tbuckley/cabot-search huggingface dataset:
Abstract LB-032: NOG-FcgR KO hIL-15 Tg mice provide a highly sensitive assay system for ADCC activity of human NK cells
Authors: Ikumi Katano, Ryoji Ito, Kenji Kawai, Mika Yagoto, Hiroshi Suemizu, Mamoru Ito, Takeshi Takahashi
Journal: Cancer Research (2019)

Abstract We have reported that a human interleukin (hIL)-15-gene introduced NOD-scidnullil2rgnull (NOG-hIL-15 Tg) mouse strain was useful for examination of in vivo antibody dependent-cellular cytotoxicity (ADCC) mediated by human NK cells in the presence of therapeutic Ab (Katano I et al. Sci. Rep. 2017). However, murine phagocytic cells including monocytes/macrophages (Mo/MΦ) in NOG mice still retain a significant capacity to kill target cells by antibody dependent-cellular phagocytosis (ADCP). Here, we newly generated a NOG-hIL-15 Tg strain deficient for Fcγ receptor genes (NOG-FcγR KO-hIL-15 Tg) and investigated whether ADCP by mouse Mo/MΦ could be abolished. The F4/80+ Mo/MΦ in NOG-FcγR KO mice did not bind human immunoglobulin, while those from NOG mice did. NOG-FcγR KO or NOG mice were intravenously transferred with a CD20+ human Burkitt’s lymphoma cell line, Daudi, followed by treatment with anti-hCD20 Ab, Rituximab (Rtx). The tumor growth in control NOG mice was significantly suppressed with Rtx-alone, whereas NOG-FcγR KO mice did not show tumor regression by Rtx treatment. After confirming engraftment of human NK cells in NOG-FcγR KO/hIL-15 Tg mice, we set up in vivo ADCC experiments. Daudi-transplanted NOG-FcγR KO/hIL-15 Tg mice were intravenously transferred with human NK cells and treated with Rtx. Only the mouse group with both human NK cells and Rtx treatment showed a significant suppression in the tumor growth. These results suggest that NOG-FcγR KO mice are free of murine cell mediated ADCP, and that NOG-FcγR KO/hIL-15 Tg mice enable more specific detection of in vivo ADCC than NOG-hIL-15 Tg mice. Citation Format: Ikumi Katano, Ryoji Ito, Kenji Kawai, Mika Yagoto, Hiroshi Suemizu, Mamoru Ito, Takeshi Takahashi. NOG-FcgR KO hIL-15 Tg mice provide a highly sensitive assay system for ADCC activity of human NK cells [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 LB-032.
Abstract 2430: Assessing patient navigation and support services at FQHCs
Authors: Lisa Aponte-Soto
Journal: Cancer Research (2019)

Abstract Cancer is the leading cause of morbidity and mortality for Latinx followed by African Americans (CDC, 2017). Screening can increase the rate of early detection and treatment success. However, the rates of compliance for screening are typically lower among Latinx, which may contribute to decreased diagnosis and increased risk of disease in comparison to their Euro-American counterparts (ACS, 2015). Access to screening services and ability to pay are among the commonly cited barriers for screening compliance. The IDPH recommends incorporating patient navigator (PN) models in community health clinics and communitywide events to increase health literacy, knowledge, and delivery, and quality of care including compliance with screening methods. The University of Illinois (UI) Cancer Center (UICC) works in partnership with the UI Health Mile Square Health Center (MSHC) to implement a bilingual, bicultural PN model for conducting comprehensive cancer prevention and screening services among Latinx, African Americans, and underserved communities in Chicago. A mixed methods approach was used to evaluate the patients’ perceptions and experiences with patient navigator encounters and support services. The authors conducted a semi-structured interviews and abstracted data from patient records. Provider interviews were conducted to understand provider knowledge and attitudes of navigator services. Navigator interviews captured benefits and challenges of incorporating navigation services at the clinics. Data were entered in REDCap and analyzed using Dedoose v. 8.0.42. This paper validates the implementation of PN models at federally qualified health centers (FQHCs) as an asset to patients and providers in facilitating health education, increasing patient screening compliance, and improving access to health care services. Comprehensive cancer screening maximizes resources and improves the quality of life and health outcomes of underserved Latinx and African American patients who are navigated to services. PN-provider partnerships are introduced as a hallmark of the program’s success in identifying at-risk patients and navigating them to appropriate and timely medical screening, diagnostic, and treatment services. Future directions for incorporating and evaluating culturally responsive, bilingual, bicultural PN models at FQHCs, community clinics, and school based clinics are shared to inform public policy for rapid cycle monitoring of protective health cancer interventions and early detection services for Latinx and African American patients in Chicago. Citation Format: Lisa Aponte-Soto. Assessing patient navigation and support services at FQHCs [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 2430.
Abstract 2619: DNA damage agents promote TFEB function and induce pro-survival autophagy signals
Authors: Benoit Marchand, Marie-Josée Boucher
Journal: Cancer Research (2019)

