tbuckley/cabot-search huggingface dataset:
CIC-Mediated Modulation of MAPK Signaling Opposes Receptor Tyrosine Kinase Inhibitor Response in Kinase-Addicted Sarcoma
Authors: Igor Odintsov, Michael V. Ortiz, Inna Khodos, Marissa S. Mattar, Allan J.W. Lui, Shinji Kohsaka, Elisa de Stanchina, Julia L. Glade Bender, Marc Ladanyi, Romel Somwar
Journal: Cancer Research (2022)

Kinase fusions have been identified in a growing subset of sarcomas, but a lack of preclinical models has impeded their functional analysis as therapeutic targets in the sarcoma setting. In this study, we generated models of sarcomas bearing kinase fusions and assessed their response to molecularly targeted therapy. Immortalized, untransformed human mesenchymal stem cells (HMSC), a putative cell of origin of sarcomas, were modified using CRISPR-Cas9 to harbor a RET chromosomal translocation (HMSC-RET). In parallel, patient-derived models of RET- and NTRK-rearranged sarcomas were generated. Expression of a RET fusion activated common proliferation and survival pathways and transformed HMSC cells. The HMSC-RET models displayed similar behavior and response to therapy as the patient-derived counterparts in vitro and in vivo. Capicua (CIC)-mediated suppression of negative MAPK pathway regulators was identified as a potential mechanism by which these sarcomas compensate for RET or NTRK inhibition. This CIC-mediated feedback reactivation was blocked by coinhibition of the MAPK pathway and RET or NTRK in the respective models. Importantly, the combination of RET and ERK inhibitors was more effective than single agents at blocking tumor growth in vivo. This work offers new tools and insights to improve targeted therapy approaches in kinase-addicted sarcomas and supports upfront combination therapy to prolong responses.Novel models of kinase-rearranged sarcomas show that MAPK pathway feedback activation dampens responses to tyrosine kinase inhibitors, revealing the potential of combinatorial therapies to combat these tumors.
142P Phase IIIb study of durvalumab plus platinum–etoposide in first-line treatment of extensive-stage small cell lung cancer (CANTABRICO): Treatment patterns of chemotherapy combination phase with durvalumab
Authors: D. Isla, E. Arriola, M.R. Garcia Campelo, C. Martí, P. Diz Tain, A.L. Moreno Vega, M.L-B. Piqueras, L. León, V. Gutierrez Calderon, J.M. Oramas Rodriguez, M. Majem, A. Sanchez-Hernandez, C. Aguado de la Rosa, R. Alvarez Cabellos, J.L. Marti-Ciriquian, A. Moreno Paul, M. Gonzalez Cordero, Á. Callejo Mellén, L. Baez, J. Zugazagoitia
Journal: Annals of Oncology (2022)
Detecting Interval Distant Metastases With 18F-FDG PET/CT After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Cancer
Authors: Tiuri E. Kroese, Jelle P. Ruurda, Anne S. Bakker, Jasvir Jairam, Stella Mook, Sylvia van der Horst, Gert J. Meijer, Nadia Haj Mohammad, Peter S.N. van Rossum, Richard van Hillegersberg
Journal: Clinical Nuclear Medicine (2022)

