tbuckley/cabot-search huggingface dataset:
Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic
Authors: Elizabeth A. Griffiths, Laura M. Alwan, Kimo Bachiashvili, Anna Brown, Rita Cool, Peter Curtin, Mark B. Geyer, Ivana Gojo, Avyakta Kallam, Wajih Z. Kidwai, Dwight D. Kloth, Eric H. Kraut, Gary H. Lyman, Sudipto Mukherjee, Lia E. Perez, Rachel P. Rosovsky, Vivek Roy, Hope S. Rugo, Sumithira Vasu, Martha Wadleigh, Peter Westervelt, Pamela S. Becker
Journal: Journal of the National Comprehensive Cancer Network (2021)

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.
Modeling tumor development and metastasis using paired organoids derived from patients with colorectal cancer liver metastases
Authors: He Li, Weixing Dai, Xi Xia, Renjie Wang, Jing Zhao, Lingyu Han, Shaobo Mo, Wenqiang Xiang, Lin Du, Guangya Zhu, Jingjing Xie, Jun Yu, Nan Liu, Mingzhu Huang, Jidong Zhu, Guoxiang Cai
Journal: Journal of Hematology & Oncology (2020)

Abstract Tumor metastasis accounts for the majority of cancer-related deaths; it is therefore important to develop preclinical models that faithfully recapitulate disease progression. Here, we generated paired organoids derived from primary tumors and matched liver metastases in the same colorectal cancer (CRC) patients. Despite the fact that paired organoids exhibit comparable gene expression and cell morphology, organoids from metastatic lesions demonstrate more aggressive phenotypes, tumorigenesis, and metastatic capacity than those from primary lesions. Transcriptional analyses of the paired organoids reveal signature genes and pathways altered during the progression of CRC, including SOX2. Further study shows that inducible knockdown of SOX2 attenuated invasion, proliferation, and liver metastasis outgrowth. Taken together, we use patient-derived paired primary and metastatic cancer organoids to model CRC metastasis and illustrate that SOX2 is associated with CRC progression and may serve as a potential prognostic biomarker and therapeutic target of CRC.
Abstract 5761: Trends and regional distribution pattern of female lung cancer in China from 1992 to 2016
Authors: Xue Ni, Bei Zhang, Ning Xu, Xinying Zeng, Qiang Wang
Journal: Cancer Research (2020)

