tbuckley/cabot-search huggingface dataset:
Abstract 3589: Targeting metabolic reprogramming and OXPHOS as a viable anti-melanoma strategy
Authors: Gang Cheng, Jacek Zielonka, Micael Hardy, Michael B. Dwinell, Balaraman Kalyanaraman
Journal: Cancer Research (2019)

Invasive melanoma is an aggressive form of skin cancer with poor clinical outcomes. Nearly 50% of melanoma patients exhibit oncogenic BRAFV600E mutations. Existing BRAF kinase inhibitor drugs provide a short-term benefit prior to the rapid onset of drug resistance. Emerging results suggest that BRAF and other kinase inhibitors induce metabolic reprogramming from glycolytic energy production to oxidative phosphorylation (OXPHOS) in a subset of malignant melanomas. Metabolic reprogramming to OXPHOS is emerging as an important mechanism of resistance to BRAF kinase inhibitors and is associated with worse prognosis. Consequently, there is a significant opportunity for multimodal therapeutic approaches that selectively target the metabolic reprogramming associated with resistance to BRAF kinase inhibitors and promote immune-targeted therapy. We have previously developed mitochondria-targeted drugs by exploiting the enhanced negative mitochondrial membrane potential of cancer cells to selectively target and disrupt tumor growth. We hypothesized that metabolic reprogramming from glycolysis to OXPHOS in BRAF inhibitor-resistant melanoma cells would make them susceptible to OXPHOS inhibitors. In this study, we have modified the structure of a naturally occurring polyphenol, magnolol into a mitochondria-targeted-magnolol (Mito-MGN). We tested the effects of Mito-MGN on mitochondrial respiration and bioenergetic function, cellular redox status, and mitophagy in wild type (WT) and BRAF-resistant (metabolically reprogrammed) melanoma cells. Our data show that Mito-MGN inhibits mitochondrial respiration, melanoma cell proliferation and invasion at concentrations more than 200-fold lower than that of magnolol. Furthermore, Mito-MGN increases ROS formation and oxidation of mitochondrial peroxiredoxin. Preliminary results also indicate that BRAF inhibitor resistant melanoma cells exhibit enhanced OXPHOS as a consequence of metabolic reprogramming and that Mito-MGN effectively inhibits proliferation and mitochondrial respiration in the resistant cells. Mito-MGN inhibited mitochondrial complex I activity in both WT and resistant cells. The IC 50  values to inhibit complex I-mediated respiration was consistent with the values calculated for inhibition of cell respiration. We conclude that inhibition of complex I is a key initial event that is responsible for the anti-proliferative effects observed in the presence of Mito-MGN against wild-type as well as drug-resistant melanoma cells.   Citation Format:  Gang Cheng, Jacek Zielonka, Micael Hardy, Michael B. Dwinell, Balaraman Kalyanaraman. Targeting metabolic reprogramming and OXPHOS as a viable anti-melanoma strategy [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 3589.
Abstract 2014: A novel small molecule inhibitor to suppress Notch1 activation in CRC
Authors: Chendil Damodaran, Ashish Tyagi, Balaji Chandrasekaran, Venkatesh Kolluru, Ibrahim Jojua, Srinivasa Ramisetti, Arun K. Sharma, Murali K. Ankem
Journal: Cancer Research (2019)

