tbuckley/cabot-search huggingface dataset:
Racial and Ethnic Disparities in Receipt of General Anesthesia for Cesarean Delivery
Authors: Caroline Leigh Thomas, Elizabeth M. S. Lange, Jennifer M. Banayan, Yinhua Zhu, Chuanhong Liao, Feyce M. Peralta, William A. Grobman, Barbara M. Scavone, Paloma Toledo
Journal: JAMA Network Open (2024)

Importance General anesthesia for cesarean delivery is associated with increased maternal morbidity, and Black and Hispanic pregnant patients have higher rates of general anesthesia use compared with their non-Hispanic White counterparts. It is unknown whether risk factors and indications for general anesthesia differ among patients of differing race and ethnicity. Objective To evaluate differences in general anesthesia use for cesarean delivery and the indication for the general anesthetic by race and ethnicity. Design, Setting, and Participants In this retrospective, cross-sectional, single-center study, electronic medical records for all 35 117 patients who underwent cesarean delivery at Northwestern Medicine’s Prentice Women’s Hospital from January 1, 2007, to March 2, 2018, were queried for maternal demographics, clinical characteristics, obstetric and anesthetic data, the indication for cesarean delivery, and the indication for general anesthesia when used. Data analysis occurred in August 2023. Exposure Cesarean delivery. Main Outcomes and Measures The rate of general anesthesia for cesarean delivery by race and ethnicity. Results Of the 35 117 patients (median age, 33 years [IQR, 30-36 years]) who underwent cesarean delivery, 1147 (3.3%) received general anesthesia; the rates of general anesthesia were 2.5% for Asian patients (61 of 2422), 5.0% for Black patients (194 of 3895), 3.7% for Hispanic patients (197 of 5305), 2.8% for non-Hispanic White patients (542 of 19 479), and 3.8% (153 of 4016) for all other groups (including those who declined to provide race and ethnicity information) ( P &amp;amp;lt; .001). A total of 19 933 pregnant patients (56.8%) were in labor at the time of their cesarean delivery. Of those, 16 363 (82.1%) had neuraxial labor analgesia in situ. Among those who had an epidural catheter in situ, there were no racial or ethnic differences in the rates of general anesthesia use vs neuraxial analgesia use (Asian patients, 34 of 503 [6.8%] vs 1289 of 15 860 [8.1%]; Black patients, 78 of 503 [15.5%] vs 1925 of 15 860 [12.1%]; Hispanic patients, 80 of 503 [15.9%] vs 2415 of 15 860 [15.2%]; non-Hispanic White patients, 255 of 503 [50.7%] vs 8285 of 15 860 [52.2%]; and patients of other race or ethnicity, 56 of 503 [11.1%] vs 1946 of 15 860 [12.3%]; P = .16). Indications for cesarean delivery and for general anesthesia were not different when stratified by race and ethnicity. Conclusions and Relevance Racial disparities in rates of general anesthesia continue to exist; however, this study suggests that, for laboring patients who had labor epidural catheters in situ, no disparity by race or ethnicity existed. Future studies should address whether disparities in care that occur prior to neuraxial catheter placement are associated with higher rates of general anesthesia among patients from ethnic and racial minority groups.
Abstract B031: Evaluating the consequence of homologous recombination deficiency in models of pediatric solid tumor
Authors: Evan Savage, Ke Xu, Jason Myer, Evadnie Rampersaud, Yawei Hui, Ti-Cheng Chang, Gang Wu, Christopher Tinkle, Anang Shelat
Journal: Cancer Research (2024)

Abstract Homologous recombination deficiency (HRD) has been extensively studied in adult cancers where its association with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitor sensitivity is well established. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and tumors often exhibit characteristic genomic scars such as elevated HRD.sum score and specific mutational signatures derived from single nucleotide variants, insertions and deletions, and structural variants. Despite its clinical relevance, the therapeutic predictive value of HRD has not been systematically studied in pediatric cancers. Consequently, our team devised a strategy to identify and validate targetable deficiencies in DNA damage response (DDR) genes and assess genomic scars in pediatric tumors. Here, we report evaluation of HRD in a cohort of &amp;gt;200 patient-derived orthotopic xenograft models from the Childhood Solid Tumor Network (CSTN), a freely sharing resource established by our institution to accelerate the development of therapies for children with cancer. We provide an overview of our pipeline and discuss the landscape of genomic scars within our cohort. We profiled somatic and germline variants from over 500 DNA damage response genes and identified TP53 as the most frequently mutated gene with biallelic loss, whereas bi-allelic loss of BRCA1/2 was not found. Overall, our study suggests that HRD exists within solid tumors, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in adult cancers where HRD is common. Importantly, the CSTN contains models of pediatric solid tumors that are amenable to in vitro and in vivo interrogation, and therefore, will facilitate examination of the functional consequences of inactivated DDR genes, characterization of the unique genomic scar profiles underlying these inactivation events, and evaluation of novel therapeutic strategies. Citation Format: Evan Savage, Ke Xu, Jason Myer, Evadnie Rampersaud, Yawei Hui, Ti-Cheng Chang, Gang Wu, Christopher Tinkle, Anang Shelat. Evaluating the consequence of homologous recombination deficiency in models of pediatric solid tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B031.
Abstract A017: Targeting <i>Tlk2</i> impairs breast cancer growth and engages immune responses
Authors: Marina Villamor-Payá, Adrià Caballé, Jordann Smak, Mohamed-Reda Benmebarek, Camille Stephan-Otto Attolini, Travis H. Stracker
Journal: Cancer Research (2024)

