tbuckley/cabot-search huggingface dataset:
Multi-omics and clustering analyses reveal the mechanisms underlying unmet needs for patients with lung adenocarcinoma and identify potential therapeutic targets
Authors: Ken Asada, Syuzo Kaneko, Ken Takasawa, Kouya Shiraishi, Norio Shinkai, Yoko Shimada, Satoshi Takahashi, Hidenori Machino, Kazuma Kobayashi, Amina Bolatkan, Masaaki Komatsu, Masayoshi Yamada, Mototaka Miyake, Hirokazu Watanabe, Akiko Tateishi, Takaaki Mizuno, Yu Okubo, Masami Mukai, Tatsuya Yoshida, Yukihiro Yoshida, Hidehito Horinouchi, Shun-Ichi Watanabe, Yuichiro Ohe, Yasushi Yatabe, Takashi Kohno, Ryuji Hamamoto
Journal: Molecular Cancer (2024)

The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days. Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets. Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options. We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.
Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial
Authors: Yan Zheng, Guanghui Liang, Dongfeng Yuan, Xianben Liu, Yufeng Ba, Zimin Qin, Sining Shen, Zhenxuan Li, Haibo Sun, Baoxing Liu, Quanli Gao, Peng Li, Zongfei Wang, Shilei Liu, Jianping Zhu, Haoran Wang, Haibo Ma, Zhenzhen Liu, Fei Zhao, Jun Zhang, He Zhang, Daoyuan Wu, Jinrong Qu, Jie Ma, Peng Zhang, Wenjie Ma, Ming Yan, Yongkui Yu, Qing Li, Jiangong Zhang, Wenqun Xing
Journal: Cancer Communications (2024)

Abstract Background In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high‐level clinical evidence. This study aimed to compare the safety and long‐term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE. Methods A prospective, single‐center, open‐label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m 2 ) + cisplatin (75 mg/m 2 ) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event‐free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed. Results Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1‐3M0 to T2‐3N0‐3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1‐year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1‐year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien‐Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed ( P = 0.460). The rates of grade 3 or 4 treatment‐related AEs did not differ between the two groups (12.5% versus 12.4%). Conclusions The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.
Tryptophan 2,3‐dioxygenase‐positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine‐mediated ferroptosis resistance of metastatic cells and T cell dysfunction
Authors: Yongcan Liu, Shanchun Chen, Xueying Wan, Rui Wang, Haojun Luo, Chao Chang, Peijin Dai, Yubi Gan, Yuetong Guo, Yixuan Hou, Yan Sun, Yong Teng, Xiaojiang Cui, Manran Liu
Journal: Cancer Communications (2024)

Abstract Background Tumor metastasis is a major threat to cancer patient survival. The organ‐specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis‐associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Methods Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single‐cell RNA‐sequencing (scRNA‐seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3‐dioxygenase‐positive matrix fibroblasts (TDO2 + MFs) in lung metastasis. Results We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet‐derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF‐depleted experimental metastatic mouse models. We found that TDO2 + MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2 + MF‐secreted chemokines C‐C motif chemokine ligand 8 (CCL8) and C‐C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2 + MF‐derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Conclusions Our study reveals crucial roles of TDO2 + MFs in promoting lung metastasis and DTCs’ immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung‐specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.
A new clinical age of aging research
Authors: Zhen Zhang, Renlei Yang, Zhike Zi, Baohua Liu
Journal: Trends in Endocrinology and Metabolism (2024)