Abstract Introduction: Earlier we reported that aberrant overexpression of Notch1 in colon cancer patients is responsible for aggressiveness and progression of the disease. Current, therapeutic interventions of notch1 inhibitors that binds catalytic unit of γ-secretase and disrupts the cleavage activity cause gastrointestinal toxicity in clinical trial. Therefore, our study aims to develop a small molecule inhibitor, which inhibits Notch1 signaling but binds outside of γ-secretase’s catalytic unit thereby substantially reducing associated toxicity attributes. Through structure-activity relationship (SAR) studies based on naturally occurring Withaferin A (WA) structure, we have recently identified a WA-difuroate analog ASR458 as one such small molecule. Methods: To analyze the effect of ASR490 on HCT116 and HCT116/Notch1 cells, we performed phenotypic, western blot and in vivo analysis. Results: Notch1 overexpressing CRC cells (HCT/Notch1) showed aggressive cell growth (42%) as compared to HCT116 cells, however, ASR490 treatment inhibited cell growth in both HCT116 (IC50: 600 nM) as well as HCT/Notch1 cells (IC50: 850 nM). ASR458 significantly inhibited Notch1 expression and its downstream events in both the transfected cell lines. As a result, we observed shutdown of pro-survival machinery and induction of pro-apoptotic events (Bax, caspases and PARP) resulting in apoptotic cell death in ASR456 treated HCT116 and Notch1/HCT116 cells. Since Notch1 is responsible for epithelial mesenchyme transition (EMT); we analyzed EMT drivers and readout invasion/migration assays. ASR458 treatment reversed the mesenchymal characteristics by restoring the function of E-cadherin, which resulted in the suppression of invasion and migration in readout assays of HCT116 transfectants. Our ongoing Xenotransplanted mice experiments may suggest whether ASR458 inhibits the growth of HCT116 and HCT116/Notch1 tumors. Conclusion: Restrained gastrointestinal toxicity of Notch1 targeting therapeutics is achievable with novel small molecules displaying a differential binding affinity to γ-secretase. ASR458 inhibits cell growth in Notch1 overexpressing cells and abrogates Notch1 induced EMT. Ongoing molecular docking and in vivo studies may confirm ASR458 binding sites in γ-secretase and validate our in vitro findings respectively. Citation Format: Chendil Damodaran, Ashish Tyagi, Balaji Chandrasekaran, Venkatesh Kolluru, Ibrahim Jojua, Srinivasa Ramisetti, Arun K. Sharma, Murali K. Ankem. A novel small molecule inhibitor to suppress Notch1 activation in CRC [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 2014.
Abstract 11546: Role of Natural Autoantibodies Among Ugandans With Rheumatic Heart Disease and HIV
Authors: Daniel M Huck, Emmy Okello, Grace Mirembe, Isaac Ssinabulya, David A Zidar, Gregg J Silverman, Lelise Getu, Amy S Nowacki, Leonard H Calabrese, Robert A Salata, Chris T Longenecker
Journal: Circulation (2015)

Introduction: Rheumatic heart disease (RHD) and HIV are prevalent diseases in sub-Saharan Africa associated with distinct immune dysregulatory abnormalities, but little is known about their potential interrelationships. Among naturally arising autoantibodies to oxidation-associated neo-determinants studied in other clinical populations, higher levels of IgM anti-phosphorylcholine (PC) correlate with protection from atherosclerotic CV and inflammatory diseases, while higher levels of IgG anti-malondialdehyde (MDA) instead correlate with greater autoimmune disease activity. The objective of this study was to assess the prevalence of natural autoantibodies among patients with and without RHD in Uganda, and to determine whether the levels of these natural autoantibodies among patients with RHD are affected by HIV status. Methods: In this cross-sectional study, we grouped patients according to RHD and HIV status. The three control groups (RHD- HIV-, RHD- HIV+, RHD+ HIV-) were age-matched to the RHD+ HIV+ participants. All participants underwent echocardiography, HIV testing, and venous blood draw. IgM anti-PC and IgG anti-MDA were measured from frozen serum using ELISA. Results: Overall, we enrolled 220 participants; 21 with both RHD and HIV. Ages ranged from 10 to 60 years, most being female (64%). After adjusting for age and gender, HIV infection and RHD were each associated with low IgM anti-PC (HIV: p&lt;.0001 and RHD: p=.01). The figure shows median levels of IgM anti-PC by group. A significant HIV*RHD interaction was identified for IgG anti-MDA (p=.049) such that HIV infection was associated with increased IgG anti-MDA in participants without RHD, whereas it was associated with decreased IgG anti-MDA in participants with RHD. Conclusions: This is the first study of natural autoantibody responses in patients with RHD. HIV appears to alter natural autoantibody levels potentially increasing risk for atherosclerosis and impacting the pathogenesis of RHD.
Helen Salisbury: Endgame for the NHS?
Authors: Helen Salisbury
Journal: BMJ (2019)

Since its foundation, the NHS has been committed to providing treatment according to clinical need. The distinction between want and need is important—there may be treatments that patients want but don’t need, such as cosmetic surgery. In these cases, they have to go to the private sector and pay up front or through insurance. This is set out in the first two points of the NHS constitution,1 which state that the NHS provides a comprehensive service, available to all, and that access is based on clinical need, not a patient’s ability to pay.