Abstract Background: The risk factors of female lung cancer in China are still unclear. The growing trend of lung cancer in Chinese women has become a global concern of public health. This study aims to explore the secular trends and regional distribution of female lung cancer in China. Method: The results of global burden of disease (GBD 2016) and the world standard population database (WHO 2000-2025) were used to extract age- sex- and province-specific incidence, mortality, and years of life lost due to premature death (YLL) for this report. The Joinpoint regression analysis was applied to fit the secular female lung cancer trends of age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and YLL rate for China and its 33 provincial administrative regions in 1992-2016. Result: From 1992 to 2016, the secular trend of female lung cancer incidence in China rose upward and the trend of mortality or rate of YLL fell down. The average annual percent change (AAPC) of the ASIR, ASMR, and YLL rate were 0.7 (95%CI: 0.6,0.8%), -0.3% (95%CI: -0.5, -0.2%), and -0.7 (95%CI: -0.8, -0.6%) respectively. However, the secular trends among 33 provincial units are inconsistent. There were 5 regional patterns of joint trends in ASIR, ASMR, and YLL rate among 33 provinces, autonomous regions, and municipalities. Conclusion: The regional pattern of the trends of female lung cancer in China suggested that the prevention and control of female lung cancer should be taken with targeted regional interventions. Citation Format: Xue Ni, Bei Zhang, Ning Xu, Xinying Zeng, Qiang Wang. Trends and regional distribution pattern of female lung cancer in China from 1992 to 2016 [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 5761.
Readmissions Reduction Program: Mortality and Readmissions for Chronic Obstructive Pulmonary Disease
Authors: Daniel A. Puebla Neira, En Shuo Hsu, Yong-Fang Kuo, Kenneth J. Ottenbacher, Gulshan Sharma
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Implementation of the Hospital Readmissions Reduction Program (HRRP) following discharge of patients with chronic obstructive pulmonary disease (COPD) has led to a reduction in 30-day readmissions with unknown effects on postdischarge mortality.Objectives: To examine the association of HRRP with 30-day hospital readmission and 30-day postdischarge mortality rate in patients after discharge from COPD hospitalization.Methods: Retrospective cohort study of readmission and mortality rates in a national cohort (N = 4,587,542) of admissions of Medicare fee-for-service beneficiaries 65 years or older with COPD from 2006 to 2017.Measurements and Main Results: Data were analyzed for three nonoverlapping periods based on implementation of the HRRP specific to COPD: 1) preannouncement (December 2006 to March 2010), 2) announcement (April 2010 to August 2014), and 3) implementation (October 2014 to November 2017). The 30-day readmission rate decreased from 20.54% in the preannouncement period (December 2006 to July 2008) to 18.74% in the implementation period (May 2016 to November 2017). The 30-day risk-standardized postdischarge mortality rates were 6.91%, 6.59%, and 7.30% for the preannouncement, announcement, and implementation periods, respectively. Generalized estimating equations analyses estimated an additional 1,196 deaths (October 2014 to April 2016) and 3,858 deaths (May 2016 to November 2017) during the HRRP implementation period.Conclusions: We found a reduction in 30-day all-cause readmission rate during the implementation period compared with the preannouncement phase. HRRP implementation was also associated with a significant increase in 30-day mortality after discharge from COPD hospitalization. Additional research is necessary to confirm our findings and understand the factors contributing to increased mortality in patients with COPD in the HRRP implementation period.
No evidence of SARS-CoV-2 transfusion transmission despite RNA detection in blood donors showing symptoms after donation
Authors: Pierre Cappy, Daniel Candotti, Virginie Sauvage, Quentin Lucas, Laure Boizeau, Johanna Gomez, Vincent Enouf, Lila Chabli, Josiane Pillonel, Pierre Tiberghien, Pascal Morel, Syria Laperche
Journal: Blood (2020)
Clinical Dissection of Infectious Event Following ATG Treatment for Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome Reveals Urgent Need for Anti-Aspergillus Prophylaxis
Authors: Hee-Ryeong Jang, Sung-Soo Yoon, Inho Kim, Soo-Mee Bang, Junshik Hong, Dong-Yeop Shin, Ji Yun Lee, Jeong-Ok Lee, Byung-Su Kim, Hyo Jung Kim, Wan Beom Park, Nam Joong Kim, Youngil Koh
Journal: Blood (2017)
How Can Hearing Loss Cause Dementia?
Authors: Timothy D. Griffiths, Meher Lad, Sukhbinder Kumar, Emma Holmes, Bob McMurray, Eleanor A. Maguire, Alexander J. Billig, William Sedley
Journal: Neuron (2020)

Epidemiological studies identify midlife hearing loss as an independent risk factor for dementia, estimated to account for 9% of cases. We evaluate candidate brain bases for this relationship. These bases include a common pathology affecting the ascending auditory pathway and multimodal cortex, depletion of cognitive reserve due to an impoverished listening environment, and the occupation of cognitive resources when listening in difficult conditions. We also put forward an alternate mechanism, drawing on new insights into the role of the medial temporal lobe in auditory cognition. In particular, we consider how aberrant activity in the service of auditory pattern analysis, working memory, and object processing may interact with dementia pathology in people with hearing loss. We highlight how the effect of hearing interventions on dementia depends on the specific mechanism and suggest avenues for work at the molecular, neuronal, and systems levels to pin this down.
Abstract 3155: Interferon-gamma-induced melanoma plasticity and response to PD-1 blockade therapy
Authors: Yeon Joo Kim, Katherine M. Sheu, Jennifer Tsoi, Gabriel Abril-Rodriguez, Catherine Grasso, Alexander Hoffmann, Stephen T. Smale, Thomas G. Graeber, Cristina Puig-Saus, Antoni Ribas
Journal: Cancer Research (2020)

