tbuckley/cabot-search huggingface dataset:
PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer
Authors: Chaohua Liu, Jiana Li, Fei Xu, Lihua Chen, Mengdong Ni, Jiangchun Wu, Haiyun Zhao, Yangjun Wu, Jiajia Li, Xiaohua Wu, Xiaojun Chen
Journal: Molecular Cancer (2024)

Abstract Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. Methods This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&amp;Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Results Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Conclusions Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.
Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs
Authors: Yufeng Li, Minkang Tan, Almira Akkari-Henić, Limin Zhang, Maarten Kip, Shengnan Sun, Jorian J. Sepers, Ningning Xu, Yavuz Ariyurek, Susan L. Kloet, Richard P. Davis, Harald Mikkers, Joshua J. Gruber, Michael P. Snyder, Xiao Li, Baoxu Pang
Journal: Nature Biomedical Engineering (2024)

Abstract The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation). The high-throughput screen, which is compatible with single-cell sequencing, may allow for the identification of druggable NCREs.
Seasonality of forest insects: why diapause matters
Authors: Martin Schebeck, Philipp Lehmann, Mathieu Laparie, Barbara J. Bentz, Gregory J. Ragland, Andrea Battisti, Daniel A. Hahn
Journal: Trends in Ecology & Evolution (2024)

Insects have major impacts on forest ecosystems, from herbivory and soil-nutrient cycling to killing trees at a large scale. Forest insects from temperate, tropical, and subtropical regions have evolved strategies to respond to seasonality; for example, by entering diapause, to mitigate adversity and to synchronize lifecycles with favorable periods. Here, we show that distinct functional groups of forest insects; that is, canopy dwellers, trunk-associated species, and soil/litter-inhabiting insects, express a variety of diapause strategies, but do not show systematic differences in diapause strategy depending on functional group. Due to the overall similarities in diapause strategies, we can better estimate the impacts of anthropogenic change on forest insect populations and, consequently, on key ecosystems.
Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer
Authors: M. Ambrosini, B. Rousseau, P. Manca, O. Artz, A. Marabelle, T. André, G. Maddalena, G. Mazzoli, R. Intini, R. Cohen, A. Cercek, N.H. Segal, L. Saltz, A.M. Varghese, R. Yaeger, M. Nusrat, Z. Goldberg, G.Y. Ku, I. El Dika, O. Margalit, A. Grinshpun, P.M. Kasi, R. Schilsky, A. Lutfi, E. Shacham-Shmueli, M. Khan Afghan, L. Weiss, C.B. Westphalen, V. Conca, B. Decker, G. Randon, E. Elez, M. Fakih, A.B. Schrock, C. Cremolini, P. Jayachandran, M.J. Overman, S. Lonardi, F. Pietrantonio
Journal: Annals of Oncology (2024)

POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.
Development and Validation of a Scoring System to Predict Response to Obeticholic Acid in Primary Biliary Cholangitis
Authors: Antonio De Vincentis, Javier Ampuero, Francesca Terracciani, Daphne D’Amato, Alessio Gerussi, Laura Cristoferi, Nora Cazzagon, Emanuela Bonaiuto, Annarosa Floreani, Vincenza Calvaruso, Luca Cadamuro, Elisabetta Degasperi, Anna Morgando, Ester Vanni, Ana Lleo, Francesca Colapietro, Domenico Alvaro, Antonino Castellaneta, Sara Labanca, Mauro Viganò, Marco Distefano, Valeria Pace Palitti, Chiara Ricci, Nicoletta De Matthaeis, Marco Marzioni, Elena Gómez-Dominguez, Jose-Luis Montero, Esther Molina, Luisa Garcia-Buey, Marta Casado, Marina Berenguer, Isabel Conde, Miguel-Angel Simon, Javier Fuentes, Pedro Costa-Moreira, Guilherme Macedo, Francisco Jorquera, Rosa-Maria Morillas, Jose Presa, Jose-Manuel Sousa, Dario Gomes, Luis Santos, Antonio Olveira, Manuel Hernandez-Guerra, Leire Aburruza, Arsenio Santos, Armando Carvalho, Juan Uriz, Maria-Luisa Gutierrez, Elia Perez, Luchino Chessa, Adriano Pellicelli, Massimo Marignani, Luigi Muratori, Grazia Anna Niro, Maurizia Brunetto, Francesca Romana Ponziani, Maurizio Pompili, Fabio Marra, Andrea Galli, Alessandro Mussetto, Giuliano Alagna, Loredana Simone, Gaetano Bertino, Floriano Rosina, Raffaele Cozzolongo, Maurizio Russello, Leonardo Baiocchi, Carlo Saitta, Natalia Terreni, Teresa Zolfino, Cristina Rigamonti, Raffaella Vigano, Giuseppe Cuccorese, Pietro Pozzoni, Claudio Pedone, Simone Grasso, Antonio Picardi, Pietro Invernizzi, Rodolfo Sacco, Antonio Izzi, Conrado Fernandez-Rodriguez, Umberto Vespasiani-Gentilucci, Marco Carbone, Miki Scaravaglio, Eugenia Nofit, Paolo Gallo, Giovanni Galati, Francesco Pezzato, Paolo Rollo, Erica D’Ovidio, Barbara Coco, Annalisa Tortora, Cecilia Fiorini, Rosanna Venere, Gaetano Scifo, Mariarita Cannavò, Valentina Feletti, Fabrizio Pizzolante, Edoardo Giovanni Giannini, Rosa Cotugno, Silvia Fanella, Francesco Losito, Giuseppe Grassi, Giulia Francesca Manfredi, Valerio Buzzanca, Barbara Omazzi, Silvia Casella, Francesca Zani, Chiara Ricci, Valentina Bellia, Ludovico Abenavoli, Olivia Morelli, Lory Saveria Crocè, Paolo Scivetti, Antonio Panero, Valentina Boano, Guido Poggi, Giancarlo Gimignani, Alessandro Conforti, Evelise Frazzetto, Laura Rapisarda, Shrin Demma
Journal: Clinical Gastroenterology and Hepatology (2024)
Refining Risk Stratification of High-risk and Locoregional Prostate Cancer: A Pooled Analysis of Randomized Trials
Authors: Praful Ravi, Wanling Xie, Marc Buyse, Susan Halabi, Philip W. Kantoff, Oliver Sartor, Gert Attard, Noel Clarke, Anthony D'Amico, James Dignam, Nicholas James, Karim Fizazi, Silke Gillessen, Wendy Parulekar, Howard Sandler, Daniel E. Spratt, Matthew R. Sydes, Bertrand Tombal, Scott Williams, Christopher J. Sweeney
Journal: European Urology (2024)
Counteracting Alzheimer's disease via normalizing neurovascular unit with a self-regulated multi-functional nano-modulator
Authors: Xue Xia, Ya Wei, Qianqian Huang, Yang Zhou, Xiaorong Wang, Yulong Shi, Xiaotong Yang, Wenqin Yang, Yiwei Zhang, Ting Lei, Yuan Huang, Hanmei Li, Meng Qin, Huile Gao
Journal: Acta Pharmaceutica Sinica B (2024)

The neurovascular unit (NVU) is highly responsible for cerebral homeostasis and its dysfunction emerges as a critical contributor to Alzheimer's disease (AD) pathology. Hence, rescuing NVU dysfunction might be a viable approach to AD treatments. Here, we fabricated a self-regulated muti-functional nano-modulator (siR/PIO@RP) that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy. The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state (low/high RAGE expression) of the target site via a feedback loop. siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy, such as reducing cerebral Aβ load, relieving neuroinflammation, and alleviating the dysfunction of NVU. Overall, the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.
Decline in Smartphone-Assessed Physical Activity Level is Associated With Clinical Outcomes in Phase I/II Clinical Cancer Trials
Authors: Calvin G. Brouwer, Joeri A.J. Douma, Evelien J.M. Kuip, Sonja Zweegman, Niels W.C.J van de Donk, Maria T.E. Hopman, Myra E. van Linde, Henk M.W. Verheul, Laurien M. Buffart
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes. Methods: Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1). Results: Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94–61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43–21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06–6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26–4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival. Conclusions: Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.
Comparative histological analysis of spleens in pediatric patients with hemolytic anemias: Insights into the pathophysiological mechanisms of spleen destruction in sickle cell anemia
Authors: Valentine Brousse, Sara El Hoss, Pierre Isnard, Sandrine Laurance, Camille Lambert, Liza Ali, Arnaud Bonnard, Carmen Capito, Sabine Sarnacki, D. Berrebi, Berengère Koehl, Malika Benkerrou, Florence Missud, Laurent Holvoet, Ghislaine Ithier, Mariane de Montalembert, Slimane Allali, Leon Tshilolo, Jacques Diebold, Thierry Jo Molina
Journal: American Journal of Hematology (2024)