This week Warrington and Halton Hospitals NHS Trust was in the news for its published list of …
Abstract 2057: Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer cells
Authors: Shengliang Zhang, Lanlan Zhou, Marie D. Ralff, Wafik S. El-Deiry
Journal: Cancer Research (2019)

Abstract Cellular FADD-like IL-1β-converting enzyme-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator in cancer cells. c-FLIP inhibits caspase 8 activation and suppresses cell apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) in malignant cells. Targeting c-FLIP is an attractive strategy for cancer therapy. We previously identified a small-molecule CB001 as a p53-restoring compound and found that CB001 induces cell death with little or no genotoxicity in human colorectal cancer cells. We now show that CB001 downregulates c-FLIP expression in cancer cells at the post-translational level via protein degradation. CB001 treatment induces an increase in caspase 8 activity which correlates with the decrease in c-FLIP at the protein level in mutant p53-expressing cancer cells. Knockdown of caspase 8 rescues cancer cells from CB001-induced apoptosis in mutant p53-expressing cancer cells, suggesting that downregulation of c-FLIP is one of the major mechanisms by which CB001 induces extrinsic cell apoptosis. Furthermore, our studies reveal a synergy between CB001 and TRAIL to induce apoptosis in TRAIL-resistant cancer cells, but not in normal cells at the tested doses. These results taken together suggest that CB001 is a promising lead for drug development with a strong capability to suppress tumor growth through targeting c-FLIP in cancer cells. Citation Format: Shengliang Zhang, Lanlan Zhou, Marie D. Ralff, Wafik S. El-Deiry. Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer 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 2057.
Abstract 2390: FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses
Authors: Dhan Chand, Jeremy D. Waight, Elena Paltrinieri, Sylvia Dietrich, Mark Bushell, Mathew Costa, Randi Gombos, Nicholas S. Wilson, Jennifer S. Buell, Robert B. Stein, Alexander Duncan, David A. Savitsky
Journal: Cancer Research (2019)

Abstract T-cell immunoreceptor with Ig and ITIM domains (TIGIT) has emerged as an important regulator of the cancer-immunity cycle. Preclinical studies have demonstrated that TIGIT antibodies can enhance T and NK cell anti-tumor immunity, and therapeutic antibodies targeting TIGIT are advancing in the clinic. Nonetheless, questions on the optimal format for TIGIT therapeutics remain unresolved. Preclinical studies have demonstrated that anti-TIGIT antibodies enhance anti-tumor immunity by (1) blocking inhibitory signaling downstream of TIGIT/PVR and TIGIT/PVRL2 receptor-ligand interactions and (2) redirecting PVR/PVRL2 ligand binding to the co-stimulatory receptor CD226. Here we describe a novel and unanticipated mechanism of action of anti-TIGIT antibodies in which interactions between the antibody Fc domain and select FcγRs, particularly FcγRIIIA, dramatically improve T cell activation and effector function. In mouse tumor models, TIGIT antibodies that promote FcγR interactions enhance anti-tumor responses, whereas Fc-inert TIGIT antibodies show no such benefit. Moreover, TIGIT antibodies that enhance binding to human FcγRIIIA or mouse FcγRIV promote superior single agent activity and combination activity with other checkpoint modulators in antigen-stimulation assays and mouse tumor models respectively. Notably, this mechanism of action is independent of regulatory T cell depletion. Our findings support a dependence on Fc-FcγR interaction for promoting T cell responsiveness and effector function upon TIGIT antagonism. We further demonstrate that this novel mechanism also extends to anti-CTLA-4, but not anti-PD-1 or anti-LAG-3 antibodies. Altogether, our data describe a novel FcγR-dependent mechanism of action that may enhance the therapeutic activity of anti-TIGIT antibodies, deepen our understanding of this class of therapies, and inform on the optimal design for a new class of Fc-engineered antibodies that could be leveraged to potentially enhance antitumor immune responses. Citation Format: Dhan Chand, Jeremy D. Waight, Elena Paltrinieri, Sylvia Dietrich, Mark Bushell, Mathew Costa, Randi Gombos, Nicholas S. Wilson, Jennifer S. Buell, Robert B. Stein, Alexander Duncan, David A. Savitsky. FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses [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 2390.
Pleural Diseases: Pleurodesis via Indwelling Pleural Catheter, Dasatinib-induced Pleural Effusion, and IL-27 in Tuberculosis Pleural Effusion
Authors: Ala-Eddin S. Sagar, Daniel L. Dodge, Moiz Salahuddin, Mark T. Warner, Garbo Mak, Saadia A. Faiz
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Association of Ambulatory Hemodynamic Monitoring With Clinical Outcomes in a Concurrent Matched Control Analysis.
Authors: Jacob Abraham, Rupinder Bharmi, Orvar Jonsson, Guilherme H Oliveira, Andre Artis, Ali Valika, Robert Capodilupo, Philip B Adamson, Gregory Roberts, Nirav Dalal, Akshay S Desai, Raymond L Benza
Journal: JAMA Cardiology (2019)
Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small cell lung cancer
Authors: Yaru Tian, Xiaoyang Zhai, Anqin Han, Hui Zhu, Jinming Yu
Journal: Journal of Hematology & Oncology (2019)

