tbuckley/cabot-search huggingface dataset:
Abstract 1474: Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models
Authors: Inhwan Bae, Yu-Yon Kim, Jisook Kim, Hyunjin Park, Taehyun Song, Joo-Yun Byun, Semi Lim, Young Hoon Kim, Young Gil Ahn, Kwee Hyun Suh
Journal: Cancer Research (2021)

Abstract Over the past decade, BRAF inhibitors, either alone or in combination with MEK inhibitors, have set a new milestone in the treatment of patients with BRAF V600 mutation melanoma, which accounts for about 50% of melanomas. More recently, anti-PD-(L)1 therapies such as nivolumab or pembrolizumab and atezolizumab have been approved as very useful treatments for patients with melanoma. Nevertheless, metastases to the brain in melanoma patients, which are highly aggressive and associated with poor outcomes, still require better treatment. Also, to date, no targeted therapy has been developed for patients with NRAS mutations, which account for about 20% of melanoma. Previously, we reported that belvarafenib (HM95573 or GDC5573) strongly inhibits the growth of various cancer cell lines harboring BRAF, NRAS or KRAS mutations and demonstrates remarkable anticancer efficacy in preclinical animal models. Belvarafenib, currently in Phase 1 clinical trials, is a potent and selective pan-RAF kinase inhibitor showing strong inhibition activities for BRAF WT, BRAF V600E and CRAF. Here, we present the results of preclinical model studies suggesting that belvarafenib could be effective in treating melanoma patients with metastases to the brain as well as NRAS mutation melanoma patients. First, belvarafenib was found to be able to accumulate in the brain of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to that in plasma (approximately 100% brain to plasma ratio). This level of brain penetration of belvarafenib differs significantly from currently approved BRAF inhibitors that are known to have low brain penetration. Belvarafenib showed excellent anti-tumor activity in an orthotopic brain tumor model using melanoma cells. Belvarafenib significantly increased the overall survival of mice implanted intracranially with BRAF V600E A375SM melanoma cells. Overall, our data demonstrated that belvarafenib has therapeutic potential to treat NRAS mutation melanoma patients. In fact, in the NRAS G13D K1735 murine melanoma cell syngeneic mice model, the combination of belvarafenib with atezolizumab (anti-PD-L1) significantly inhibited tumor growth and effectively induced infiltration of cytotoxic T-cells into tumor tissues. These effects of belvarafenib identified in the above preclinical studies need to be immediately warranted through appropriate clinical trials. Citation Format: Inhwan Bae, Yu-Yon Kim, Jisook Kim, Hyunjin Park, Taehyun Song, Joo-Yun Byun, Semi Lim, Young Hoon Kim, Young Gil Ahn, Kwee Hyun Suh. Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1474.
Abstract 2397: Significance of the combination of biguanides and fatty acid β-oxidation inhibitors in triple-negative breast cancer
Authors: Junhyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Dharaniya Sakthivel, Abha Tiwari, José N. Onuchic, Benny Abraham Kaipparettu
Journal: Cancer Research (2021)