Aging is a major risk factor for a variety of diseases, thus, translation of aging research into practical applications is driven by the unmet need for existing clinical therapeutic options. Basic and translational research efforts are converging at a critical stage, yielding insights into how fundamental aging mechanisms are used to identify promising geroprotectors or therapeutics. This review highlights several research areas from a clinical perspective, including senescent cell targeting, alleviation of inflammaging, and optimization of metabolism with endogenous metabolites or precursors. Refining our understanding of these key areas, especially from the clinical angle, may help us to better understand and attenuate aging processes and improve overall health outcomes.
Reply to Andrés Gutiérrez, Julio Cesar Boada, and Sebastián Peña’s Letter to the Editor re: Pieter Vynckier, Lieven Annemans, Sarah Raes, et al. Systematic Review on the Cost-effectiveness of Prostate Cancer Screening in Europe. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.04.036
Authors: Pieter Vynckier, Lieven Annemans, Monique Roobol
Journal: European Urology (2024)
Sustained HIV remission after allogeneic hematopoietic stem cell transplantation with wild-type CCR5 donor cells
Authors: Asier Sáez-Cirión, Anne-Claire Mamez, Véronique Avettand-Fenoel, Mitja Nabergoj, Caroline Passaes, Paul Thoueille, Laurent Decosterd, Maxime Hentzien, Federico Perdomo-Celis, Maria Salgado, Monique Nijhuis, Adeline Mélard, Elise Gardiennet, Valérie Lorin, Valérie Monceaux, Anaïs Chapel, Maël Gourvès, Marine Lechartier, Hugo Mouquet, Annemarie Wensing, Javier Martinez-Picado, Sabine Yerly, Mathieu Rougemont, Alexandra Calmy
Journal: Nature Medicine (2024)
Mavacamten-Associated Temporal Changes in Left Atrial Function in Obstructive HCM
Authors: Milind Y. Desai, Yuichiro Okushi, Kathy Wolski, Jeffrey B. Geske, Anjali Owens, Sara Saberi, Andrew Wang, Paul C. Cremer, Mark Sherrid, Neal K. Lakdawala, Albree Tower-Rader, David Fermin, Srihari S. Naidu, Kathy L. Lampl, Amy J. Sehnert, Steven E. Nissen, Zoran B. Popovic, M. Desai, J. Geske, M. Sherrid, A.T. Owens, S. Saberi, A. Wang, A. Tower-Rader, D. Fermin, N. Lakdawala, A. Masri, M. Zenker, J. Stendahl, M. Wheeler, R. Bach, J. Orford, S. Naidu, F. Rader, P. Bajona
Journal: JACC. Cardiovascular imaging (2024)

In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) trial showed that mavacamten reduced the eligibility for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients. Mavacamten also resulted in favorable cardiac remodeling, including improvement in biomarkers (eg, N-terminal pro-B-type natriuretic peptide and troponin T). However, the impact of mavacamten on left atrial (LA) function is unknown. The aim of this study was to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial. VALOR-HCM included 112 symptomatic patients with obstructive HCM (mean age 60 years; 51% male). Patients assigned to receive mavacamten at baseline (n = 56) continued therapy for 56 weeks and those assigned to placebo transitioned to mavacamten (n = 52) from week 16 to week 56. Echocardiographic LA strain (reservoir, conduit, and contraction) was measured by using a vendor-neutral postprocessing software. At baseline, the mean LA volume index (LAVI) and LA strain values (conduit, contraction, and reservoir) were 41.3 ± 16.5 mL/m2, -11.8% ± 6.5%, -8.7% ± 5.0%, and 20.5% ± 8.7%, respectively (all worse than reported normal). LAVI significantly improved by -5.6 ± 9.7 mL/m2 from baseline to week 56 (P < 0.001). There was a significant (P < 0.05) improvement in absolute LA strain values from baseline to week 56 (conduit [-1.7% ± 6%], contraction [-1.2% ± 4.5%], and reservoir [2.8% ± 7.7%]). Patients originally receiving placebo had no differences in LA measurements up to week 16. There was no significant improvement in LA strain values (conduit [-0.9% ± 3.8%], contraction [-0.4% ± 3.4%], and reservoir [1.4% ± 6.1%]; all; P = not significant) from baseline to week 56 in patients with history of atrial fibrillation. In VALOR-HCM, mavacamten resulted in an improvement in LAVI and LA strain at week 56, suggesting sustained favorable LA remodeling and improved function, except in the atrial fibrillation subgroup. Whether the advantageous LA remodeling associated with long-term treatment with mavacamten results in a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM remains to be proven. (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy [VALOR-HCM]; NCT04349072).
Epidemiology of acute hypoxaemic respiratory failure in Australian and New Zealand intensive care units during 2005–2022. A binational, registry-based study
Authors: Ryan Ruiyang Ling, Mallikarjuna Ponnapa Reddy, Ashwin Subramaniam, Benjamin Moran, Kollengode Ramanathan, Mahesh Ramanan, Aidan Burrell, David Pilcher, Kiran Shekar
Journal: Intensive Care Medicine (2024)