Small cell lung cancer (SCLC) is one of the deadliest cancer types in the world. Despite the high response rate to frontline platinum-containing doublets, relapse is inevitable for the majority of patients and the prognosis is poor. Topotecan, which has limited efficacy, has remained the standard second-line therapy for approximately three decades. Although SCLC has a high mutation burden, the clinical efficacy of immune checkpoint blockades (ICBs) in SCLC is far less pronounced than that in non-small cell lung cancer (NSCLC). Only atezolizumab in combination with chemotherapy improved overall survival over chemotherapy alone in the phase III CheckMate 133 trial and has recently received FDA approval as first-line therapy. Most studies concerning ICBs in SCLC are limited to early-phase studies and found that ICBs were not superior to traditional chemotherapy. Why is there such a large difference between SCLC and NSCLC? In this review, comparative analyses of previous studies indicate that SCLC is even more immunodeficient than NSCLC and the potential immune escape mechanisms in SCLC may involve the low expression of PD-L1 and the downregulation of major histocompability complex (MHC) molecules and regulatory chemokines. In consideration of these immune dysfunctions, we speculate that chemotherapy and radiotherapy prior to immunotherapy, the combination of ICBs with antiangiogenic treatment, and selecting tumor mutation burden in combination with PD-L1 expression as biomarkers could be promising strategies to improve the clinical efficacy of immunotherapy for SCLC.
ANCHOR CRC: a phase 2, open-label, single arm, multicenter study of encorafenib (ENCO), binimetinib (BINI), plus cetuximab (CETUX) in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC)
Authors: A. Grothey, R. Yaeger, D. Paez, J. Tabernero, J. Taïeb, T. Yoshino, M. Groc, J. Vedovato, E. Chetaille, E. Van Cutsem
Journal: Annals of Oncology (2019)
Abstract 129: Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-alpha and MMP-9
Authors: Seungeun Lee, Eunhye Lee, EunYi Ko, Mina Ham, Hye Min Lee, Eun-Sook Kim, Minsoo Koh, Hyun Kyung Lim, Joohee Jung, So Yeon Park, Aree Moon
Journal: Cancer Research (2019)

