tbuckley/cabot-search huggingface dataset:
Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors
Authors: Matthew R. Fleming, Ling Xiao, Klarissa D. Jackson, Joshua A. Beckman, Ana Barac, Javid J. Moslehi
Journal: Circulation Research (2021)

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.
IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells
Authors: Ksenia Magidey-Klein, Tim J Cooper, Ksenya Kveler, Rachelly Normand, Tongwu Zhang, Michael Timaner, Ziv Raviv, Brian P. James, Roi Gazit, Ze'ev A. Ronai, Shai Shen-Orr, Yuval Shaked
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Metastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored. Methods We used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets. Results Mice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)–IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors—through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness. Conclusions Our study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.
Racial disparity in uterine cancer treatment and survival: A matter of Black women’s lives.
Authors: Alexandrina Balanean, Angelica Falkenstein, Marjorie E. Zettler, Andrew J. Klink, Kristin M. Zimmerman Savill, Jonathan Kish, Cherrishe Brown-Bickerstaff, Yolaine Jeune-Smith, Ajeet Gajra
Journal: Journal of Clinical Oncology (2021)

6550 Background: Despite similar incidence rates of uterine cancer (UC) in Black and White women, the former have worse prognosis and survival. Absence of denominator correction for UC hysterectomy (prevalence varies within the United States [US] by race/region) may underestimate incidence. The objective of this study is to compare treatment and survival of patients with UC by race in a large, contemporary, population-based study with at least 5 years of follow-up. Methods: With the latest available data from the Surveillance, Epidemiology, and End Results database, comparisons between Black and White patients were made using chi-square and Mann-Whitney tests. Cox proportional hazards regression estimated the adjusted risk of mortality by including age at diagnosis, race, US region, tumor histology/stage/grade, and receipt of hysterectomy as covariates. Results: A total of 105,036 women (11,028 Black and 94,008 White) newly diagnosed with UC in 2000-2013 and followed through 2018 were identified. Median age at diagnosis was 62 years, and more patients in the South were Black (41% vs 17%, P&lt;.0001). Higher rates of type 2 (15% vs 6%), late-stage (44% vs 28%), and high-grade (48% vs 25%) tumors at diagnosis were also found in Black women (all Ps&lt;.0001; Table). Compared with White women, Black women had lower 5-year survival rate (18% vs 37%, P&lt;.0001), shorter survival (median 49 vs 78 months, P&lt;.0001), and higher adjusted mortality risk (hazard ratio [HR]: 1.3, 95% CI: [1.3, 1.4], P&lt;.0001). Lack or unknown status of hysterectomy was also associated with higher death risk (HR: 3.6, 95% CI: [3.4, 3.9], P&lt;.0001). Conclusions: Correcting for hysterectomy attenuates racial disparity in incidence; however, black women have inferior outcomes primarily due to increased aggressive histology, late-stage, and high-grade tumors as well as decreased use of hysterectomy. Underestimation of at-risk populations may be misdirecting cancer control efforts, highlighting the importance of accurate reporting to inform potential treatment adaptations. Next steps are to assess cancer-specific mortality with Fine-Gray competing risk models.[Table: see text]
Treatment outcomes of stage IE intestinal extra-nodal marginal zone lymphoma: A National Cancer Database study.
Authors: Reggie M Thomes, Benjamin Marshall Parsons, Andrew J. Borgert, Susan M. Frankki
Journal: Journal of Clinical Oncology (2021)