Abstract The Tousled like kinases 1 and 2 (TLK1 and TLK2) are evolutionarily conserved Ser/Thr kinases that are required for genome stability and normal development in numerous organisms. Both kinases contribute to histone deposition by targeting the histone chaperones ASF1A and ASF1B and are regulated by the DNA damage response (DDR). TLK1/2 expression is ubiquitous and often elevated in human cancers with suppressed immune gene expression. In some cancer types, elevated TLK levels correlate with decreased disease-free survival. In cultured cells, TLK depletion causes replication stress, DNA damage and altered chromatin maintenance. TLK1/2 depletion increases the efficacy of DNA damage checkpoint inhibitors and PARP inhibitors and induces the Alternative-lengthening of telomeres pathway and innate immune signaling. Collectively, this data suggests that TLK activity may be a druggable anti-cancer target. To test this, we generated a conditional Tlk2 allele in mice and introduced the Mouse Mammary Tumor Virus-Polyoma Middle Tumor-antigen (MMTV-PyMT) transgene to generate breast cancers. Deletion of Tlk2 in developing breast cancer resulted in impaired primary tumor growth and a complete inhibition of lung metastasis. Characterization of the tumor microenvironment revealed elevated immune infiltration that includes activated T cells with higher levels of PD-1, which could potentially sensitize these tumors to immune checkpoint blockade. To test this possibility, we established a syngeneic breast cancer model to allow us to combine Tlk2 depletion or deletion with DDR inhibitor and anti-PD-1 therapy in vivo. Preliminary data supports the strategy of targeting Tlk2 in cancer and we will share current data from tumor models and preliminary characterization of small molecule inhibitors. Citation Format: Marina Villamor-Payá, Adrià Caballé, Jordann Smak, Mohamed-Reda Benmebarek, Camille Stephan-Otto Attolini, Travis H. Stracker. Targeting Tlk2 impairs breast cancer growth and engages immune responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A017.
Abstract IA001: Single strand DNA GAP accumulation as a functional biomarker for USP1 inhibitor sensitivity
Authors: Alan D. D'Andrea
Journal: Cancer Research (2024)

Abstract Recent studies suggest that PARP inhibitors and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA gaps (ssDNA gaps) at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetic lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Here, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells. USP1 inhibition increased monoubiquitinated PCNA at replication forks and resulted in accumulation of ssDNA gaps in BRCA1-deficient cancer cells. Knockdown of RAD18, the E3 ubiquitin ligase known to ubiquitinate PCNA, caused USP1 inhibitor resistance and suppression of ssDNA gaps. ssDNA gap accumulation induced by USP1 inhibition correlates with drug sensitivity of BRCA1-mutated cancer cells and overcomes PARP inhibitor resistance in cell line and xenograft models. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. A set of patient-derived ovarian cancer organoids (PDOs) were used to confirm the sensitivity of BRCA1-deficient cells to USP1 inhibition. Five PDOs were derived from patients with high grade-serous ovarian cancer (HGSOC). Among the five PDOs, two of them were from tumors harboring germline BRCA1 pathogenic mutations. BRCA1-mutant PDOs, but not BRCA1-WT PDOs, were sensitive to a USP1 inhibitor and to PARP inhibitor monotherapies. The accumulation of ssDNA gaps after treatment with a USP1 inhibitor or PARP inhibitor correlated with the sensitivity to these drugs in all the models tested. Moreover, the combination of a PARP inhibitor and USP1 inhibitor showed synergy in a BRCA1-WT model, which was resistant to both monotherapies. Interestingly, ssDNA gaps accumulated with the combination treatment and not with monotherapy in this model. Ovarian cancer PDOs therefore provide a powerful tool for rapid in vitro sensitivity testing. The detection of ssDNA gap accumulation may be a useful predictive biomarker for response to USP1 inhibition as monotherapy or in combination in ongoing clinical trials. Citation Format: Alan D. D'Andrea. Single strand DNA GAP accumulation as a functional biomarker for USP1 inhibitor sensitivity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA001.
Zinc finger protein ZNF638 regulates triglyceride metabolism via ANGPTL8 in an estrogen dependent manner
Authors: Meiyao Meng, Yuxiang Cao, Jin Qiu, Guangyu Shan, Yingwen Wang, Ying Zheng, Mingwei Guo, Jian Yu, Yuandi Ma, Cen Xie, Cheng Hu, Lingyan Xu, Elisabetta Mueller, Xinran Ma
Journal: Metabolism (2024)
Targeted chemotherapy via HER2-based chimeric antigen receptor (CAR) engineered T-cell membrane coated polymeric nanoparticles
Authors: Serkan Yaman, Harish Ramachandramoorthy, Priyanka Iyer, Uday Chintapula, Tam Nguyen, Manoj Sabnani, Tanviben Kotadia, Soroush Ghaffari, Laurentiu M. Pop, Raquibul Hannan, Jon A. Weidanz, Kytai T. Nguyen
Journal: Bioactive Materials (2024)

