SLC35A2 expression drives breast cancer progression via ERK pathway activation.

Alterations in glycosylation are associated with breast tumor formation and progression. Nevertheless, the specific functions and mechanisms of the human major UDP-galactose transporter-encoding gene solute carrier family 35 member A2 (SLC35A2) in breast invasive carcinoma (BRCA) have not been fully determined. Here, we report that SLC35A2 promotes BRCA progression by activating extracellular signal regulated kinase (ERK). SLC35A2 expression and prognosis-predictive significance in pan-cancer were evaluated using public databases. The upstream non-coding RNAs (ncRNAs) of SLC35A2 were analyzed, and their expression and regulations were validated in breast tissues and cell lines by a quantitative PCR and dual-luciferase assays. We used bioinformatic tools to assess the link between SLC35A2 expression and immune infiltration and performed immunohistochemistry for validation. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, transwell, flow cytometer and western blotting were used to assess the proliferation, motility, cell cycle and apoptosis of BRCA cells in vitro. The xenograft models were constructed to assess the effect of SLC35A2 on BRCA tumor growth in vivo. The results indicated that SLC35A2 expression was upregulated and linked to an unfavorable prognosis in BRCA. The most likely upstream ncRNA-associated pathway of SLC35A2 in BRCA was the AC074117.1/hsa-let-7b-5p axis. SLC35A2 expression had positive correlations with the presence of Th2 cells, regulatory T cells and immune checkpoints. Knockdown of SLC35A2 could reduce BRCA cell proliferation, motility, and cause G2/M arrest and cell apoptosis via ERK signaling. Moreover, ERK activation can rescue the inhibitory effects of knockdown SLC35A2 in BRCA. In conclusion, AC074117.1/hsa-let-7b-5p axis-mediated high expression of SLC35A2 acts as a tumor promoter in BRCA via ERK signaling, which provides a potential target for BRCA treatment.

Role of LncRNA MIR99AHG in breast cancer: Bioinformatic analysis and preliminary verification.

Objective: This research was aimed to preliminarily explore the clinical roles and potential molecular mechanisms of MIR99AHG and its significant transcripts in breast cancer (BRCA). Methods: Public databases were utilized to analyze the expression and prognostic roles of MIR99AHG and its transcripts. Relationships between MIR99AHG expression and immune cells infiltration were analyzed in Xiantao platform. In addition, co-expressed genes and interacting proteins of MIR99AHG were predicted. CancerSEA analyzed its relationship with functional states. Next, CNV status, DNA methylation, interacting transcription factors (TFs) and ceRNA network were analyzed to explore its possible mechanisms. Then, RNA ISH and FISH assays were used to detect its expression and location in BRCA tissues and cell lines, respectively. Finally, qRT-PCR was utilized to investigate MIR99AHG expression in cell lines. Results: Compared with the corresponding normal tissues, MIR99AHG expression levels were lower in all BRCA subtypes, and luminal B's was the lowest one. And MIR99AHG expression was negatively related to the tumor stage. In addition, 4 transcripts (ENST00000619222.4, ENST00000418813.6, ENST00000602901.5 and ENST00000453910.5) of MIR99AHG showed significant differences in the expression. Databases also suggested that the high MIR99AHG expression levels indicated good prognosis, especially in patients without lymph node metastasis. Xiantao found that MIR99AHG was positively related to 17 immune cells and negatively linked with 2 immune cells. CancerSEA analysis showed no relationships between MIR99AHG and functional states. From GEPIA and BCIP databases, 19 co-expressed genes were highly related to these four significant transcripts of MIR99AHG. StarBase, RNAct and HDOCK showed that several tumor-associated proteins, including U2AF65, hnRNPC, AEBP2, CHIC1 and so on, might interact with MIR99AHG. Genetically, BRCA had a higher proportion of MIR99AHG CNV loss than CNV gain, and the high level of DNA methylation indicated a good prognosis. Furthermore, 19 TFs were predicted to combine with the promoter of MIR99AHG. Then, we screened out 10 miRNAs potentially interacting with the significant transcripts of MIR99AHG, and five were significantly increased in breast tumors compared to normal tissues, including miR-194-5p, miR-320 b and so on, which could combine 14 mRNAs. Through ISH and FISH assays, we verified that MIR99AHG was down-regulated in BRCA samples and cell lines in comparison to non-tumor tissues and mammary epithelial cell line (MCF10A), and MIR99AHG was located both in cytoplasm and nucleus. qRT-PCR assay also showed the lower expression of MIR99AHG in breast cancer cells than that in MCF10A. Conclusion: These results indicate that MIR99AHG can be a favorable prognostic indicator for BRCA. ENST00000619222.4, ENST00000418813.6, ENST00000602901.5 and ENST00000453910.5 are significant transcripts and their down-regulation may play crucial roles in the progression of BRCA.