e19530 Background: Extra-nodal marginal zone lymphoma is a rare, indolent non-Hodgkin lymphoma. Classically it involves the gastric mucosa and is associated with chronic infection, but it can also be found in the lower gastrointestinal (GI) tract. No standard therapy has been established for early stage disease in the small intestine, colon or rectum though multiple strategies have been employed. Little is known regarding the natural history and long-term outcomes of this disease when confined to the lower GI tract. We used the National Cancer Database (NCDB) to evaluate this patient population based upon treatment modality and disease site. Methods: Patients meeting the inclusion criteria were extracted from the 2017 Extra-Nodal Non-Hodgkin’s Lymphoma NCDB. Patients were grouped by primary treatment or observation status. Clinical and demographic factors were compared between the treatment groups via chi-square, Fisher’s exact and the Kruskal-Wallis tests. Comparison of Overall Survival (OS) between groups utilized either univariable log-rank comparison of the Kaplan-Meier estimator or multivariable Cox proportional hazards regression modelling, with patients censored at date of last contact. All analyses were performed with the SAS software suite, version 9.4. Results: 775 patients were identified with stage IE extra-nodal marginal zone lymphoma of the small intestine, colon or rectum with treatment and follow-up data. Prevalence increased over time. Median age at diagnosis was 65, with a ten-year overall survival for the entire cohort of 74.8% (69.8% - 79.0%). Location of disease was small intestine in 286 patients (36.9%), colon in 361 patients (46.6%) and rectum in 128 patients (16.5%). Ten-year overall survival was significantly worse for a small intestine primary site compared to colon and rectum primary sites (64.9% (55.6% - 72.6%) vs 81.5% (74.9% - 86.5%) and 80.9% (68.5% - 88.8%) respectively; p-value 0.013). Initial treatment was surgery in 361 patients (46.6%), radiation in 99 patients (12.8%), chemotherapy and/or immunotherapy in 120 patients (15.5%), and observation in 195 patients (25.1%). No significant differences in 5-year or 10-year survival were seen between treatment groups. Conclusions: Observation is a reasonable management strategy in patients with stage IE lower intestinal tract extra-nodal marginal zone lymphoma; survival is similar to those who received surgery, radiation or systemic therapy. Those with small intestine primary site had worse overall survival, irrespective of treatment modality, when compared to colon and rectum disease sites.
Breaking Links in the Chain of Racial Disparities for COVID-19
Authors: David W. Baker
Journal: JAMA Network Open (2021)

David A. Asch, MD, MBA; Md Nazmul Islam, PhD, MBA; Natalie E. Sheils, PhD; Yong Chen, PhD; Jalpa A. Doshi, PhD; John Buresh, MS; Rachel M. Werner, MD, PhD
Down regulation of the Rabphillin-3A-Like gene, located on 17p 13.3, is associated with the metastasis of colorectal adenocarcinoma.
Authors: Venkat Katkoori, Xu Jia, Chandrakumar Shanmugam, Selvarangan Ponnazhagan, Hui-Yi Lin, William E Grizzle, Upender Manne
Journal: Cancer Research (2008)

