tbuckley/cabot-search huggingface dataset:
Cryptosporidiosis Outbreaks — United States, 2009–2017
Authors: Radhika Gharpure, Ariana Perez, Allison D. Miller, Mary E. Wikswo, Rachel Silver, Michele C. Hlavsa
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Cryptosporidium is a parasite that causes cryptosporidiosis, a profuse, watery diarrhea that can last up to 3 weeks in immunocompetent patients and can lead to life-threatening malnutrition and wasting in immunocompromised patients.* Fecal-oral transmission can occur by ingestion of contaminated recreational water, drinking water, or food, or through contact with infected persons or animals. For the period 2009-2017, public health officials from 40 states and Puerto Rico voluntarily reported 444 cryptosporidiosis outbreaks resulting in 7,465 cases. Exposure to treated recreational water (e.g., in pools and water playgrounds) was associated with 156 (35.1%) outbreaks resulting in 4,232 (56.7%) cases. Other predominant outbreak exposures included contact with cattle (65 outbreaks; 14.6%) and contact with infected persons in child care settings (57; 12.8%). The annual number of reported cryptosporidiosis outbreaks overall increased an average of approximately 13% per year over time. Reversing this trend will require dissemination of prevention messages to discourage swimming or attending child care while ill with diarrhea and encourage hand washing after contact with animals. Prevention and control measures can be optimized by improving understanding of Cryptosporidium transmission through regular analysis of systematically collected epidemiologic and molecular characterization data.
A Pitiful Sanctuary
Authors: Jessie M. Gaeta
Journal: JAMA (2019)

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Abstract 5064: Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin
Authors: DongJun Fu, Noriko N. Yokoyama, Mattew Tippin, Xiaolin Zi
Journal: Cancer Research (2019)

Abstract Sirtuin 6 (SIRT6) plays an important role in longevity, metabolism, DNA-repair, and inflammatory response. In human urothelial cancer, a high level of SIRT6 expression predicts a better survival for patients. We found that overexpression of SIRT6 in human muscle-invasive bladder cancer cell line J82 reduced cell migration and invasion, but didn’t reduce the in vitro cell growth. Kava is a traditional psychotropic beverage made from the rhizomes of Piper methysticum G. Forst. Previous epidemiological studies have shown an inverse relationship between cancer incidence and kava consumption in South Pacific Island Nations. We have shown that Methysticin, a major kavalactone in the Kava plant, inhibits the growth, migration and invasion of bladder cancer lines. However, these anti-cancer activities of Methysticin are attenuated in cells with low expression of SIRT6, expression of enzymatically mutant SIRT6 or SIRT6 knockout, which suggested that the anti-cancer activities of Methysticin are at least in part dependent on SIRT6 expression. Molecular modelling indicates that Methysticin docks into the site next to a loop near the acetylated peptide substrate binding site of SIRT6. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that Methysticin significantly decreased heat-induced protein degradation of SIRT6. Treatment of J82 cells with Methysticin also resulted in a dose-dependent reduction of H3K18 acetylation. Taken together, these results suggest that Methysticin acts a novel SIRT6 activator for its anti-bladder activity. Further studies have demonstrated that Methysticin activates the TBK1/IRF3/STING pathway by increasing the protein expression of TBK1 and the phosphorylation of TBK1 and STING, which suggest that Methysticin may be able to enhance anti-tumor immunity. Therefore, our results support further investigation of Methylation for bladder cancer prevention. Note: This abstract was not presented at the meeting. Citation Format: DongJun Fu, Noriko N. Yokoyama, Mattew Tippin, Xiaolin Zi. Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5064.
Safety-Net Hospitals, Neighborhood Disadvantage, and Readmissions Under Maryland's All-Payer Program
Authors: Stephen F. Jencks, Alyson Schuster, Geoff B. Dougherty, Sule Gerovich, Jane E. Brock, Amy J.H. Kind
Journal: Annals of Internal Medicine (2019)