Patients with esophageal cancer can develop distant metastases between the start of neoadjuvant chemoradiotherapy (nCRT) and planned surgery (ie, interval distant metastases). 18F-FDG PET/CT restaging after nCRT detects interval distant metastases in ~8% of patients. This study aimed to identify patients for whom 18F-FDG PET/CT restaging after nCRT could be omitted using an existing prediction model predicting for interval distant metastases or by using clinical stage groups.Patients with locally advanced esophageal cancer who underwent baseline and restaging 18F-FDG PET/CT, nCRT, and were planned for esophagectomy between 2017 and 2021 were eligible for inclusion in this retrospective study. The primary outcome was the existing model's external performance (ie, discrimination and calibration) for predicting interval distant metastases. The existing model predictors included tumor length, cN status, squamous cell carcinoma histology, and baseline SUVmax. The secondary outcome determined the clinical stage groups (AJCC/UICC eighth edition) for adenocarcinoma and squamous cell carcinoma for which the incidence of interval distant metastases was <10%.In total, 127 patients were included, of whom 17 patients developed interval distant metastases (13%; 95% confidence interval [CI], 8%-21%) and 9 patients were deemed to have false-positive lesions on 18F-FDG PET/CT (7%; 95% CI, 2%-11%). Applying the existing model to this cohort yielded a discriminatory c-statistic of 0.56 (95% CI, 0.40-0.72). The calibration of the existing model was poor (ie, mostly underestimating the actual risk). The incidence of true-positive versus false-positive interval distant metastases for patients with clinical stage II disease was 5% versus 0%; clinical stage III, 14% versus 8%; and clinical stage IVa, 22% versus 9%.The existing prediction model cannot reliably identify patients at risk for developing interval distant metastases after nCRT for esophageal cancer. Omission of 18F-FDG PET/CT restaging after nCRT could be considered in patients with clinical stage II esophageal cancer.
Mortality Trends in Multiple Myeloma after the Introduction of Novel Therapies in the United States
Authors: Bharat Nandakumar, Moritz Binder, S. Vincent Rajkumar, Prashant Kapoor, Francis K. Buadi, David Dingli, Martha Q. Lacy, Morie A. Gertz, Suzanne R. Hayman, Nelson Leung, Amie Fonder, Miriam A. Hobbs, Yi L. Hwa, Eli Muchtar, Rahma M Warsame, Taxiarchis Kourelis, Wilson I Gonsalves, Stephen J. Russell, Yi Lin, Mustaqeem A. Siddiqui, Robert A. Kyle, Angela Dispenzieri, Shaji Kumar
Journal: Blood (2021)
Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives
Authors: Stéphanie Debette, Hugh S. Markus
Journal: Circulation Research (2022)

Stroke is the second leading cause of death worldwide and a complex, heterogeneous condition. In this review, we provide an overview of the current knowledge on monogenic and multifactorial forms of stroke, highlighting recent insight into the continuum between these. We describe how, in recent years, large-scale genome-wide association studies have enabled major progress in deciphering the genetic basis for stroke and its subtypes, although more research is needed to interpret these findings. We cover the potential of stroke genetics to reveal novel pathophysiological processes underlying stroke, to accelerate the discovery of new therapeutic approaches, and to identify individuals in the population who are at high risk of stroke and could be targeted for tailored preventative interventions.
Role of Hepatocyte- and Macrophage-Specific PPARγ in Hepatotoxicity Induced by Diethylhexyl Phthalate in Mice
Authors: Miao Xu, Yongning Li, Xiaohong Wang, Qiannan Zhang, Lei Wang, Xin Zhang, Wenming Cui, Xiaomin Han, Ning Ma, Haishan Li, Hongyun Fang, Song Tang, Jingguang Li, Zhaoping Liu, Hui Yang, Xudong Jia
Journal: Environmental Health Perspectives (2022)

Background: Phthalates may disturb metabolic homeostasis in the liver by interfering with the peroxisome proliferator-activated receptors (PPARs). However, the role of hepatic macrophages in the lipid metabolic dysregulation induced by diethylhexyl phthalate (DEHP) remains unclear. Objectives: We aimed to evaluate the respective role of hepatocyte- and macrophage-specific PPARγ in the hepatotoxicity induced by DEHP. Methods: Wild-type (WT), hepatocyte-specific PPARγ knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP (625mg/kg body weight) by daily gavage for 28 d, followed by hepatotoxicity examination and macrophage analysis. RNA sequencing and lipid metabolomic analysis were used to characterize the molecular changes in mouse liver. Mouse bone marrow-derived macrophages (BMDMs) and human monocytic THP-1 cell-derived macrophages were used to investigate the mechanistic regulation of macrophages' polarization by DEHP and mono(2-ethylhexyl) phthalate (MEHP). Results: The levels of hepatic steatosis and triglyceride were significantly higher in the mice treated with DEHP compared with the control mice in the WT and Hep-KO model. Lipid accumulation induced by DEHP was notably attenuated in the Mac-KO mice, but M2-polarization of hepatic macrophages in the Mac-KO mice was significantly higher compared with the WT mice under DEHP treatment. The M2-polarization of BMDMs and human macrophages was suppressed by DEHP and MEHP. Transcriptomic and lipidomic data suggested lower levels of lipid biosynthesis, fatty acid oxidation, and oxidative phosphorylation in the Mac-KO mice compared with the WT and Hep-KO mice under DEHP treatment. Conclusions: Our data suggested that the orchestrated activation of PPARα and PPARγ by MEHP may reprogram hepatic macrophages' polarization, thereby affecting lipid homeostasis in the mouse liver. Although this conclusion was based on studies conducted in mice and in vitro, these findings may aid in elucidating the health effect of environmental phthalate exposure. https://doi.org/10.1289/EHP9373
Racial and Ethnic Disparities in Excess Deaths During the COVID-19 Pandemic, March to December 2020
Authors: Meredith S. Shiels, Anika T. Haque, Emily A. Haozous, Paul S. Albert, Jonas S. Almeida, Montserrat García-Closas, Anna M. Nápoles, Eliseo J. Pérez-Stable, Neal D. Freedman, Amy Berrington de González
Journal: Annals of Internal Medicine (2021)

