Auraptene-ameliorating depressive-like behaviors induced by lipopolysaccharide combined with chronic unpredictable mild stress in mice mitigate hippocampal neuroinflammation mediated by microglia.

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.

Incidence of surgical site infection in minimally invasive colorectal surgery.

BACKGROUND: Surgical site infection (SSI) is a common complication of colorectal surgery. Minimally invasive surgery notably reduces the incidence of SSI. This study aimed to compare the incidences of SSI after robot-assisted colorectal surgery (RACS) vs that after laparoscopic assisted colorectal surgery (LACS) and to analyze associated risk factors for SSI in minimally invasive colorectal surgery. AIM: To compare the incidences of SSI after RACS and LACS, and to analyze the risk factors associated with SSI after minimally invasive colorectal surgery. METHODS: Clinical data derived from patients who underwent minimally invasive colorectal surgery between October 2020 and October 2022 at the First Affiliated Hospital of Soochow University were collated. Differences in clinical characteristics and surgeryrelated information associated with RACS and LACS were compared, and possible risk factors for SSI were identified. RESULTS: A total of 246 patients (112 LACS and 134 RACS) were included in the study. Fortythree (17.5%) developed SSI. The proportions of patients who developed SSI were similar in the two groups (17.9% vs 17.2%, P = 0.887). Diabetes mellitus, intraoperative blood loss ≥ 100 mL, and incision length were independent risk factors for SSI. Possible additional risk factors included neoadjuvant therapy, lesion site, and operation time. CONCLUSION: There was no difference in SSI incidence in the RACS and LACS groups. Diabetes mellitus, intraoperative blood loss ≥ 100 mL, and incision length were independent risk factors for postoperative SSI.

dbEBV: A database of Epstein-Barr virus variants and their correlations with human health.

Since Epstein-Barr virus (EBV) was discovered in 1964, it has been reported to be associated with various malignancies as well as benign diseases, and the pathogenicity of EBV has been widely studied. Several databases have been established to provide comprehensive information on the virus and its relation to diseases and introduce convenient analysis tools. Although they have greatly facilitated the analysis of EBV at the genome, gene, protein, or epitope level, they did not provide enough insight into the genomic variants of EBV, which have been suggested as relevant to diseases by multiple studies. Here, we introduce dbEBV, a comprehensive database of EBV genomic variation landscape, which contains 942 EBV genomes with 109,893 variants from different tissues or cell lines in 24 countries. The database enables the visualization of information with varying global frequencies and their relationship with the human health of each variant. It also supports phylogenetic analysis at the genome or gene level in subgroups of different characteristics. Information of interest can easily be reached with functions such as searching, browsing, and filtering. In conclusion, dbEBV is a convenient resource for exploring EBV genomic variants, freely available at http://dbebv.omicsbio.info.

Machine Learning Assisted Experimental Characterization of Bubble Dynamics in Gas-Solid Fluidized Beds.

This study introduces a machine learning (ML)-assisted image segmentation method for automatic bubble identification in gas-solid quasi-2D fluidized beds, offering enhanced accuracy in bubble recognition. Binary images are segmented by the ML method, and an in-house Lagrangian tracking technique is developed to track bubble evolution. The ML-assisted segmentation method requires few training data, achieves an accuracy of 98.75%, and allows for filtering out common sources of uncertainty in hydrodynamics, such as varying illumination conditions and out-of-focus regions, thus providing an efficient tool to study bubbling in a standard, consistent, and repeatable manner. In this work, the ML-assisted methodology is tested in a particularly challenging case: structured oscillating fluidized beds, where the spatial and time evolution of the bubble position, velocity, and shape are characteristics of the nucleation-propagation-rupture cycle. The new method is validated across various operational conditions and particle sizes, demonstrating versatility and effectiveness. It shows the ability to capture challenging bubbling dynamics and subtle changes in velocity and size distributions observed in beds of varying particle size. New characteristic features of oscillating beds are identified, including the effect of frequency and particle size on the bubble morphology, aspect, and shape factors and their relationship with the stability of the flow, quantified through the rate of coalescence and splitting events. This type of combination of classic analysis with the application of the ML assisted techniques provides a powerful tool to improve standardization and address the reproducibility of hydrodynamic studies, with the potential to be extended from gas-solid fluidization to other multiphase flow systems.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and Macrophage Repolarization-Enhanced Immune Response.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

Tumor-associated neutrophils suppress CD8+ T cell immunity in urothelial bladder carcinoma through the COX-2/PGE2/IDO1 Axis.