Safety-net hospitals have higher-than-expected readmission rates. The relative roles of the mean disadvantage of neighborhoods the hospitals serve and the disadvantage of individual patients in predicting a patient's readmission are unclear.To examine the independent contributions of the patient's neighborhood and the hospital's service area to risk for 30-day readmission.Retrospective observational study.Maryland.All Maryland residents discharged from a Maryland hospital in 2015.Predictors included the disadvantage of neighborhoods for each Maryland resident (area disadvantage index) and the mean disadvantage of each hospital's discharged patients (safety-net index). The primary outcome was unplanned 30-day hospital readmission. Generalized estimating equations and marginal modeling were used to estimate readmission rates. Results were adjusted for clinical readmission risk.13.4% of discharged patients were readmitted within 30 days. Patients living in neighborhoods at the 90th percentile of disadvantage had a readmission rate of 14.1% (95% CI, 13.6% to 14.5%) compared with 12.5% (CI, 11.8% to 13.2%) for similar patients living in neighborhoods at the 10th percentile. Patients discharged from hospitals at the 90th percentile of safety-net status had a readmission rate of 14.8% (CI, 13.4% to 16.1%) compared with 11.6% (CI, 10.5% to 12.7%) for similar patients discharged from hospitals at the 10th percentile of safety-net status. The association of readmission risk with the hospital's safety-net index was approximately twice the observed association with the patient's neighborhood disadvantage status.Generalizability outside Maryland is unknown. Confounding may be present.In Maryland, residing in a disadvantaged neighborhood and being discharged from a hospital serving a large proportion of disadvantaged neighborhoods are independently associated with increased risk for readmission.National Institute on Minority Health and Health Disparities and Maryland Health Services Cost Review Commission.
Frequent promoter hypermethylation of the plasma-type glutathione peroxidase (GPX3) gene in lung cancer
Authors: Jeanne Harvey, Allison Gannon, Zheng Li, John Lechner
Journal: Cancer Research (2004)

4191  Repression of tumor suppressor genes by methylation at CpG island of promoter region is frequently found in various human cancers. Aberrant methylation of CpG islands has been associated with the transcriptional inactivation of some genes, including tumor suppressor genes, and with immortalized or transformed cells. This means that hypermethylation of promoter regions offers an alternative to exonal mutation in terms of eliminating tumor suppressor gene function. Recently it was reported that RUNX3 gene was down-regulated in gastric cancer and colorectal cancer cell lines, which was cause by hypermethylation of promoter regions. We comprehensively examined the methylation status of several genes that were related oncogenesis in osteosarcoma including RUNX3 gene. Tumor samples were obtained from 30 osteosarcoma patients. Normal bone was obtained from fracture patients or from iliac bone graft materials. A normal portion of bone in the final resection specimen was regarded as a normal internal control. We performed methylation-specific PCR after sodium bisulfite modification to investigate of genes such as Runx3, APC, COX2, DAPK, GSTP1, MGMT, hMLH1, TIMP3, THBS1, and RASSF1A. Gastric cancer cell lines purchased from the Korean Cell Line Bank were used as positive controls of methylated DNA. Methylation of RUNX3 was observed in 54% of the osteosarcoma samples, whereas methylation of other genes such as APC, COX2, DAPK, GSTP1, MGMT, hMLH1, TIMP3 and THBS1. RASSF1A (a novel tumor suppressor gene) methylation was detected in 20%. Runx family proteins consist of Runx1, Runx2, and Runx3, and they are involved in the transcriptional control. In humans, mutations in each of three Runx genes are associated with disease caused by defective control of cell proliferation and differentiation. Runx1 is essential for hematopoietic stem cell differentiation, Runx2 is essential for osteoblast differentiation, and Runx3 plays an important role in the regulation of gastric epithelial cell. So, it has been suggested that inactivation of Runx 1, 2, or 3 genes may cause leukemia, cleidocranial dysplasia, or stomach cancer, respectively. Among these Runx genes, Runx3 has been reported to be inactivated by aberrant methylation of promoter CpG island in addition to hemizygous deletion in sporadic gastric carcinoma. CpG island methylation of Runx3 was demonstrated in liver, larynx, lung, breast, colon and prostate cancers at a frequency ranging from 4% to 73%. In the current study, we designed methylated primers which produce 121 bp-sized PCR products and the positive reaction with these primers was demonstrated to be closely associated with transcriptional loss of Runx3 RNA in osteosarcoma. Considering that the very low methylation frequencies of other genes in the same osteosarcoma tissues except RASSF1A, the high frequency of Runx3 methylation in the current study suggests that Runx3 methylation may play an important role in the development of osteosarcoma.
Abstract 363: CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors
Authors: Tyler Maclay, Melinda Day, Kevin Mills
Journal: Cancer Research (2019)

