Knowledge mapping of anaplastic thyroid cancer treatments: a bibliometric analysis (2000-2023).

Context: Anaplastic thyroid cancer (ATC) is a relatively rare and extensively malignant kind of thyroid carcinoma. The poor prognosis and high mortality rate of ATC can be attributed to its invasive features and undifferentiated phenotype. At present, there is a lack of efficacious therapeutic options. In light of the elevated fatality rate, it is vital to possess a comprehensive comprehension of the scientific terrain pertaining to ATC. To gather the perspectives of different researchers about the topic of ATC treatment, we did a bibliometric network analysis, which offers a comprehensive view of the scholarly literature. Methodology: A systematic search was conducted on the WoSCC database to identify publications pertaining to ATC treatment between the years 2000 and 2023. In this bibliometric investigation, the tools VOSviewers, CiteSpace, and the R package "bibliometrix" were employed to investigate the general attributes, developmental framework, and academic frontiers of the subject matter. Results: 1223 publications in total, written by 6937 scholars from 53 areas and 1402 institutions and published in 358 scholarly journals, were analyzed. There has been a gradual increase in the quantity of publications pertaining to ATC treatment. The United States and China emerged as the most prominent nations. The University of Texas MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Counseling Center are prominent research institutions in highly productive countries. The journal Thyroid holds a prominent position within its discipline, being widely recognized as both the most popular and highly co-cited publication. According to the available data, Maria Cabanillas has authored the highest number of published articles, while RC Smallridge has received the highest number of co-citations. It turned out that the prevailing keywords encompassed expression, therapy, apoptosis, survival, activation, proliferation, metastasis, and other related terms. Immunotherapy, targeted therapy, and prognostic factors are the emerging research hotspots and trends. Conclusions: This paper presents a complete overview of research trends and advancements in the treatment of ATC using bibliometric analysis. The acquisition of information will offer vital insights for funding and potential creative strategies in researching the treatment of ATC, which indicates the research frontiers as well as prevalent directions in recent years.

Isocitrate dehydrogenase 2 regulates the proliferation of triple-negative breast cancer through the ferroptosis pathway.

Triple-negative breast cancer (TNBC) is currently the type of breast cancer with the worst prognosis; it lacks specific treatments, such as ER/PR antagonistic endocrine and anti-HER2 targeted therapies. Although immunotherapy with immune checkpoints has shown some efficacy in many solid tumors, clinical data in TNBC suggest significant limitations. The essence of ferroptosis is the impaired metabolism of intracellular lipid oxides, which in turn causes the activation and abnormalities of the immune system, including ROS, and not only plays an important role in liver injury and organ aging but also a large amount of data points to the close correlation between the ferroptosis process and tumor development. In this study, through the analysis of large-throughput biological data of breast tumors, combined with the characteristics of the biological process of ferroptosis, the specific gene IDH2 was found to be significantly highly expressed in TNBC and functionally correlated with ferroptosis. Through clinical specimens validated at the gene and protein levels, in vitro tumor cell line validation, and in vivo mouse models, we found that the high expression of IDH2 in TNBC has a role in inhibiting the ferroptosis process in TNBC, thus promoting the proliferation of TNBC cells and other malignant features.

Role of macrophage colony stimulating factor and interferon regulatory factor 7 in modulating the immune profile of mouse testicular macrophages.

Testicular macrophages (TM) are critical for the function of the testis by regulating homeostasis and inflammatory responses. However, the mechanisms by which TM fulfil these roles remain elusive. In this study, we explored the impact of two key testicular microenvironmental factors, namely 25-hydroxycholesterol (25HC), an oxysterol related to sex hormones and macrophage colony-stimulating factor (M-CSF), a factor crucial for macrophage survival and differentiation, on the regulation of the TM phenotype. Specifically, we examined their role in controlling the expression of the transcription factor interferon regulatory factor 7 (Irf7), a factor critical for maintaining the alternative macrophage phenotype. To achieve this, we used an in vitro bone marrow-derived macrophage (BMDM) model as a surrogate for TM to investigate the roles of 25HC and M-CSF in regulating the expression of Irf7 during the polarization of murine TM. M-CSF was identified as the main regulator of Irf7 expression, while 25HC production is a consequence of Irf7 activation in BMDM. In turn, 25HC plays a role in a negative feedback loop on the expression levels of Irf7 in BMDM. Using flow cytometry in Irf7-/- mouse testis the CD64loMHChi TM subpopulation was found to be decreased. Together with lower IL-10 protein levels in Irf7-/- TM this indicates a shift towards an M1-like macrophage profile. In summary, our data indicates that M-CSF could act as an inducer of high Irf7 expression levels in the mouse testis. However, the exact role of the high 25HC concentration in the testis in maintaining the local immune milieu still needs further study.

