tbuckley/cabot-search huggingface dataset:
IGF-1R ubiquitination: A new dimension in IGF-1 signaling pathways
Authors: Leonard Girnita, Ada Girnita, Olle Larsson
Journal: Cancer Research (2004)

4346  The insulin-like growth factor 1 receptor (IGF-1R) plays an essential role in malignant processes in at least three different ways: 1) IGF-1R is a promoting factor; 2) it is an antiapoptotic factor; and 3) it is quasi-obligatory for the establishment and maintenance of the malignant phenotype. The IGF-1R, activated by its ligands, signals through several pathways including the MAP kinase pathway and the phosphatidyl inositol 3-kinase (PI3K) pathway. Phosphorylation is known to be the central mechanism in regulation of IGF-1R signaling. However, recently we described the involvement of another process, namely ubiquitination, in IGF-1R function (1). Our present work aimed to investigate the relationship between these two events, and their role on biological effects of IGF-1R activation. Since the IGF-1R ubiquitination is dependent on the ubiquitin ligase MDM2, we used a dominat negative MDM2 construct to inhibit ubiquitination and wild type MDM2 to enhance it. An IGF-1R-specific tyrosine kinase inhibitor(2), recently discovered in our laboratory, was employed to modulate the IGF-1R phosphorylation. Using malignant MDM2 positive cells and MDM2 negative mouse fibroblasts, we found that IGF-1R ubiquitination is dependent on the status of IGF-1R phosphorylation. However, activation of the MAPK/mitogenic signaling pathway did not occur in the absence of competent MDM2 suggesting that ubiquitination is a critical for the IGF-1R mitogenic function. Conversly, the PI3K/antiapoptotic signaling pathway was not affected by the ubiquitination blockade. Our results demonstrate a cross talk between phosphorylation and ubiquitination in IGF-1 dependent signal transduction. Future investigations could reveal the mechanisms behind this cross talk. These mechanisms may be important for biological role of IGF-1R in cancer. 1. Girnita, L., Girnita, A., and Larsson, O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A, 100: 8247-8252, 2003. 2. Girnita, A., Girnita, L., del Prete F, Bartolazzi A, Larsson O and Axelson M Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malig-nant cell growth Cancer Res, (in press)
Novel approaches to mechanism-based atrial fibrillation ablation
Authors: Jorge G Quintanilla, Shlomo Shpun, José Jalife, David Filgueiras-Rama
Journal: Cardiovascular Research (2021)

Modern cardiac electrophysiology has reported significant advances in the understanding of mechanisms underlying complex wave propagation patterns during atrial fibrillation (AF), although disagreements remain. One school of thought adheres to the long-held postulate that AF is the result of randomly propagating wavelets that wonder throughout the atria. Another school supports the notion that AF is deterministic in that it depends on a small number of high-frequency rotors generating three-dimensional scroll waves that propagate throughout the atria. The spiralling waves are thought to interact with anatomic and functional obstacles, leading to fragmentation and new wavelet formation associated with the irregular activation patterns documented on AF tracings. The deterministic hypothesis is consistent with demonstrable hierarchical gradients of activation frequency and AF termination on ablation at specific (non-random) atrial regions. During the last decade, data from realistic animal models and pilot clinical series have triggered a new era of novel methodologies to identify and ablate AF drivers outside the pulmonary veins. New generation electroanatomical mapping systems and multielectrode mapping catheters, complimented by powerful mathematical analyses, have generated the necessary platforms and tools for moving these approaches into clinical procedures. Recent clinical data using such platforms have provided encouraging evidence supporting the feasibility of targeting and effectively ablating driver regions in addition to pulmonary vein isolation in persistent AF. Here, we review state-of-the-art technologies and provide a comprehensive historical perspective, characterization, classification, and expected outcomes of current mechanism-based methods for AF ablation. We discuss also the challenges and expected future directions that scientists and clinicians will face in their efforts to understand AF dynamics and successfully implement any novel method into regular clinical practice.
Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway
Authors: Jin Yang, Xueke Shi, Miao Yang, Jingjing Luo, Qinghong Gao, Xiangjian Wang, Yang Wu, Yuan Tian, Fanglong Wu, Hongmei Zhou
Journal: International Journal of Oral Science (2021)