Acute hypoxaemic respiratory failure (AHRF) is a common reason for intensive care unit (ICU) admission. However, patient characteristics, outcomes, and trends over time are unclear. We describe the epidemiology and outcomes of patients with AHRF over time. In this binational, registry-based study from 2005 to 2022, we included all adults admitted to an Australian or New Zealand ICU with an arterial blood gas within the first 24 h of ICU stay. AHRF was defined as a partial pressure of oxygen/inspired oxygen ratio (PaO2/FiO2) ≤ 300. The primary outcome was adjusted in-hospital mortality, categorised based on PaO2/FiO2 (mild: 200–300, moderate: 100–200, and severe < 100, and non-linearly). We investigated how adjusted mortality evolved based on temporal trends (by year of admission), sex, age, admission diagnosis and the receipt of mechanical ventilation. Of 1,560,221 patients, 826,106 (52.9%) were admitted with or developed AHRF within the first 24 h of ICU stay. Of these 826,106 patients, 51.4% had mild, 39.3% had moderate, and 9.3% had severe AHRF. Compared to patients without AHRF (5.3%), patients with mild (8%), moderate (14.2%) and severe (29.9%) AHRF had higher in-hospital mortality rates. As PaO2/FiO2 ratio decreased, adjusted in-hospital mortality progressively increased, particularly below an inflection point at a PaO2/FiO2 ratio of 200. The adjusted in-hospital mortality for all patients decreased over time (13.3% in 2005 to 8.2% in 2022), and this trend was similar in patients with and without AHRF. The healthcare burden due to AHRF may be larger than expected, and mortality rates remain high in severe AHRF. Although mortality has decreased over time, this may reflect improvements in ICU care in general, rather than specifically in AHRF. More research is required to earlier identify AHRF and stratify these patients at risk of deterioration early, and to validate our findings.
Microchip Based Isolation and Drug Delivery of Patient‐Derived Extracellular Vesicles Against Their Homologous Tumor
Authors: Ke Ge, Yongan Ren, Zichen Hong, Zhenjun Mao, Bo Yao, Kai Ye, Changku Jia
Journal: Advanced Healthcare Materials (2024)

Abstract Extracellular vesicles (EVs) have demonstrated significant potential in drug delivery and anti‐tumor therapy. Despite this promising strategy, challenges such as specific targeting, EVs purification persist. In this study, a personalized nanodrug delivery platform using patient‐derived tumor EVs (PT‐EVs) based on a microchip is presented. The microchip integrates multiple functions, including capture, enrichment, drug loading, and elution of PT‐EVs. The isolation and drug‐carrying procedures are completed within a 12 h timeframe, achieving a recovery rate of 65%, significantly surpassing the conventional ultracentrifuge (UC) method. Furthermore, PT‐EVs derived from patient tumor models are first utilized as natural drug carriers, capitalizing on their inherent homing ability to precisely target homologous tumors. Lenvatinib and doxorubicin (DOX), two commonly utilized drugs in the clinical treatment of hepatocellular carcinoma (HCC), are loaded into PT‐EVs and delivered to a matched in vitro tumor model that recapitulates original tumors for drug susceptibility testing. As is proven, PT‐EVs exhibit robust tumor cell targeting and efficient receptor‐mediated cellular uptake, and the efficacy of chemotherapeutic drugs is improved significantly. These results suggest that this platform could be a valuable tool for efficient isolation of PT‐EVs and personalized drug customization, particularly when working with limited clinical samples, thus supporting personalized and precision medicine.
Transcriptomic Analysis Reveals the Heterogeneous Role of Conducting Films Upon Electrical Stimulation
Authors: Nicholas B. Lawler, Uditi Bhatt, Vipul Agarwal, Cameron W. Evans, Priya Kaluskar, Sebastian E. Amos, Kai Chen, Yin Yao, Haibo Jiang, Yu Suk Choi, Minghao Zheng, Dino Spagnoli, Irene Suarez‐Martinez, Per B. Zetterlund, Vincent P. Wallace, Alan R. Harvey, Stuart I. Hodgetts, K. Swaminathan Iyer
Journal: Advanced Healthcare Materials (2024)