Abstract Compared to hormone receptor (HR) positive breast cancer (BC), basal or triple-negative BC (TNBC) suffers a poor prognosis, attributed to the limited understanding of its driver signaling pathways. Although TNBC exhibits unique characteristics, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are essential to reduce its severity. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a dominant metabolic pathway in TNBC. We have also reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC, via autophosphorylation of Src at Y419. However, single drug therapy using FAO inhibitors or Src inhibitors did not show a significant therapeutic advantage in TNBC. Biguanide such as metformin is one of the most widely administered anti-diabetic agents. Recently increasing evidence demonstrates that biguanide therapy can have an anticancer effect in various cancer types, including BC. Phenformin, a biguanide derivative similar to metformin, has greater potency than metformin. Both biguanides can suppress mitochondrial electron transport chain (ETC) function because of its inhibitory effect on ETC complex I activity. However, biguanides also lead to the activation of AMPK, which plays a vital role in insulin signaling and energy-sensing. Notably, AMPK is an upstream regulator of the FAO pathway because it can phosphorylate ACC and activate FAO. Considering the dependency of TNBC on mitochondrial FAO and the role of AMPK in the activation of FAO, our computational modeling predicted that the combined targeting of both ‘arms' of the pathway could provide a significant advantage to the anticancer effect in TNBC. Thus, we have used the combination of biguanides and FAO inhibitors to target both ETC and FAO respectively. Pharmacological and genetic approaches with multiple in vitro and in vivo analysis using TNBC cell lines and PDX models suggest that the combination of biguanides and FAO inhibitors can provide significant advantage in TNBC therapy. Further studies also show that the combination of biguanides with Src inhibitors can provide a better therapeutic option to target metastatic TNBC. We are currently evaluating these findings' translational significance as a cost-effective approach to managing non-targetable TNBCs. Citation Format: Junhyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Dharaniya Sakthivel, Abha Tiwari, José N. Onuchic, Benny Abraham Kaipparettu. Significance of the combination of biguanides and fatty acid β-oxidation inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2397.
Total protein, not amino acid composition, differs in plant-based versus omnivorous dietary patterns and determines metabolic health effects in mice
Authors: Michael R. MacArthur, Sarah J. Mitchell, J. Humberto Treviño-Villarreal, Yohann Grondin, Justin S. Reynolds, Peter Kip, Jonathan Jung, Kaspar M. Trocha, C. Keith Ozaki, James R. Mitchell
Journal: Cell Metabolism (2021)
Successful therapy of experimental, orthotopic renal cell carcinoma with two different types of Axl inhibiting agents
Authors: T.J. Chen, P. Mydel, M. Benedyk-Machaczka, S. Malicki, J. Furriol, G. Gausdal, J. Lorens, T. Osman, H-P. Marti
Journal: European Urology (2021)
Abstract 1975: Tumor treating fields triggers OFD1 removal from primary cilia to promote glioma cell survival
Authors: Ping Shi, Jia Tian, Matthew R. Sarkisian
Journal: Cancer Research (2021)

Abstract Tumor Treating Fields (TTFields) significantly prolongs the survival of patients with glioblastoma, but glioma cells can still escape this therapy creating significant problems. Recent studies suggest glioma cells resist TTFields exposure by triggering AMP activated protein kinase (AMPK)-dependent autophagy pathway activation. Our group has been studying primary cilia, microtubule-based ‘antenna' whose growth is stimulated by autophagy-activated removal of Oral-Facial-Digital Syndrome 1 protein (OFD1) from the cilia base. Here we asked whether TTFields affect glioma primary cilia and/or play any role in the prosurvival response to TTFields. Using a low grade (S7) glioma cell line, we found that 1 or 3 intermittent cycles of 72hr 200kHz TTFields treatment in vitro caused a significant lengthening of primary cilia after cells were allowed to recover 3-4 days after TTFields. At the cilia base, TTFields led to recruitment of microtubule-associated protein 1A/1B light chain 3B (LC3B) and phospho-AMPK, and removal of OFD1, changes associated with autophagy pathway activation. Acutely after TTFields, we observed fewer cilia and apparent ‘ciliophagy' because the cilia appeared to detach or ‘dissolve' from the basal body. In U87 cells, TTFields induced a significant reduction of extranuclear clusters of OFD1 while increasing a dramatic formation of nuclear islands of OFD1, two phenomena that were disrupted by addition of the autophagy inhibitor chloroquine (CQ). TTFields also stimulated surprising growth of primary cilia in U87 cells which normally rarely elaborate cilia. Further, we found that TTFields was less effective at killing cilia-depleted S7 cells. Finally, TTFields plus inhibition of autophagy using CQ or a histone deacetylase 6 (HDAC6) inhibitor led to dramatically fewer cells and cilia, thus promoting TTFields toxicity. Altogether, our results suggest that primary cilia are potential membrane ‘hotspots' triggered by TTFields to promote glioma cell survival via OFD1. Citation Format: Ping Shi, Jia Tian, Matthew R. Sarkisian. Tumor treating fields triggers OFD1 removal from primary cilia to promote glioma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1975.
Penile skin flap dorsal onlay urethroplasty for reconstruction of penile urethral strictures
Authors: B.T. Enganti, C.M. Chiruvella, P.R. Reddy, M.T.B. Bendigeri, R.D. Ragoori, S.M.G Ghouse, G.R.T Ramdas, S.P. Pandya
Journal: European Urology (2021)
Gender analysis of publishing among medical students in dermatology
Authors: Michelle Militello, Mindy D. Szeto, Kayd J. Pulsipher, Abigail L. Meckley, Kristen H. Ward, Taylor Harp, Colby L. Presley, Cara Barber, Hope R. Rietcheck, Taylor M. Runion, Chandler W. Rundle, Robert P. Dellavalle
Journal: Journal of the American Academy of Dermatology (2021)
Transactions of the American Orthopedic Association.
Journal: JAMA (1889)