Abstract While sickle cell anemia (SCA) and hereditary spherocytosis (HS) share common features of increased spleen erythrophagocytosis due to increased red blood cell (RBC) turnover, SCA is specifically characterized by susceptibility to infections. In this study, histological lesions in the spleens of pediatric patients with SCA were analyzed, in close correlation with past clinical history and comparatively to HS, healthy and transfused β‐thalassemia patients (TDT). An evaluation of red pulp elementary lesions (red pulp fibrosis, iron deposition, number of Gandy–Gamna, and RBC trapping) combined into a severity score was established, as well as B‐cell follicles analysis. Quantification on digitalized slides of iron deposition, RBC trapping, and red pulp fibrosis was additionally performed. Spleens from 22 children with SCA, eight with HS, eight with TDT, and three healthy controls (HC) were analyzed. Median age at splenectomy was not different between SCA and HS patients, 6.05 years (range: 4.5–16.0) versus 4.75 (range: 2.2–9.5). Marked heterogeneity was found in SCA spleens in contrast to other conditions . Contrary to previous reports, B‐cell follicles were generally preserved in SCA. While RBC trapping was significantly increased in both SCA and HS (compared to TDT and HC), quantitative fibrosis and overall red pulp severity score were significantly increased in SCA spleens compared to other conditions. Moreover, there was an inverse correlation between quantitative fibrosis and number of B‐cell follicles, linking these two compartments as well as spleen fibrosis to infectious susceptibility in SCA, potentially through impaired red pulp macrophage scavenging and B‐cell subpopulations defects.
The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond
Authors: Clémence Ngo, Clémence Garrec, Elena Tomasello, Marc Dalod
Journal: Cellular and Molecular Immunology (2024)

Abstract Type I and III interferons (IFNs) are essential for antiviral immunity and act through two different but complimentary pathways. First, IFNs activate intracellular antimicrobial programs by triggering the upregulation of a broad repertoire of viral restriction factors. Second, IFNs activate innate and adaptive immunity. Dysregulation of IFN production can lead to severe immune system dysfunction. It is thus crucial to identify and characterize the cellular sources of IFNs, their effects, and their regulation to promote their beneficial effects and limit their detrimental effects, which can depend on the nature of the infected or diseased tissues, as we will discuss. Plasmacytoid dendritic cells (pDCs) can produce large amounts of all IFN subtypes during viral infection. pDCs are resistant to infection by many different viruses, thus inhibiting the immune evasion mechanisms of viruses that target IFN production or their downstream responses. Therefore, pDCs are considered essential for the control of viral infections and the establishment of protective immunity. A thorough bibliographical survey showed that, in most viral infections, despite being major IFN producers, pDCs are actually dispensable for host resistance, which is achieved by multiple IFN sources depending on the tissue. Moreover, primary innate and adaptive antiviral immune responses are only transiently affected in the absence of pDCs. More surprisingly, pDCs and their IFNs can be detrimental in some viral infections or autoimmune diseases. This makes the conservation of pDCs during vertebrate evolution an enigma and thus raises outstanding questions about their role not only in viral infections but also in other diseases and under physiological conditions.
Unravelling the molecular landscape of endometrial cancer subtypes: insights from multi-omics analysis
Authors: Yufei Shen, Yan Tian, Jiashan Ding, Zhuo Chen, Rong Zhao, Yingnan Lu, Lucia Li, Hui Zhang, Haiyue Wu, Xi Li, Yu Zhang
Journal: International Journal of Surgery (2024)