Abstract As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.
Abstract 10202: Minority Stress, Social Support, and Cardiovascular Risk Factors in Transgender and Gender Nonconforming Persons
Authors: Billy A Caceres, Kasey Jackman, Donald Edmondson, Walter Bockting
Journal: Circulation (2019)

Introduction: Transgender and gender nonconforming (TGNC) persons experience health disparities related to discrimination and marginalization. Despite potentially elevated risk for CVD related to s...
P15.03 A Phase 1/1b Study of Lazertinib as Monotherapy and in Combination with Amivantamab in Advanced EGFR-Mutated NSCLC
Authors: K. Goto, T. Hida, N. Funami, R. Iwasawa, S. Mita, Y. Botilde, A. Yamashita, Y. Inoh, N. Haddish-Berhane, J. Xie, A. Roshak, R.E. Knoblauch, Y. Ohe
Journal: Journal of Thoracic Oncology (2021)
P39.06 Surviving Metastatic Non-Small Cell Lung Cancer – Experience and Supportive Care Needs of Patients Receiving Novel Therapies
Authors: S. Heynemann, J. Lai-Kwon, J. Flore, H. Dhillon, M. Duffy, J. Burke, L. Briggs, L. Leigh, L. Mileshkin, B. Solomon, D. Ball, R. Kokanovic, M. Jefford
Journal: Journal of Thoracic Oncology (2021)
P39.01 Satisfaction with the Lung Cancer Care Pathway. Is it time to Revise the way we Monitor and Assess Patient Experience?
Authors: Y. Nartey, L. Tata, A. Khakwani, V. Beattie, A. Wilcock, I. Woolhouse, P. Beckett, R. Hubbard, I. Stewart
Journal: Journal of Thoracic Oncology (2021)
Androgen receptor-negative human prostate cancer cells induce osteogenesis through FGF9-mediated mechanisms
Authors: Zhi-Gang Li, Nora Navone, Jun Yang, Jie Liu, Paul Mathew, Michael Starbuck, Amado Zurita, Charles Sikes, Asha Multani, Eleni Efstathiou, Adriana Lopez, Jing Wang, Tina Fanning, Victor Prieto, Vikas Kundra, Patricia Troncoso, Austin Raymond, Sue-Hwa Lin, Elba Vazquez
Journal: Cancer Research (2008)

1612  In prostate cancer, androgen-blockade strategies are commonly used to treat osteoblastic bone metastases, but responses to these therapies are of short duration, and eventually tumor progression occurs. The mechanism for androgen-independent progression in bone is not clear. We established two prostate cancer xenografts (MDA PCa 118a and MDA PCa 118b) from an osteoblastic bone metastasis in a man with castration-resistant prostate cancer. These xenografts are androgen-receptor negative and can grow in castrated as well as intact male mice. Also, these cells induce a robust osteoblastic reaction in bone and in the subcutis of immunodeficient mice. We found that these cells display a pattern of gene expression similar to that of the osteolytic prostate cancer cell line PC3, in that both MDA PCa 118 and PC3 express bone morphogenetic proteins, Wnts, and endothelin-1 as well as the Wnt inhibitor dickkopf-1 and the osteoclast-activating factor parathyroid hormone-related peptide, suggesting that other factors are involved in MDA PCa 118-induced osteogenesis. In a gene array analysis, we identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells of mildly blastic (MDA PCa 2b) or lytic (PC3) phenotypes and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. We also found that the MDA PCa 118-induced osteoblast proliferation was blocked by FGF9 antibody. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Findings were confirmed by RT-PCR analysis of RNA obtained by laser capture microdissection of normal prostate epithelial cells and prostate cancer epithelial cells derived from two bone metastases Collectively, these results suggest that FGF9 contributes to MDA PCa 118-induced osteogenesis and may participate in the osteoblastic progression of prostate cancer in bone. MDA PCa 118 is the first human prostate cancer xenograft that does not express androgen receptor, yet it induces strong osteogenic response both in bone and the subcutis of immunodeficient mice. These observations suggest that androgen receptor-null cells contribute to the castration-resistant osteoblastic progression of prostate cancer and imply that targeting these cells will be critical in the treatment of prostate cancer bone metastases. In addition, this new osteogenic xenograft will be an important preclinical model for therapy testing.
Development of nucleic acid aptamer-based lateral flow assays: A robust platform for cost-effective point-of-care diagnosis
Authors: Tao Wang, Lanmei Chen, Arpitha Chikkanna, Suxiang Chen, Isabell Brusius, Nabayet Sbuh, Rakesh N Veedu
Journal: Theranostics (2021)

