NAD metabolism-related genes provide prognostic value and potential therapeutic insights for acute myeloid leukemia.

Introduction: Acute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear. Methods: We utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature. Results: An 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target. Conclusion: Our study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.

Neonatal X-linked myotubular myopathy with a de novo mutation: A case report and literature review. / æ–°å‘çªå˜åŸºå› çš„æ–°ç”Ÿå„¿X-è¿žé”è‚Œå°ç®¡è‚Œç— 1例并文献回顾.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy. In February 2021, a male neonate was admitted to the West China Second University Hospital, Sichuan University, with clinical manifestations of hypotonia, accompanied by distinctive facial features, and requiring continuous ventilatory support. He was born prematurely at 36+2 weeks gestation and developed respiratory distress postnatally, followed by difficulty in weaning from mechanical ventilation. Additional clinical features included hypotonia of the limbs, swallowing dysfunction, and specific facial characteristics (elongated limbs, narrow face, high-arched palate, wrist drop, empty scrotum, elongated fingers/toes). Genetic testing confirmed the diagnosis of XLMTM. Whole-exome sequencing analysis of the family revealed no mutations in the father, paternal grandfather, or paternal grandmother, while the mother had a heterozygous mutation. The pathogenic mutation was identified as MTM1 gene (OMIM: 300415), chromosome position chrX-150649714, with a nucleotide change of c.868-2A>C. The patient exhibited typical facial features. Genetic testing is crucial for accurate diagnosis of XLMTM in infants presenting with abnormal muscle tone and distinctive facial features.

Behavioural, autonomic, and neural responsivity in depersonalisation-derealisation disorder: A systematic review of experimental evidence.

Depersonalisation-derealisation disorder (DDD) is characterised by distressing experiences of separation from oneself and/or one's surroundings, potentially resulting from alterations in affective, cognitive, and physiological functions. This systematic review aimed to synthesise current experimental evidence of relevance to proposed mechanisms underlying DDD, to appraise existing theoretical models, and to inform future research and theoretical developments. Studies were included if they tested explicit hypotheses in DDD samples, with experimental manipulations of at least one independent variable, alongside behavioural, subjective, neurological, affective and/or physiological dependent variables. Some evidence for diminished subjective responsivity to aversive images and sounds, and hyperactivation in neurocircuits associated with emotional regulation when viewing aversive images emerged, corroborating neurobiological models of DDD. Inconsistencies were present regarding behavioural and autonomic responsivity to facial expressions, emotional memory, and self-referential processing. Common confounds included small sample sizes, medication, and comorbidities. Alterations in affective reactivity and regulation appear to be present in DDD; however, further research employing more rigorous research designs is required to provide stronger evidence for these possible mechanisms.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

Photosynthesis and stress response of coal fly ash on stem elongation in wheat.

Coal is one of the primary energy sources in China and is widely used for electricity generation. Crops growing in overlapped areas of farmland and coal resources (OAFCR) suffer from coal fly ash stress, especially during stem elongation, which is a key stage that impacts wheat yield and is sensitive to environmental stress. As a primary food crop of China, wheat is essential for food security. However, the characteristics of wheat under the combined stress of fly ash and various heavy metals have not been sufficiently investigated. In this study, we explored the response of stem elongation in wheat to different levels of coal fly ash stress and determined the content of heavy metals (HMs) in wheat leaves. We found that with an increase in fly ash content, the Cu content in the shoots increased, while that in the roots decreased. Coal fly ash exposure reduced the proportions of Pb and Zn in the cytoderm, and the proportion of Cu in the soluble constituents decreased from 58.3% to 45.7%. Total chlorophyll, chlorophyll a, and chlorophyll b levels decreased significantly, whereas peroxidase (POD) and catalase (CAT) activities generally increased with increasing fly ash dose. Meanwhile, chloroplasts, mitochondria, and their internal structures were damaged, and the cell structures of leaves, such as the internal membrane structure, were damaged.

Desensitization Strategies for Donor-Specific Antibodies in HLA-Mismatched Stem Cell Transplantation Recipients: What We Know and What We Do Not Know.