Cell membrane-derived nanoparticles (NPs) have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells, impeding systemic clearance, and altering foreign body responses. Besides NP technology, adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy. In this research, we developed a biomimetic drug carrier based on chimeric antigen receptor (CAR) transduced T-cell membranes. For that purpose, anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids. Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction. Anti-cancer drug Cisplatin-loaded poly (D, l-lactide-co-glycolic acid) (PLGA) NPs were coated with anti-human epidermal growth factor receptor 2 (HER2)-specific CAR engineered T-cell membranes. Anti-HER2 CAR-T-cell membrane-coated PLGA NPs (CAR-T-MNPs) were characterized and confirmed via fluorescent microscopy and flow cytometry. Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions. Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+ cancer cells in vitro. In addition, in vitro uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells. These results were also confirmed via in vivo biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice. CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice. In Conclusion, the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both in vitro and in vivo. Therefore, CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.
Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial
Authors: B Joseph Elmunzer, Lydia D Foster, Jose Serrano, Gregory A Coté, Steven A Edmundowicz, Sachin Wani, Raj Shah, Ji Young Bang, Shyam Varadarajulu, Vikesh K Singh, Mouen Khashab, Richard S Kwon, James M Scheiman, Field F Willingham, Steven A Keilin, Georgios I Papachristou, Amitabh Chak, Adam Slivka, Daniel Mullady, Vladimir Kushnir, James Buxbaum, Rajesh Keswani, Timothy B Gardner, Nauzer Forbes, Amit Rastogi, Andrew Ross, Joanna Law, Patrick Yachimski, Yen-I Chen, Alan Barkun, Zachary L Smith, Bret Petersen, Andrew Y Wang, John R Saltzman, Rebecca L Spitzer, Collins Ordiah, Cathie Spino, Valerie Durkalski-Mauldin, B. Joseph Elmunzer, Lydia D. Foster, Jose Serrano, Gregory A. Coté, Steven A. Edmundowicz, Sachin Wani, Raj Shah, Ji Young Bang, Shyam Varadarajulu, Vikesh K. Singh, Mouen Khashab, Richard S. Kwon, James M. Scheiman, Field F. Willingham, Steven A. Keilin, Georgios I. Papachristou, Amitabh Chak, Adam Slivka, Daniel Mullady, Vladimir Kushnir, James Buxbaum, Rajesh Keswani, Timothy B. Gardner, Nauzer Forbes, Amit Rastogi, Andrew Ross, Joanna Law, Patrick Yachimski, Yen-I Chen, Alan Barkun, Zachary L. Smith, Bret Petersen, Andrew Y. Wang, John R. Saltzman, Rebecca L. Spitzer, Collins Ordiah, Cathie Spino, Peter D.R. Higgins, Erin Forster, Robert A. Moran, Brian Brauer, Erik J. Wamsteker, Qiang Cai, Emad Qayed, Royce Groce, Somashekar G. Krishna, Ashley Faulx, Brooke Glessing, Mordechai Rabinovitz, Gabriel Lang, Aziz Aadam, Srinadh Komanduri, Jefferey Adler, Stuart Gordon, Rachid Mohamed, Mojtaba Olyaee, April Wood-Williams, Emily K. Depue Brewbaker, Andre Thornhill, Mariana Gould, Kristen Clasen, Jama Olsen, Violette C. Simon, Ayesha Kamal, Sarah L. Volk, Ambreen A. Merchant, Ali Lahooti, Nancy Furey, Gulsum Anderson, Thomas Hollander, Alejandro Vazquez, Thomas Y. Li, Steven M. Hadley, Millie Chau, Robinson Mendoza, Tida Tangwongchai, Casey L. Koza, Olivia Geraci, Lizbeth Nunez, Alexander M. Waters, Valerie Durkalski-Mauldin
Journal: The Lancet (2024)
The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia
Authors: Martí Català, Núria Mercadé-Besora, Raivo Kolde, Nhung T H Trinh, Elena Roel, Edward Burn, Trishna Rathod-Mistry, Kristin Kostka, Wai Yi Man, Antonella Delmestri, Hedvig M E Nordeng, Anneli Uusküla, Talita Duarte-Salles, Daniel Prieto-Alhambra, Annika M Jödicke
Journal: The Lancet Respiratory Medicine (2024)