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Dietary recommendations for prevention of atherosclerosis
Authors: Gabriele Riccardi, Annalisa Giosuè, Ilaria Calabrese, Olga Vaccaro
Journal: Cardiovascular Research (2021)

This review aims at summarizing updated evidence on cardiovascular disease (CVD) risk associated with consumption of specific food items to substantiate dietary strategies for atherosclerosis prevention. A systematic search on PubMed was performed to identify meta-analyses of cohort studies and RCTs with CVD outcomes. The evidence is highly concordant in showing that, for the healthy adult population, low consumption of salt and foods of animal origin, and increased intake of plant-based foods-whole grains, fruits, vegetables, legumes, and nuts-are linked with reduced atherosclerosis risk. The same applies for the replacement of butter and other animal/tropical fats with olive oil and other unsaturated-fat-rich oil. Although the literature reviewed overall endorses scientific society dietary recommendations, some relevant novelties emerge. With regard to meat, new evidence differentiates processed and red meat-both associated with increased CVD risk-from poultry, showing a neutral relationship with CVD for moderate intakes. Moreover, the preferential use of low-fat dairies in the healthy population is not supported by recent data, since both full-fat and low-fat dairies, in moderate amounts and in the context of a balanced diet, are not associated with increased CVD risk; furthermore, small quantities of cheese and regular yogurt consumption are even linked with a protective effect. Among other animal protein sources, moderate fish consumption is also supported by the latest evidence, although there might be sustainability concerns. New data endorse the replacement of most high glycemic index (GI) foods with both whole grain and low GI cereal foods. As for beverages, low consumption not only of alcohol, but also of coffee and tea is associated with a reduced atherosclerosis risk while soft drinks show a direct relationship with CVD risk. This review provides evidence-based support for promoting appropriate food choices for atherosclerosis prevention in the general population.
ファスジル,Rhoキナーゼ阻害剤,はSHRにおけるL-NAME-悪化腎硬化症の腎障害を逆転する-eNOS/NO/cGMPシステムの存在の重要性-
Authors: Koshikawa Shogo, Nishikimi Toshio, Ishimura Kimihiko, Inaba Chikako, Ishikawa Yayoi, Matsuoka Hiroaki
Journal: Circulation (2007)
Abstract 93: Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression
Authors: Xi Chen, Jennifer Rui Wang, Ying Henderson, Yuanqing Yan, Shanshan Bai, Rachel Kieser, Min Hu, Jiping Wang, Nicholas Navin, Stephen Lai, Ruli Gao
Journal: Cancer Research (2021)

Abstract Anaplastic thyroid cancer (ATC) is arguably the most lethal human malignancy, with a median survival of ~12 weeks. About half of ATC tumors arise from within differentiated forms of thyroid cancer types, most commonly papillary thyroid cancer (PTC), suggesting an evolutionary continuum from PTC to ATC. In contrast to the extreme lethality of ATC, PTC are typically indolent with long life-histories. The molecular mechanisms driving ATC progression from PTC have been challenging to resolve, mostly due to the heterogenous cellular populations that are undergoing dynamic changes during ATC progression. In this study, we applied high throughput 3'-scRNAseq in an unbiased analysis of cell populations in thyroid tumors. We analyzed 90,990 single cell transcriptomes from 8 ATC tumors, 8 PTC tumors and 5 normal thyroids. To make the precise inference of tumor cell lineages, we stratified the epithelial cells into 5 categories by calculating genotypes from scRNAseq data that include: (1) normal epithelial cells in normal thyroids, (2) PTC epithelial cells in PTC tumors, (3) PTC tumor cells in PTC tumors, (4) ATC epithelial cells in ATC tumors, (5) ATC tumor cells in ATC tumors. We then constructed the full epithelial cell development trajectories from normal epithelial to PTC and ATC tumor cells. Our results show that co-existing epithelial and mesenchymal phenotypes is a major characteristic of ATC tumor cells and epithelial-mesenchymal transition (EMT) drives ATC developmental trajectory. We further analyzed the transcriptional programs of immune cell types and their interactions with tumor cells. Our data suggested a unique sub-population of helper T cell and a distinct B cell subtype arise in the tumor microenvironment in response to ATC progression. Collectively, our results identify EMT as the major driving force of thyroid cancer aggressiveness and provide novel insights regarding the immunological remodeling in response to ATC progression. Citation Format: Xi Chen, Jennifer Rui Wang, Ying Henderson, Yuanqing Yan, Shanshan Bai, Rachel Kieser, Min Hu, Jiping Wang, Nicholas Navin, Stephen Lai, Ruli Gao. Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 93.
Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Authors: Khi Pin Chua, Yvonne H.F. Teng, Aaron C. Tan, Angela Takano, Jacob J.S. Alvarez, Rahul Nahar, Neha Rohatgi, Gillianne G.Y. Lai, Zaw Win Aung, Joe P.S. Yeong, Kiat Hon Lim, Marjan Mojtabavi Naeini, Irfahan Kassam, Amit Jain, Wan Ling Tan, Apoorva Gogna, Chow Wei Too, Ravindran Kanesvaran, Quan Sing Ng, Mei Kim Ang, Tanujaa Rajasekaran, Devanand Anantham, Ghee Chee Phua, Bien Soo Tan, Yin Yeng Lee, Lanying Wang, Audrey S.M. Teo, Alexis Jiaying Khng, Ming Jie Lim, Lisda Suteja, Chee Keong Toh, Wan-Teck Lim, N. Gopalakrishna Iyer, Wai Leong Tam, Eng-Huat Tan, Weiwei Zhai, Axel M. Hillmer, Anders J. Skanderup, Daniel S.W. Tan
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M−) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M− tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M− tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M− and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Prevalence of Serious Bacterial Infections Among Febrile Infants 90 Days or Younger in a Canadian Urban Pediatric Emergency Department During the COVID-19 Pandemic
Authors: Brett Burstein, Gregory Anderson, Alexandra Yannopoulos
Journal: JAMA Network Open (2021)