Abstract The transcription factor EB (TFEB) was identified as a master regulator of autophagy and lysosomal biogenesis. We recently demonstrated that TFEB is aberrantly regulated in pancreatic cancer (PDAC) cells. Interference with TFEB impairs PDAC cell growth supporting an important role for TFEB in maintaining PDAC cell phenotype. Given the limited impact of chemotherapeutic drugs in the context of PDAC, we aimed at testing whether the aberrantly regulated TFEB in PDAC cells could confer resistance to DNA damage agents, commonly used in PDAC therapeutic regimens. Methods: Experiments were performed in PDAC cells (MIA PaCa2, PANC1). The DNA damage agents gemcitabine, 5-FU, cisplatin and doxorubicin were used. Autophagic flux was measured upon 4-hours treatment with bafilomycin A1. Results: Treatment with DNA damage agents 1) increased the autophagic flux in PDAC cells. This autophagic signal was associated with 2) the dephosphorylation and nuclear accumulation of TFEB. The mTORC1 pathway is well-known to regulate TFEB phosphorylation and nuclear localization of TFEB. 3) However, the impact of the DNA damage agents on TFEB appeared independent of the mTORC1 pathway since no modulation in the phosphorylation of the mTORC1 target S6K1 was observed. To delineate whether TFEB influenced the response to DNA damage agents, we generated stable populations of PDAC cells expressing a non-targeting or shRNA targeting TFEB. Interfering with TFEB function 4) prevented the autophagic response upon treatment with DNA damage agents. This correlated with 5) increased accumulation of DNA damage and 6) increased sensitivity to the DNA damage agents. Conclusion: Our results suggest that DNA damage agents can induce a pro-survival autophagic response involving TFEB. Interfering with TFEB function limits the autophagic response and leads to increased sensitivity to DNA damage agents. Altogether, our results suggest that the aberrantly expressed TFEB in PDAC cells could confer resistance to DNA damage agents by, among others, promoting autophagy and limiting DNA damage accumulation. Citation Format: Benoit Marchand, Marie-Josée Boucher. DNA damage agents promote TFEB function and induce pro-survival autophagy signals [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 2619.
Limitations in the Methodology Assessing Subjective Data With Lack of Blinding in Mammography Screening
Authors: Payal Trupti Kotecha, Vijay Ramadoss
Journal: JAMA Internal Medicine (2019)

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Diagnosis of <i>Mycoplasma pneumoniae</i> Pneumonia with Measurement of Specific Antibody-Secreting Cells
Authors: Patrick M. Meyer Sauteur, Michelle Seiler, Johannes Trück, Wendy W. J. Unger, Paolo Paioni, Christa Relly, Georg Staubli, Thorsten Haas, Claudine Gysin, Lucas M. Bachmann, Annemarie M. C. van Rossum, Christoph Berger
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Diagnosis of Mycoplasma pneumoniae Pneumonia with Measurement of Specific Antibody-Secreting CellsMycoplasma pneumoniae (Mp) is reported to be the most common bacterial cause of community-acquired pneumonia (CAP) in hospitalized U.S. children (1).However, current diagnostic tests, including PCR of upper respiratory tract (URT) specimens and serology, do not differentiate between Mp infection and carriage (2).Mp carriage in the URT is found in up to 56% of healthy children (2, 3).A >4-fold increase in IgG levels is still used in most centers to confirm Mp infection but has low sensitivity (4) and is not helpful in acute clinical management (3).In the absence of an accurate diagnostic test, it is not surprising that studies and meta-analyses on the efficacy of antibiotics are inconclusive for Mp CAP in children (5,6).Circulating antibody-secreting cell (ASC) responses have been demonstrated to be more rapid and shorter-lived than antibody responses (7).We hypothesized that Mp-IgM-ASCs circulate in peripheral blood only for a few days or weeks after Mp infection, whereas Mp-DNA in the URT and serum antibodies persist for months.We aimed to evaluate the measurement of Mp-IgM-ASCs by enzyme-linked immunospot (ELISpot) assay as a new test for diagnosing Mp CAP.
Вікові особливості структурних та гемодинамічних показників магістральних судин шиї при неалкогольній жировій хворобі печінки та підвищеній масі тіла
Authors: V.I. Bulda, O.D. Tersina
Journal: GASTROENTEROLOGY (2020)

