAN-HDAC inhibitor (M166) and ICI. M166 showed growth inhibition in mouse lung cancer cell (TC-1) line, mouse lung carcinoma (LLC) and human lung cancer cell (A549) line compared with normal epithelial cell lines (NIH3T3 and HEK293. Also, we checked ten kinds of immune-related cytokines and chemokines in mRNA level by treated with M166 using RT-PCR methods. CCL2 and CXCL10 chemokines are significantly increased by dose-dependently. These results indicate that M166 regulates immune response by CCL2 and CXCL10 chemokine related pathways. In order to check the synergistic effect of ICI plus HDACi co-treatment, we explored the employment of M166 in combination with ICI in a preclinical mouse model. For in vivo experiment, the mice were divided into four groups: group 1 received no treatment after the E7-expressing TC-1 tumor challenge, group 2 was treated with M166, group 3 was treated with mouse PD-1 antibody, and group 4 was both treated with M166 and mouse PD-1 antibody. The combination therapy of M166 and mouse PD-1 antibody significantly inhibited tumor growth. These results indicate that ICI plus HDACi treatment induces tumor growth inhibition through an immune response. These findings have important implications for future clinical translation. Citation Format: Sung Yong Lee, Hyun-Seock Shin, Juwhan Choi. New HDAC inhibitor (M166) has a synergistic effect with immune checkpoint inhibitor in lung cancer treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4458.
Abstract 4647: Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study
Authors: Hung N. Luu, Nithya Neelakantan, Ting-ting Geng, Renwei Wang, Jennifer Adams-Haduch, Aizhen Jin, Rob M. Van Dam, Woon-Puay Koh, Jian-Min Yuan
Journal: Cancer Research (2020)

Abstract Background. There is a limited research on the association between combined dietary measures and liver cancer risk. We investigated the association between the four diet-quality index (DQI) scores, the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED); Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI) with liver cancer risk, using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up. Methods. The Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with each DQI after adjustment for multiple potential confounders. The unconditional logistic regression method was used to evaluate the associations between the DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). Results. During an average 17.7 years of follow-up, 561 incident HCC cases were identified. High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend&amp;lt;0.05). Compared with the lowest quartile, HRs (95% CIs) of HCC risk for the highest quartile of AHEI-2010, aMED and DASH were 0.71 (0.55-0.91), 0.73 (0.54-0.98), and 0.68 (0.52-0.89), respectively. These inverse associations were stronger in men than in women. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED that reached statistically significance level (HRQ4vsQ1=0.48, 95% CI: 0.24-0.98). Conclusion. Higher scores of AHED, aMED, and DASH were significantly associated with reduced risk of HCC in this Asian population. The findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC. Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876). Citation Format: Hung N. Luu, Nithya Neelakantan, Ting-ting Geng, Renwei Wang, Jennifer Adams-Haduch, Aizhen Jin, Rob M. Van Dam, Woon-Puay Koh, Jian-Min Yuan. Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4647.
Nonfatal Occupational Injuries to Younger Workers — United States, 2012–2018
Authors: Rebecca J. Guerin, Audrey A. Reichard, Susan Derk, Kitty J. Hendricks, Lauren M. Menger-Ogle, Andrea H. Okun
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Adolescents and young adults represent approximately 13% of the U.S. workforce (1). Compared with adult workers, young workers (aged 15-24 years) experience higher rates of job-related injury (2,3). To describe injuries among young workers and inform research and prevention activities, CDC's National Institute for Occupational Safety and Health (NIOSH) analyzed national data for 2012-2018 from the occupational supplement to the National Electronic Injury Surveillance System* (NEISS-Work) and for 2018 from the Bureau of Labor Statistics (BLS) Survey of Occupational Injuries and Illnesses (SOII).† During the 7-year period, an estimated 3.2 million (95% confidence interval [CI] = 2.6-3.7) nonfatal, job-related injuries to young workers were treated in hospital emergency departments (EDs). From 2012 to 2018, annual rates of work-related injuries§ treated in the ED (ED-treated injuries) declined overall across all age groups but ranged from 1.2 to 2.3 times higher for workers aged 15-24 years compared with those for adults aged 25-44 years. Workers aged 18-19 years had the highest rate of ED-treated injuries. In 2018, among all age groups, workers in service occupations¶ had the highest percentage of injuries requiring at least 1 day away from work. Among workers aged 15-17 years, those in the leisure and hospitality industry had the highest percentage of work-related injuries requiring at least 1 day away from work. Occupational injuries can have long-term impacts on health (4). The disproportionate risk of injury among young workers highlights the need for sustained, targeted public health efforts to prepare this population with essential workplace safety and health competencies before they enter the workforce and to provide high-quality safety training and close supervision on the job. NIOSH and its partners developed a free curriculum to teach adolescents workplace safety and health competencies, which includes identification of workplace hazards and methods for addressing them, how to understand their rights and responsibilities as workers, and how to voice concerns about work safety issues (5).
Abstract 1557: Landscape of tumor cell states and cellular ecosystems in diffuse large B cell lymphoma
Authors: Chloe B. Steen, Bogdan Luca, Mohammad S. Esfahani, Barzin Y. Nabet, Brian Sworder, Farshad Farshidfar, David Kurtz, Chih Long Liu, Ranjana H. Advani, Yasodha Natkunam, June H. Myklebust, Maximilian Diehn, Andrew Gentles, Ash Alizadeh, Aaron M. Newman
Journal: Cancer Research (2020)