334  Background: Our previous studies have demonstrated that frequent allelic loss (60%) of Rabphillin-3A-Like gene (RPH3AL) was associated with nodal metastasis, early recurrence and patient poor survival in colorectal adenocarcinoma (CRC). In this study, we analyzed gene expression profiles of CRCs based on nodal metastasis to identify the involvement of RPH3AL in tumor progression.  Methods: Gene expression studies were performed on mRNAsamples extracted from fresh frozen CRCs and their matching control samples. TheAffymetrix Human Genome U133 Plus 2.0 arrays, which consistover 47,000 transcripts including wereused for these studies. Additionally, the gene chip data wereprocessed by using the Affymetrix Microarray Suite (MAS 5.0). The regulated genes were then classified using gene ontologyannotation and KEGG pathway. We estimated mRNA levels of RPH3AL by real-time reverse transcription-polymerase chain reaction (qRT-PCR). Phenotypic expression of RPH3AL was detected in 103 CRC tissues by immunohistochemistry (IHC) using polyclonal antibodies. We also performed cell migration assays in RPH3AL stably over expressing colon cancer cell lines.  Results: Microarray analysis based on nodal status has identified a distinct gene expression pattern. The list of 262 genes which are down-regulated in node positive CRCs includes RPH3AL , Protein Kinase C-beta1, Adenyl Succinate Synthase-Like 1, Cyclin-Dependent Kinase Inhibitor 1a , Glutathione S Transferase a1 and others. The list of 245 genes which are up-regulated in node positive CRCs includes Laminin Gamma 2, Glutathione Peroxidase 2, MAP Kinase Kinase Kinase 4, Matrix Metallo Peptidase 7, Matrix Metalloproteinase 11, Axin 2, Claudins 2 and 4, and others. Genes that were significantly down-regulated (≥ 4 folds change) were validated by estimating their mRNA levels. For examples, mRNA expression of RPH3AL was significantly reduced in CRCs with nodal metastasis (mean=0.20, range 0.012-0.98) when compared to their matching control tissues (2.36, 0.15-10.32) (p
EMBR-30. A NOVEL PLK1 INHIBITOR ONVANSERTIB EFFECTIVELY SENSITIZES GROUP 3 MEDULLOBLASTOMA TO RADIOTHERAPY
Authors: Dong Wang, Bethany Veo, Angela Pierce, Susan Foamier, Ilango Balakrishnan, Andrew Donson, Irina Alimova, Mark Erlander, Maya Ridinger, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is often accompanied by MYC amplification. PLK1 is an oncogenic kinase that controls cell cycle and proliferation, and it has been preclinically validated as a cancer therapeutic target. Onvansertib (PCM-075) is a novel, orally available PLK1 inhibitor, which shows tumor growth inhibition in many types of cancer. We examined the effect of Onvansertib on MYC-driven medulloblastoma as a monotherapy or in combination with radiation. A Crisper-Cas9 screen was used to discover essential genes for MB tumor growth. Microarray and immunohistochemistry on pediatric patient samples were performed to examine the expression of PLK1. The effect of Onvansertib in vitro was measure by cell viability, colony-forming assays, extreme limiting dilution assay, and RNA-Seq. ALDH activity, cell-cycle distribution, and apoptosis were analyzed by flow cytometry. DNA damage was assessed by immunofluorescence staining. Medulloblastoma xenografts were generated to explore the monotherapy or radio-sensitizing effect. PLK1 is overexpressed in Group 3 MB. The IC50 concentrations of Onvansertib in Group 3 MB cell lines were between 4.9 and 6 nM. Onvansertib reduced colony formation, cell proliferation, stem cell renewal, and induced G2/M arrest in vitro. Moreover, Onvansertib in combination with radiation increased DNA damage and apoptosis compared with radiation alone. The combination of Onvansertib with radiotherapy resulted in marked tumor regression in orthotopic xenografts. These findings suggest that Onvansertib is an effective strategy in combination with radiotherapy in MB.
Comments and Concerns on the LASER Trial
Authors: Sergio A. Acuna, Fahima Dossa, Tyler R. Chesney
Journal: JAMA Surgery (2021)

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Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity
Authors: Michael Hiltensperger, Eduardo Beltrán, Ravi Kant, Sofia Tyystjärvi, Gildas Lepennetier, Helena Domínguez Moreno, Isabel J. Bauer, Simon Grassmann, Sebastian Jarosch, Kilian Schober, Veit R. Buchholz, Selin Kenet, Christiane Gasperi, Rupert Öllinger, Roland Rad, Andreas Muschaweckh, Christopher Sie, Lilian Aly, Benjamin Knier, Garima Garg, Ali M. Afzali, Lisa Ann Gerdes, Tania Kümpfel, Sören Franzenburg, Naoto Kawakami, Bernhard Hemmer, Dirk H. Busch, Thomas Misgeld, Klaus Dornmair, Thomas Korn
Journal: Nature Immunology (2021)
Frequency of Administration of Standardized Screening Questions in Federally Qualified Health Centers
Authors: Jodi Simon, Jeffrey Panzer, Elizabeth Adetoro, Katherine M. Wright, Lisa Masinter, Nivedita Mohanty, Christine A. Sinsky
Journal: JAMA Internal Medicine (2021)

clude that the entities responsible for organizing this automated campaign cannot be determined, only public Facebook groups were studied, and only a single high-profile study over a few days was evaluated.Scientific journals are easy targets of automated software.Possible approaches to prevent misinformation due to dissemination of articles by automated software include legislation that penalizes those behind automation; greater enforcement of rules by social media companies to prohibit automation; and counter-campaigns by health experts.
Associations between patient-centered communication and quality of life in patients with ovarian cancer.
Authors: Rachel A. Pozzar, Niya Xiong, Fangxin Hong, Alexi A. Wright, Barbara Ann Goff, James A. Tulsky, Meghan Underhill-Blazey, Marilyn J. Hammer, Donna Lynn Berry
Journal: Journal of Clinical Oncology (2021)