Although racial/ethnic disparities in U.S. COVID-19 death rates are striking, focusing on COVID-19 deaths alone may underestimate the true effect of the pandemic on disparities. Excess death estimates capture deaths both directly and indirectly caused by COVID-19.To estimate U.S. excess deaths by racial/ethnic group.Surveillance study.United States.All decedents.Excess deaths and excess deaths per 100 000 persons from March to December 2020 were estimated by race/ethnicity, sex, age group, and cause of death, using provisional death certificate data from the Centers for Disease Control and Prevention (CDC) and U.S. Census Bureau population estimates.An estimated 2.88 million deaths occurred between March and December 2020. Compared with the number of expected deaths based on 2019 data, 477 200 excess deaths occurred during this period, with 74% attributed to COVID-19. Age-standardized excess deaths per 100 000 persons among Black, American Indian/Alaska Native (AI/AN), and Latino males and females were more than double those in White and Asian males and females. Non-COVID-19 excess deaths also disproportionately affected Black, AI/AN, and Latino persons. Compared with White males and females, non-COVID-19 excess deaths per 100 000 persons were 2 to 4 times higher in Black, AI/AN, and Latino males and females, including deaths due to diabetes, heart disease, cerebrovascular disease, and Alzheimer disease. Excess deaths in 2020 resulted in substantial widening of racial/ethnic disparities in all-cause mortality from 2019 to 2020.Completeness and availability of provisional CDC data; no estimates of precision around results.There were profound racial/ethnic disparities in excess deaths in the United States in 2020 during the COVID-19 pandemic, resulting in rapid increases in racial/ethnic disparities in all-cause mortality between 2019 and 2020.National Institutes of Health Intramural Research Program.
Targeting Fc Receptor-Mediated Effects and the “Don't Eat Me” Signal with an Oncolytic Virus Expressing an Anti-CD47 Antibody to Treat Metastatic Ovarian Cancer
Authors: Lei Tian, Bo Xu, Kun-Yu Teng, Mihae Song, Zheng Zhu, Yuqing Chen, Jing Wang, Jianying Zhang, Mingye Feng, Balveen Kaur, Lorna Rodriguez, Michael A. Caligiuri, Jianhua Yu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the “don't eat me” pathway. However, this strategy is associated with severe toxicity. Experimental Design: To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4). Results: Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47–SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection. Conclusions: Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.
First-in-Human Experience With 177Lu-DOTAGA.(SA.FAPi)2 Therapy in an Uncommon Case of Aggressive Medullary Thyroid Carcinoma Clinically Mimicking as Anaplastic Thyroid Cancer
Authors: Sanjana Ballal, Madhav Prasad Yadav, Euy Sung Moon, Frank Rösch, Sreedharan Thankarajan ArunRaj, Shipra Agarwal, Madhavi Tripathi, Ranjit Kumar Sahoo, Chandrasekhar Bal
Journal: Clinical Nuclear Medicine (2022)

Abstract A 56-year-old man was diagnosed with calcitonin negative, plasma chromogranin A–positive, immunohistochemistry-negative, high-grade MTC (medullary thyroid cancer) behaving clinically like anaplastic thyroid cancer and presented with progressive disease after conventional therapies. A theranostic approach of 68 Ga-DOTA.SA.FAPi–guided 177 Lu-DOTAGA.(SA.FAPi) 2 radionuclide therapy was administered on compassionate grounds as per the Declaration of Helsinki because known standard lines of treatment were ineffective. Treatment with a single cycle of 1.65 GBq 177 Lu-DOTAGA.(SA.FAPi) 2 demonstrated a sustainable reduction in the neck mass with significant improvement in the quality of life of the patient. 177 Lu-DOTAGA.(SA.FAPi) 2 is a potential theranostic option for high-grade MTC refractory to standard therapeutic options.
Abstract 10689: C-src Contributes to Mitochondrial Ca <sup>2+</sup> Uniporter Increase and Arrhythmic Risk in Ischemic Cardiomyopathy
Authors: An Xie, Gyeoung-Jin Kang, Eun Ji Kim, Iuliia Polina, Feng Feng, Bong Sook Jhun, Jin O-uchi, Samuel C Dudley
Journal: Circulation (2021)