Lateral flow assay (LFA) has made a paradigm shift in the
TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis: Erratum
Authors: Han-Li Huang, Yi-Min Liu, Ting-Yi Sung, Tsui-Chin Huang, Ya-Wen Cheng, Jing-Ping Liou, Shiow-Lin Pan
Journal: Theranostics (2020)
Deep-learning and MR images to target hypoxic habitats with evofosfamide in preclinical models of sarcoma
Authors: Bruna V Jardim-Perassi, Wei Mu, Suning Huang, Michal R Tomaszewski, Jan Poleszczuk, Mahmoud A Abdalah, Mikalai M Budzevich, William Dominguez-Viqueira, Damon R Reed, Marilyn M Bui, Joseph O Johnson, Gary V Martinez, Robert J Gillies
Journal: Theranostics (2021)

Rationale: Hypoxic regions (habitats) within tumors are heterogeneously distributed and can be widely variant. Hypoxic habitats are generally pan-therapy resistant. For this reason, hypoxia-activated prodrugs (HAPs) have been developed to target these resistant volumes. The HAP evofosfamide (TH-302) has shown promise in preclinical and early clinical trials of sarcoma. However, in a phase III clinical trial of non-resectable soft tissue sarcomas, TH-302 did not improve survival in combination with doxorubicin (Dox), possibly due to a lack of patient stratification based on hypoxic status. Therefore, we used magnetic resonance imaging (MRI) to identify hypoxic habitats and non-invasively follow therapies response in sarcoma mouse models. Methods: We developed deep-learning (DL) models to identify hypoxia, using multiparametric MRI and co-registered histology, and monitored response to TH-302 in a patient-derived xenograft (PDX) of rhabdomyosarcoma and a syngeneic model of fibrosarcoma (radiation-induced fibrosarcoma, RIF-1). Results: A DL convolutional neural network showed strong correlations (>0.76) between the true hypoxia fraction in histology and the predicted hypoxia fraction in multiparametric MRI. TH-302 monotherapy or in combination with Dox delayed tumor growth and increased survival in the hypoxic PDX model (p<0.05), but not in the RIF-1 model, which had a lower volume of hypoxic habitats. Control studies showed that RIF-1 resistance was due to hypoxia and not other causes. Notably, PDX tumors developed resistance to TH-302 under prolonged treatment that was not due to a reduction in hypoxic volumes. Conclusion: Artificial intelligence analysis of pre-therapy MR images can predict hypoxia and subsequent response to HAPs. This approach can be used to monitor therapy response and adapt schedules to forestall the emergence of resistance.
Abstract 9515: TAVR in Patients With Dialysis- The Next Frontier? Readmission Rates and Mortality Differences in Comparison to SAVR- A Nationwide Analysis
Authors: Aaqib H Malik, Srikanth Yandrapalli, Syed Zaid, Suchith Shetty, Senada Malik, Wilbert S Aronow, Cenap Undemir, Hasan Ahmad
Journal: Circulation (2019)

Introduction: Transcatheter aortic valve replacement (TAVR) is considered a high-risk procedure for patients who are on dialysis. We sought to determine the differences in 6-months outcomes for dia...
MA13.08 Genomic and Transcriptomic Features of Distinct Resistance Trajectories in EGFR Mutant Non-Small Cell Lung Cancer (NSCLC)
Authors: A. Tan, K.P. Chua, Y. Teng, A. Takano, J. Alvarez, R. Nahar, N. Rohatgi, G. Lai, Z. Aung, J. Yeong, K.H.T. Lim, M. Naeini, I. Kassam, A. Jain, W. Tan, A. Gogna, C.W. Too, R. Kanesvaran, Q.S. Ng, M. Ang, T. Rajasekaran, A. Devanand, G.C. Phua, B.S. Tan, Y.Y. Lee, L. Wang, A. Teo, A. Khng, M.J. Lim, L. Suteja, C.K. Toh, W. Lim, N.G. Iyer, W.L. Tam, E. Tan, W. Zhai, A. Hillmer, A. Skanderup, D. Tan
Journal: Journal of Thoracic Oncology (2021)
Environmental impact of personal protective equipment distributed for use by health and social care services in England in the first six months of the COVID-19 pandemic
Authors: Chantelle Rizan, Malcolm Reed, Mahmood F Bhutta
Journal: Journal of the Royal Society of Medicine (2021)

