tbuckley/cabot-search huggingface dataset:
TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes
Authors: Y. Loriot, D.P. Petrylak, A. Rezazadeh Kalebasty, A. Fléchon, R.K. Jain, S. Gupta, M. Bupathi, P. Beuzeboc, P. Palmbos, A.V. Balar, C.E. Kyriakopoulos, D. Pouessel, C.N. Sternberg, J. Tonelli, M. Sierecki, H. Zhou, P. Grivas, P. Barthélémy, S.T. Tagawa
Journal: Annals of Oncology (2024)

Background Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US FDA approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor (CPI), based on Cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. Patients and methods TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and CPI-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. Results Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2-37.6). Median PFS and OS were 5.4 (95% CI 3.5-6.9) and 10.9 months (95% CI 8.9-13.8), respectively. Occurrence of grade ≥3 treatment-related AEs (TRAEs) and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (*1|*1) in 40%, heterozygous (*1|*28) in 42%, homozygous (*28|*28) in 12%, and missing in 6% of patients. In patients with *1|*1, *1|*28, and *28|*28 genotypes, any grade TRAEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. Conclusions With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.
Prognostic impact of resection margin status on survival after neoadjuvant treatment for pancreatic cancer: systematic review and meta-analysis
Authors: Carl-Stephan Leonhardt, Thomas Hank, Dietmar Pils, Charlotte Gustorff, Klaus Sahora, Martin Schindl, Caroline S. Verbeke, Oliver Strobel, Ulla Klaiber
Journal: International Journal of Surgery (2023)

Background: A greater than 1 mm tumour-free resection margin (R0 &gt;1 mm) is a prognostic factor in upfront-resected pancreatic ductal adenocarcinoma. After neoadjuvant treatment (NAT); however, the prognostic impact of resection margin (R) status remains controversial. Methods: Randomised and non-randomised studies assessing the association of R status and survival in resected pancreatic ductal adenocarcinoma after NAT were sought by systematic searches of MEDLINE, Web of Science and CENTRAL. Hazard ratios (HR) and their corresponding 95% CI were collected to generate log HR using the inverse-variance method. Random-effects meta-analyses were performed and the results presented as weighted HR. Sensitivity and meta-regression analyses were conducted to account for different surgical procedures and varying length of follow-up, respectively. Results: Twenty-two studies with a total of 4929 patients were included. Based on univariable data, R0 greater than 1 mm was significantly associated with prolonged overall survival (OS) (HR 1.76, 95% CI 1.57–1.97; P &lt;0.00001) and disease-free survival (DFS) (HR 1.66, 95% CI 1.39–1.97; P &lt;0.00001). Using adjusted data, R0 greater than 1 mm was significantly associated with prolonged OS (HR 1.65, 95% CI 1.39–1.97; P &lt;0.00001) and DFS (HR 1.76, 95% CI 1.30–2.39; P =0.0003). Results for R1 direct were comparable in the entire cohort; however, no prognostic impact was detected in sensitivity analysis including only partial pancreatoduodenectomies. Conclusion: After NAT, a tumour-free margin greater than 1 mm is independently associated with improved OS as well as DFS in patients undergoing surgical resection for pancreatic cancer.
Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair
Authors: Yafei Han, Yan Wu, Fuxiao Wang, Guangfeng Li, Jian Wang, Xiang Wu, Anfu Deng, Xiaoxiang Ren, Xiuhui Wang, Jie Gao, Zhongmin Shi, Long Bai, Jiacan Su
Journal: Bioactive Materials (2024)

Segmental bone defects, stemming from trauma, infection, and tumors, pose formidable clinical challenges. Traditional bone repair materials, such as autologous and allogeneic bone grafts, grapple with limitations including source scarcity and immune rejection risks. The advent of nucleic acid nanotechnology, particularly the use of DNA hydrogels in tissue engineering, presents a promising solution, attributed to their biocompatibility, biodegradability, and programmability. However, these hydrogels, typically hindered by high gelation temperatures (∼46 °C) and high construction costs, limit cell encapsulation and broader application. Our research introduces a novel polymer-modified DNA hydrogel, developed using nucleic acid nanotechnology, which gels at a more biocompatible temperature of 37 °C and is cost-effective. This hydrogel then incorporates tetrahedral Framework Nucleic Acid (tFNA) to enhance osteogenic mineralization. Furthermore, considering the modifiability of tFNA, we modified its chains with Aptamer02 (Apt02), an aptamer known to foster angiogenesis. This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs), with cell sequencing confirming their targeting efficacy, respectively. In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation. This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction, marking a significant advancement in tissue engineering and regenerative medicine.
Noma: neglected no more?
Authors: None The Lancet Global Health
Journal: The Lancet Global Health (2024)