Abstract The tumor microenvironment (TME) plays critical roles in cancer development, tumor progression, and susceptibility to therapy. However, the phenotypic states and interaction patterns of its underlying cell types remain poorly understood. To address this challenge, we developed a new computational framework, EcoTyper, for large-scale dissection of cell states and cellular communities (i.e., ecosystems) from tumor genomic profiles. EcoTyper integrates single-cell RNA sequencing (scRNA-seq) with CIBERSORTx, an algorithm for bulk RNA-seq deconvolution (Newman et al., Nat Biotechnol, 2019), to identify and validate cellular states and ecosystems that reflect fundamental distinctions in TME biology. Here we applied EcoTyper to diffuse large B cell lymphoma (DLBCL), an aggressive B cell malignancy with clinically distinct molecular subtypes and several immunologically-active therapies. We sought to determine whether EcoTyper could reveal novel biological variation in the DLBCL TME linked to tumor subtypes and genotypes, therapeutic responses, and clinical outcomes. We applied our approach to define transcriptional states from 13 cell types, including malignant, immune, and stromal cells, in over 1,500 DLBCL tumors. Remarkably, nearly all cell states identified by EcoTyper were validated in independent scRNA-seq and bulk RNA-seq datasets. Moreover, many cells states reflected novel phenotypic groupings, and the majority showed strong associations with overall survival, specific mutational profiles, and tumor molecular subtypes. Additionally, by identifying DLBCL tumors with similar communities of cellular states, we defined novel cellular ecosystems, or “ecotypes”, with distinct biological characteristics and clinical outcomes. Several ecotypes showed significant enrichments in canonical or novel tumor genotypes, suggesting an evolutionary interplay between the tumor and host TME. In summary, we developed a novel computational framework to dissect the TME at scale and present the most comprehensive atlas to date of cell states and cellular communities in DLBCL. Our approach is extensible to nearly any cancer type and may lead to the development of novel diagnostics and individualized immunotherapies. Citation Format: Chloe B. Steen, Bogdan Luca, Mohammad S. Esfahani, Barzin Y. Nabet, Brian Sworder, Farshad Farshidfar, David Kurtz, Chih Long Liu, Ranjana H. Advani, Yasodha Natkunam, June H. Myklebust, Maximilian Diehn, Andrew Gentles, Ash Alizadeh, Aaron M. Newman. Landscape of tumor cell states and cellular ecosystems in diffuse large B cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1557.
Abstract 4873: Molecular mechanism of neddylation-dependent suppression of cancer cell migration
Authors: Yang-Sook Chun, Jieun Seo, Jun Bum Park
Journal: Cancer Research (2020)

Abstract Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor-1α through the PI3K-Akt pathway, which eventually regulates the EMT-activator zinc finger E-box binding homeobox 1 in various cancer cell lines. As induction of hypoxia-inducible factor-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the novel association of hypoxia-inducible factor-1α and zinc finger E-box binding homeobox 1 through the process of neddylation. Citation Format: Yang-Sook Chun, Jieun Seo, Jun Bum Park. Molecular mechanism of neddylation-dependent suppression of cancer cell migration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4873.