Objective To quantify the environmental impact of personal protective equipment (PPE) distributed for use by the health and social care system to control the spread of SARS-CoV-2 in England, and model strategies for mitigating the environmental impact. Design Life cycle assessment was used to determine environmental impacts of PPE distributed to health and social care in England during the first six months of the COVID-19 pandemic. The base scenario assumed all products were single-use and disposed of via clinical waste. Scenario modelling was used to determine the effect of environmental mitigation strategies: (1) eliminating international travel during supply; (2) eliminating glove use; (3) reusing gowns and face shields; and (4) maximal recycling. Setting Royal Sussex County Hospital, Brighton, UK. Main outcome measures The carbon footprint of PPE distributed during the study period totalled 106,478 tonnes CO 2 e, with greatest contributions from gloves, aprons, face shields and Type IIR surgical masks. The estimated damage to human health was 239 DALYs (disability-adjusted life years), impact on ecosystems was 0.47 species.year (loss of local species per year), and impact on resource depletion was costed at US $12.7m (GBP £9.3m). Scenario modelling indicated UK manufacture would have reduced the carbon footprint by 12%, eliminating gloves by 45%, reusing gowns and gloves by 10% and maximal recycling by 35%. Results A combination of strategies may have reduced the carbon footprint by 75% compared with the base scenario, and saved an estimated 183 DALYS, 0.34 species.year and US $7.4m (GBP £5.4m) due to resource depletion. Conclusion The environmental impact of PPE is large and could be reduced through domestic manufacture, rationalising glove use, using reusables where possible and optimising waste management.
P09.38 2020: COVID19 Impact in Lung Cancer Resection in a University Hospital of Brazil
Authors: P.A. Schulze, M.T. Tsukazan, G.F. Schneider, L. Bittencourt Hinrichsen, M. Iglesias, A. Vigo, M.L. Santos, A.H. Furlanetto, L.E. Canton, R. Ribeiro, J.A. Figueiredo Pinto
Journal: Journal of Thoracic Oncology (2021)
P84.06 Alectinib in ALK-Rearranged NSCLC Patients Following Crizotinib. Final Results and Biological Outcomes - Phase II ATALK Study
Authors: A. Cortot, F. Escande, R. Gervais, L. Greillier, R. Corre, R. Veillon, M. Ionescu, H. Felicio, D. Pau, V. Grégoire, N. Girard
Journal: Journal of Thoracic Oncology (2021)
P81.02 Neoadjuvant PD-1/PD-L1 Immune Checkpoint Inhibitors in Solid Tumors
Authors: S. Zhao, X. Li, S. Wang, Y. Wang, D. Huang, Y. Da, Z. Song, J. Chen, C. Manegold, L. Peng, S. Xu
Journal: Journal of Thoracic Oncology (2021)
Age dependent associations of risk factors with heart failure: pooled population based cohort study
Authors: Jasper Tromp, Samantha M A Paniagua, Emily S Lau, Norrina B Allen, Michael J Blaha, Ron T Gansevoort, Hans L Hillege, Douglas E Lee, Daniel Levy, Ramachandran S Vasan, Pim van der Harst, Wiek H van Gilst, Martin G Larson, Sanjiv J Shah, Rudolf A de Boer, Carolyn S P Lam, Jennifer E Ho
Journal: BMJ (2021)