BACKGROUND: Many urothelial bladder carcinoma (UBC) patients don't respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs) suppressing lymphocyte immune response. METHODS: We conducted a meta-analysis on the predictive value of neutrophil-lymphocyte ratio (NLR) in ICB response and investigated TANs' role in UBC. We used RNA-sequencing, HALO spatial analysis, single-cell RNA-sequencing, and flow cytometry to study the impacts of TANs and prostaglandin E2 (PGE2) on IDO1 expression. Animal experiments evaluated celecoxib's efficacy in targeting PGE2 synthesis. RESULTS: Our analysis showed that higher TAN infiltration predicted worse outcomes in UBC patients receiving ICB therapy. Our research revealed that TANs promote IDO1 expression in cancer cells, resulting in immunosuppression. We also found that PGE2 synthesized by COX-2 in neutrophils played a key role in upregulating IDO1 in cancer cells. Animal experiments showed that targeting PGE2 synthesis in neutrophils with celecoxib enhanced the efficacy of ICB treatment. CONCLUSIONS: TAN-secreted PGE2 upregulates IDO1, dampening T cell function in UBC. Celecoxib targeting of PGE2 synthesis represents a promising approach to enhance ICB efficacy in UBC.

Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer.

Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.

FGFR3 Alterations in Bladder Cancer Stimulate Serine Synthesis to Induce Immune-Inert Macrophages That Suppress T-cell Recruitment and Activation.

FGFR3 alterations are common in patients with bladder cancer. While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for patients with FGFR3-altered (aFGFR3) bladder cancer, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 bladder cancer and demonstrated that mutant FGFR3 indirectly induces a "cold" TME in mouse bladder cancer models. Single-cell RNA sequencing revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T-cell recruitment and antigen presentation capabilities. Increased serine synthesis in bladder cancer cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy. SIGNIFICANCE: Metabolic reprogramming of bladder cancer cells driven by mutant FGFR3 increases serine synthesis that suppresses macrophage immunostimulatory functions to generate an immunosuppressive TME, which can be overcome by targeting PI3K.

Facile Synthesis of Basic Copper Carbonate Nanosheets for Photoacoustic Imaging-Guided Tumor Apoptosis and Ferroptosis and the Extension Exploration of the Synthesis Method.

Elimination of tumor cells using carbonate nanomaterials with tumor microenvironment-responsive capacity has been explored as an effective strategy. However, their therapeutic outcomes are always compromised by the relatively low intratumoral accumulation and limited synthesis method. Herein, a novel kind of basic copper carbonate nanosheets was designed and prepared using a green synthesis method for photoacoustic imaging-guided tumor apoptosis and ferroptosis therapy. These nanosheets were synthesized with the assistance of dopamine and ammonium bicarbonate (NH4HCO3) and the loading of glucose oxidase (GOx). NH4HCO3 could not only provide an alkaline environment for the polymerization of dopamine but also supply carbonates for the growth of nanosheets. The formed nanosheets displayed good acid and near-infrared light responsiveness. After intercellular uptake, they could be degraded to release Cu2+ and GOx, generating hydroxyl radicals through a Cu+-mediated Fenton-like reaction, consuming glucose, up-regulating H2O2 levels, and down-regulating GSH levels. Tumor elimination could be achieved by hydroxyl radical-induced apoptosis and ferroptosis. More amusingly, this synthesis method can be extended to several kinds of mono-element and multi-element carbonate nanomaterials (e.g., Fe, Mn, and Co), showing great potential for further tumor theranostics.

Establishment of a risk stratification model based on the combination of post-treatment serum squamous cell carcinoma antigen levels and FIGO stage of cervical cancer for treatment and surveillance decision-making.

