Impact of lymph node retrieval on prognosis in elderly and non-elderly patients with T3-4/N+ rectal cancer following neoadjuvant therapy: a retrospective cohort study.

PURPOSE: The optimal number of lymph nodes to be resected in patients with rectal cancer who undergo radical surgery after neoadjuvant therapy remains controversial. This study evaluated the prognostic variances between elderly and non-elderly patients and determined the ideal number of lymph nodes to be removed in these patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) datasets were used to gather information on 7894 patients diagnosed with stage T3-4/N+ rectal cancer who underwent neoadjuvant therapy from 2010 to 2019. Of these patients, 2787 were elderly and 5107 were non-elderly. A total of 152 patients from the Longyan First Affiliated Hospital of Fujian Medical University were used for external validation. Overall survival (OS) and cancer-specific survival (CSS) were evaluated to determine the optimal quantity of lymph nodes for surgical resection. RESULTS: The study found significant differences in OS and CSS between elderly and non-elderly patients, both before and after adjustment for confounders (P < 0.001). The removal of 14 lymph nodes may be considered a benchmark for patients with stage T3-4/N+ rectal cancer who undergo radical surgery following neoadjuvant therapy, as this number provides a more accurate foundation for the personalized treatment of rectal cancer. External data validated the differences in OS and CSS and supported the 14 lymph nodes as a new benchmark in these patients. CONCLUSION: For patients with T3-4/N+ stage rectal cancer who undergo radical surgery following neoadjuvant therapy, the removal of 14 lymph nodes serves as a cutoff point that distinctly separates patients with a favorable prognosis from those with an unfavorable one.

EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion.

BACKGROUND: Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential. METHODS: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors. RESULTS: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice. CONCLUSIONS: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.

Fresh Insights Into SLC25A26: Potential New Therapeutic Target for Cancers: A Review.

SLC25A26 is the only known human mitochondrial S-adenosylmethionine carrier encoding gene. Recent studies have shown that SLC25A26 is abnormally expressed in some cancers, such as cervical cancer, low-grade glioma, non-small cell lung cancer, and liver cancer, which suggests SLC25A26 can affect the occurrence and development of some cancers. This article in brief briefly reviewed mitochondrial S-adenosylmethionine carrier in different species and its encoding gene, focused on the association of SLC25A26 aberrant expression and some cancers as well as potential mechanisms, summarized its potential for cancer prognosis, and characteristics of mitochondrial diseases caused by SLC25A26 mutation. Finally, we provide a brief expectation that needs to be further investigated. We speculate that SLC25A26 will be a potential new therapeutic target for some cancers.

Heterologous overexpression of heat shock protein 20 genes of different species of yellow Camellia in Arabidopsis thaliana reveals their roles in high calcium resistance.

Yellow Camellia (Camellia sect. chrysantha) is a rare ornamental plant and an important germplasm resource globally. Camellia nitidissima thrives in normal acidic soils, while Camellia limonia can adapt to the calcareous soils found in karst areas. Our previous study on the karst adaptation of yellow camellias revealed that the expression levels of heat shock protein 20(HSP20) were higher in Camellia limonia than in Camellia nitidissima. However, the functions of the HSP20 gene of Camellia limonia remain unclear to data. In this study, the HSP20 genes of Camellia limonia (ClHSP20-OE lines) and Camellia. nitidissima (CnHSP20-OE lines) were cloned and overexpressed heterologously in Arabidopsis thaliana. Additionally, we overexpressed the HSP20 gene of Arabidopsis (AtHSP20-OE lines) was also overexpressed, and the T-DNA inserted mutants (athspmutant lines) were also used to determine the functions of HSP20 genes. Under high calcium stress, the chlorophyll, nitrogen, water content and humidity of leaves were increased in ClHSP20-OE lines, while those of other lines were declined. The size of the stomatal apertures, stomatal conductance, and the photosynthetic efficiency of ClHSP20-OE lines were higher than those of the other lines. However, the accumulation of H2O2 and O2- in the leaves of ClHSP20-OE lines was the lowest among all the lines. Energy spectrum scanning revealed that the percentage of calcium on the surfaces of the leaves of ClHSP20-OE lines was relatively low, while that of athspmutant lines was the highest. The ClHSP20 gene can also affected soil humidity and the contents of soil nitrogen, phosphorus, and potassium. Transcriptome analysis revealed that the expressions of FBA5 and AT5G10770 in ClHSP20-OE lines was significantly up-regulated compared to that of CnHSP20-OE lines. Compared to that of athspmutant lines, the expressions of DREB1A and AT3G30460 was significantly upregulated in AtHSP20-OE lines, and the expression of POL was down-regulated. Our findings suggest that the HSP20 gene plays a crucial role in maintained photosynthetic rate and normal metabolism by regulating the expression of key genes under high-calcium stress. This study elucidates the mechanisms underlying the karst adaptation in Camellia. limonia and provides novel insights for future research on karst plants.