The central role of neutrophil extracellular traps (NETs) and by-products in COVID-19 related pulmonary thrombosis.

Extracellular trap networks (neutrophil extracellular traps [NETs]) of polymorphonuclear neutrophils are mesh-like substances that prevent the spread of pathogens. They primarily consist of DNA skeletons, histones, granule components, and cytoplasmic proteins. NETs formation requires a certain environment and there are different pathways for NETs production. However, it is still not clear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes NETs. NETs exert antiinflammatory effects through immune response, while they can also lead to certain adverse outcomes, such as the development of immunothrombosis. Coronavirus disease 2019 (COVID-19) is an inflammatory reaction affecting various organs caused by SARS-CoV-2, especially the lungs. NETs production and disease severity are linked with unique neutrophil clusters by single-cell RNA sequencing. NETs might exert an anti-inflammatory role in the initial stage of lung tissue inflammation. Nevertheless, numerous studies and cases have shown that they can also result in pulmonary thrombosis. There is mounting evidence that NETs are tightly related with COVID-19 pulmonary thrombosis, and many studies on the mechanisms are involved. The role and mechanism of NETs in the development of pulmonary thrombosis will be the main topics of this manuscript. Additionally, we address the potential targeting of NETs in COVID-19 patients.

Hierarchical transcriptional network governing heterogeneous T cell exhaustion and its implications for immune checkpoint blockade.

The fundamental principle of immune checkpoint blockade (ICB) is to protect tumor-infiltrating T cells from being exhausted. Despite the remarkable success achieved by ICB treatment, only a small group of patients benefit from it. Characterized by a hypofunctional state with the expression of multiple inhibitory receptors, exhausted T (Tex) cells are a major obstacle in improving ICB. T cell exhaustion is a progressive process which adapts to persistent antigen stimulation in chronic infections and cancers. In this review, we elucidate the heterogeneity of Tex cells and offer new insights into the hierarchical transcriptional regulation of T cell exhaustion. Factors and signaling pathways that induce and promote exhaustion are also summarized. Moreover, we review the epigenetic and metabolic alterations of Tex cells and discuss how PD-1 signaling affects the balance between T cell activation and exhaustion, aiming to provide more therapeutic targets for applications of combinational immunotherapies.

Expression and Clinical Significance of TIGIT in Primary Breast Cancer.

Purpose: The roles of T cell immunoreceptor with Ig and ITIM domains (TIGIT) in the diagnosis of primary breast cancer (PBC) are still unclear. This study was designed to investigate the expression of TIGIT in PBC patients, with an aim to analyze its diagnostic value in PBC. Patients and Methods: We first explore the expression of TIGIT in cancer patients based on TCGA database, and then we analyzed its correlation with clinicopathological features. Afterwards, we compared the protein and mRNA expressions of TIGIT in two BC cell lines (MCF-7 and MDA-MB-231) and normal breast epithelial cell line (MCF-10A). Subsequently, 56 PBC female patients admitted to the Taizhou People's Hospital from October 2018 to June 2021 were included in this study. Flow cytometry was used to detect TIGIT level on peripheral blood CD3+ T cells of PBC patients and healthy controls. TIGIT expression in PBC tissues was detected by immunohistochemistry (IHC) and immunofluorescence staining. Results: TCGA database showed that compared with adjacent tissues, TIGIT was significantly upregulated in tumor tissues. High TIGIT expression was positively correlated with tumor stage and negatively correlated with recurrence free survival (RFS) and overall survival (OS). TIGIT level in BC cell lines, peripheral blood and tumor tissues of PBC patients was significantly higher than that of control (P < 0.05). TIGIT level was correlated with age (P < 0.05), rather than tumor size, pathological type, lymph node metastasis, ER, PR, HER-2, and P53. ROC curve showed that the optimal critical value of peripheral blood TIGIT for BC screening was 23.38%. Postoperative TIGIT level in peripheral blood was significantly decreased compared to the preoperative TIGIT level (P < 0.05). Conclusion: TIGIT was upregulated in PBC and was correlated with age. It may be a potential target for the diagnosis and immunotherapy of PBC.