BackgroundAlthough vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2).MethodsWe conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates.FindingsA total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44–0·67) in CPRD GOLD, 0·48 (0·34–0·68) in CPRD AURUM, 0·71 (0·55–0·91) in SIDIAP, and 0·59 (0·40–0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60–1·20] in CPRD GOLD and 0·84 [0·74–0·94] in CPRD AURUM).InterpretationVaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults.FundingNational Institute for Health and Care Research.
Term planned delivery based on fetal growth assessment with or without the cerebroplacental ratio in low-risk pregnancies (RATIO37): an international, multicentre, open-label, randomised controlled trial
Authors: Marta Rial-Crestelo, Marek Lubusky, Mauro Parra-Cordero, Ladislav Krofta, Anna Kajdy, Eyal Zohav, Elena Ferriols-Perez, Rogelio Cruz-Martinez, Marian Kacerovsky, Elena Scazzocchio, Lucie Roubalova, Pamela Socias, Lubomir Hašlík, Jan Modzelewski, Eran Ashwal, Julia Castellá-Cesari, Monica Cruz-Lemini, Eduard Gratacos, Francesc Figueras, Annalisa Cancemi, Mariella Giannone, Ana Rosy Velasco-Santiago, Beatriz Sánchez-Hoyo, Nora Izquierdo-Sánchez, Cristina Cobos-Serrano, Sonia Matías-Ponce, Sonia Mayordomo-Gallardo, Alicia Castejón-Abad, Raigam-Jafet Martinez-Portilla, Esther Crespo-Mirasol, Carmen España-Calancha, Beatriz Lorente-Silva, Marta Herrera-Julve, Rocío Astudillo-Alonso, Ilaria Bianchi, Alex Biterna-Tejeiro, Vladimira Kroutilova, Veronika Kolarova, Katerina Hermanova, Veronika Durdova, Tereza Kratochvilova, Michaela Maderkova-Tozzi, Álvaro Sepulveda-Martinez, Luis Aravena, Javiera Urquieta, Katerina Macková, Anna Brandejsová, Monika Jakubiak-Proć, Sys Dorota, Katarzyna Muzyka-Placzyńska, Michal Rabijewski, Beata Mazur, Lucasz Jóźwiak, Dagmara Filipecka-Tyczka, Krzysztof Berbeka, Lucasz Pydyś, Ilan Gull, Nina Krajden Haratz, Gustavo Malinger, José-Luis Hernández-Sánchez, María Prat-Om, Ricardo Rubio-Salazar, Carolina Rueda-García, Maite López-Yarto-Elejabeitia, Paula-Daniela Diaz-Rodríguez, Antoni Payà-Panadés, Sophie Buob, Erika Ros-de-los-Santos, Andrea Garriga-Parra, Margalida-Esperanza Sastre-Cuadri, Miguel Martínez-Rodríguez, Rosa Villalobos-Gómez, Hugo López-Briones, Eréndira Chávez-González
Journal: The Lancet (2024)
Hematopoietic stem cell quiescence and DNA replication dynamics maintained by the resilient β-catenin/Hoxa9/Prmt1 axis
Authors: Jennifer Lynch, Estelle Troadec, Tsz Kan Fung, Kornelia Gladysz, Clemence Virely, Priscilla Nga Ieng Lau, Ngai Cheung, Bernd Zeisig, Jason W. H. Wong, Massimo Lopes, Suming Huang, Chi Wai Eric So
Journal: Blood (2024)

Maintenance of quiescence and DNA replication dynamics are 2 paradoxical requirements for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are required to preserve the stem cell reservoir and replenish the blood cell system in response to hematopoietic stress, respectively. Here, we show that key self-renewal factors, β-catenin or Hoxa9, largely dispensable for HSC integrity, in fact, have dual functions in maintaining quiescence and enabling efficient DNA replication fork dynamics to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs). Although β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis, their coinactivation led to severe hematopoietic defects stemmed from aberrant cell cycle, DNA replication, and damage in HSPCs. Mechanistically, β-catenin and Hoxa9 function in a compensatory manner to sustain key transcriptional programs that converge on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects the quiescent state and ensures an adequate supply of DNA replication and repair factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1 expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their intricate regulation but also a potential tractable target for therapeutic intervention.