b a SBI IBI ED visits IBI indicates invasive bacterial infection; SBI, severe bacterial infection.a P < .001for the proportion of patients with SBI during vs before the COVID-19 pandemic.b P = .005for the proportion of patients with IBIs before vs during the COVID-19 pandemic.Table.Demographic Characteristics,
Abstract 2032: Vitamin B12 augments Ca2+ dependent cytotoxicity of diethyldithiocarbamate through excessive ER-vacuolization, oxidative stress and mitochondrial depolarization in MCF-7 cells in culture
Authors: Marina E. Solovieva
Journal: Cancer Research (2021)

Abstract Coordinated organization of intracellular organelles into functional networks is vital for cells. Mitochondrial and endoplasmic reticulum (ER) interaction in regulation of cell Ca2+ homeostasis is crucial for cell death and survival. Function of these intracellular organelles involved in two-way regulation of the status of major cell metabolites including protein, lipid exchange and intracellular Ca2+ homeostasis. Disulfiram and its derivatives recently attracted attention as a potential anticancer treatment (Kona et al., 2011). Combined use of hydroxycobalamin (vitamin B12b) and diethyldithiocarbamate (DDTC) demonstrated synergistic effect (combination index=0.25) and enhanced the cytotoxic effect of DDTC in number of transformed cell lines in culture (Solovieva et al., 2020). In the present work using MCF-7, human breast cancer cells in culture we demonstrate that combined action of DDTC and B12b resulted in induction of UPRER manifested by dilation of ER cisterns, increased level of polyubiquitinated proteins, and increased expression of CHOP. Confocal microscopy revealed disorganization of mitochondrial network and ER and treatment of these cells with B12b/DDTC and accompanied by mitochondrial depolarization (~50% after 6 h of exposure to drugs). Treatments also induced changes in morphology of mitochondrial network, and within 6 h of exposure, mitochondria demonstrated large amplitude swelling, characteristic feature of mitochondrial permeability transition pore opening. Drug exposure induced mitochondrial oxidative stress and increase in superoxide anion level (monitored with MitoSOX) and increased content of mitochondrial Ca2+ (xRhod-1) which almost doubled following treatment with B12b/DDTC. Short-time exposure of MCF-7 cells to mixture of drugs in Ca2+-free incubation media (2.5 mM EGTA) resulted in generation of significantly smaller size of vacuoles as compared with control. Similarly, pre-loading of cells with intracellular Ca2+ chelator (BAPTA, 5 µM, 30 min, 37oC) or inhibition of IP3 receptor(s) with 2-APB, delayed the drug-induced vacuolization. Taken together, our data indicate that the mechanism of B12b/DDTC-induced cytotoxicity in human MCF-7 cancer cell lines involves mitochondrial oxidative stress, activation of MPT pore and Ca2+ overload. Support of Funding Information: Russian Science Foundation № 19-75-20145 Citation Format: Marina E. Solovieva. Vitamin B12 augments Ca2+ dependent cytotoxicity of diethyldithiocarbamate through excessive ER-vacuolization, oxidative stress and mitochondrial depolarization in MCF-7 cells in culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2032.