Childhood maltreatment and engaging in NSSI for automatic-negative reinforcement: The mediating role of alexithymia and moderating role of help-seeking attitudes.

BACKGROUND: There is evidence indicating that childhood maltreatment is linked to the occurrence of non-suicidal self-injury (NSSI). Nevertheless, the association between childhood maltreatment and the automatic-negative reinforcement aspect of NSSI remains understudied. Chapman's (2006) experiential avoidance model posits that the main factor in sustaining NSSI is negative reinforcement, specifically through the avoidance or escape from distressful emotional experiences. The current study examines a conceptual framework based on this theory and the available literature that explores the potential mediation role of alexithymia in the relation between childhood maltreatment and the automatic-negative reinforcement of NSSI. Additionally, this study investigates how this process may be influenced by individuals' attitudes toward seeking professional help. METHODS: 3657 adolescents (1616 females) completed questionnaires regarding childhood maltreatment, alexithymia, help-seeking attitudes, the NSSI, and its functions. RESULTS: The findings of the study exposed a positive link between childhood maltreatment and the automatic-negative reinforcement of NSSI, with the mediating role of alexithymia. Interestingly, it was unexpected to discover that individuals with high help-seeking attitudes experienced an intensification of the relationship between childhood maltreatment and both alexithymia and the automatic-negative reinforcement of NSSI. LIMITATION: The study's cross-sectional design hindered the inference of causality. CONCLUSION: The present study demonstrated that it is crucial to consider the impact of both alexithymia and help-seeking attitudes in adolescents who have experienced maltreatment. These findings hold implications for preventive interventions that target the reduction of NSSI behaviors driven by automatic-negative reinforcement.

Circulating Tumor DNA Profiling Approach Based on In Silico Background Elimination Guides Chemotherapy in Nasopharyngeal Carcinoma.

Circulating tumor DNA (ctDNA) analysis increasingly provides a promising minimally invasive alternative to tissue biopsies in precision oncology. However, there are no ctDNA analysis approaches available in nasopharyngeal carcinoma (NPC) and current methods of ctDNA mutation profiling have limited resolution because of the high background noise and false-positive rate caused by benign variants in plasma cell-free DNA (cfDNA), majorly generated during clonal hematopoiesis. Although personalized parallel white blood cell genome sequencing suppresses the noise of clonal hematopoiesis variances, the system cost and complexity restrict its extensive application in clinical settings. We developed Matched WBC Genome sequencing Independent CtDNA profiling (MaGIC) approaches, which synergically integrated a ctDNA capturing panel for a hybrid capture cfDNA deep sequencing, in silico background elimination, and a reliable readout measurement. We profiled the ctDNAs of 80 plasma samples from 40 patients with NPC before and during chemotherapy by MaGICs. In addition, the public cfDNA sequencing data and The Cancer Genome Atlas project data were analyzed by MaGICs to evaluate their application in other scenarios of patient classification. The MaGIC version-2 has the ability to predict the chemosensitivity of patients with NPC with high accuracy by utilizing a single sample of liquid biopsy from each patient prior to a standardized treatment regimen. Moreover, both versions of MaGICs are of ideal performance in the diagnosis of patients with prostate cancer by liquid biopsy and prognosis prediction of multiple cancers by tissue biopsy. This study has the potential to enhance the sensitivity and expand the application scope of ctDNA detection, independently of other paired genome sequencing methods. As a result, it might further increase the clinical utilization of liquid biopsy based on ctDNA.