Megamitochondria plasticity: Function transition from adaption to disease.

As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission to alter their size, shape, and position, with mitochondrial fusion and fission being interdependent to maintain the balance of mitochondrial morphological changes. However, in response to metabolic and functional damage, mitochondria can grow in size, resulting in a form of abnormal mitochondrial morphology known as megamitochondria. Megamitochondria are characterized by their considerably larger size, pale matrix, and marginal cristae structure and have been observed in various human diseases. In energy-intensive cells like hepatocytes or cardiomyocytes, the pathological process can lead to the growth of megamitochondria, which can further cause metabolic disorders, cell damage and aggravates the progression of the disease. Nonetheless, megamitochondria can also form in response to short-term environmental stimulation as a compensatory mechanism to support cell survival. However, extended stimulation can reverse the benefits of megamitochondria leading to adverse effects. In this review, we will focus on the findings of the different roles of megamitochondria, and their link to disease development to identify promising clinical therapeutic targets.

Evaluating the effectiveness of a new student-centred laboratory training strategy in clinical biochemistry teaching.

BACKGROUND: The error-proneness in the preanalytical and postanalytical stages is higher than that in the analytical stage of the total testing process. However, preanalytical and postanalytical quality management has not received enough attention in medical laboratory education and tests in clinical biochemistry courses. METHODS/APPROACH: Clinical biochemistry teaching program aim to improve students' awareness and ability of quality management according to international organization for standardization 15,189 requirements. We designed a student-centred laboratory training program, according to case-based learning that included 4 stages: "establish an overall testing process based on the patient's clinical indicator, clarify principles, improve operational skills, and review process and continuous improvement". The program was implemented in our college during the winter semesters of 2019 and 2020. A total of 185 undergraduate students majoring in medical laboratory science participated in the program as a test group, and the other 172 students were set up as the control group and adopted the conventional method. The participants were asked to finish an online survey to evaluate the class at the end. RESULTS/OUTCOMES: The test group had significantly better examination scores not only in experimental operational skills (89.27 ± 7.16 vs. 77.51 ± 4.72, p < 0.05 in 2019 grade, 90.31 ± 5.35 vs. 72.87 ± 8.41 in 2020 grade) but also in total examination (83.47 ± 6.16 vs. 68.90 ± 5.86 in 2019 grade, 82.42 ± 5.72 vs. 69.55 ± 7.54 in 2020 grade) than the control group. The results of the questionnaire survey revealed that the students in the test group better achieved classroom goals than those in the control group (all p < 0.05). CONCLUSIONS: The new student-centred laboratory training program based on case-based learning in clinical biochemistry is an effective and acceptable strategy compared with the conventional training program.

A Computationally Constructed lncRNA-Associated Competing Triplet Network in Clear Cell Renal Cell Carcinoma.

Long noncoding RNAs (lncRNAs) are revealed to be involved in the tumorigenesis and progression of human malignancies mediated by microRNA (miRNA) via the competing endogenous RNA (ceRNA) mechanism, a newly proposed "RNA language." However, the lncRNA-associated competing triplet (lncACT) network among ceRNA transcripts in clear cell renal cell carcinoma (ccRCC) is currently lacking. We carried out differential expression analysis to identify aberrantly expressed lncRNAs, miRNAs, and mRNAs by analyzing the RNA-seq data of 420 ccRCC tissues and 71 noncancerous kidney tissues obtained from The Cancer Genome Atlas (TCGA). Then, a ccRCC-specific ceRNA network was built using computational algorithms, including miRcode, TargetScan, miRanda, and miRTarBase. In total, 1491 dysregulated lncRNAs were found between normal renal tissues and ccRCC (fold change > 4 and false discovery rate < 0.01). A ceRNA network that comprised of 46 DElncRNAs, 11 DEmiRNAs, and 55 DEmRNAs was established by integrating the lncRNA/miRNA and miRNA/mRNA interactions into lncACTs. Several lncRNAs were identified to be significantly associated with clinical features of ccRCC patients. Notably, four key lncRNAs (TCL6, HOTTIP, HULC, and PCGEM1) were tightly correlated with both patients' clinical characteristics and overall survival (log-rank P < 0.05), indicating their potential important roles in ccRCC. HOTTIP may be a potential prognostic and therapeutic molecular marker for ccRCC patients. Collectively, our results provide a comprehensive view of the lncRNA-associated ceRNA regulatory network for a better understanding of the mechanisms and prognosis biomarkers for ccRCC.