Couples' skills training intervention in young breast cancer patients with fear of cancer recurrence: A randomized controlled trial.

PURPOSE: This study adapted the Chinese version of the Couple Skills Training intervention program to couples of young breast cancer patients in China and investigated its effects on fear of cancer recurrence (FCR), cancer-related communication, and level of hope among the couples. METHODS: Ninety young breast cancer patients and their spouses were recruited and randomly assigned to the intervention group (45 couples) and the control group (45 couples). Couples in the intervention group received skills training and were assessed at baseline, post-intervention, and 3 months post-intervention to measure outcomes. Differences in scores between the two groups were analyzed using two-sample t-tests and generalized estimating equations (GEE) controlling for demographic and health-related variables. RESULTS: Couples' skills training intervention effectively reduced FCR and improved cancer-related communication in young breast cancer patients compared to the control group (both p < 0.001). Spouses' expectations significantly increased (p < 0.001). At 3 months post-intervention, couples in the intervention group showed significant improvements in FCR, cancer-related communication, and hope (all p < 0.001). CONCLUSION: Couples' skills training interventions are beneficial for helping young breast cancer patients cope with FCR. Couples-based interventions play a crucial role in addressing FCR in these patients and their spouses. Future research should consider larger samples and longer follow-up periods to enhance intervention effectiveness. CLINICAL TRIAL CENTER REGISTRATION NUMBER: This study has also been registered with the Chinese Clinical Trial Registry (No: ChiCTR2200063327).

An enzyme-free method for isolating testicular macrophages from rodent models.

Macrophages are the major type of immune cell in the testis of both humans and rodents. Testicular macrophages (TMs) play critical roles in maintaining the testicular microenvironment, such as Leydig cell-dependent hormone production, spermatogenesis, and immune balance. A substantial number of studies have used rodent models to investigate the functions of TMs with various methods and harvest macrophages from the testis. Studies have demonstrated that enzyme digestion, an essential part of these methods, can improve the number and purity of TMs while unavoidably altering the immunoprofile of macrophages, which is detrimental for further study in terms of immune investigation. Here, we modified the existing method of microglia isolation and set up a novel method without the enzyme digestion step to isolate TMs. According to the characteristics of testicular tissue looseness and the physical and biological characteristics of macrophages, by combining mechanical separation, gradient centrifugation, and immuno-magnetic bead selection, we can effectively avoid the enzymatic digestion of testis tissue and maintain the immune characteristics of macrophages. Additionally, we verified the purity of TM with flow cytometry (FC) at approximately 91-95%, and the production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) was lower than that isolated with enzyme digestion. In contrast to the traditional method, this novel protocol can assist those who have no convenient access to fluorescence-activated cell sorting (FACS) to isolate a sufficient number of TMs and, most importantly, avoid altering the immunoprofile of TMs without enzyme digestion.

Exploration of epithelial-mesenchymal transition-related lncRNA signature and drug sensitivity in breast cancer.