Mirabegron displays anticancer effects by globally browning adipose tissues.

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers.

BRD9-mediated control of the TGF-ß/Activin/Nodal pathway regulates self-renewal and differentiation of human embryonic stem cells and progression of cancer cells.

Bromodomain-containing protein 9 (BRD9) is a specific subunit of the non-canonical SWI/SNF (ncBAF) chromatin-remodeling complex, whose function in human embryonic stem cells (hESCs) remains unclear. Here, we demonstrate that impaired BRD9 function reduces the self-renewal capacity of hESCs and alters their differentiation potential. Specifically, BRD9 depletion inhibits meso-endoderm differentiation while promoting neural ectoderm differentiation. Notably, supplementation of NODAL, TGF-ß, Activin A or WNT3A rescues the differentiation defects caused by BRD9 loss. Mechanistically, BRD9 forms a complex with BRD4, SMAD2/3, ß-CATENIN and P300, which regulates the expression of pluripotency genes and the activity of TGF-ß/Nodal/Activin and Wnt signaling pathways. This is achieved by regulating the deposition of H3K27ac on associated genes, thus maintaining and directing hESC differentiation. BRD9-mediated regulation of the TGF-ß/Activin/Nodal pathway is also demonstrated in the development of pancreatic and breast cancer cells. In summary, our study highlights the crucial role of BRD9 in the regulation of hESC self-renewal and differentiation, as well as its participation in the progression of pancreatic and breast cancers.

Epigenetic regulation of plant immunity: from chromatin codes to plant disease resistance.

Facing a deteriorating natural environment and an increasing serious food crisis, bioengineering-based breeding is increasing in importance. To defend against pathogen infection, plants have evolved multiple defense mechanisms, including pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). A complex regulatory network acts downstream of these PTI and ETI pathways, including hormone signal transduction and transcriptional reprogramming. In recent years, increasing lines of evidence show that epigenetic factors act, as key regulators involved in the transcriptional reprogramming, to modulate plant immune responses. Here, we summarize current progress on the regulatory mechanism of DNA methylation and histone modifications in plant defense responses. In addition, we also discuss the application of epigenetic mechanism-based resistance strategies in plant disease breeding.

Association Between Hemoglobin Glycation Index and Metabolic Syndrome in Middle-Aged and Older People.

Purpose: Hemoglobin glycation index (HGI) is used to describe the difference between estimated and measured glycated hemoglobin A1c (HbA1c). The present study aimed to investigate the association between metabolic syndrome (MetS) and HGI in middle-aged and elderly Chinese. Patients and Methods: In this cross-sectional study, a multi-stage random sampling method was used to select objects from the permanent residents aged 35 years and above living in Ganzhou, Jiangxi, China. The demographic information, history of illness, physical examination, and blood biochemistry data were obtained. HGI was calculated from fasting plasma glucose (FPG) and HbA1c (HGI = measured HbA1c value - predicted HbA1c value). All participants were divided into low HGI and high HGI groups using the median HGI as a cut-off value. Univariate analysis was used to detect the influencing factors of HGI, and Logistic regression analysis was adopted to analyze the relationship between significant variables found in univariate analysis, MetS, or MetS's components and HGI. Results: A total of 1826 participants were enrolled in the study, and the prevalence of MetS was 27.4%. There were 908 in the low HGI group and 918 in the high HGI group, and the prevalence of MetS was 23.7% and 31.0%, respectively. Logistic regression analysis showed that the prevalence of MetS in the high HGI group was higher than that in the low HGI group (OR=1.384, 95% CI:1.110~1.725), further analysis showed that HGI was related with abdominal obesity (OR=1.287, 95% CI:1.061~1.561), hypertension (OR=1.349, 95% CI:1.115~1.632), and hypercholesterolemia (OR=1.376, 95% CI:1.124~1.684) (all P < 0.05). After adjusting for age, sex, and serum uric acid (UA), the relationship still existed. Conclusion: This study found that HGI is directly associated with MetS.