OBJECTIVE: To develop a risk stratification model based on the International Federation of Gynecology and Obstetrics (FIGO) staging combined with squamous cell carcinoma antigen (SCC-Ag) for the classification of patients with cervical squamous cell carcinoma (CSCC) into different risk groups. METHODS: We retrospectively reviewed the data of 664 women with stage IIA-IVB CSCC according to the 2018 FIGO staging system who received definitive radiotherapy from March 2013 to December 2017 at the department of radiation oncology of Sun Yat-sen University Cancer Center. Cutoff values for continuous variables were estimated using receiver operating characteristic curve analysis. Using recursive partitioning analysis (RPA) modeling, overall survival was predicted based on the prognostic factors determined via Cox regression analysis. The predictive performance of the RPA model was assessed using the consistency index (C-index). Intergroup survival differences were determined and compared using Kaplan-Meier analysis and the log-rank test. RESULTS: Multivariate Cox regression analysis identified post-treatment SCC-Ag (< 1.35 ng/mL and > 1.35 ng/mL; hazard ratio (HR), 4.000; 95% confidence interval (CI), 2.911-5.496; P < 0.0001) and FIGO stage (II, III, and IV; HR, 2.582, 95% CI, 1.947-3.426; P < 0.0001) as the independent outcome predictors for overall survival. The RPA model based on the above prognostic factors divided the patients into high-, intermediate-, and low-risk groups. Significant differences in overall survival were observed among the three groups (5-year overall survival: low vs. intermediate vs. high, 91.3% vs. 76.7% vs. 29.5%, P < 0.0001). The predictive performance of the RPA model (C-index, 0.732; 95% CI, 0.701-0.763) was prominently superior to that of post-treatment SCC-Ag (C-index, 0.668; 95% CI, 0.635-0.702; P < 0.0001) and FIGO stage (C-index, 0.663; 95% CI, 0.631-0.695; P < 0.0001). CONCLUSIONS: The RPA model based on FIGO staging and post-treatment SCC-Ag can predict the overall survival of patients with CSCC, thereby providing a guide for the formulation of risk-adaptive treatment and individualized follow-up strategies.

Repolarizing tumor-associated macrophages by layered double hydroxide-based deacidification agent for tumor chemodynamic therapy and immunotherapy.

Tumor-associated macrophages (TAMs)-mediated immunotherapy has attracted extensive attention in tumor elimination. However, the acidic tumor microenvironment (TME) severely limits the phenotype of TAMs to pro-tumoral M2 state, suppressing immune response efficacy against tumors. Herein, novel poly(acrylic acid) (PAA)-coated, doxorubicin (DOX)-loaded layered double hydroxide (LDH) nanosheets (NSs) were developed as deacidification agent to repolarize TAMs from pro-tumoral M2 to anti-tumoral M1 phenotype for tumor elimination through combined chemodynamic therapy and immunotherapy. When located in tumor regions, LDH-PAA@DOX NSs display good deacidification capacity to neutralize acidic TME, achieving the repolarization of TAMs to M1 phenotype and further activating CD8+ T cells. During the deacidification process, these NSs are acid-responsive and degrade to release Fe3+ and DOX. The former can be reduced to Fe2+ by intracellular glutathione, meanwhile disrupting the antioxidant defense system of tumor cells. The latter can damage tumor cells directly and further stimulate the production of hydrogen peroxide, providing abundant substrate for the Fenton reaction. Toxic hydroxyl radical is excessively produced through Fe2+-mediated Fenton reaction to cause intratumoral oxidative stress. In vivo data revealed that significant tumor elimination can be achieved under LDH-PAA@DOX treatment. This work not only provides a promising paradigm for neutralizing acidic TME using deacidification agent but also highlights the effectiveness of combined chemodynamic therapy and immunotherapy in tumor treatment.

Mesoporous polydopamine-based nanoplatform for enhanced tumor chemodynamic therapy through the reducibility weakening strategy.

Polydopamine (PDA)-based Fenton agents attract increasing attention in tumor photothermal-enhanced chemodynamic therapy (CDT) due to their good biocompatibility and excellent loading capacity. However, PDA tends to eliminate the Fenton reaction-generated hydroxyl radical (∙OH) by its strong reducibility, which is an intractable hinder to the efficacy of CDT that need to be solved. Herein, a kind of mesoporous PDA-gold-manganese dioxide (MPDA-Au-MnO2, MPAM) nanoplatform was constructed for photothermal-enhanced CDT against tumor through the reducibility weakening strategy. The reducibility of original MPDA is effectively weakened by the oxidation role of HAuCl4 and KMnO4 during the preparation process, reducing the ∙OH scavenging ability of MPDA and benefiting the production of ∙OH. The MnO2 shell could react with GSH to release Mn2+, acting as the Fenton-like agent to generate ∙OH. The exposed Au NPs can further deplete GSH through the Au-S bond interaction. MPDA acts as the photothermal agent to generate hyperthermia under laser irradiation. MPAM shows excellent intracellular GSH scavenging ability and enhanced ∙OH production ability. After intravenous injection, MPAM can significantly suppress the growth of tumors under laser irradiation, meanwhile showing good biosafety. The developed MPDA-based nanoplatform can not only display good potential in further tumor treatments but also provide meaningful enlightenment for developing high-performance PDA or MPDA-based nanoplatforms in CDT-related applications.