Abstract Genomic instability is recognized as a driver of tumorigenesis and cancer progression. Loss of tumor suppressors or activation of oncogenes can induce DNA damage stress, promoting genomic instability and creating dependencies upon key DNA repair pathways. These dependencies can be targeted therapeutically to induce synthetic lethality. We have developed a novel RAD51 inhibitor, CYT01B, which we have previously shown to be preferentially active in Activation Induced Cytidine Deaminase (AID) expressing cells, and in other tumor derived cell lines with elevated levels of DNA damage and/or reduced DNA repair capabilities. CYT01B acts by reducing RAD51 focus formation, and depleting the nuclear pool of RAD51. We have observed anti-tumor effects with CYT01B in preclinical models, but have yet to determine if RAD51 could act as a sensitizer to current therapeutics. A main resistance mechanism to PARP inhibitors is the overexpression of RAD51, making it an attractive potential combination for our RAD51 inhibitor. To determine potential drug synergy, a matrix study was performed with CYT01B (concentration range of 20nM to 5µM) and 5 different PARP inhibitors including olaparib (78nM to 5µM), niraparib (78nM to 5µM), veliparib (780nM to 50µM), rucaparib (156nM to 10µM), and talazoparib (39nM to 2.5µM). The combination matrix was tested in cell lines of varying AID expression and PARP inhibitor sensitivity: ARPE19/HPV16 (HPV immortalized epithelial cell line), KYSE-70 (head and neck cancer cell line), Daudi (Burkitt’s Lymphoma cell line), HCC1143 (TNBC), and BT20 (TNBC). We used both the Loewe Additivity model and the Bliss Independence model to determine drug interaction (synergistic, independent, or antagonistic). In general, we observed synergy with all the combinations in the tumor derived cell lines. In the transformed epithelial cell line, synergy was observed only in the olaparib combination. The strength of the synergistic effect differed amongst the PARP inhibitors, with olaparib giving the strongest synergy scores. From this data we hypothesize that the synergistic activity with CYT01B is related to the PARP trapping efficiency of the PARP inhibitors; greater trapping efficiency the greater the synergy. These data suggest that CYT01B may be active as a combinatorial therapy with PARP inhibitors. Overall, we conclude that there is significant potential for combining RAD51 and PARP inhibition in future cancer treatment strategies, and warrants future exploration in vivo. Citation Format: Tyler Maclay, Melinda Day, Kevin Mills. CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 363.
A single center experience with oral chemotherapy with capecitabine and temozolomide in metastatic neuroendocrine tumors
Authors: I. Rego, F. Pontes, J. Carvalho, E. Pratas, A. Chaves, R. Martins, J. Couto, J. Ribeiro, F. Rodrigues, G. Sousa
Journal: Annals of Oncology (2019)
Abstract 1968: Tumor necrosis factor-α upregulation of CCR7 induces prostate cancer cell migration in lymphatic metastasis
Authors: Tomoyuki Makino, Kouji Izumi, Aerken Maolake, Ariunbold Natsagdorj, Hiroaki Iwamoto, Suguru Kadomoto, Renato Naito, Kaoru Hiratsuka, Yoshifumi Kadono, Atsushi Mizokami
Journal: Cancer Research (2019)

Abstract Objectives: Prostate cancer (PCa) with lymph node (LN) metastasis has a poor patient prognosis. Broader understanding of the causes of LN metastasis and disease dissemination will assist in developing novel treatments. C-C chemokine receptor 7 (CCR7) and its ligand CCL21 are abundantly expressed in LN metastasis and during PCa progression. Tumor necrosis factor-alpha (TNF-α) is present at low levels within the tumor microenvironment. TNF-α and C-C chemokines interact in tumorigenesis. The study aim was to determine whether TNF-α might promote PCa dissemination from metastatic LN by activating the CCL21/CCR7 axis. Methods: TNF-α and CCR7 mRNA and protein expression were assayed in PC-3, DU145, and LNCaP, and human PCa cells by reverse transcription-polymerase chain reaction and western blotting. Promotion of transmembrane migration by TNF-α was assayed in CCL21-pretreated PCa cells. Phosphorylation of several mitogen-activated protein kinases expressed downstream of TNF-α was assayed. Results: Low-dose TNF-α induced CCR7 expression in PCa cells and promoted migration of CCL21-pretreated PCa cells. TNF-α-mediated CCR7 upregulation via the ERK signaling pathway. p38 was a downstream target of CCL21/CCR7 signaling and a key factor in the promotion of PCa cell migration. Conclusions: This is the first demonstration of the influence of the TNF-α-CCL21/CCR7 axis on PCa cell migration in the microenvironment of LN metastasis. Because it is activated in PCa LN metastasis, the CCL21/CCR7 axis might be a novel therapeutic target and biomarker of PCa. Citation Format: Tomoyuki Makino, Kouji Izumi, Aerken Maolake, Ariunbold Natsagdorj, Hiroaki Iwamoto, Suguru Kadomoto, Renato Naito, Kaoru Hiratsuka, Yoshifumi Kadono, Atsushi Mizokami. Tumor necrosis factor-α upregulation of CCR7 induces prostate cancer cell migration in lymphatic metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1968.
Abstract 21125: Long-Term Outcome of Administration of Hypoxia-Preconditioned Mesenchymal Stem Cells After Acute Myocardial Infarction in Nonhuman Primate Angiogenesis Persist for at Least 17 Months
Authors: Xinyang Hu, Yinchuang Xu, Qingju Li, Chen Ni, Minjian Kong, Fengjiang Zhang, Jianzhong Sun, Qian Li, Yan Wu, Zhiwei Zhong, Jian’an Wang
Journal: Circulation (2017)

