tbuckley/cabot-search huggingface dataset:
Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial
Authors: Ying Cheng, Jianhua Chen, Wei Zhang, Chao Xie, Qun Hu, Ningning Zhou, Chun Huang, Shihong Wei, Hong Sun, Xingya Li, Yan Yu, Jinhuo Lai, Huaping Yang, Haohui Fang, Hualin Chen, Peng Zhang, Kangsheng Gu, Qiming Wang, Jianhua Shi, Tienan Yi, Xingxiang Xu, Xianwei Ye, Daqing Wang, Conghua Xie, Chunling Liu, Yulong Zheng, Daren Lin, Wu Zhuang, Ping Lu, Guohua Yu, Jinzhang Li, Yuhai Gu, Baolan Li, Rong Wu, Ou Jiang, Zaiyi Wang, Guowu Wu, Haifeng Lin, Diansheng Zhong, Yanhua Xu, Yongqian Shu, Di Wu, Xingwu Chen, Jie Wang, Minghui Wang, Runxiang Yang
Journal: Nature Medicine (2024)

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .
RNF149 Destabilizes IFNGR1 in Macrophages to Favor Post-Infarction Cardiac Repair
Authors: Chun-Kai Huang, Zhiyong Chen, Zhongxing Zhou, Shuaijie Chen, Longqing Chen, Liliang Li, Tao Li, Xiaoxiang Yan, Dajun Chai
Journal: Circulation Research (2024)

Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (ring finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 (signal transducer and activator of transcription 1) activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.
Multimodal Imaging-Assisted Intravascular Theranostic Photoactivation on Atherosclerotic Plaque
Authors: Jin Hyuk Kim, Joon Woo Song, Yeon Hoon Kim, Hyun Jung Kim, Ryeong Hyun Kim, Ye Hee Park, Hyeong Soo Nam, Dong Oh Kang, Hongki Yoo, Kyeongsoon Park, Jin Won Kim
Journal: Circulation Research (2024)

BACKGROUND: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution. METHODS: We fabricated a Dectin-1–targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence–emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks. RESULTS: The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway. CONCLUSIONS: Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1–targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β–dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.
Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis
Authors: Frederik Mølgaard Nielsen, Thomas L. Klitgaard, Niels Henrik Bruun, Morten H. Møller, Olav L. Schjørring, Bodil S. Rasmussen
Journal: Intensive Care Medicine (2024)

Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8–12 kPa in adult ICU patients, assessing both benefits and harms. We assessed 90-day all-cause mortality and days alive without life support in 90 days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). At 90 days, mortality was 40.4% (724/1792) in the 8 kPa group and 40.9% (733/1793) in the 12 kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92–1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8 kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12 kPa (low credibility). This study reported no overall differences comparing a PaO2 target of 8–12 kPa on mortality or days alive without life support in 90 days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).
Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study
Authors: Gustavo S. Oderich, Ying Huang, William S. Harmsen, Emanuel R. Tenorio, Andres Schanzer, Carlos H. Timaran, Darren B. Schneider, Bernardo C. Mendes, Matthew J. Eagleton, Mark A. Farber, Warren J. Gasper, Adam W. Beck, Matthew P. Sweet, W. Anthony Lee, F. Ezequiel Parodi, Sara L. Zettervall
Journal: Circulation (2024)

BACKGROUND: Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs. METHODS: Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions. RESULTS: A total of 1109 patients were analyzed; 589 (53.1%) had extent I–III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1–78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22–8.02]; P =0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%–5.4%); older age and extent I–III TAAAs were independently associated with late ARM (each P &lt;0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%–4.3%); extent I–III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31–26.2]; P =0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%–49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%–44.5%). CONCLUSIONS: ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.
Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306)
Authors: Chuan Liu, Hong You, Qing-Lei Zeng, Yu Jun Wong, Bingqiong Wang, Ivica Grgurevic, Chenghai Liu, Hyung Joon Yim, Wei Gou, Bingtian Dong, Shenghong Ju, Yanan Guo, Qian Yu, Masashi Hirooka, Hirayuki Enomoto, Amr Shaaban Hanafy, Zhujun Cao, Xiemin Dong, Jing LV, Tae Hyung Kim, Yohei Koizumi, Yoichi Hiasa, Takashi Nishimura, Hiroko Iijima, Chuanjun Xu, Erhei Dai, Xiaoling Lan, Changxiang Lai, Shirong Liu, Fang Wang, Ying Guo, Jiaojian Lv, Liting Zhang, Yuqing Wang, Qing Xie, Chuxiao Shao, Zhensheng Liu, Liu Ravaioli, Antonio Colecchia, Jie Li, Gao-Jun Teng, Xiaolong Qi
Journal: Clinical and Molecular Hepatology (2024)

Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model.
Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives
Authors: Mengyao Yan, Shuli Man, Long Ma, Lanping Guo, Luqi Huang, Wenyuan Gao
Journal: Clinical and Molecular Hepatology (2024)

Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt; T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.
Clonal competition assays identify fitness signatures in cancer progression and resistance in multiple myeloma
Authors: Larissa Haertle, Umair Munawar, Hipólito N. C. Hernández, Andres Arroyo‐Barea, Tobias Heckel, Isabel Cuenca, Lucia Martin, Carlotta Höschle, Nicole Müller, Cornelia Vogt, Thorsten Bischler, Paula L. del Campo, Seungbin Han, Natalia Buenache, Xiang Zhou, Florian Bassermann, Johannes Waldschmidt, Torsten Steinbrunn, Leo Rasche, Thorsten Stühmer, Joaquin Martinez‐Lopez, K. Martin Kortüm, Santiago Barrio
Journal: HemaSphere (2024)

Abstract Multiple myeloma (MM) is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. TP53 alterations are established high‐risk markers and are included in the current disease staging criteria. KRAS is the most frequently mutated gene affecting around 20% of MM patients. Applying Clonal Competition Assays (CCA) by co‐culturing color‐labeled genetically modified cell models, we recently showed that mono‐ and biallelic alterations in TP53 transmit a fitness advantage to the cells. Here, we report a similar dynamic for two mutations in KRAS (G12A and A146T), providing a biological rationale for the high frequency of KRAS and TP53 alterations at MM relapse. Resistance mutations, on the other hand, did not endow MM cells with a general fitness advantage but rather presented a disadvantage compared to the wild‐type. CUL4B KO and IKZF1 A152T transmit resistance against immunomodulatory agents, PSMB5 A20T to proteasome inhibition. However, MM cells harboring such lesions only outcompete the culture in the presence of the respective drug. To better prevent the selection of clones with the potential of inducing relapse, these results argue in favor of treatment‐free breaks or a switch of the drug class given as maintenance therapy. In summary, the fitness benefit of TP53 and KRAS mutations was not treatment‐related, unlike patient‐derived drug resistance alterations that may only induce an advantage under treatment. CCAs are suitable models for the study of clonal evolution and competitive (dis)advantages conveyed by a specific genetic lesion of interest, and their dependence on external factors such as the treatment.
Digital biomarkers for non-motor symptoms in Parkinson’s disease: the state of the art
Authors: Jules M. Janssen Daalen, Robin van den Bergh, Eva M. Prins, Mahshid Sadat Chenarani Moghadam, Rudie van den Heuvel, Jeroen Veen, Soania Mathur, Hannie Meijerink, Anat Mirelman, Sirwan K. L. Darweesh, Luc J. W. Evers, Bastiaan R. Bloem
Journal: npj Digital Medicine (2024)

Digital biomarkers that remotely monitor symptoms have the potential to revolutionize outcome assessments in future disease-modifying trials in Parkinson's disease (PD), by allowing objective and recurrent measurement of symptoms and signs collected in the participant's own living environment. This biomarker field is developing rapidly for assessing the motor features of PD, but the non-motor domain lags behind. Here, we systematically review and assess digital biomarkers under development for measuring non-motor symptoms of PD. We also consider relevant developments outside the PD field. We focus on technological readiness level and evaluate whether the identified digital non-motor biomarkers have potential for measuring disease progression, covering the spectrum from prodromal to advanced disease stages. Furthermore, we provide perspectives for future deployment of these biomarkers in trials. We found that various wearables show high promise for measuring autonomic function, constipation and sleep characteristics, including REM sleep behavior disorder. Biomarkers for neuropsychiatric symptoms are less well-developed, but show increasing accuracy in non-PD populations. Most biomarkers have not been validated for specific use in PD, and their sensitivity to capture disease progression remains untested for prodromal PD where the need for digital progression biomarkers is greatest. External validation in real-world environments and large longitudinal cohorts remains necessary for integrating non-motor biomarkers into research, and ultimately also into daily clinical practice.
Abstract 322: Acute Inhibition of GTP Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure
Authors: Shuangxi Wang, Jian Xu, Ping Song, Yong Wu, Junhua Zhang, Hyoung C Choi, Ming-hui Zou
Journal: Circulation (2008)