HDAC inhibitor chidamide overcomes drug resistance in chronic myeloid leukemia with the T315i mutation through the Akt-autophagy pathway.

Currently, therapy for Chronic Myeloid Leukemia (CML) patients with the T315I mutation is a major challenge in clinical practice due to its high degree of resistance to first- and second-generation Tyrosine Kinase Inhibitors (TKIs). Chidamide, a Histone Deacetylase Inhibitor (HDACi) drug, is currently used to treat peripheral T-cell lymphoma. In this study, we investigated the anti-leukemia effects of chidamide on the CML cell lines Ba/F3 P210 and Ba/F3 T315I and primary tumor cells from CML patients with the T315I mutation. The underlying mechanism was investigated, and we found that chidamide could inhibit Ba/F3 T315I cells at G0/G1 phase. Signaling pathway analysis showed that chidamide induced H3 acetylation, downregulated pAKT expression and upregulated pSTAT5 expression in Ba/F3 T315I cells. Additionally, we found that the antitumor effect of chidamide could be exerted by regulating the crosstalk between apoptosis and autophagy. When chidamide was used in combination with imatinib or nilotinib, the antitumor effects were enhanced compared with chidamide alone in Ba/F3 T315I and Ba/F3 P210 cells. Therefore, we conclude that chidamide may overcome T315I mutation-related drug resistance in CML patients and works efficiently if used in combination with TKIs.

JMJ28 guides sequence-specific targeting of ATX1/2-containing COMPASS-like complex in Arabidopsis.

Despite extensive investigations in mammals and yeasts, the importance and specificity of COMPASS-like complex, which catalyzes histone 3 lysine 4 methylation (H3K4me), are not fully understood in plants. Here, we report that JMJ28, a Jumonji C domain-containing protein in Arabidopsis, recognizes specific DNA motifs through a plant-specific WRC domain and acts as an interacting factor to guide the chromatin targeting of ATX1/2-containing COMPASS-like complex. JMJ28 associates with COMPASS-like complex in vivo via direct interaction with RBL. The DNA-binding activity of JMJ28 is essential for both the targeting specificity of ATX1/2-COMPASS and the deposition of H3K4me at specific loci but exhibit functional redundancy with alternative COMPASS-like complexes at other loci. Finally, we demonstrate that JMJ28 is a negative regulator of plant immunity. In summary, our findings reveal a plant-specific recruitment mechanism of COMPASS-like complex. These findings help to gain deeper insights into the regulatory mechanism of COMPASS-like complex in plants.

Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating ß-hydroxybutyrate (ß-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-ß-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked ß-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.

Prime Editing: An All-Rounder for Genome Editing.

Prime editing (PE), as a "search-and-replace" genome editing technology, has shown the attractive potential of versatile genome editing ability, which is, in principle, currently superior to other well-established genome-editing technologies in the all-in-one operation scope. However, essential technological solutions of PE technology, such as the improvement of genome editing efficiency, the inhibition of potential off-targets and intended edits accounting for unexpected side-effects, and the development of effective delivery systems, are necessary to broaden its application. Since the advent of PE, many optimizations have been performed on PE systems to improve their performance, resulting in bright prospects for application in many fields. This review briefly discusses the development of PE technology, including its functional principle, noteworthy barriers restraining its application, current efforts in technical optimization, and its application directions and potential risks. This review may provide a concise and informative insight into the burgeoning field of PE, highlight the exciting prospects for this powerful tool, and provide clues for questions that may propel the field forward.

Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.

Brown-fat-mediated tumour suppression by cold-altered global metabolism.

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.

Comprehensive Analysis of hsa-miR-654-5p's Tumor-Suppressing Functions.