On Dec 15, 2023, WHO updated its list of neglected tropical diseases (NTDs) to add noma. NTDs are conditions that are mostly prevalent in low-income and middle-income countries and that disproportionately affect women and children. The inclusion of noma on the list of NTDs is long overdue, and marks the first step in prioritising the disease in treatment, policy, funding, and research.
Latent viral infections as neglected risk factors for long COVID – Authors' reply
Authors: Sophie Alice Müller, Lynda Isaaka, Rebekka Mumm, Christa Scheidt-Nave, Katharina Heldt, Angela Schuster, Mohammed Abdulaziz, Charbel El-Bcheraoui, Johanna Hanefeld, Ambrose Agweyu
Journal: The Lancet Global Health (2024)

We appreciate the perspective offered by Amir Abdoli and colleagues regarding the potential role of latent viral infections, such as Epstein-Barr virus and herpes simplex virus, in dysregulating the immune system and hence influencing the development of long COVID. Although our systematic review1 primarily focused on the burden, epidemiological correlates, and systemic or sociocultural determinants of reporting long COVID in Africa, we acknowledge the importance of these insights as they contribute to broadening our understanding of the subject.
Cost-effectiveness of the expansion of PrEP for HIV infection in the Asia Pacific region
Authors: Benjamin R Bavinton, Nila J Dharan
Journal: The Lancet Global Health (2024)

Oral and long-acting injectable HIV pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV infection among men who have sex with men (MSM) who are adherent to recommended dosing.1–4 Although the scale-up of oral PrEP has resulted in large reductions in HIV diagnoses at the population level in multiple high-income settings including Australia, the UK, and certain US cities, the population-level impacts of oral PrEP have not been as large or widespread as they could (or should) be in many settings.
Racial disparities in breast cancer survival after treatment initiation in Brazil: a nationwide cohort study
Authors: Lívia Lovato Pires Lemos, Mirian Carvalho Souza, Augusto Afonso Guerra, Thais Piazza, Rodrigo Moura Araújo, Mariangela Leal Cherchiglia
Journal: The Lancet Global Health (2024)

BackgroundBreast cancer is a public health priority in Brazil and ensuring equity in health care is one of the cancer control plan goals. Our aim was to present the first assessment on the influence of race or skin colour on breast cancer survival at the national level.MethodsIn this nationwide cohort study, data on women who initiated treatment for breast cancer in the public health-care system (Sistema Unico de Saúde), Brazil, were assembled through record linkage of administrative and mortality information systems. The administrative information systems were the Outpatient Information System (data from high complexity procedure authorisations) and the Hospital Information System (data from hospitalisation authorisations). We included women aged 19 years or older who started treatment between Jan 1, 2008, and Nov 30, 2010; self-identified as having White, Black, or Brown race or skin colour; had tumour stage I–IV; and were treated with chemotherapy or radiotherapy, or both. Patients were followed up until Dec 31, 2015. Patients with only hormone therapy records or who underwent only surgery were excluded. The Kaplan-Meier method was used to estimate crude overall survival for race or skin colour by time since treatment initiation, and Cox regression to estimate all-cause mortality hazard ratios (HRs) before and after adjustment for other covariates.FindingsWe identified 59 811 women treated for stage I–IV breast cancer. 37 318 (62·4%) women identified themselves as White, 18 779 (31·4%) as Brown, and 3714 (6·2%) as Black. 5-year overall survival probability was higher for White women (74% [95% CI 73–74]) than Black women (64% [62–65]; p<0·0001). In adjusted regression models stratified by the absence of hormone therapy, Black women had a 24% (HR 1·24 [95% CI 1·16–1·34]; p<0·0001) higher risk of all-cause death than White women, and in the presence of hormone therapy Black women had a 25% (1·25 [1·14–1·38]; p<0·0001) higher risk of all-cause death than White women.InterpretationBlack skin colour was identified as a statistically significant risk marker for lower 5-year survival probability and higher risk of all-cause death among women treated for breast cancer by the Sistema Unico de Saúde. Actions to understand and mitigate this unfair difference in health results are urgently needed.FundingConselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior and Pró-Reitoria de Pesquisa da Universidade Federal de Minas Gerais.
Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity
Authors: Yoshihiro Sakano, Kei Sakano, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Mohammad H Kazemi, Xin Li, Stephen Shen, James R Hilser, Jaana A Hartiala, Hooman Allayee, Richard Barbers, Omid Akbari
Journal: Journal of Allergy and Clinical Immunology (2024)
Fertility and parenthood in patients with acute promyelocytic leukemia treated with Arsenic Trioxide and All-Trans retinoic acid
Authors: Charanpreet Singh, Manpreet Saini, Arihant Jain, Deepesh Lad, Gaurav Prakash, Alka Khadwal, Shano Naseem, Pankaj Malhotra
Journal: Blood Cancer Journal (2024)
Sema3A secreted by sensory nerve induces bone formation under mechanical loads
Authors: Hongxiang Mei, Zhengzheng Li, Qinyi Lv, Xingjian Li, Yumeng Wu, Qingchen Feng, Zhishen Jiang, Yimei Zhou, Yule Zheng, Ziqi Gao, Jiawei Zhou, Chen Jiang, Shishu Huang, Juan Li
Journal: International Journal of Oral Science (2024)