Background: Breast cancer (BRCA) has become the most diagnosed cancer worldwide for female and seriously endanger female health. The epithelial-mesenchymal transition (EMT) process is associated with metastasis and drug resistance in BRCA patients. However, the prognostic value of EMT-related lncRNA in BRCA still needs to be revealed. The aim of this study is to construct an EMT-related lncRNA (ERL) signature with accuracy predictive ability for the prognosis of BRCA patients. Methods: RNA-seq expression data and Clinical characteristics obtained from the TCGA (The Cancer Genome Atlas) were used in the study. First, we identified the EMT-related lncRNA by the Pearson correlation analysis. An EMT-related lncRNAs prognostic risk signature was constructed using univariate Cox regression and Lasso-penalized Cox regression analyses. The model's performance was validated using Kaplan-Meier (KM) survival analysis, ROC curve and C-index. Finally, a nomogram was constructed for clinical practice in evaluating the patients with BRCA and validated by calibration curve and decision curve analysis (DCA). We also evaluated the drug sensitivity of signature lncRNA and the tumor immune cell infiltration in breast cancer. Results: We constructed a 10-lncRNA risk score signature based on the lncRNAs associated with the EMT process. We could assign BRCA patients to the high- and low-risk group according to the median risk score. The prognostic risk signature showed excellent accuracy and demonstrated sufficient independence from other clinical characteristics. The immune cell infiltration analysis showed that the prognostic risk signature was related to the infiltration of the immune cell subtype. Drug sensitivity analysis proved ERLs signature could effectively predict the sensitivity of patients to common chemotherapy drugs in BRCA and provide guidance for chemotherapy drugs for high-risk and low-risk patients. Conclusion: Our ERL signature and nomogram have excellent prognostic value and could become reliable tools for clinical guidance.

T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems.

The immune system provides full protection for the body by specifically identifying 'self' and removing 'others'; thus protecting the body from diseases. The immune system includes innate immunity and adaptive immunity, which jointly coordinate the antitumor immune response. T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are the main tumor-killing immune cells active in three antitumor immune cycle. Cancer immunotherapy focusses on activating and strengthening immune response or eliminating suppression from tumor cells in each step of the cancer-immunity cycle; thus, it strengthens the body's immunity against tumors. In this review, the antitumor immune cycles of T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are discussed. Co-stimulatory and co-inhibitory molecules in the three activity cycles and the development of drugs and delivery systems targeting these molecules are emphasized, and the current state of the art of drug delivery systems for cancer immunotherapy are summarized.

The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN.

Innate immune signaling in macrophages during viral infection is regulated by ISGylation, the covalent attachment of the ubiquitin-like protein interferon-stimulated gene 15 (ISG15) to protein targets. Here, we explored the role of ISGylation in the macrophage response to infection with Mycobacterium tuberculosis. In human and mouse macrophages, the E3 ubiquitin ligases HERC5 and mHERC6, respectively, mediated the ISGylation of the phosphatase PTEN, which promoted its degradation. The decreased abundance of PTEN led to an increase in the activity of the PI3K-AKT signaling pathway, which stimulated the synthesis of proinflammatory cytokines. Bacterial growth was increased in culture and in vivo when human or mouse macrophages were deficient in the major E3 ISG15 ligase. The findings expand the role of ISGylation in macrophages to antibacterial immunity and suggest that HERC5 signaling may be a candidate target for adjunct host-directed therapy in patients with tuberculosis.

Prophylactic Central Neck Dissection Based on Preoperative Imaging and Intraoperative Surgeon's Palpation Versus Total Thyroidectomy Alone for Papillary Thyroid Cancer.

INTRODUCTION: To compare the overall morbidity and recurrence of papillary thyroid cancer (PTC) after total thyroidectomy (TT) with or without prophylactic central compartment neck dissection (CCND) in cases of both preoperative and intraoperative nonsuspicious central lymph nodes (CLNs). METHODS: A total of 570 PTC patients who harbored no preoperative and intraoperative suspicious CLNs at two institutions were enrolled. They were randomly assigned to TT alone or TT with prophylactic CCND (pCCND) after intraoperative assessment of CLNs during the surgery. Lymph nodes that were hard or large enough to be palpated were regarded as suspicious metastatic lymph nodes during the surgery. The characteristics, postoperative complications, and locoregional recurrence of the two groups were recorded and compared. RESULTS: With a median follow-up of 5 y, the rates of lymph node recurrence in the TT alone and TT with pCCND groups were similar (7.3% versus 4.6%, P = 0.247), but there were significantly higher rates of overall morbidity (6.6% versus 19.1%, P < 0.001) when pCCND was performed. CONCLUSIONS: pCCND is not recommended for patients with clinically node-negative PTC preoperatively and intraoperatively because of the high complication rate and lack of benefit of reducing recurrence.