Rationale: Hypoxia preconditioning (HP) could improve the effectiveness of bone marrow mesenchymal stem cells (MSCs) for cardiac repair. However, the long-term (&gt;1 year) effects, potential arrhythmogenic complications of transplanted HP-MSCs are unknown. Objective: The present study was designed to assess the long term (17 months) outcome of HP-MSCs administration for the treatment of myocardial infarction (MI) in a small scale (N=10), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein (GFP), cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then delivered into the infarcted hearts of Cynomolgus monkeys (1X10 7 cells per heart). 17 months later, HP-MSCs-treated monkeys tended to exhibited smaller scars, along with improvement of global left ventricular function. No ventricular arrhythmia were observed. It is worth mentioning that HP-MSCs transplantation triggered a prolonged response of angiogenesis, resulting in increased density of endothelial cells (CD31 POS cells) and smooth muscle cells (SMA POS cells) for 17 months. However, HP failed to enhance the long-term retention of transplanted cells in the injured heart (No GFP POS cells were detected), indicating that the paracrine actions were the pivotal mechanisms of HP. Therefore, we further evaluated the therapeutic effects of exosomes, the major paracrine components, for the cardiac repair, and found that monkey HP-MSCs-derived exosomes injection displayed equivalent beneficial angiogenesis with HP-MSC per se administration for the treatment of MI in mice model. Conclusions: The beneficial effects of HP-MSCs on cardiac repair tended to be sustained for at least 17 months in non-human primates without increasing the occurrence of arrhythmogenic complications. This is the first report that administration of HP-MSCs in the heart induces angiogenesis via exosome secretion that persist for at least 17 months which support the safety and feasibility of HP-MSCs therapy.
Abstract 1877: The role played by SLUG, an epithelial-mesenchymal transition factor, in invasion and therapeutic resistance of malignant glioma
Authors: Kyung-Hwa Lee, Se-Jeong Oh, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Hangun Kim, Kyung-Sub Moon
Journal: Cancer Research (2019)

Abstract Purpose: In malignant gliomas, invasive phenotype and cancer stemness promoting resurgence of residual tumor cells, render treatment very difficult. Hence, identification of epithelial-mesenchymal transition (EMT) factors associated with invasion and stemness of glioma cells is critical. Methods: To address the issue, we investigated several EMT factors in hypermotile U87MG and U251 cells, mouse xenograft model, and human glioma samples. Of several EMT markers, SLUG expression was notably increased at the invasive fronts of gliomas, both in mouse tumor xenografts and human glioma samples. The biological role played by SLUG was investigated using a colony-forming assay after chemotherapy and irradiation, and by employing a neurosphere culture assay. The effect of SLUG on glioma progression was examined in our patient cohort and samples, and compared to large public data from the REMBRANDT and TCGA. Results: Genetic upregulation of SLUG was associated with increased levels of stemness factors and enhanced resistance to radiation and temozolomide. In our cohort, patients exhibiting lower-level SLUG expression evidenced longer progression-free survival (P=0.042). Also, in the REMBRANDT dataset, a group in which SLUG was downregulated exhibited a significant survival benefit (P&amp;lt;0.001). Although paired gliblastoma multiforme (GBM) samples from our patients did not showed significant increase of SLUG expression, increased mRNA levels of SLUG was found in recurred GBM from TCGA (P=0.052), and in TMZ-treated glioma cells and mouse xenograft. Conclusion: SLUG may contribute to glioma progression by controlling invasion at infiltrating margins, associated with increased stemness and therapeutic resistance. Citation Format: Kyung-Hwa Lee, Se-Jeong Oh, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Hangun Kim, Kyung-Sub Moon. The role played by SLUG, an epithelial-mesenchymal transition factor, in invasion and therapeutic resistance of malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1877.
Nivolumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use
Authors: Robert L. Ferris, Lisa Licitra, Jerome Fayette, Caroline Even, George Blumenschein, Kevin J. Harrington, Joel Guigay, Everett E. Vokes, Nabil F. Saba, Robert Haddad, Shanmugasundaram Ramkumar, Jeffery Russell, Peter Brossart, Makoto Tahara, A. Dimitrios Colevas, Fernando Concha-Benavente, Mark Lynch, Li Li, Maura L. Gillison
Journal: Clinical Cancer Research (2019)

Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy.In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety.In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62-1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35-0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression (<1% or ≥1%). Grade 3-4 treatment-related adverse event rates favored nivolumab versus IC in both subgroups.Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.