Abstract Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
Multienzyme Active Manganese Oxide Alleviates Acute Liver Injury by Mimicking Redox Regulatory System and Inhibiting Ferroptosis
Authors: Aimin Wu, Min Li, Yinyin Chen, Wei Zhang, Haoran Li, Junzhou Chen, Ke Gu, Xianxiang Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Drug‐induced liver injury (DILI) is a severe condition characterized by impaired liver function and the excessive activation of ferroptosis. Unfortunately, there are limited options currently available for preventing or treating DILI. In this study, MnO 2 nanoflowers (MnO 2 Nfs) with remarkable capabilities of mimicking essential antioxidant enzymes, including catalase, superoxide dismutase (SOD), and glutathione peroxidase are successfully synthesized, and SOD is the dominant enzyme among them by density functional theory. Notably, MnO 2 Nfs demonstrate high efficiency in effectively eliminating diverse reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ), superoxide anion (O 2 •− ), and hydroxyl radical (•OH). Through in vitro experiments, it is demonstrated that MnO 2 Nfs significantly enhance the recovery of intracellular glutathione content, acting as a potent inhibitor of ferroptosis even in the presence of ferroptosis activators. Moreover, MnO 2 Nfs exhibit excellent liver accumulation properties, providing robust protection against oxidative damage. Specifically, they attenuate acetaminophen‐induced ferroptosis by inhibiting ferritinophagy and activating the P62‐NRF2‐GPX4 antioxidation signaling pathways. These findings highlight the remarkable ROS scavenging ability of MnO 2 Nfs and hold great promise as an innovative and potential clinical therapy for DILI and other ROS‐related liver diseases.
Phenotypic and genetically predicted leucocyte telomere length and lung cancer risk in the prospective UK Biobank
Authors: Jason YY Wong, Batel Blechter, Aubrey K Hubbard, Mitchell J Machiela, Jianxin Shi, Shahinaz M Gadalla, Wei Hu, Mohammad L Rahman, Nathaniel Rothman, Qing Lan
Journal: Thorax (2024)

We investigated phenotypic leucocyte telomere length (LTL), genetically predicted LTL (gTL), and lung cancer risk among 371 890 participants, including 2829 incident cases, from the UK Biobank. Using multivariable Cox regression, we found dose-response relationships between longer phenotypic LTL (p-trend continuous =2.6×10 -5 ), longer gTL predicted using a polygenic score with 130 genetic instruments (p-trend continuous =4.2×10 -10 ), and overall lung cancer risk, particularly for adenocarcinoma. The associations were prominent among never smokers. Mendelian Randomization analyses supported causal associations between longer telomere length and lung cancer (HR per 1 SD gTL =1.87, 95% CI: 1.49 to 2.36, p=4.0×10 -7 ), particularly adenocarcinoma (HR per 1 SD gTL =2.45, 95%CI: 1.69 to 3.57, p=6.5×10 -6 ).
Controllable Assembly of Cu<sup>2+</sup> and Chlorin E6 for H<sub>2</sub>S‐Activatable Recognition of Bacterial Infection and Enhanced Antibacterial Therapy
Authors: Henggang Wang, Ke Cheng, Shan Sun, Peng Wang, Yonghua Zhou, Haoyi Sun, Xinxin Wang, Hongzhe Shen, Si Li, Hengwei Lin
Journal: Advanced Healthcare Materials (2024)