Abstract Objective To assess age differences in risk factors for incident heart failure in the general population. Design Pooled population based cohort study. Setting Framingham Heart Study, Prevention of Renal and Vascular End-stage Disease Study, and Multi-Ethnic Study of Atherosclerosis. Participants 24 675 participants without a history of heart failure stratified by age into young (&lt;55 years; n=11 599), middle aged (55-64 years; n=5587), old (65-74 years; n=5190), and elderly (≥75 years; n=2299) individuals. Main outcome measure Incident heart failure. Results Over a median follow-up of 12.7 years, 138/11 599 (1%), 293/5587 (5%), 538/5190 (10%), and 412/2299 (18%) of young, middle aged, old, and elderly participants, respectively, developed heart failure. In young participants, 32% (n=44) of heart failure cases were classified as heart failure with preserved ejection fraction compared with 43% (n=179) in elderly participants. Risk factors including hypertension, diabetes, current smoking history, and previous myocardial infarction conferred greater relative risk in younger compared with older participants (P for interaction &lt;0.05 for all). For example, hypertension was associated with a threefold increase in risk of future heart failure in young participants (hazard ratio 3.02, 95% confidence interval 2.10 to 4.34; P&lt;0.001) compared with a 1.4-fold risk in elderly participants (1.43, 1.13 to 1.81; P=0.003). The absolute risk for developing heart failure was lower in younger than in older participants with and without risk factors. Importantly, known risk factors explained a greater proportion of overall population attributable risk for heart failure in young participants (75% v 53% in elderly participants), with better model performance (C index 0.79 v 0.64). Similarly, the population attributable risks of obesity (21% v 13%), hypertension (35% v 23%), diabetes (14% v 7%), and current smoking (32% v 1%) were higher in young compared with elderly participants. Conclusions Despite a lower incidence and absolute risk of heart failure among younger compared with older people, the stronger association and greater attributable risk of modifiable risk factors among young participants highlight the importance of preventive efforts across the adult life course.
P79.03 A Phase 3 Study of the PD-1 Inhibitor Retifanlimab (INCMGA00012) Plus Platinum-Based Chemotherapy in 1L mNSCLC: POD1UM-304
Authors: S. Lu, A. Chand, C. Vaz De Melo Sette, I. Bondarenko, H. Fang, S. Shankar, C. Tian, M. Munteanu, P. Ruff
Journal: Journal of Thoracic Oncology (2021)
MA01.04 A Randomized Study Comparing Cisplatin/Paclitaxel Liposome vs Cisplatin/Gemcitabine in Chemonaive, Advanced Squamous NSCLC
Authors: C. Zhou, L. Jiang, X. Dong, K. Gu, Y. Pan, Q. Shi, G. Zhang, H. Wang, X. Zhang, N. Yang, Y. Li, J. Xiong, T. Yi, M. Peng, Y. Song, Y. Fan, J. Cui, G. Chen, W. Tan, A. Zang, Q. Guo, G. Zhao, Z. Wang, J. He, W. Yao, X. Wu, K. Chen, X. Hu, C. Hu, L. Yue, D. Jiang, G. Wang, J. Liu, G. Yu
Journal: Journal of Thoracic Oncology (2021)
Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear <i>Staphylococcus aureus</i> bacteremia
Authors: Josh Sun, Satoshi Uchiyama, Joshua Olson, Yosuke Morodomi, Ingrid Cornax, Nao Ando, Yohei Kohno, May M. T. Kyaw, Bernice Aguilar, Nina M. Haste, Sachiko Kanaji, Taisuke Kanaji, Warren E. Rose, George Sakoulas, Jamey D. Marth, Victor Nizet
Journal: Science Translational Medicine (2021)

The clinically approved drugs ticagrelor and oseltamivir fortify a pathway of platelet-mediated immunity to clear staphylococcal bacteremia in mice.
Looking back and moving forward
Authors: Pierre Ronco, Brad H. Rovin, P. Toby Coates, Olivier Devuyst, Tilman B. Drueke, Jürgen Floege, Agnes B. Fogo, T. Alp Ikizler, Masaomi Nangaku, Jai Radhakrishnan, Germaine Wong, Christina Wyatt
Journal: Kidney International (2021)
FP12.08 The Survival Impact of Circulating T Regulatory Cells Subsets in Patients with Untreated Lung Cancer
Authors: D. Amarillo, A. Brugnini, N. Trias, M.C. Rodríguez, V. Rodríguez, S. Salisbury, M. Cuello, D. Lens
Journal: Journal of Thoracic Oncology (2021)
Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics
Authors: Daniel I Swerdlow, David A Rider, Arash Yavari, Marie Wikström Lindholm, Giles V Campion, Steven E Nissen
Journal: Cardiovascular Research (2021)

Abstract Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining ‘high risk’ is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.