The pivotal roles of miRNAs in carcinogenesis, metastasis, and prognosis have been demonstrated recently in various cancers. This study intended to investigate the specific roles of hsa-miR-654-5p in lung cancer, which is, in general, rarely discussed. A series of closed-loop bioinformatic functional analyses were integrated with in vitro experimental validation to explore the overall biological functions and pan-cancer regulation pattern of miR-654-5p. We found that miR-654-5p abundance was significantly elevated in LUAD tissues and correlated with patients' survival. A total of 275 potential targets of miR-654-5p were then identified and the miR-654-5p-RNF8 regulation axis was validated in vitro as a proof of concept. Furthermore, we revealed the tumor-suppressing roles of miR-654-5p and demonstrated that miR-654-5p inhibited the lung cancer cell epithelial-mesenchymal transition (EMT) process, cell proliferation, and migration using target-based, abundance-based, and ssGSEA-based bioinformatic methods and in vitro validation. Following the construction of a protein-protein interaction network, 11 highly interconnected hub genes were identified and a five-genes risk scoring model was developed to assess their potential prognostic ability. Our study does not only provide a basic miRNA-mRNA-phenotypes reference map for understanding the function of miR-654-5p in different cancers but also reveals the tumor-suppressing roles and prognostic values of miR-654-5p.

Serum uric acid is not associated with major depressive disorder in European and South American populations: a meta-analysis and two-sample bidirectional Mendelian Randomization study.

OBJECTIVE: Although previous epidemiological studies have demonstrated that serum uric acid (SUA) is associated with major depressive disorder (MDD), these analyses are prone to biases. Here, we applied the Mendelian Randomization approach to determine whether SUA is causally associated with MDD. METHODS: We conducted a meta-analysis to evaluate the relationship between SUA and MDD, then applied summary data from the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium to estimate their causal effect using a two-sample bidirectional Mendelian Randomization (MR) analysis. Thereafter, the causal effect was further researched using genetic risk scores (GRS) as instrumental variables (IVs). RESULTS: Results of a meta-analysis of articles comprising 6975 and 13,589 MDD patients and controls, respectively, revealed that SUA was associated with MDD (SMD = -0.690, 95% CI: -0.930 to -0.440, I2 = 97.4%, P < 0.001). In addition, the five MR methods revealed no causal relationship existed between SUA and MDD, which corroborated the results obtained via the GRS approach. CONCLUSION: This paper found little evidence that this association between SUA and MDD is casual. Genetically, there was no significant causal association between SUA and MDD.

MORTALIN-Ca2+ axis drives innate rituximab resistance in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with the combination of rituximab and chemotherapy being the standard treatment for it. Although rituximab monotherapy has a remarkable response rate, drug resistance with unclear mechanisms and lack of effective second-line therapy limit the survival benefits of patients with lymphoma. Here, we report that MORTALIN is highly expressed and correlates with resistance to rituximab-based therapy and poor survival in patients with DLBCL. Mechanistically, gain- and loss-of-function experiments revealed that the voltage-dependent anion channel 1-binding protein, MORTALIN, regulated Ca2+ release from the endoplasmic reticulum through mitochondria-associated membrane, facilitating AP1-mediated cell proliferation and YY-1-mediated downregulation of FAS in DLBCL cells. These dual mechanisms contribute to rituximab resistance. In mouse models, genetic depletion of MORTALIN markedly increased the antitumor activity of rituximab. We shed mechanistic light on MORTALIN-Ca2+-CaMKII-AP1-mediated proliferation and MORTALIN-Ca2+-CaMKII-inhibited death receptor in DLBCL, leading to rituximab resistance, and propose MORTALIN as a novel target for the treatment of DLBCL.

FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis.

Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here, we report that an elevation of FGF-2 signaling in samples from patients with nasopharyngeal carcinoma (NPC) and xenograft mouse models promoted NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1/AHR signaling. Gain- and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization toward an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposome treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2/FGFR1/pericyte/CXCL14/TAM stromal communication axis in NPC and propose an effective antimetastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2hi tumors.