Abstract Melanoma is a cancer of melanocytes, which develop from neural crest cells during embryogenesis. One of the ways melanoma can resist targeted therapy or adoptive T cell transfer therapy (ACT) is by dedifferentiation, whereby the tumor becomes less melanocytic and more neural crest-like. ACT-induced dedifferentiation and therapy resistance was a result of tumor necrosis factor (TNF) from antitumor T cells (Landsberg, Nature 2012), which can serve as a positive control for inflammatory cytokine-induced melanoma plasticity. To study whether immune checkpoint blockade induces melanoma dedifferentiation, we analyzed RNA-seq data from paired biopsies of 68 patients before and during anti-PD-1 therapy. Surprisingly, the tumors of patients with complete or partial response dedifferentiate following therapy (paired p= 0.00015), but those of stable or progressive disease do not (paired p= 0.31 and 0.32, respectively). As the presence of interferon-gamma signatures in biopsies is best correlated with response to anti-PD-1 therapy, we hypothesized that interferon-gamma mediates dedifferentiation. We dedifferentiated four human melanoma cell lines by in vitro exposure to long-term (three to five weeks) interferon-gamma and compared it to three days of TNF as positive control. Although TNF and long-term interferon-gamma induced similar phenotypic changes based on flow cytometry, ATAC-seq showed that they each drive different global chromatin remodeling. Motif enrichment analyses revealed STAT6, TFAP2C, and SOX proteins are key transcription factors involved in interferon-gamma-induced dedifferentiation. Inferred protein activity analysis of the matching RNA-seq data showed that these regulators, as well as IRF3 and HMGA1, alter in activity selectively with dedifferentiation. In conclusion, dedifferentiation may be a marker of positive response to anti-PD-1 therapy, mediated by chronic exposure to T cells producing interferon-gamma. Citation Format: Yeon Joo Kim, Katherine M. Sheu, Jennifer Tsoi, Gabriel Abril-Rodriguez, Catherine Grasso, Alexander Hoffmann, Stephen T. Smale, Thomas G. Graeber, Cristina Puig-Saus, Antoni Ribas. Interferon-gamma-induced melanoma plasticity and response to PD-1 blockade therapy [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 3155.
Abstract 2838: Peritoneal immune evasion can be overcome with STING agonist treatment in peritoneal carcinomatosis of colon cancer
Authors: Hannah Yang, Seung Jun Lee, Yu Seong Lee, Won Suk Lee, So Jung Kong, Beodeul Kang, Hong Jae Chon, Chan Kim
Journal: Cancer Research (2020)