Pan-cancer analysis of LncRNA XIST and its potential mechanisms in human cancers.

Background: X-inactive specific transcript (XIST), it has been found, is abnormal expression in various neoplasms. This work aims to explore its potential molecular mechanisms and prognostic roles in types of malignancies. Methods: This research comprehensively investigated XIST transcription across cancers from Oncomine, TIMER 2.0 and GEPIA2. Correlations of XIST expression with prognosis, miRNAs, interacting protens, immune infiltrates, checkpoint markers, mutations of tumor-associated genes and promoter methylation were also analyzed by public databases. In addition, 98 BRCA samples were collected to investigate XIST expression and evaluate its clinicopathological value. Results: In public databases, compared to normal tissues, XIST was lower in BRCA, CESC, COAD and so on, but increased in KIRC and PRAD. Databases also showed that XIST was a good indicator of prognosis in BRCA, COAD and so on, but a bad one in KIRC, KIRP and so on. From starBase, we found 29 proteins interacting with XIST, and identified 4 miRNAs which might be sponged by XIST in cancers. Furthermore, XIST was linked with immune infiltration, especially T cell CD4+, and was related to over 20 immune checkpoint markers. Moreover, several tumor-associated gene mutations and promoter methylation were negatively related to its expression. In addition, IHC showed that XIST in BRCA was obviously lower in comparison of normal tissues and was negatively related to lymph node invasion and TNM stage. Conclusion: In summary, abnormal expression of XIST influenced prognosis, miRNAs and immune infiltration across cancers, especially BRCA.

Case report: Phenotype expansion and analysis of TRIO and CNKSR2 variations.

Introduction: TRIO and CNKSR2 have been demonstrated as the important regulators of RAC1. TRIO is a guanine exchange factor (GEF) and promotes RAC1 activity by accelerating the GDP to GTP exchange. CNKSR2 is a scaffold and adaptor protein and helps to maintain Rac1 GTP/GDP levels at a concentration conducive for dendritic spines formation. Dysregulated RAC1 activity causes synaptic function defects leading to neurodevelopmental disorders (NDDs), which manifest as intellectual disability, learning difficulties, and language disorders. Case presentation: Here, we reported two cases with TRIO variation from one family and three cases with CNKSR2 variation from another family. The family with TRIO variation carries a novel heterozygous frameshift variant c.3506delG (p. Gly1169AlafsTer11), where a prenatal case and an apparently asymptomatic carrier mother with only enlarged left lateral ventricles were firstly reported. On the other hand, the CNKSR2 family carries a novel hemizygous non-sense variant c.1282C>T (p. Arg428*). Concurrently, we identified a novel phenotype never reported in known pathogenic CNKSR2 variants, that hydrocephalus and widening lateral ventricle in a 6-year-old male of this family. Furthermore, the genotype-phenotype relationship for TRIO, CNKSR2, and RAC1 was explored through a literature review. Conclusion: The novel variants and unique clinical features of these two pedigrees will help expand our understanding of the genetic and phenotypic profile of TRIO- and CNKSR2-related diseases.

RNA m6A modification orchestrates the rhythm of immune cell development from hematopoietic stem cells to T and B cells.

RNA, one of the major building blocks of the cell, participates in many essential life processes. RNA stability is well-established to be closely related to various RNA modifications. To date, hundreds of different RNA modifications have been identified. N6-methyladenosine (m6A) is one of the most important RNA modifications in mammalian cells. An increasing body of evidence from recently published studies suggests that m6A modification is a novel immune system regulator of the generation and differentiation of hematopoietic stem cells (HSCs) and immune cells. In this review, we introduce the process and relevant regulatory mechanisms of m6A modification; summarize recent findings of m6A in controlling HSC generation and self-renewal, and the development and differentiation of T and B lymphocytes from HSCs; and discuss the potential mechanisms involved.

Differential Expression and Prognostic Correlation of Immune Related Factors Between Right and Left Side Colorectal Cancer.