Усього було обстежено 290 пацієнтів (85 чоловіків та 205 жінок). Порівнювались показники пацієнтів із неалкогольною жировою хворобою печінки (НАЖХП) (стеатоз), поєднаною з підвищеною масою тіла, та показники пацієнтів контрольних груп з нормальною масою тіла без патології печінки. Обстежені були розподілені на чотири вікові групи (за критерієм ВООЗ): 1-ша вікова група — від 25 до 34 років, 2-га — від 35 до 44 років, 3-тя — від 45 до 59 років, 4-та — від 60 до 75 років. Проаналізовані структурні та гемодинамічні показники магістральних судин шиї, отримані при комплексному дуплексному обстеженні (ультразвукова сонографія в В-режимі, режимі колірного допплерівського картування й допплер-обстеження).Встановлені зміни структурних та гемодинамічних показників магістральних судин шиї (стовщення комплексу інтима-медія, зменшення лінійних швидкостей кровотоку). НАЖХП (стеатоз), поєднана з підвищеною масою тіла, справляє прямий вплив на структурний та гемодинамічний стан магістральних судин шиї. Виявлений кореляційний зв’язок між НАЖХП (стеатоз), поєднаною з підвищеною масою тіла, та швидкісним показником кровотоку — піковою систолічною швидкістю кровотоку (p &lt; 0,05). Порушення структури та гемодинаміки магістральних судин шиї, виявлені при комплексному дуплексному обстеженні, є результатом прямого впливу НАЖХП (стеатоз) та підвищеної маси тіла та призводять до зростання кардіоваскулярного ризику переважно в групах середнього та похилого віку.
FDA enforcement actions have plummeted under Trump
Authors: Owen Dyer
Journal: BMJ (2019)

The Food and Drug Administration, which is tasked with the regulation of food, medicine, and medical devices in the United States, has been regulating far less since the Trump administration took power in January 2017, says a review of the agency’s records by the journal Science .1

FDA warning letters, in which the agency cites violations and demands compliance, have fallen by a third in the first 29 months of Donald Trump’s governance, as just 1033 were sent out, compared with 1532 during an equivalent period at the start of Barack Obama’s presidency. The rate has continued to decline in recent months.

Warning letters from the …
Abstract 140: Comprehensive analysis of immune evasion in breast cancer by single-cell RNA-seq
Authors: Jianhua Yin, Hanlin Zhou, Chen Yan, Ruqian lv, Ting Wang, Chenyang He, Chen Huang, Yong Hou, Shida Zhu, Ling Wang, Michael Dean, Kui Wu, Hong Hu, Guibo Li
Journal: Cancer Research (2019)

Abstract The tumor microenvironment is composed of numerous cell types, including tumor, immune and stromal cells. Cancer cells interact with the tumor microenvironment to suppress anticancer immunity. In this study, we molecularly dissected the tumor microenvironment of breast cancer by single-cell RNA-seq. The breast tumor microenvironment was profiled by analyzing the single-cell transcriptomes of 52,163 cells from the tumor tissues of 15 breast cancer patients. The tumor cells and immune cells from individual patients were analyzed simultaneously at the single-cell level. Among more than 40,000 tumor cells, we identified distinct cell clusters with different molecular subtypes and gene signatures in the same tumor, which revealed intra-tumor heterogeneity in breast cancer. We comprehensively profiled the functional state of T cells, macrophages, B cells, CAFs in breast cancer tumor microenvironment, which highlight the immune cell and CAF diversity in the breast cancer TME. Moreover, we analyzed intercellular communication in the breast cancer TME using a dataset of human ligand receptor pairs, which showed distinct cell interaction models across tumors. The evolution of the tumor microenvironment during clinical treatment was dissected by comparing tumor microenvironment of breast cancer pre- and post-chemotherapy. This study investigated the diversity of the cell types in the tumor microenvironment and provided information on the mechanisms of escape from clearance by immune cells in breast cancer, which could be a beneficial resource for immunotherapy development. Citation Format: Jianhua Yin, Hanlin Zhou, Chen Yan, Ruqian lv, Ting Wang, Chenyang He, Chen Huang, Yong Hou, Shida Zhu, Ling Wang, Michael Dean, Kui Wu, Hong Hu, Guibo Li. Comprehensive analysis of immune evasion in breast cancer by single-cell RNA-seq [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 140.
Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.
Authors: Francesca Gay, Chiara Cerrato, Maria Teresa Petrucci, Renato Zambello, Barbara Gamberi, Stelvio Ballanti, Paola Omedè, Salvatore Palmieri, Rossella Troia, Stefano Spada, Alessandro Gozzetti, Tommaso Caravita, Antonio Spadano, Antonio Palumbo, Vittorio Montefusco, Pellegrino Musto, Michele Cavo, Mario Boccadoro
Journal: Journal of Clinical Oncology (2019)

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10 -5 ) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (&lt;18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]
Abstract 304: Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity
Authors: Masashi Arita, Satoshi Watanabe, Nobumasa Aoki, Miho Takahashi, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Shoji Kuwahara, Junta Tanaka, Toshiyuki Koya, Akihiko Saito, Toshiaki Kikuchi
Journal: Cancer Research (2019)