Sorafenib-Loaded Copper Peroxide Nanoparticles with Redox Balance Disrupting Capacity for Enhanced Chemodynamic Therapy against Tumor Cells.

Chemodynamic therapy (CDT) is a promising hydroxyl radical (•OH)-mediated tumor therapeutic method with desirable tumor specificity and minimal side effects. However, the efficiency of CDT is restricted by the pH condition, insufficient H2O2 level, and overexpressed reductive glutathione (GSH), making it challenging to solve these problems simultaneously to improve the efficacy of CDT. Herein, a kind of polyvinylpyrrolidone-stabilized, sorafenib-loaded copper peroxide (CuO2-PVP-SRF) nanoparticle (NPs) was designed and developed for enhanced CDT against tumor cells through the synergetic pH-independent Fenton-like, H2O2 self-supplying, and GSH depletion strategy. The prepared CuO2-PVP-SRF NPs can be uptaken by 4T1 cells to specifically release Cu2+, H2O2, and SRF under acidic conditions. The intracellular GSH can be depleted by SRF-induced system xc- dysfunction and Cu2+-participated redox reaction, causing the inactivation of GPX4 and generating Cu+. A great amount of •OH was produced in this reducing capacity-disrupted condition by the Cu+-mediated Fenton-like reaction, causing cell apoptosis and lipid hydroperoxide accumulation-induced ferroptosis. They display an excellent 4T1 cell killing outcome through the improved •OH production capacity. The CuO2-PVP-SRF NPs display elevated therapeutic efficiency of CDT and show good promise in further tumor treatment applications.

Radiomics Analysis of Lymph Nodes with Esophageal Squamous Cell Carcinoma Based on Deep Learning.

Purpose: To assess the role of multiple radiomic features of lymph nodes in the preoperative prediction of lymph node metastasis (LNM) in patients with esophageal squamous cell carcinoma (ESCC). Methods: Three hundred eight patients with pathologically confirmed ESCC were retrospectively enrolled (training cohort, n = 216; test cohort, n = 92). We extracted 207 handcrafted radiomic features and 1000 deep radiomic features of lymph nodes from their computed tomography (CT) images. The t-test and least absolute shrinkage and selection operator (LASSO) were used to reduce the dimensions and select key features. Handcrafted radiomics, deep radiomics, and clinical features were combined to construct models. Models I (handcrafted radiomic features), II (Model I plus deep radiomic features), and III (Model II plus clinical features) were built using three machine learning methods: support vector machine (SVM), adaptive boosting (AdaBoost), and random forest (RF). The best model was compared with the results of two radiologists, and its performance was evaluated in terms of sensitivity, specificity, accuracy, area under the curve (AUC), and receiver operating characteristic (ROC) curve analysis. Results: No significant differences were observed between cohorts. Ten handcrafted and 12 deep radiomic features were selected from the extracted features (p < 0.05). Model III could discriminate between patients with and without LNM better than the diagnostic results of the two radiologists. Conclusion: The combination of handcrafted radiomic features, deep radiomic features, and clinical features could be used clinically to assess lymph node status in patients with ESCC.

A Prognostic Model Based on Nutritional Risk Index in Operative Breast Cancer.

BACKGROUND: The nutritional risk index (NRI) is an independent prognostic factor for overall survival in various cancers, but its prognostic value in breast cancer remains unclear. This study aimed to explore the relationship between the NRI and overall survival (OS) in breast cancer and to develop a predictive nomogram. METHODS: We retrospectively enrolled 1347 breast cancer patients who underwent mastectomy or lumpectomy between January 2011 and November 2012. Using a cutoff value of 110.59, patients were divided into a high-NRI group and a low-NRI group. OS was compared between the two groups. Clinicopathological factors independently associated with survival were used to construct a predictive nomogram. RESULTS: Of the 1347 patients, 534 patients were classified as high NRI and 813 as low NRI. OS was significantly shorter in low-NRI patients. The 3- and 5-year OS rates were 87.3% and 73.4%, respectively, in the high-NRI group whereas they were 83.0% and 67.2%, respectively, in the low-NRI group. Cox regression analysis found that histopathological type, tumor size, lymph node status, progesterone receptor (PR) status, Ki-67, and NRI were independently associated with OS. CONCLUSIONS: NRI is an independent prognostic factor of OS in breast cancer patients. The proposed nomogram model may be a useful tool for individualized survival prediction.

SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

Cancer cells modulate their metabolic activities to adapt to their growth and proliferation. Despite advances in breast cancer biology having led to the widespread use of molecular targeted therapy and hormonal drugs, the molecular mechanisms in metabolism related to the regulation of breast cancer cell proliferation are still poorly understood. Here, we investigate the possible role of SHMT2, a key enzyme in serine metabolism, in breast cancer. Firstly, SHMT2 is found highly expressed in both breast cancer cells and tissues, and patients with high expression of SHMT2 have a worse prognosis. Moreover, the intervention of SHMT2 by either knockdown or over-expression in vitro induces the effect on breast cancer proliferation. Mechanistically, RNA-seq shows that over-expression of SHMT2 affect multiple signaling pathways and biological process in breast cancer cells. Furthermore, we confirm that SHMT2 promotes breast cancer cell growth through MAPK and VEGF signaling pathways. Finally, we verify the role of SHMT2 in promoting breast cancer growth in the xenograft tumor model. Our results indicate that SHMT2 plays a critical role in regulating breast cancer growth through MAPK, and VEGF signaling pathways, and maybe serve as a therapeutic target for breast cancer therapy.

Both subthalamic and pallidal deep brain stimulation are effective for GNAO1-associated dystonia: three case reports and a literature review.

Background: Mutations in the G-protein subunit alpha o1 (GNAO1) gene have recently been shown to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. The clinical manifestations of GNAO1-associated movement disorders are highly heterogeneous. However, the genotype-phenotype correlations in this disease remain unclear, and the treatments for GNAO1-associated movement disorders are still limited. Objective: The objective of this study was to explore diagnostic and therapeutic strategies for GNAO1-associated movement disorders. Methods: This study describes the cases of three Chinese patients who had shown severe and progressive dystonia in the absence of epilepsy since early childhood. We performed genetic analyses in these patients. Patients 1 and 2 underwent globus pallidus internus (GPi) deep brain stimulation (DBS) implantation, and Patient 3 underwent subthalamic nucleus (STN) DBS implantation. In addition, on the basis of a literature review, we summarized and discussed the clinical characteristics and outcomes after DBS surgery for all reported patients with GNAO1-associated movement disorders. Results: Whole-exome sequencing (WES) analysis revealed de novo variants in the GNAO1 gene for all three patients, including a splice-site variant (c.724-8G > A) in Patients 1 and 3 and a novel heterozygous missense variant (c.124G > A; p. Gly42Arg) in Patient 2. Both GPi and STN DBS were effective in improving the dystonia symptoms of all three patients. Conclusion: DBS is effective in ameliorating motor symptoms in patients with GNAO1-associated movement disorders, and both STN DBS and GPi DBS should be considered promptly for patients with sustained refractory GNAO1-associated dystonia.

Identification of an IDO1-based immune classifier for survival prediction of upper tract urothelial carcinoma.

The limited response rate of immunotherapy in upper tract urothelial carcinoma (UTUC) might be attributed to additional immunosuppressive mechanisms in vivo. As a promising immune checkpoint target, the expression and prognostic role of indoleamine 2,3-dioxygenase 1 (IDO1) in UTUC remains unknown. In this study, the expression and prognostic value of IDO1 was analyzed in 251 patients from 3 independent cohorts. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to construct an IDO1-based immune classifier and external validation was performed to further validate the classifier. RNA sequencing and immunofluorescence were used to explore the immune contexture of different risk groups stratified by classifier. We found that high IDO1 expression on tumor cells (TC) indicated a poorer overall survival and disease-free survival in all cohorts. Patients with high expression of IDO1 TC possessed increased infiltration of CD4+ , CD8+ and Foxp3+ T cells. An immune classifier based on intratumoral CD8+ lymphocytes, IDO1 TC, and stromal PD-L1 expression status was developed, with its area under the curves (AUCs) values for overall survival at 5 y being 0.79 (95% confidence interval [CI] 0.65-0.93) in the discovery cohort, 0.75 (95% CI 0.58-0.92) and 0.78 (95% CI 0.65-0.92) in the internal and external validation cohorts, respectively. The high-risk group stratified by the immune classifier was associated with immunosuppressive contexture, accompanied by enhanced CD8+ T cells exhaustion patterns. Our IDO1-based immune classifier can provide a superior accuracy for survival prediction and lead to individual stratification of UTUC immune subtypes.