Introduction: We have described previously an arrhythmic mechanism in nonischemic heart failure (HF) involving an increased mitochondrial Ca 2+ uptake that results in QT prolongation and lethal arrhythmias during cardiomyopathy. This arrhythmic mechanism is associated with mitochondrial Ca 2+ uniporter (MCU) tyrosine phosphorylation (p-Tyr). Hypothesis: Here, we determined which kinase was responsible for MCU phosphorylation in ischemic cardiomyopathy. Methods: Ischemic HF was induced in wild type FVB/NJ mice for three weeks by ligated left anterior descending coronary artery. Western blot, immunoprecipitation, fluorescence resonance energy transfer (FRET) and patch-clamp techniques were employed in isolated mouse cardiomyocytes. Results: When compared to sham hearts, the protein level of p-Src increased significantly in ischemic HF mouse hearts. In a heterologous expression system, c-Src could bind MCU and tyrosine phosphorylate MCU. This phosphorylation was blocked by a c-Src inhibitor, PP1. Overexpression of constitutive active c-Src (Src-Y527F) significantly increased MCU inward current at -160 mV. Downregulation of C-terminal Src kinase (CSK), a regulatory kinase inversely related to c-Src activity, increased p-Src, enhanced mitochondrial and SR contact, and facilitated mitochondrial Ca 2+ uptake in ischemic HF mouse cardiomyocytes. Protein expression of CaMKII, PyK2, and p-PyK2 did not change during ischemic HF. MI activated c-Src by S-nitrosylation of caveolin-1 with subsequent release of the kinase. c-Src activation was associated with APD prolongation and arrhythmia following myocardial infarction in mice. Human heart tissue showed that ischemic HF patients had significantly increased p-Src associated with increased QTc prolongation and arrhythmia. Conclusions: During ischemic HF, c-Src activation directly increased MCU current that contributed to QT prolongation and arrhythmic risk in ischemic cardiomyopathy.
Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial
Authors: Matthew R Smith, Howard I Scher, Shahneen Sandhu, Eleni Efstathiou, Primo N Lara, Evan Y Yu, Daniel J George, Kim N Chi, Fred Saad, Olof Ståhl, David Olmos, Daniel C Danila, Gary E Mason, Byron M Espina, Xin Zhao, Karen A Urtishak, Peter Francis, Angela Lopez-Gitlitz, Karim Fizazi, Francis Parnis, Anthony M. Joshua, Lisa G. Horvath, Christopher Steer, Gavin Marx, Shahneen Sandhu, Howard Gurney, Thomas Ferguson, Siska Van Bruwaene, Daisy Luyten, Peter Schatteman, Nicolaas Lumen, Luc Dirix, Jean-Charles Goeminne, Thierry Gil, Emmanuel Seront, Christof Vulsteke, Celio Kussumoto, Fabio A. Franke, Fabricio Augusto Martinelli de Oliveira, Andrea Juliana Pereira de Santana Gomes, Hélio Pinczowski, Daniel D'Almeida Preto, Luis Eduardo Zucca, Giuliano Santos Borges, Andre M. Murad, Fred Saad, Kim N. Chi, Yves Fradet, Neil E. Fleshner, Urban Emmenegger, Klaus Brasso, Karim Fizazi, Stephane Culine, Antoine Thiery-Vuillemin, Florence Joly, Aude Fléchon, Werner Hilgers, Jean-Christophe Eymard, Delphine Borchiellini, Philippe Barthélémy, Raanan Berger, Raya Leibowitz-Amit, Wilmosh Mermershtain, Keren Rouvinov, Avivit Peer, Svetlana Kovel, Avishay Sella, Martijn P. Lolkema, Alfonsus J.M. van den Eertwegh, Johannes Voortman, Maureen J. Aarts, Jourik A. Gietema, Choung-Soo Kim, Young-Deuk Choi, Byung-Ha Chung, Rustem A. Gafanov, Evgeniy Kopyltsov, Evgeny A. Usynin, Joan Carles, Begoña Mellado, José Pablo Maroto, Jesús García-Donás, Juan Francisco Rodríguez Moreno, Ignacio Durán, Begoña Pérez-Valderrama, Elena Castro, David Olmos, María José Méndez-Vidal, David Lorente Estellés, Regina Gironés Sarrió, José Muñoz-Langa, Urbano Anido Herranz, Javier Puente Vázquez, Enrique Castellanos, Martin Hellström, Anders Widmark, Ingela Franck Lissbrant, Åsa Jellvert, Cecilia Külich, René Blom, Olof Ståhl, Po-Hui Chiang, Chih-Hsiung Kang, Yen-Chuan Ou, Shian-Shiang Wang, Hsi-Chin Wu, Yu-Chuan Lu, Gerhardt Attard, Vincent Khoo, Amit Bahl, Prasad Kellati, Omi Parikh, Rajaguru Srinivasan, Jason F. Lester, John N. Staffurth, Heather H. Cheng, Eleni Efstathiou, Patrick G. Pilié, Daniel J. George, Lawrence I. Karsh, W. Kevin Kelly, Daniel C. Danila, Paul R. Sieber, Matthew R. Smith, Elisabeth I. Heath, Ulka N. Vaishampayan, Thomas W. Flaig, Hamid Emamekhoo, Jacek K. Pinski, Arash Rezazadeh Kalebasty, Joseph J. Maly, Helen Moon
Journal: The Lancet Oncology (2022)
Changes in Health Care Spending, Use, and Clinical Outcomes After Nonfatal Firearm Injuries Among Survivors and Family Members
Authors: Zirui Song, José R. Zubizarreta, Mia Giuriato, Erica Paulos, Katherine A. Koh
Journal: Annals of Internal Medicine (2022)