Background: Growing evidence suggests that colorectal cancer (CRC) should be considered a heterogeneous disease. The right side (RCC) and left side (LCC) colorectal cancer have different clinical characteristics and immune landscapes. The aim of this study was to analyze differential expression and prognostic correlation of immune-related factors between RCC and LCC. Methods: The gene expression profile and clinical characteristics of CRC patients were retrieved from The Cancer Genome Atlas data portal (n=525). Using a deconvolution algorithm, immune cell infiltration in RCC and LCC based on the RNA-seq data was analyzed. Differentially expressed genes (DEGs) were obtained by performing differential gene expression analysis. Immune-related DEGs were derived by the intersection with immune-related factors downloaded from the IMMPORT database. To further validate the findings, we applied immunohistochemical (IHC) staining of a CRC tissue microarray (TMA). The distribution of immune cells in RCC and LCC and changes in the expression of immune molecules on their membranes were verified. The expression levels of circulating cytokines were measured by flow cytometry to detect the cytokines secreted by immune cells in RCC and LCC. Furthermore, to reveal the prognostic value of differential immune factors on RCC and LCC patients, survival analysis based on mRNA levels using TCGA cohort and survival analysis using protein levels was performed using our CRC patients. Results: The infiltration of immune cells differed between RCC and LCC, the infiltration degree of macrophages M0 was significantly higher in LCC, while the infiltration degree of differentiated macrophages M1 and M2, CD4+ T and CD8+ T cells was significantly higher in RCC. The expression of related molecules by immune cells also differed between RCC and LCC. The expression of 7 genes in RCC was higher than that in LCC, which were CCR5, CD209, CD8A, HCK, HLA-DPB1, HLA-DQA1, HLA-DRA, respectively. Meanwhile, the expression of 2 genes in LCC was higher than in RCC, which were IL-34 and PROCR. Patients with RCC having high expression of HLA-DQA1 mRNA or proteins had better survival and LCC patients with high expression of IL 34 mRNA or protein had better survival. Conclusions: In this study, we comprehensively compared differences in immune cells and regulating factors between left and right colorectal cancer. Different expression patterns and their effects on survival were identified. The analysis of immune-related factors may provide a theoretical basis for precise immunotherapy of RCC and LCC.

T-cell-specific Sel1L deletion exacerbates EAE by promoting Th1/Th17-cell differentiation.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are demyelinating neuroinflammatory diseases identified by the accumulation and aggregation of misfolded proteins in the brain. The Sel1L-Hrd1 complex comprising endoplasmic reticulum associated degradation (ERAD) is an ER-protein quality control system (ERQC) in the cell. Unfortunately, the contribution of ERAD to the development of these diseases has not been well explored. In this study, we used mice with a conditional deletion (KO) of Sel1L in T cells to dissect the role of ERAD on T cells and its contribution to the development of EAE. The results showed that Sel1L KO mice developed more severe EAE than the control wild type (WT) mice. Although, no obvious effects on peripheral T cells in steady state, more CD44-CD25+ double-negative stage 3 (DN3) cells were detected in the thymus. Moreover, Sel1L deficiency promoted the differentiation of Th1 and Th17 cells and upregulated the proliferation and apoptosis of CD4 T cells in vitro. Regarding the mechanism analyzed by RNA sequencing, 437 downregulated genes and 271 upregulated genes were detected in Sel1L deletion CD4 T cells, which covered the activation, proliferation, differentiation and apoptosis of these T cells. Thus, this study declared that the dysfunction of Sel1L in ERAD in T cells exacerbated the severity of EAE and indicated the important role of ERQC in maintaining immune homeostasis in the central nervous system.

CHD4 orchestrates the symphony of T and B lymphocytes development and a good mediator in preventing from autoimmune disease.

Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the nucleosome remodeling and deacetylation complex. It has been implicated in gene transcription, DNA damage repair, maintenance of genome stability, and chromatin assembly. Meanwhile, it is highly related to cell cycle progression and the proceeding of malignancy. Most of the previous studies were focused on the function of CHD4 with tumor cells, cancer stem cells, and cancer cells multidrug resistance. Recently, some researchers have explored the CHD4 functions on the development and differentiation of adaptive immune cells, such as T and B lymphocytes. In this review, we will discuss details of CHD4 in lymphocyte differentiation and development, as well as the critical role of CHD4 in the pathogenesis of the autoimmune disease.