12120 Background: Patient-centered communication (PCC) occurs when clinicians respond to patients’ needs, preferences, concerns, and emotions. The National Cancer Institute (NCI) Framework for PCC in Cancer Care highlights the potential of PCC to improve health-related quality of life (HRQoL), but to date few studies have empirically examined associations between PCC and HRQoL in patients with ovarian cancer. We assessed associations between perceived PCC and HRQoL in patients with ovarian cancer. Methods: Cross-sectional, descriptive survey of English-speaking adults with ovarian cancer recruited both online and from one NCI-designated cancer center. We assessed perceived PCC with the Patient-Centered Communication in Cancer Care (PCC-Ca)-36 and HRQoL with the Functional Assessment of Cancer Therapy: General (FACT-G). We used simple linear regression to identify univariate associations between participant characteristics, PCC-Ca-36 total, FACT-G total, and FACT-G subscale (physical, social and family, emotional, and functional well-being) scores. We identified significant predictors of FACT-G total and subscale scores by entering variables associated with each outcome at p ≤ 0.25 into a multiple linear regression model and using backward elimination. Results: One hundred seventy-six participants completed the survey. In multivariable analyses, older age, working (vs. not working), no current treatment (vs. any current treatment), and greater perceived PCC were associated with better overall HRQoL. Working and no current treatment were associated with better physical well-being. Older age, not being cared for by a gynecologic oncologist (vs. being cared for by a gynecologic oncologist), and greater perceived PCC were associated with better social and family well-being. Older age, being recruited online (vs. in clinic), and greater perceived PCC were associated with better emotional well-being. Older age, working, rural residence (vs. not), no current treatment, and greater perceived PCC were associated with better functional well-being (all p ≤ 0.05). Conclusions: Greater perceived PCC was significantly associated with better overall HRQoL and better social, emotional, and functional well-being in this cross-sectional study of patients with ovarian cancer. The NCI Framework for PCC in Cancer Care posits that PCC promotes HRQoL by strengthening the therapeutic alliance, enhancing social support, and improving patient knowledge. Although PCC is theorized to promote patient self-management, PCC was not significantly associated with physical well-being in this sample. Future research should (a) identify mediators of the associations between PCC and HRQoL; (b) examine inter-individual variability in characteristics that may compromise HRQoL; (c) and examine associations between PCC and HRQoL over time.
Complete ablation of tumors using synchronous chemoradiation with bimetallic theranostic nanoparticles
Authors: Hamed Nosrati, Elahe Attari, Fatemeh Abhari, Murat Barsbay, Mohammadreza Ghaffarlou, Navid Mousazadeh, Rasoul Vaezi, Taras Kavetskyy, Hamed Rezaeejam, Thomas J. Webster, Behrooz Johari, Hossein Danafar
Journal: Bioactive Materials (2021)

Synchronous chemotherapy and radiotherapy, termed chemoradiation therapy, is now an important standard regime for synergistic cancer treatment. For such treatment, nanoparticles can serve as improved carriers of chemotherapeutics into tumors and as better radiosensitizers for localized radiotherapy. Herein, we designed a Schottky-type theranostic heterostructure, Bi2S3-Au, with deep level defects (DLDs) in Bi2S3 as a nano-radiosensitizer and CT imaging contrast agent which can generate reactive free radicals to initiate DNA damage within tumor cells under X-ray irradiation. Methotrexate (MTX) was conjugated onto the Bi2S3-Au nanoparticles as a chemotherapeutic agent showing enzymatic stimuli-responsive release behavior. The designed hybrid system also contained curcumin (CUR), which cannot only serve as a nutritional supplement for chemotherapy, but also can play an important role in the radioprotection of normal cells. Impressively, this combined one-dose chemoradiation therapeutic injection of co-drug loaded bimetallic multifunctional theranostic nanoparticles with a one-time clinical X-ray irradiation, completely eradicated tumors in mice after approximately 20 days after irradiation showing extremely effective anticancer efficacy which should be further studied for numerous anti-cancer applications.
SARS-CoV-2 takes its Toll
Authors: Alan Sariol, Stanley Perlman
Journal: Nature Immunology (2021)

SARS-CoV-2 infection activates TLR2 signaling, which results in the robust expression of proinflammatory cytokines that may contribute to disease in severe COVID-19. Inhibition of this signaling pathway represents a potential target for COVID-19 therapeutics.