Background: Despite increasing awareness of firearm-related deaths, evidence on the clinical and economic implications of nonfatal firearm injuries is limited. Objective: To measure changes in clinical and economic outcomes after nonfatal firearm injuries among survivors and their family members. Design: Cohort study. Setting: MarketScan Medicare and commercial claims data, 2008 to 2018. Participants: 6498 survivors of firearm injuries matched to 32 490 control participants and 12 489 family members of survivors matched to 62 445 control participants. Intervention: Exposure to nonfatal firearm injury as a survivor or family member of a survivor. Measurements: Changes in health care spending, use, and morbidity from preinjury through 1 year postinjury relative to control participants, on average and by type and severity of firearm injury. Results: After nonfatal firearm injury, medical spending increased $2495 per person per month (402%) and cost sharing increased $102 per person per month (176%) among survivors relative to control participants (P < 0.001) in the first year after injury, driven by an increase in the first month of $25 554 (4122%) in spending and $1112 (1917%) in cost sharing per survivor (P < 0.001). All categories of health care use increased relative to the control group. Survivors had a 40% increase in pain diagnoses, a 51% increase in psychiatric disorders, and an 85% increase in substance use disorders after firearm injury relative to control participants (P < 0.001), accompanied by increased pain and psychiatric medications. Family members had a 12% increase in psychiatric disorders relative to their control participants (P = 0.003). These overall clinical and economic changes were driven by intentional firearm injuries and more severe firearm injuries. Limitation: Precision of diagnostic codes and generalizability to other patient populations, including Medicaid and uninsured patients. Conclusion: In survivors, nonfatal firearm injuries led to increases in psychiatric disorders, substance use disorders, and pain diagnoses, alongside substantial increases in health care spending and use. In addition, mental health worsened among family members. Primary Funding Source: National Institutes of Health.
Beyond T Cells: IgA Incites Immune Recognition in Endometrial Cancer
Authors: Juan C. Osorio, Dmitriy Zamarin
Journal: Cancer Research (2022)

While T cells are established major players in antitumor immunity, tumor-associated B cells and antibodies have recently emerged as critical components in modulating immunity in the tumor microenvironment. In the current issue of Cancer Research, Mandal and colleagues show that tumor-infiltrating B cells are associated with improved outcomes in endometrial cancers. Mechanistically, the investigators demonstrate that the immune response is mediated by class-switched IgA binding to the polymeric immunoglobulin receptor in tumor cells, resulting in tumor cell–intrinsic activation of inflammatory pathways. These findings highlight that coordinated B-cell and T-cell responses may predict improved outcomes in patients with endometrial cancer and set the groundwork to further investigate the mechanisms by which humoral immunity could be exploited for cancer immunotherapy. See related article by Mandal et al., p. 859