Abstract Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that promote invasion and metastasis of cancer cells. In this study, we investigated the effect of TAMs on phenotypic conversion of non-neoplastic MCF10A human breast epithelial cells using an indirect co-culture system. Co-culture with TAMs induced epithelial-to-mesenchymal transition, invasive phenotype, and MMP-9 upregulation in MCF10A cells. Comparative proteomic analysis revealed that endoplasmic reticulum oxidoreductase (ERO)1-alpha was increased in MCF10A cells co-cultured with TAMs compared to that in mono-cultured cells. ERO1-alpha was crucial for TAMs-induced invasive phenotype and MMP-9 upregulation involving transcription factors c-fos and c-Jun. Cytokine array analysis showed that levels of interleukin (IL)-6, C-X-C motif ligand (CXCL)1, C-C motif ligand (CCL)2, growth-regulated protein (GRO), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in conditioned media of co-cultured cells. Among these cytokines increased in conditioned media of co-cultured cells, CCL2 was secreted from TAMs, leading to induction of ERO1-alpha, MMP-9 upregulation, and invasiveness in MCF10A cells. Our findings elucidated a molecular mechanism underlying the aggressive phenotypic change of non-neoplastic breast cells by co-culture with TAMs, providing useful information for prevention or treatment of recurrent breast cancer Note: This abstract was not presented at the meeting. Citation Format: Seungeun Lee, Eunhye Lee, EunYi Ko, Mina Ham, Hye Min Lee, Eun-Sook Kim, Minsoo Koh, Hyun Kyung Lim, Joohee Jung, So Yeon Park, Aree Moon. Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-alpha and MMP-9 [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 129.
New Guidelines Aim to Expand Palliative Care Beyond Specialists
Authors: Jennifer Abbasi
Journal: JAMA (2019)

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Deliberations on giant cell arteritis
Authors: Colm McAlinden, Eirini Skiadaresi
Journal: BMJ (2019)

Lazarewicz and Watson provide a timely and authoritative clinical update on giant cell arteritis.1 We expand on a few points regarding clinical examination and management.

An important clinical sign is the absence of a palpable superficial temporal pulse. This is best palpated just anterior and superior to the tragus (above the zygomatic arch of the …
Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer
Authors: Nicola E. Annels, David Mansfield, Mehreen Arif, Carmen Ballesteros-Merino, Guy R. Simpson, Mick Denyer, Sarbjinder S. Sandhu, Alan A. Melcher, Kevin J. Harrington, Bronwyn Davies, Gough Au, Mark Grose, Izhar Bagwan, Bernard Fox, Richard Vile, Hugh Mostafid, Darren Shafren, Hardev S. Pandha
Journal: Clinical Cancer Research (2019)

The CANON [
Abstract 2804: Metabolic-immunoregulatory role of CCRK-mTOR signaling in NAFLD-associated hepatocellular carcinoma
Authors: Wenshu TANG, Jingying ZHOU, Weiqin YANG, Yu FENG, Myth MOK, Alfred Sze CHENG
Journal: Cancer Research (2019)

Abstract Obesity increases the risks of steatosis, non-alcoholic steatohepatitis (NASH) and HCC development. Non-alcoholic fatty liver disease (NAFLD) associated-hepatocellular carcinoma (HCC) is a male-predominant cancer mainly caused by metabolic disorder. Our previous findings demonstrated that cell cycle-related kinase (CCRK), through upregulates mTORC1 pathway, resulting in deregulated lipid/glucose metabolism and tumorigenesis (Nat Communs accepted). In this study, we further elucidate that CCRK activates mTORC1 through SLC3A2 and SLC7A5 dependent amino acid transportation. We performed comprehensive immune cell profiling in a high-fat high-carbohydrate diet (HFHC)-induced obesity and NASH murine model and uncovered activation of CCRK-mTORC1 signaling cascade and specific induction of myeloid-derived suppressor cell (MDSC), reduction in CD8+ T cells, which subsequently enhanced tumor growth of orthotopically-implanted HCC tumor cells. Notably, treatment of the mTORC1/C2 dual kinase inhibitor vistusertib (AZD2014), currently undergone phase I/II clinical trials, abrogated mTORC1/SREBP2 signaling and metabolic dysregulation especially cholesterol levels. Further immune profiling in liver and blood of AZD2014 treated mice will be performed. Furthermore, mTORC1/SREBP2 positively associated with cholesterol level in the streptozotocin (STZ)-HFHC induced spontaneous NAFLD-HCC mouse model, which will be utilized to further study the therapeutic effect of vistusertib in vivo. Collectively, this study will elucidate the metabolic-immunosuppressive role of CCRK-mTOR signaling in NAFLD-associated HCC and further provide insights into development of therapeutic strategies against the CCRK-mTOR reinforced NAFLD-HCC. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309. Citation Format: Wenshu TANG, Jingying ZHOU, Weiqin YANG, Yu FENG, Myth MOK, Alfred Sze CHENG. Metabolic-immunoregulatory role of CCRK-mTOR signaling in NAFLD-associated hepatocellular carcinoma [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 2804.