Abstract Introduction: Peritoneal immune system plays an important role during the peritoneal dissemination of colon cancers. Therefore, tumor-induced T cell anergy in peritoneal cavity could lead to immune evasion and the progression of peritoneal carcinomatosis. Here, we aimed to reverse the immune evasion in peritoneal cavity and effectively suppress the peritoneal carcinomatosis of colon cancer by STING-based immunotherapy. Methods: We established an animal model of peritoneal carcinomatosis by intraperitoneal injection of MC38 colon cancer cells to C57BL/6 mice. Temporal changes in peritoneal immune microenvironment during peritoneal tumor dissemination were first characterized by analyzing tumor nodules, malignant ascites, and peritoneum lavage by flow cytometry. Then, tumor-bearing mice were treated with either STING agonist (ADU-S100), and/or anti-PD-1 antibody. Tumor burden and the volume of ascites were assessed after the treatment. The tumors were analyzed with flow cytometric, histologic, and RNA sequencing analyses. Results: The intraperitoneal inoculation of MC38 colon cancer cells led to dramatic immune cell changes in peritoneal cavity. While the number of myeloid-derived suppressor cells (MDSCs) were markedly increased, the number of CD8+ T cells and dendritic cells gradually decreased after initial influx in the peritoneal cavity. Treatment with STING agonist remarkably suppressed the growth of peritoneal seeding nodules (75%). Moreover, normalization and reduction of peritoneal tumor blood vessels resulted in an overt decrease in malignant ascites (85%) in the peritoneal cavity after STING agonist treatment. In addition, the number of dendritic cells and CD8+ T cells had markedly increased, but that of MDSCs was decreased in the peritoneal cavity. Moreover, the number of IFN-gamma-secreting cytotoxic T cells were increased in tumor nodules and peritoneal cavity after STING agonist treatment. Finally, the combination immunotherapy of STING agonist and anti-PD1 antibody induced stronger adaptive immunity against peritoneal carcinomatosis than monotherapy and showed potent anti-cancer activity with reduced ascites formation. Conclusion: STING immunotherapy can normalize peritoneal tumor vasculature and immune system, and synergize with immune checkpoint blockade to control peritoneal carcinomatosis of colon cancer. Citation Format: Hannah Yang, Seung Jun Lee, Yu Seong Lee, Won Suk Lee, So Jung Kong, Beodeul Kang, Hong Jae Chon, Chan Kim. Peritoneal immune evasion can be overcome with STING agonist treatment in peritoneal carcinomatosis of colon cancer [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 2838.
Abstract 3348: Exogenous DNA upregulates DUOX2 expression in pancreatic cancer via activation of the cGAS-STING signaling pathway
Authors: Stephen L. Wang, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Jennifer Meitzler, Goujian Jiang, Iris Dahan, Jiamo Lu, Krishnendu Roy, James Doroshow
Journal: Cancer Research (2020)

Abstract Dual oxidase 2 (DUOX2) is a transmembrane protein that produces hydrogen peroxide in the extracellular environment, mediates innate immunity at mucosal surfaces, contributes to chronic inflammation-related tissue injury and angiogenesis, and can promote the initiation of epithelial-derived cancers. In pancreatic adenocarcinomas (PDAC), the composition of the tumor microbiome significantly affects patient outcomes. However, it remains unclear how microbes in the tumor microbiome affect PDAC on a cellular level. In recent years, the cGAS-STING signaling pathway has been identified as a crucial mediator of anti-viral defense by recognizing the presence of DNA in the cytosol and subsequently producing Type I interferons (IFNs) as well as a host of other anti-viral genes. Using Western blot and qPCR, we show that the introduction of exogenous DNA into the cytosol significantly upregulates DUOX2 expression in human PDAC cells after activating cGAS-STING signaling. Expression of DUOX2 occurs most strongly 2 days post-transfection of DNA, while cGAS-STING signaling is activated within hours. Treatment of BxPC-3 cells with exogenous cyclic GMP-AMP (cGAMP) for 24 hrs increases DUOX2 expression in a concentration-dependent manner, suggesting the necessity of cGAS activity for DUOX2 induction. Furthermore, Western analysis of phospho-NF-κB p65 in BxPC-3 cells demonstrates activation of NF-κB that mirrors the time-dependent induction of DUOX2. In CFPAC-1 cells, another PDAC line, Jak-Stat signaling is activated along with the components of cGAS-STING. These data suggest that DNA-induced DUOX2 upregulation in PDAC cells may be mediated in a cell context-specific fashion, beyond the canonical components of the cGAS-STING pathway. Upregulation of DUOX2 by exogenous DNA is not observed in colon cancer cell lines. In summary, these data suggest that extracellular DNA could contribute to a DUOX2-induced, H2O2-mediated pro-inflammatory milieu that specifically contributes to the pathogenesis of PDAC, in part through activation of the cGAS-STING pathway. Citation Format: Stephen L. Wang, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Jennifer Meitzler, Goujian Jiang, Iris Dahan, Jiamo Lu, Krishnendu Roy, James Doroshow. Exogenous DNA upregulates DUOX2 expression in pancreatic cancer via activation of the cGAS-STING signaling pathway [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 3348.
Abstract 3643: HDAC6 modulates colon cancer cell migration and invasion
Authors: Hui Li
Journal: Cancer Research (2020)