Abstract Central nervous system (CNS) injuries and neurodegenerative diseases have markedly poor prognoses and can result in permanent dysfunction due to the general inability of CNS neurons to regenerate. Differentiation of transplanted stem cells has emerged as a therapeutic avenue to regenerate tissue architecture in damaged areas. Electrical stimulation is a promising approach for directing the differentiation outcomes and pattern of outgrowth of transplanted stem cells, however traditional inorganic bio‐electrodes can induce adverse effects such as inflammation. This study demonstrates the implementation of two organic thin films, a polymer/reduced graphene oxide nanocomposite (P(rGO)) and PEDOT:PSS, that have favorable properties for implementation as conductive materials for electrical stimulation, as well as an inorganic indium tin oxide (ITO) conductive film. Transcriptomic analysis reveals that electrical stimulation improves neuronal differentiation of SH‐SY5Y cells on all three films, with the greatest effect for P(rGO). Unique material‐ and electrical stimuli‐mediated effects are observed, associated with differentiation, cell‐substrate adhesion, and translation. The work demonstrates that P(rGO) and PEDOT:PSS are highly promising organic materials for the development of biocompatible, conductive scaffolds that will enhance electrically‐aided stem cell therapeutics for CNS injuries and neurodegenerative diseases.
METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma
Authors: Jialin Wang, Mengxi Xiu, Jin Wang, Yong Gao, Yandong Li
Journal: Journal of Hematology & Oncology (2024)

Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising avenue for hepatocellular carcinoma (HCC) intervention due to its tumor susceptibility. RNA N6-methyladenosine (m6A) modification has been involved in several types of regulated cell death. However, the roles and molecular mechanisms of m6A-related regulators in HCC cell ferroptosis remain unclear. By examining a series of m6A modification enzymes upon ferroptosis induction or inhibition, we identified METTL16 as a novel ferroptotic repressor in HCC cells. The roles of METTL16 on ferroptosis and HCC development were investigated in multiple cell lines, human HCC organoids, subcutaneous xenografts and MYC/Trp53−/− HCC model in hepatocyte-specific Mettl16 knockout and overexpression mice. The underlying mechanism was elucidated with MeRIP/RIP-qPCR, luciferase assay, Co-IP assay and Mass Spectrometry. The clinical significance and relevance were evaluated in human samples. High METTL16 expression confers ferroptosis resistance in HCC cells and mouse models, and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner, and the latter impedes the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates the chelation of free iron and reduces liable iron pool level. SENP3 and LTF are implicated in METTL16-mediated HCC progression and anti-ferroptotic effects both in vivo and in vitro. Clinically, METTL16 and SENP3 expression were positively correlated, and high METTL16 and SENP3 expression predicts poor prognosis in human HCC samples. Our study reveals a new METTL16-SENP3-LTF signaling axis regulating ferroptosis and driving HCC development. Targeting this axis is a promising strategy for sensitizing ferroptosis and against HCC.
Atomically Engineered Chlorine Coordination of Iron in Active Centers for Selectively Catalytic H<sub>2</sub>O<sub>2</sub> Decomposition Toward Efficient Antitumor‐Specific Therapy
Authors: Wei Li, Daomei Chen, Chungang Min, Xiaoqian Ma, Xikun Yang, Jiaqiang Wang
Journal: Advanced Healthcare Materials (2024)

Abstract The intervention of endogenous H 2 O 2 via nanozymes provides a potential antitumor‐specific therapy; however, the role of the nanozyme structure in relation to the selective decomposition of H 2 O 2 to hydroxyl radicals (•OH) is yet to be fully understood, which limits the development of this therapeutic approaches. Herein, an iron single‐atom nanozyme (Fe─N 2 Cl 2 ─C SAzyme) is reported, which is prepared through precise Fe─Cl coordination based on the construction of a characteristic Fe‐containing molecule. Fe─N 2 Cl 2 ─C exhibits efficient catalytic H 2 O 2 decomposition (2.19 × 10 6 m m −1 s −1 ), which is the highest among reported SAzymes. More importantly, it is found that H 2 O 2 selectively decomposed into •OH on the Fe─N 2 Cl 2 ─C surface, which is attributable to the d orbitals of the Fe active center matching the O‐2 p electrons of the adsorbed hydroxide (*OH) intermediate. Fe─N 2 Cl 2 ─C is strongly cytotoxic toward a variety of cancer‐cell lines in vitro but not to normal cells. Furthermore, Fe─N 2 Cl 2 ─C shows an outstanding specific therapeutic effect in vivo; it efficiently destroys solid malignant tumors without injuring normal tissue. Altogether, these findings highlight the selective catalytic decomposition of H 2 O 2 to •OH, which is achieved by engineering the active center on the atomic level, thereby providing an avenue for the development of specific nanomedicines with efficient antitumor activities.