In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application.

UV-B Radiation Disrupts Membrane Lipid Organization and Suppresses Protein Mobility of GmNARK in Arabidopsis.

While it is well known that plants interpret UV-B as an environmental cue and a potential stressor influencing their growth and development, the specific effects of UV-B-induced oxidative stress on the dynamics of membrane lipids and proteins remain underexplored. Here, we demonstrate that UV-B exposure notably increases the formation of ordered lipid domains on the plasma membrane (PM) and significantly alters the behavior of the Glycine max nodule autoregulation receptor kinase (GmNARK) protein in Arabidopsis leaves. The GmNARK protein was located on the PM and accumulated as small particles in the cytoplasm. We found that UV-B irradiation interrupted the lateral diffusion of GmNARK proteins on the PM. Furthermore, UV-B light decreases the efficiency of surface molecule internalization by clathrin-mediated endocytosis (CME). In brief, UV-B irradiation increased the proportion of the ordered lipid phase and disrupted clathrin-dependent endocytosis; thus, the endocytic trafficking and lateral mobility of GmNARK protein on the plasma membrane are crucial for nodule formation tuning. Our results revealed a novel role of low-intensity UV-B stress in altering the organization of the plasma membrane and the dynamics of membrane-associated proteins.

On-mask detection of SARS-CoV-2 related substances by surface enhanced Raman scattering.

We have developed a convenient surface-enhanced Raman scattering (SERS) platform based on vertical standing gold nanowires (v-AuNWs) which enabled the on-mask detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related substances such as the Spike-1 protein and the corresponding pseudo-virus. The Spike-1 protein was clearly distinguished from BSA protein with an accuracy above 99 %, and the detection limit could be achieved down to 0.01 µg/mL. Notably, a similar accuracy was achieved for the pseudo-SARS-CoV-2 (pSARS-2) virus as compared to the pseudo-influenza H7N9 (pH7N9) virus. The sensing strategy and setups could be easily adapted to the real SARS-CoV-2 virus and other highly contagious viruses. It provided a promising way to screen the virus carriers by a fast evaluation of their wearing v-AuNWs integrated face-mask which was mandatory during the pandemic.

Effect of acupuncture and moxibustion on artery elasticity for early carotid atherosclerosis. / é’ˆç¸å¯¹é¢ˆåŠ¨è„‰ç²¥æ ·ç¡¬åŒ–æ—©æœŸæ‚£è€ è¡€ç®¡å¼¹æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of acupuncture and moxibustion on arterial elasticity in patients with early carotid atherosclerosis. METHODS: A total of 62 patients with early carotid atherosclerosis were randomly divided into a blank group (12 cases, 1 cases dropped-off), a sham-acupuncture group (25 cases, 5 cases dropped-off) and an acupuncture group (25 cases, 3 cases dropped-off). Patients in the acupuncture group received acupuncture treatment, including ①acupuncture：Baihui (GV20), Yintang (GV24+), Renying (ST9), Neiguan (PC6), Yanglingquan (GB34)；②moxibustion：Yinqiguiyuan (Zhongwan ［CV12］, Xiawan ［CV10］, Qihai ［CV6］, Guanyuan ［CV4］), Sihua (Geshu ［BL17］, Danshu ［BL19］)；③Intradermal needle：Xinshu (BL15), Danshu (BL19). Patients in the sham acupuncture group received placebo acupuncture, moxibustion, an intradermal needle, and the acupoints were the same as the acupuncture group. The above treatments were performed twice a week for 12 weeks. No intervention was given to the patients in the blank group. Diet and lifestyle education was given to the three groups. The ultrafast pulse wave velocity, including beginning-systolic pulse wave velocity (BS) and end-systolic pulse wave velocity (ES), was observed before treatment and 1, 2, 3 months after treatment in the three groups. The blood lipid level and platelet count (PLT) at each time point were observed. The safety of the treatments was also evaluated. RESULTS: Compared with those before treatment, the BS and ES values of both sides in the acupuncture group decreased at 2 and 3 months after treatment (P<0.05). Compared with the blank group, the bilateral ES of the acupuncture group were decreased at 2 months after treatment (P<0.05), and the bilateral BS and ES were decreased at 3 months (P<0.05). Compared with the sham-acupuncture group, the acupuncture group showed a decrease in left BS and left ES after 3 months of treatment (P<0.05), and the overall decrease on the left side of the acupuncture group was better than that on the right side. There were no significant differences between three groups in the levels of blood lipid and PLT at each time point. No serious adverse safety events occurred in the three groups during the treatment. CONCLUSIONS: Acupuncture and moxibustion therapy can improve arterial elasticity in patients with early carotid atherosclerosis, and it is safe and effective.

AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

Integrating Single-Cell and Spatial Transcriptomics to Uncover and Elucidate GP73-Mediated Pro-Angiogenic Regulatory Networks in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.

Areca palm velarivirus 1 infection caused disassembly of chloroplast and reduction of photosynthesis in areca palm.

The expansion of betel palm cultivation is driven by rising demand for betel nut, yet this growth is accompanied by challenges such as decreased agricultural biodiversity and the spread of infectious pathogens. Among these, Yellow Leaf Disease (YLD) emerges as a prominent threat to betel palm plantation. Areca Palm Velarivirus 1 (APV1) has been identified as a primary causative agent of YLD, precipitating leaf yellowing, stunted growth, and diminished yield. However, the precise mechanisms underlying APV1-induced damage remain elusive. Our study elucidates that APV1 infiltrates chloroplasts, instigating severe damage and consequential reductions in chlorophyll a/b and carotene levels, alongside notable declines in photosynthetic efficiency. Moreover, APV1 infection exerts broad regulatory effects on gene expression, particularly suppressing key genes implicated in chloroplast function and photosynthesis. These disruptions correlate with growth retardation, yield diminishment, and compromised nut quality. Intriguingly, the paradoxical destruction of the host's photosynthetic machinery by APV1 prompts inquiry into its evolutionary rationale, given the virus's dependence on host resources for replication and proliferation. Our findings reveal that APV1-induced leaf yellowing acts as a beacon for transmission vectors, hinting at a nuanced "host-pathogen-vector co-evolutionary" dynamic.

CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation.

Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.

The effect of oral motor intervention with different initiation times to improve feeding outcomes in preterm infants: protocol for a single-blind, randomized controlled trial.

BACKGROUND: Premature infants commonly encounter difficulties with oral feeding, a complication that extends hospital stays, affects infants' quality of life, and imposes substantial burdens on families and society. Enhancing preterm infants' oral feeding skills and facilitating their transition from parenteral or nasal feeding to full oral feeding pose challenges for neonatal intensive care unit (NICU) healthcare professionals. Research indicates that oral motor interventions (OMIs) can enhance preterm infants' oral feeding capabilities and expedite the transition from feeding initiation to full oral feeding. Nonetheless, the most suitable timing for commencing these interventions remains uncertain. METHODS: This is a single-blind, randomized controlled trial. Preterm with a gestational age between 29+0 to 34+6 weeks will be eligible for the study. These infants will be randomized and allocated to one of two groups, both of which will receive the OMIs. The intervention commences once the infant begins milk intake during the early OMIs. Additionally, in the late OMIs group, the intervention will initiate 48 h after discontinuing nasal continuous positive airway pressure. DISCUSSION: OMIs encompass non-nutritive sucking and artificial oral stimulation techniques. These techniques target the lips, jaw, muscles, or tongue of premature infants, aiming to facilitate the shift from tube feeding to oral feeding. The primary objective is to determine the ideal intervention timing that fosters the development of oral feeding skills and ensures a seamless transition from parenteral or nasal feeding to full oral feeding among preterm infants. Furthermore, this study might yield insights into the long-term effects of OMIs on the growth and neurodevelopmental outcomes of preterm infants. Such insights could bear substantial significance for the quality of survival among preterm infants and the societal burden imposed by preterm birth. TRIAL REGISTRATION: chictr.org.cn ChiCTR2300076721. Registered on October 17, 2023.