Abstract Introduction: Non-histone protein acetylation in cancer cell regulates diverse biological functions that have been associated with tumorigenesis and cancer progression. HDAC6 is a tubulin-specific deacetylase which regulates microtubule-dependent cell movement. Here we investigated the role of HDAC6 on colon cancer progression. Methods: Colon tumor tissues were analyzed by immunohistochemistry to measure the expression of HDAC6. Attenuation of HDAC6 function was achieved using either inhibitors (Tubastatin and ACY-738) or siRNAs. Cell migration and invasion were determined using transwell assays. CCK8 and flow cytometry were used to assess the cell proliferation and cell survival respectively. We performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. Immunoprecipitation assay was used to determine protein acetylation level and protein-protein interaction. Results: We identified that HDAC6 was highly expressed in metastatic colon cancer than non-metastatic colon cancer, indicating that HDAC6 is related with tumor metastasis. Selective suppression of HDAC6 or knocking down of HDAC6 significantly decreased colon cancer cell migration and invasion ability in vitro, without affecting cell proliferation and cell survival. In order to further clarify the role of HDAC6 in cell motility, we employed mass spectrometry-based label-free quantitative proteomics using human colon cancer cell line. We identified 42 proteins with &amp;gt; 2-fold increase of the acetylation level in the absence of HDAC6. These proteins are significantly enriched in processes related to cell-cell adhesion, cell division and several signaling pathways including cAMP and FoxO signaling pathway. We selected ENAH, an actin associated protein, as a potential new substrate of HDAC6, which has been previously reported to play important roles in cytoskeleton remodeling and cell polarity establishment. Immunoprecipitation analysis showed that HDAC6 can associate with ENAH under physical conditions. Besides, ENAH showed elevated acetylation in response to HDAC6 deletion. Conclusions: Our findings showed that inhibition of HDAC6 decreased the colon cancer cell migration and metastasis probably through regulating the acetylation level of ENAH. Our study also provided a resource of putative cytoplasmic targets of this deacetylase for further investigation. Considering that small molecule compounds targeting HDACs are currently undergoing clinical trials for the treatment of cancer, a better understanding of HDAC6-dependent cellular processes would be highly valuable for the evaluation of the clinical relevance and therapeutic efficacy of HDAC6 inhibitors. Citation Format: Hui Li. HDAC6 modulates colon cancer cell migration and invasion [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 3643.
Representation of Women in Cardiovascular Clinical Trial Leadership
Authors: Kara J. Denby, Natalie Szpakowski, Julie Silver, Mary Norine Walsh, Steve Nissen, Leslie Cho
Journal: JAMA Internal Medicine (2020)

Jessica A. Gold, MD, MS; Danielle Roubinov, PhD; Lena S. Jia, MPHS; Kent A. Griffith, MPH, MS; John M. Carethers, MD, MACP; Christina Mangurian, MD, MAS; Reshma Jagsi, MD, DPhil
The Adaptive Potential of the Middle Domain of Yeast Hsp90
Authors: Pamela A Cote-Hammarlof, Inês Fragata, Julia Flynn, David Mavor, Konstantin B Zeldovich, Claudia Bank, Daniel N A Bolon
Journal: Molecular Biology and Evolution (2020)

The distribution of fitness effects (DFEs) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in others. So far, results regarding the cost of adaptation across environments have been mixed, and most studies have sampled random mutations across different genes. Here, we quantify systematically how costs of adaptation vary along a large stretch of protein sequence by studying the distribution of fitness effects of the same ≈2,300 amino-acid changing mutations obtained from deep mutational scanning of 119 amino acids in the middle domain of the heat shock protein Hsp90 in five environments. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-terminal-Middle and Middle-C-terminal interdomains, and regulation of ATPase-chaperone activity. Interestingly, we find that fitness correlates well across diverse stressful environments, with the exception of one environment, diamide. Consistent with this result, we find little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client-binding interfaces, or residues that are involved in ATPase-chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information.