bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted memory reactivation during sleep improves emotional memory modulation following imagery rescripting
Authors: Recher Dominique , Rohde Judith , Da Poian Giulia , Henninger Mirka , Brogli Luzius , Huber Reto , Karlen Walter , Lustenberger Caroline , Kleim Birgit 
Published: December 2024

AbstractTargeted Memory Reactivation (TMR) during sleep benefits memory integration and consolidation. In this pre-registered study, we investigated the effects of TMR applied during non-rapid eye movement (NREM) sleep following modulation and updating of aversive autobiographical memories using imagery rescripting (ImR). During 2–5 nights postImR, 80 healthy participants were repeatedly presented with either idiosyncratic words from an ImR updated memory during sleep (experimental group) or with no or neutral words (control groups) using a wearable EEG device (Mobile Health Systems Lab-Sleepband, MHSL-SB) [1] implementing a close-loop cueing procedure. Multivariate analysis were conducted to assess change score trajectories in five key emotional memory characteristics (positive and negative valence, emotional distress, arousal, and vividness) across assessments (timepoints, t) and between the study groups (TMR condition). While ImR showed significant effects on all memory characteristics (d = 0.76–1.66), there were significant additional improvements in the experimental group. Memories were significantly less vivid and afflicted with less emotional distress and arousal following ImR-words cueing. TMR during sleep in individuals’ homes was feasible and further improved some ImR’s adaptive memory effects. If replicated in clinical samples, TMR may be utilized to augment the effects of ImR and other clinical memory modulation procedures and create personalized treatment options. Such advances in emotional memory treatments are direly needed, as aversive memories are a salient feature across mental disorders, such as post-traumatic stress disorder (PTSD).
Prefrontal cortex stimulation normalizes deficient adaptive learning from outcome contingencies in low mood
Authors: Sarrazin Verena , Overman Margot Juliëtte , Mezossy-Dona Luca , Browning Michael , O’Shea Jacinta 
Published: December 2024

AbstractDepression and anxiety are associated with deficits in adjusting learning behaviour to changing outcome contingencies. This is likely to drive and maintain symptoms, for instance, by perpetuating negative biases or a sense of uncontrollability. Normalising such deficits in adaptive learning might therefore be a novel treatment target for affective disorders. The aim of this experimental medicine study was to test whether prefrontal cortex transcranial direct current stimulation (tDCS) could normalise these aberrant learning processes in depressed mood. To test proof-of-concept, we combined tDCS with a decision-making paradigm that manipulates the volatility of reward and punishment associations. 85 participants with low mood received tDCS during (or before) the task. In two sessions participants received real or sham tDCS in counter-balanced order. Compared to healthy controls (n = 40), individuals with low mood showed significantly impaired adjustment of learning rates to the volatility of loss outcomes. Prefrontal tDCS applied during task performance normalised this deficit, by increasing the adjustment of loss learning rates. As predicted, prefrontal tDCS before task performance (control) had no effect. Thus, the effect was cognitive-state dependent. Our study shows, for the first time, that a candidate depression treatment, prefrontal tDCS, when paired with a task, can reverse deficits in adaptive learning from outcome contingencies in low mood. Thus, combining neurostimulation with a concurrent cognitive manipulation is a potential novel strategy to enhance the effect of tDCS in depression treatment.
Fludarabine melphalan reduced intensity conditioning vs radiation-based myeloablative conditioning in patients undergoing allogeneic transplantation for acute myeloid leukemia with measurable residual disease
Authors: Blackmon Amanda , Afkhami Michelle , Yang Dongyun , Mokhtari Sally , Samara Yazeed , Pourhassan Hoda , Ball Brian , Salhotra Amandeep , Agrawal Vaibhav , Sandhu Karamjeet , Desai Amrita , Otoukesh Salman , Arslan Shukaib , Amanam Idoroenyi , Koller Paul , Tinajero Jose , Aribi Ahmed , Aldoss Ibrahim , Becker Pamela , Artz Andy , Ali Haris , Stein Anthony , Smith Eileen , Pullarkat Vinod , Forman Stephen J. , Marcucci Guido , Nakamura Ryotaro , Al Malki Monzr M. 
Published: December 2024

Abstract
Patients with AML and measurable residual disease (MRD) undergoing allogeneic hematopoietic cell transplantation (HCT) may benefit from myeloablative conditioning (MAC) when feasible to reduce relapse risk. Fludarabine-Melphalan (FluMel) is a common reduced intensity conditioning (RIC) regimen; however, data in MRD+ patients is sparse. We performed a retrospective review of AML patients who underwent their first HCT (2016–2021) without morphologic disease at City of Hope who had pre-transplant marrow evaluated for MRD using multicolor flow cytometry (MFC) and received radiation-based MAC or FluMel conditioning. We identified 312 patients; 44 with MRD+ disease pre-HCT. The 24-month overall survival (OS), leukemia-free survival (LFS) and cumulative incidence of relapse (CIR) were 47.7%, 40.9%, and 38.6% in MRD+, and 78.0%, 73.9%, and 14.6% in MRD− patients. Radiation-based MAC was given to 136 (43.5%) patients (n = 20 with MRD+) and FluMel was given to 174 (55.8%) patients (n = 24 with MRD+). In patients with MRD+, there was no statistically significant difference between those who received MAC vs. FluMel in 24-month OS (60% vs. 38%, p = 0.21), or CIR (35% vs. 42%, p = 0.59), respectively. Our data substantiates the adverse impact of MRD in patients with AML undergoing HCT; FluMel is a reasonable option for MRD+ patients unfit for MAC.
MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress
Authors: Yang Zhengmeng , Hou Nan , Cheng Wenxiang , Lu Xuan , Wang Ming , Bai Shanshan , Lin Yuejun , Wang Yaofeng , Lin Sien , Zhang Peng , Tortorella Micky D. , Feng Lu , Li Gang 
Published: December 2024

AbstractRheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.
Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis
Authors: Su Xin , Bai Mi , Shang Yaqiong , Du Yang , Xu Shuang , Lin Xiuli , Xiao Yunzhi , Zhang Yue , Chen Huimei , Zhang Aihua 
Published: December 2024

AbstractAcute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI.
PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer
Authors: Feng Tingting , Xu Xiaoying , Wang Xiao , Tang Wei , Lu Yi 
Published: December 2024

AbstractProgranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.
Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer
Authors: Sampson Josephina , Ju Hyun-min , Zhang Nan , Yeoh Sharon , Choi Jene , Bayliss Richard 
Published: December 2024

AbstractThe fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.
Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis
Authors: Yuan Zengzhuang , Han Xinyan , Xiao Manyu , Zhu Taoyu , Xu Yaping , Tang Qian , Lian Chen , Wang Zijin , Li Junming , Wang Boyu , Li Changhui , Xiang Xiaochen , Jin Ruobai , Liu Yufei , Yu Xinyu , Zhang Kehang , Li Songsong , Ray Madhumita , Li Rong , Gruzdev Artiom , Shao Shiqun , Shao Fangwei , Wang Hua , Lian Wang , Tang Yong , Chen Di , Lei Ying , Jin Xuru , Li Qinglin , Long Weiwen , Huang Huaqiong , DeMayo Francesco J. , Liu Jian 
Published: December 2024

Abstract
Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SLC7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SLC7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SLC7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SLC7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SLC7A11 expression levels were negatively associated with lung cancer patients’ survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.
Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader
Authors: Chen Li , Zou Yahui , Sun Renhong , Huang Mei , Zhu Xiaotong , Tang Xiao , Yang Xiaobao , Li Dake , Fan Gaofeng , Wang Yu 
Published: December 2024

AbstractPoly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.
Marcks overexpression in retinal ganglion cells promotes optic nerve regeneration
Authors: Peng Xue-Qi , Li Yan-Zhong , Gu Chen , He Xuan-Cheng , Li Chang-Ping , Sun Yong-Quan , Du Hong-Zhen , Teng Zhao-Qian , Liu Chang-Mei 
Published: December 2024

AbstractRegeneration of injured central nervous system (CNS) axons is highly restricted, leading to permanent neurological deficits. The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells, plays critical roles in development, brain plasticity, and tissues regeneration. However, little is known about the role of Marcks in CNS axon regeneration. Here we show that Marcks overexpression promotes robust axon regeneration either before or after optic nerve crush, but insignificantly impacts neuronal survival. Notably, immunostaining and RNA sequencing demonstrate that Marcks overexpression does not affect known regeneration-associated genes and pathways. Furthermore, combining CNTF which activates the JAK-STAT3 pathway and Marcks overexpression further enhances axon regeneration. Finally, we demonstrate functionally essential effector domain (ED) of MARCKS has similar effects on inducing axon regeneration in RGCs. These results suggest that manipulating Marcks and its ED may become a therapeutic approach to promote axon regeneration after CNS injury.
SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation
Authors: Gao Tingwen , Guo Zhenyang , Weng Xinyu , Cui Yikai , Li Peng , Hu Tao , Luo Wei , Dong Zheng , Wei Peng , Cai Yun , Lu Yijing , Gao Rifeng , Li Hua , Zhong Xin , Ge Junbo 
Published: December 2024

AbstractThe macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI.
Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells
Authors: Kim Justin , Brunetti Bryce , Kumar Ayanesh , Mangla Ankit , Honda Kord , Yoshida Akihiro 
Published: December 2024

AbstractThe cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.
CPNE7 promotes colorectal tumorigenesis by interacting with NONO to initiate ZFP42 transcription
Authors: Zhao Liangbo , Sun Xiao , Hou Chenying , Yang Yanmei , Wang Peiwen , Xu Zhaoyuan , Chen Zhenzhen , Zhang Xiangrui , Wu Guanghua , Chen Hong , Xing Hao , Xie Huimin , He Luyun , Jin Shuiling , Liu Benyu 
Published: December 2024

AbstractColorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death globally. Also, there is still a lack of effective therapeutic strategies for CRC patients owing to a poor understanding of its pathogenesis. Here, we analysed differentially expressed genes in CRC and identified CPNE7 as a novel driver of colorectal tumorigenesis. CPNE7 is highly expressed in CRC and negatively correlated with patients’ prognosis. Upregulation of CPNE7 promotes proliferation and metastasis of cancer cells in vitro and in vivo, and vice versa. Mechanistically, CPNE7 interacts with NONO to initiate ZFP42 transcription, thus promoting CRC progression. Moreover, ZFP42 knockdown inhibits tumor cell proliferation and migration while promoting apoptosis. Notably, delivery of CPNE7 shRNA or the small molecule gramicidin, which blocks the interaction between CPNE7 and NONO, hinders tumor growth in vivo. In conclusion, our findings demonstrate that the CPNE7-NONO-ZFP42 axis promotes colorectal tumorigenesis and may be a new potential therapeutic target.