Abstract Cisplatin is an anticancer drug widely used in the treatment of many cancers, including lung cancers. Although cisplatin causes various types of adverse events, the main dose-limiting toxicity of cisplatin is nephrotoxicity. Megalin is an endocytic receptor expressed at the apical membranes of proximal tubules. We previously demonstrated that cisplatin was reabsorbed through megalin and caused kidney injury. Cilastatin, an inhibitor of renal dehydropeptidase-I and used with imipenem, blocked the binding of cisplatin to megalin and reduced the nephrotoxicity induced by cisplatin. In the current study, we precisely evaluated the effect of cilastatin-mediated suppression of cisplatin nephrotoxicity to safely enhance the antitumor activity of cisplatin. BALB/c mice were administrated cisplatin with or without cilastatin. Tubular dilation or atrophy, brush border loss, tubular cell lysis and cast formation were observed in mice treated with cisplatin alone. However, these kidney injuries were decreased or disappeared in mice treated with cisplatin and cilastatin. Cilastatin also decreased the urinary levels of N-acetyl-β-D-glucosaminidase and neutrophil gelatinase-associated lipocalin, proximal tubular injury markers. Next, SCID mice were injected s.c. with A549, a human lung cancer cell line, and treated with cisplatin with or without cilastatin. Cilastatin did not affect the antitumor activity of cilastatin. Notably, A549 did not express megalin. Combined with cilastatin, the mice were successfully treated with 1.5 times dose of cisplatin with enhanced antitumor effects of cisplatin but without nephrotoxicity. In conclusion, cilastatin effectively suppressed nephrotoxicity of cisplatin by blocking the binding of cisplatin to megalin. These findings indicated that we could administer cisplatin into cancer patients without nephrotoxicity if we used cilastatin. Moreover, we might increase the dose of cisplatin and improve the outcome of cancer patients. Citation Format: Masashi Arita, Satoshi Watanabe, Nobumasa Aoki, Miho Takahashi, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Shoji Kuwahara, Junta Tanaka, Toshiyuki Koya, Akihiko Saito, Toshiaki Kikuchi. Combination therapy of cisplatin with cilastatin enables to increase the dose of cisplatin for enhancing its antitumor effect by suppressing nephrotoxicity [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 304.
Abstract 2441: Association between NRF1 regulatory gene networks and cancer and aging
Authors: Kaumudi Bhawe, Quentin Felty, Changwon Yoo, Deodutta Roy
Journal: Cancer Research (2019)

Abstract There is a growing convergence between molecular aspects of aging and cancer. Cellular senescence acts as a barrier through preventing the proliferation of cells under oncogenic stress. Therefore, we decided to examine the role of nuclear respiratory factor 1 (NRF1) transcription factor in human brain cancer and brain aging. In contrast to higher expression of NRF1 in human glioma tumors, lower NRF1 levels are observed in Alzheimer’s disease (AD) brain tissue. Using the glioma and AD transcriptomic data of NRF1 target genes, we conducted Transcription Factor Target Enrichment Analysis that detects transcription factor (TF) activity based on quantification of the collective transcriptional activation of their target genes. NRF1 TF activity was significantly lower in AD brain tissues from four independent cohorts compared to non-AD brain tissues. In contrast, we observed higher NRF1 transcription factor activity in glioma. NRF1 activity as well as expression of several cell cycle pathway genes including CDK1,2,6,9 and NRF1 target genes such as NR2E1, APOE and MAPT are significantly altered in these two population cohorts. We also discovered that expression of NRF1, RB1 and E2F influenced survival in glioma. Specifically, the mean overall survival for patients with a high NRF1, E2F1,2,6,7,8 and RB1 gene signature was 20.91 months (95% CI = 9.37-32.46), compared to 101.99 months (95% CI = 74.28-129.70), in high NRF1 expressing patients that lacked the specific gene signature. NRF1 based gene signatures combined with IDH1 mutation status are necessary and sufficient for explaining the observed differences in survival curves. We examined the association of NRF1, the E2Fs and RB1 through Bayesian graphical modeling and observed gender differences in gene networks between NRF1 and E2F family members in the glioma patient sub-populations as compared to normal aging human brain samples. Furthermore, the differentially expressed NRF1 regulated genes are part of the KEGG pathways associated with spliceosome, ribosome and lysosome function as well as a diverse array of other functions are enriched, indicating ways in which NRF1 may be involved in glioma biology. In summary these findings support our postulate that NRF1 is an important transcription factor in the human brain, where it plays an active role in both aging and cancer. Citation Format: Kaumudi Bhawe, Quentin Felty, Changwon Yoo, Deodutta Roy. Association between NRF1 regulatory gene networks and cancer and aging [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 2441.