Background: Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multiomics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. Methods: Two-sample mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and nonendometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. Results: The authors identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and nonendometrioid EC, and 125 causal relationships between plasma proteins and nonendometrioid EC were observed. Substantial differences were observed between endometrioid and nonendometrioid histological types of EC at both the metabolite and protein levels. The authors identified seven overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and six overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in nonendometrioid subtype and conducted network analysis of above proteins and metabolites to identify coregulated nodes. Conclusions: Our findings observed substantial differences between endometrioid and nonendometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.
A commentary on “An anti-infection and biodegradable TFRD-loaded porous scaffold promotes bone regeneration in segmental bone defects -experimental studies”
Authors: Yanan Li, Xiaoang Ye, Lianguo Wu
Journal: International Journal of Surgery (2024)

aThe Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China bDepartment of Orthopaedics, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang,People's Republic of China Yanan Li and Xiaoang Ye contributed equally to this work and share first authorship. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author Address: The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Gongshu District, Hangzhou, Zhejiang 310005, People's Republic of China. E-mail address: [email protected] (L. Wu). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Commentary on “Endovascular treatment versus standard medical treatment in patients with established large infarct: A cohort study”
Authors: Olabisi Oluwagbemiga Ogunleye, Ayush Anand, Mahalaqua Nazli Khatib, Abass Oluwaseyi Ajayi, Quazi Syed Zahiruddin, Sarvesh Rustagi, Prakasini Satapathy, Nathnael Abera Woldehana
Journal: International Journal of Surgery (2024)

Ogunleye, Olabisi Oluwagbemiga MBBS, FWACS; Anand, Ayush MD; Khatib, Mahalaqua Nazli MD, PhD; Ajayi, Abass Oluwaseyi MBBS MWACS MMCS MRCSEd; Zahiruddin, Quazi Syed MD, PhD; Rustagi, Sarvesh PhD; Satapathy, Prakasini PhD; Woldehana, Nathnael Abera MD Author Information
Enlightenment of robotic gastrectomy from 527 patients with gastric cancer in the minimally invasive era: 5 years of optimizing surgical performance in a high-volume center - a retrospective cohort study
Authors: Zhen Xue, Jun Lu, Jia Lin, Kai-Xiang Xu, Bin-Bin Xu, Dong Wu, Hua-Long Zheng, Jian-Wei Xie, Jia-Bin Wang, Jian-Xian Lin, Qi-Yue Chen, Ping Li, Chang-Ming Huang, Chao-Hui Zheng
Journal: International Journal of Surgery (2024)

Background: Learning curves have been used in the field of robotic gastrectomy (RG). However, it should be noted that the previous study did not comprehensively investigate all changes related to the learning curve. This study aims to establish a learning curve for radical RG and evaluate its effect on the short-term outcomes of patients with gastric cancer. Methods: The clinicopathological data of 527 patients who underwent RG between August 2016 and June 2021 were retrospectively analyzed. Learning curves related to the operation time and postoperative hospital stay were determined separately using cumulative sum (CUSUM) analysis. Then, the impact of the learning curve on surgical efficacy was analyzed. Results: Combining the CUSUM curve break points and technical optimization time points, the entire cohort was divided into three phases (patients 1–100, 101–250, and 251–527). The postoperative complication rate and postoperative recovery time tended to decrease significantly with phase advancement ( P &lt;0.05). More extraperigastric examined lymph nodes (LN) were retrieved in phase III than in phase I (I vs. III, 15.12±6.90 vs. 17.40±7.05, P =0.005). The rate of LN noncompliance decreased with phase advancement. Textbook outcome (TO) analysis showed that the learning phase was an independent factor in TO attainment ( P &lt;0.05). Conclusion: With learning phase advancement, the short-term outcomes were significantly improved. It is possible that our optimization of surgical procedures could have contributed to this improvement. The findings of this study facilitate the safe dissemination of RG in the minimally invasive era.