Association between omega-3 polyunsaturated fatty acids and osteoarthritis: results from the NHANES 2003-2016 and Mendelian randomization study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) exhibit potential as therapeutics for a variety of diseases. This observational and Mendelian randomization (MR) study aims to explore the relationship between omega-3 PUFAs and osteoarthritis (OA). METHODS: Excluding individuals under 20 years old and those with missing data on relevant variables in the National Health and Nutrition Examination Survey (NHANES) spanning from 2003 to 2016, a total of 22 834 participants were included in this cross-sectional study. Weighted multivariable-adjusted logistic regression was used to estimate the association between omega-3 PUFAs and OA in adults. Moreover, restricted cubic splines were utilized to examine the dose-response relationship between omega-3 PUFAs and OA. To further investigate the potential causal relationship between omega-3 PUFAs and OA risk, a two-sample MR study was conducted. Furthermore, the robustness of the findings was assessed using various methods. RESULTS: Omega-3 PUFAs intake were inversely associated with OA in adults aged 40 ∼ 59 after multivariable adjustment [Formula: see text], with a nonlinear relationship observed between omega-3 PUFAs intake and OA [Formula: see text]. The IVW results showed there was no evidence to suggest a causal relationship between omega-3 PUFAs and OA risk [Formula: see text]. CONCLUSIONS: Omega-3 PUFAs were inversely associated with OA in adults aged 40 ∼ 59. However, MR studies did not confirm a causal relationship between the two.

Recent developments in photocatalytic production of hydrogen peroxide.

Hydrogen peroxide (H2O2), an environmentally friendly strong oxidant and energy carrier, has attracted widespread attention in photocatalysis. Artificial photosynthesis of H2O2 using water and oxygen as raw materials, solar energy as an energy source, and semiconductor materials as catalysts is considered a promising technology. In the past few decades, encouraging progress has been made in the photocatalytic production of H2O2. Therefore, we summarize the research achievements in this field in recent years. This review first briefly introduces the reaction pathway, detection techniques and evaluation metrics. Then, the recent advances in photocatalysts are highlighted. Furthermore, the existing challenges and possible solutions in this field are presented. At last, we look forward to the future development direction of this field. This review provides valuable insights and guidance for efficient photocatalytic H2O2 production.

Subregions of the fusiform gyrus are differentially involved in the attentional mechanism supporting visual mental imagery in depression.

BACKGROUND: Impaired visual mental imagery is an important symptom of depression and has gradually become an intervention target for cognitive behavioral therapy. METHODS: Our study involved a total of 25 healthy controls (HC) and 23 individuals with moderate depressive symptoms (MD). This study explored the attentional mechanism supporting visual mental imagery impairments in depression using the Vividness of Visual Imagery Questionnaire (VVIQ), attentional network test (ANT), and resting-state functional magnetic resonance imaging (rs-fMRI). The intrinsic activity of attention-related regions relative to those supporting visual mental imagery was identified in depression patients. In addition, a meta-analysis was used to describe the cognitive function related to this intrinsic activity. RESULTS: The global correlation (GCOR) of the right anterior fusiform gyrus (FG) was decreased in depression patients. Attention-related areas were concentrated in the right posterior FG; the anterior and posterior functional connectivity (FC) of the FG was decreased in depression patients. Graph theoretic analysis showed that the degree of the right anterior FG was decreased, the degree of the anterior insula was increased, and the negative connection between these two regions was strengthened in depression patients. In addition, the degree of the right anterior FG, the FC between the subregions of the right FG, and the FC between the right anterior FG and insula were correlated with VVIQ scores; however, this correlation was not significant in depression patients. The meta-analysis suggested that the changes in the anterior FG in depressed patients may stem from difficulties of semantic memory retrieval. CONCLUSION: The changed intrinsic activity of subregions of the FG relative to the semantic memory retrieval may be associated with visual mental imagery impairments in depression.

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy.

BACKGROUND: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy. METHODS: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort. RESULTS: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05). CONCLUSION: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.