Objective: GTP cyclohydrolase 1 (GTPCH1) is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) dictating at least partly, the balance of nitric oxide (NO) and superoxide (O 2 .− ) produced by this enzyme. The aim of this study is to determine the effects of acute inhibition of GTPCH1 on BH4, eNOS function, and blood pressure. Methods: The biopterin content was detected by HPLC. O 2 .− and NO productions were assayed by using DHE and DAF fluorescence respectively. The vessel relaxation was assayed by organ chamber. The blood pressure in wild-type (WT) or eNOS −/− mice was determined by a carotid catheter method. Results: Exposure of bovine or mouse aortic endothelial cells to GTPCH1 inhibitors (10 mM DAHP or 1 mM NAS) for 24 hours or GTPCH1 siRNA transfection significantly reduced both BH4 and NO levels, but increased O 2 .− levels. This increase was abolished by 10 μM L-sepiapterin (BH4 precursor) or 1 mM L-NAME (non-selective NOS inhibitor). Incubation of isolated WT mice aortas with DAHP or NAS for 24 hours impaired acetylcholine-induced endothelium-dependent relaxation, but not endothelium-independent relaxation. Aortas from GTPCH1 siRNA-injected mice, but not their control-siRNA injected mice, also exhibited impaired endothelium-dependent relaxation. Furthermore, GT-PCH1 siRNA injection in mice reduced BH4 levels in aortas, associated with increased aortic levels of O 2 .− , 3-nitrotyrosine, and adhesion molecules (ICAM1 and VCAM1). In addition, an elevated mean, systolic, and diastolic blood pressure was induced by GTPCH1 siRNA injection in vivo , but not control siRNA (mean blood pressure: 114.28±4.48 vs . 136.81±2.45 mmHg) in WT mice. GTPCH1 siRNA was unable to elicit the similar effects in eNOS −/− mice, including increased oxidative stress (O 2 .− , 3-nitrotyrosine, ICAM1, VCAM1) and blood pressure. Finally, sepiapterin supplementation, which had no effect on high blood pressure in eNOS −/− mice, partially reversed GTPCH1 siRNA-induced elevation of systemic blood pressure in WT mice. Conclusion: GTPCH1 via BH4 maintains normal blood pressure and endothelial function by preserving eNOS-dependent NO biosynthesis. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma &amp; Texas).
ESRP1-mediated biogenesis of circPTPN12 inhibits hepatocellular carcinoma progression by PDLIM2/ NF-κB pathway
Authors: Yang Ji, Chuangye Ni, Yanjun Shen, Zhenggang Xu, Lei Tang, Fei Yu, Lingbang Zhu, Hao Lu, Chuanyong Zhang, Shikun Yang, Xuehao Wang
Journal: Molecular Cancer (2024)

Abstract Background Emerging evidence indicates the pivotal involvement of circular RNAs (circRNAs) in cancer initiation and progression. Understanding the functions and underlying mechanisms of circRNAs in tumor development holds promise for uncovering novel diagnostic indicators and therapeutic targets. In this study, our focus was to elucidate the function and regulatory mechanism of hsa-circ-0003764 in hepatocellular carcinoma (HCC). Methods A newly discovered hsa-circ-0003764 (circPTPN12) was identified from the circbase database. QRT-PCR analysis was utilized to assess the expression levels of hsa-circ-0003764 in both HCC tissues and cells. We conducted in vitro and in vivo experiments to examine the impact of circPTPN12 on the proliferation and apoptosis of HCC cells. Additionally, RNA-sequencing, RNA immunoprecipitation, biotin-coupled probe pull-down assays, and FISH were employed to confirm and establish the relationship between hsa-circ-0003764, PDLIM2, OTUD6B, P65, and ESRP1. Results In HCC, the downregulation of circPTPN12 was associated with an unfavorable prognosis. CircPTPN12 exhibited suppressive effects on the proliferation of HCC cells both in vitro and in vivo. Mechanistically, RNA sequencing assays unveiled the NF-κB signaling pathway as a targeted pathway of circPTPN12. Functionally, circPTPN12 was found to interact with the PDZ domain of PDLIM2, facilitating the ubiquitination of P65. Furthermore, circPTPN12 bolstered the assembly of the PDLIM2/OTUD6B complex by promoting the deubiquitination of PDLIM2. ESRP1 was identified to bind to pre-PTPN12, thereby fostering the generation of circPTPN12. Conclusions Collectively, our findings indicate the involvement of circPTPN12 in modulating PDLIM2 function, influencing HCC progression. The identified ESRP1/circPTPN12/PDLIM2/NF-κB axis shows promise as a novel therapeutic target in the context of HCC. Graphical Abstract