Abstract Antibacterial photodynamic therapy (APDT) has emerged as one of the intriguing strategies to combat bacterial resistance. However, the antibacterial efficacy of APDT is found to be severely impacted by the hydrogen sulfide (H 2 S)‐overproduced bacterial infection microenvironment. Herein, a multifunctional APDT platform is developed by assembling Cu 2+ and chlorin e6 (Ce6), which exhibits unique H 2 S‐activatable fluorescence (FL) and antibacterial features. Noteworthily, the assembly conditions are crucial for achievement of Cu‐Ce6 nanoassemblies (NAs) with the on‐demand responsive properties. The quenched FL and photosensitization of Cu‐Ce6 NAs can be selectively activated by the overexpressed H 2 S in infected area, enabling specific recognition of bacterial infection and localized antibacterial therapy with minimized side effects. Significantly, amplified oxidative stress is achieved owning to the effective consumption of H 2 S by Cu 2+ in the NAs, leading to an enhanced APDT. The antibacterial mechanisms including broad‐spectrum APDT activity of released Ce6, inherent sterilization effects of produced copper polysulfides and the accompanying disturbance of bacterial sulphide metabolism are further identified. This study may pave a new avenue for the rational design of intelligent APDT platform using minimalist biological building units and thus facilitating the clinical translation of nano‐antibacterial agents.
Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Yongheng Chen, Ying Ying, Wenlong Ma, Hongchao Ma, Liang Shi, Xuefeng Gao, Min Jia, Meiqi Li, Xiaoman Song, Weixiao Kong, Wei Chen, Xiangyi Zheng, Tobias Achu Muluh, Xiaobin Wang, Maolin Wang, Xing-sheng Shu
Journal: Cancer Research (2024)

Abstract Epigenetic alterations at cis-regulatory elements (CRE) fine-tune transcriptional output. Epigenetic readers interact with CREs and can cooperate with other chromatin regulators to drive oncogene transcription. Here, we found that the YEATS domain-containing histone acetylation reader ENL (eleven–nineteen leukemia) acts as a key regulator of super-enhancers (SE), which are highly active distal CREs, across cancer types. ENL occupied the majority of SEs with substantially higher preference over typical enhancers, and the enrichment of ENL at SEs depended on its ability to bind acetylated histones. Rapid depletion of ENL by auxin-inducible degron tagging severely repressed the transcription of SE-controlled oncogenes, such as MYC, by inducing the decommissioning of their SEs, and restoring ENL protein expression largely reversed these effects. Additionally, ENL was indispensable for the rapid activation of SE-regulated immediate early genes in response to growth factor stimulation. Furthermore, ENL interacted with the histone chaperone FACT complex and was required for the deposition of FACT over CREs, which mediates nucleosome reorganization required for transcription initiation and elongation. Proper control of transcription by ENL and ENL-associated FACT was regulated by the histone reader BRD4. ENL was overexpressed in colorectal cancer and functionally contributed to colorectal cancer growth and metastasis. ENL degradation or inhibition synergized with BET inhibitors that target BRD4 in restraining colorectal cancer progression. These findings establish the essential role of epigenetic reader ENL in governing SE-driven oncogenic transcription and uncover the potential of ENL intervention to increase sensitivity to BET inhibition. Significance: ENL plays a key role in decoding epigenetic marks at highly active oncogenic super-enhancers and can be targeted in combination with BET inhibition as a promising synergistic strategy for optimizing cancer treatment.
<i>N6</i>-Methyladenosine Reader YTHDF1 Promotes Stemness and Therapeutic Resistance in Hepatocellular Carcinoma by Enhancing NOTCH1 Expression
Authors: Xinyue Zhang, Tianhong Su, Yifan Wu, Yuhong Cai, Lina Wang, Cong Liang, Lei Zhou, Shiyan Wang, Xiao-Xing Li, Sui Peng, Ming Kuang, Jun Yu, Lixia Xu
Journal: Cancer Research (2024)

Abstract N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of HCC spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSC). Stem cell–specific conditional Ythdf1 knockin (CKI) mice treated with diethylnitrosamine showed elevated tumor burden as compared with wild-type mice. YTHDF1 promoted CSCs renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. Multiomic analysis, including RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1-deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through an YTHDF1–m6A–NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC. Significance: Inhibition of YTHDF1 expression suppresses stemness of hepatocellular carcinoma cells and enhances sensitivity to targeted therapies, indicating that targeting YTHDF1 may be a promising therapeutic strategy for liver cancer.