Glutathione Peroxidase GPX1 and Its Dichotomous Roles in Cancer.

As the first identified selenoprotein, glutathione peroxidase 1 (GPX1) is a widely and abundantly expressed antioxidant enzyme. GPX1 utilizes glutathione as a substrate to catalyze hydrogen peroxide, lipid peroxide, and peroxynitrite, thereby reducing intracellular oxidative stress. The GPX1 gene is regulated at transcriptional, post-transcriptional, and translational levels. Numerous case-control studies and meta-analyses have assessed the association between a functional genetic polymorphism of the GPX1 gene, named Pro198Leu (rs1050450 C>T), and cancer susceptibility in different populations. GPX1 polymorphism has type-specific effects as a candidate marker for cancer risk, but the association between GPX1 variants and cancer susceptibility remains controversial in different studies. GPX1 is abnormally elevated in most types of cancer but has complex dichotomous roles as tumor suppressor and promoter in different cancers. GPX1 can participate in various signaling pathways to regulate tumor biological behaviors, including cell proliferation, apoptosis, invasion, immune response, and chemoresistance. In this review, we comprehensively summarize the controversial associations between GPX1 polymorphism and cancer risks and further discuss the relationships between the aberrant expressions of GPX1 and tumorigenesis. Further studies are needed to elucidate the clinical significance of GPX1 as a potential prognostic biomarker and novel therapeutic target in various malignancies.

Overexpression of sonic hedgehog enhances the osteogenesis in rat ectomesenchymal stem cells.

Ectoderm-derived mesenchymal stem cells (EMSCs) were used as potential seed cells for bone tissue engineering to treat bone defects due to their capability of rapid proliferation and osteogenic differentiation. Sonic hedgehog (Shh) signaling was reported to play an important role in the development of bone tissue, but its role is not understood. The present study investigated the role of Shh molecule in osteogenic differentiation of rat EMSCs in vitro. Rat EMSCs were isolated form nasal respiratory mucosa and identified with immunofluorescence and analyzed with other methods, including reverse transcriptase polymerase chain reaction (qPCR) and western blotting. EMSCs expressed CD90, CD105, nestin, and vimentin. On the seventh day of osteogenic induction, expression levels of Shh and Gli1 was higher according to the result of qPCR and Western blotting. After induction for 14 days, higher alkaline phosphatase (ALP) activity and more mineralized nodules were seen in comparison to the cells that did not undergo induction. Shh signaling appears to enhance osteogenic differentiation of rat EMSCs, suggesting that Shh signaling directs the lineage differentiation of ectodermal stem cells and represents a promising strategy for skeletal tissue regeneration.

Citrate Promotes Excessive Lipid Biosynthesis and Senescence in Tumor Cells for Tumor Therapy.

Metabolic disorder is one of the hallmarks of cancers, and reprogramming of metabolism is becoming a novel strategy for cancer treatment. Citrate is a key metabolite and critical metabolic regulator linking glycolysis and lipid metabolism in cellular energy homeostasis. Here it is reported that citrate treatment (both sodium citrate and citric acid) significantly suppresses tumor cell proliferation and growth in various tumor types. Mechanistically, citrate promotes excessive lipid biosynthesis and induces disruption of lipid metabolism in tumor cells, resulting in tumor cell senescence and growth inhibition. Furthermore, ATM-associated DNA damage response cooperates with MAPK and mTOR signaling pathways to control citrate-induced tumor cell growth arrest and senescence. In vivo studies further demonstrate that citrate administration dramatically inhibits tumor growth and progression in a colon cancer xenograft model. Importantly, citrate administration combined with the conventional chemotherapy drugs exhibits synergistic antitumor effects in vivo in the colon cancer models. These results clearly indicate that citrate can reprogram lipid metabolism and cell fate in cancer cells, and targeting citrate can be a promising therapeutic strategy for tumor treatment.

Systemic immune inflammation index and peripheral blood carbon dioxide concentration at admission predict poor prognosis in patients with severe traumatic brain injury.

Background: Recent studies have shown that systemic inflammation responses and hyperventilation are associated with poor outcomes in patients with severe traumatic brain injury (TBI). The aim of this retrospective study was to investigate the relationships between the systemic immune inflammation index (SII = platelet × neutrophil/lymphocyte) and peripheral blood CO2 concentration at admission with the Glasgow Outcome Score (GOS) at 6 months after discharge in patients with severe TBI. Methods: We retrospectively analyzed the clinical data for 1266 patients with severe TBI at three large medical centers from January 2016 to December 2021, and recorded the GOS 6 months after discharge. The receiver operating characteristic (ROC) curve was used to determine the best cutoff values for SII, CO2, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR), and chi-square tests were used to evaluate the relationships among SII, CO2 and the basic clinical characteristics of patients with TBI. Multivariate logistic regression analysis was used to determine the independent prognostic factors for GOS in patients with severe TBI. Finally, ROC curve, nomogram, calibration curve and decision curve analyses were used to evaluate the value of SII and coSII-CO2 in predicting the prognosis of patients with severe TBI. And we used the multifactor regression analysis method to build the CRASH model and the IMPACT model. The CRASH model included age, GCS score (GCS, Glasgow Coma Scale) and Pupillary reflex to light: one, both, none. The IMPACT model includes age, motor score and Pupillary reflex to light: one, both, none. Results: The ROC curves indicated that the best cutoff values of SII, CO2, PLR, NLR and LMR were 2651.43×109, 22.15mmol/L, 190.98×109, 9.66×109 and 1.5×109, respectively. The GOS at 6 months after discharge of patients with high SII and low CO2 were significantly poorer than those with low SII and high CO2. Multivariate logistic regression analysis revealed that age, systolic blood pressure (SBP), pupil size, subarachnoid hemorrhage (SAH), SII, PLR, serum potassium concentration [K+], serum calcium concentration [Ca2+], international normalized ratio (INR), C-reactive protein (CRP) and co-systemic immune inflammation index combined with carbon dioxide (coSII-CO2) (P < 0.001) were independent prognostic factors for GOS in patients with severe TBI. In the training group, the C-index was 0.837 with SII and 0.860 with coSII-CO2. In the external validation group, the C-index was 0.907 with SII and 0.916 with coSII-CO2. Decision curve analysis confirmed a superior net clinical benefit with coSII-CO2 rather than SII in most cases. Furthermore, the calibration curve for the probability of GOS 6 months after discharge showed better agreement with the observed results when based on the coSII-CO2 rather than the SII nomogram. According to machine learning, coSII-CO2 ranked first in importance and was followed by pupil size, then SII. Conclusions: SII and CO2 have better predictive performance than NLR, PLR and LMR. SII and CO2 can be used as new, accurate and objective clinical predictors, and coSII-CO2, based on combining SII with CO2, can be used to improve the accuracy of GOS prediction in patients with TBI 6 months after discharge.

PCAT6 May Be a Whistler and Checkpoint Target for Precision Therapy in Human Cancers.

LncRNAs are involved in the occurrence and progressions of multiple cancers. Emerging evidence has shown that PCAT6, a newly discovered carcinogenic lncRNA, is abnormally elevated in various human malignant tumors. Until now, PCAT6 has been found to sponge various miRNAs to activate the signaling pathways, which further affects tumor cell proliferation, migration, invasion, cycle, apoptosis, radioresistance, and chemoresistance. Moreover, PCAT6 has been shown to exert biological functions beyond ceRNAs. In this review, we summarize the biological characteristics of PCAT6 in a variety of human malignancies and describe the biological mechanisms by which PCAT6 can facilitate tumor progression. Finally, we discuss its diagnostic and prognostic values and clinical applications in various human malignancies.

GSDMD-mediated pyroptosis: a critical mechanism of diabetic nephropathy.

Pyroptosis is a recently identified mechanism of programmed cell death related to Caspase-1 that triggers a series of inflammatory reactions by releasing several proinflammatory factors such as IL-1ß and IL-18. The process is characterised by the rupture of cell membranes and the release of cell contents through the mediation of gasdermin (GSDM) proteins. GSDMD is an important member of the GSDM family and plays a critical role in the two pathways of pyroptosis. Diabetic nephropathy (DN) is a microvascular complication of diabetes and a major cause of end-stage renal disease. Recently, it was revealed that GSDMD-mediated pyroptosis plays an important role in the occurrence and development of DN. In this review, we focus on two types of kidney cells, tubular epithelial cells and renal podocytes, to illustrate the mechanism of pyroptosis in DN and provide new ideas for the prevention, early diagnosis and molecular therapy of DN.