Development of the expression and prognostic significance of m5 C-related LncRNAs in breast cancer.

BACKGROUND: 5-Methylcytosine (m5C) methylation is a major epigenetic RNA modification and is closely related to tumorigenesis in various cancers. This study aimed to explore the prognostic value of m5C-related lncRNAs in breast cancer. METHODS: Clinical characteristics and RNA-seq expression data from TCGA (The Cancer Genome Atlas) were used in the study. First, we performed differentially expressed gene (DEG) analysis and constructed a PPI network for the 12 m5C regulators. Then, we identified the m5C-related LncRNAs by the "cor. test." An m5C-related lncRNA prognostic risk signature was developed using univariate Cox regression and Lasso-penalized Cox regression analyses. The model's performance was determined using Kaplan-Meier (KM) survival analysis and ROC curves. Finally, a nomogram was constructed for clinical application in evaluating patients with BRCA. We also researched the drug sensitivity of signature lncRNAs and immune cell infiltration. Finally, we validated the expression of the signature lncRNAs through qRT-PCR in a breast cancer cell line and a breast epithelial cell line. RESULTS: Overall, we constructed an 11-lncRNA risk score signature based on the lncRNAs associated with m5C regulators. According to the median risk score, we divided BRCA patients into high- and low-risk groups. The prognostic risk signature displayed excellent accuracy and demonstrated sufficient independence from other clinical characteristics. The immune cell infiltration analysis showed that the prognostic risk signature was related to the infiltration of immune cell subtypes. Drug sensitivity proved that our prognostic risk signature potentially has therapeutic value. CONCLUSIONS: The m5C-related lncRNA signature reliably predicted the prognosis of breast cancer patients and may provide new insight into the breast cancer tumor immune microenvironment.

Weighted gene co-expression network reveals driver genes contributing to phenotypes of anaplastic thyroid carcinoma and immune checkpoint identification for therapeutic targets.

Background: Anaplastic thyroid carcinoma (ATC) is a rare but extremely malignant tumor, with a rapid growth rate and early metastasis thus leading to poor survival of patients. The molecular mechanisms underlying these aggressive traits of ATC remain unknown, which impedes the substantial progress in treatment to prolong ATC patient survival. Methods: We applied weighted gene co-expression network analysis (WGCNA) to identify ATC-specific modules. The Metascape web and R package clusterProfiler were employed to perform enrichment analysis. Combined with differentially expressed gene analysis, we screened out the most potential driver genes and validated them using receiver operator characteristic (ROC) analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry (IHC), and triple immunofluorescence staining. Results: A gene expression matrix covering 75 normal samples, 83 papillary thyroid carcinoma (PTC), 26 follicular thyroid carcinoma (FTC), 19 poor-differentiated thyroid carcinoma (PDTC), and 41 ATC tissue samples were integrated, based on which we detected three most potential ATC-specific modules and found that hub genes of these modules were enriched in distinct biological signals. Hub genes in the turquoise module were mainly enriched in mitotic cell cycle, tube morphogenesis, and cell differentiation, hub genes in the magenta module were mainly clustered in the extracellular matrix organization, positive regulation of cell motility, and regulation of Wnt signaling pathway, while hub genes in the blue module primarily participated in the inflammatory response, innate immune response, and adaptive immune response. We showed that 9 top genes, 8 transcription factors (TFs), and 4 immune checkpoint genes (ICGs) were differentially expressed in ATC compared to other thyroid samples and had high diagnostic values for ATC, among which, 9 novel ATC-specific genes (ADAM12, RNASE2, CASP5, KIAA1524, E2F7, MYBL1, SRPX2, HAVCR2, and TDO2) were validated with our clinical samples. Furthermore, we illustrated that ADAM12, RNASE2, and HAVCR2 were predominantly present in the cytoplasm. Conclusion: Our study identified a set of novel ATC-specific genes that were mainly related to cell proliferation, invasion, metastasis, and immunosuppression, which might throw light on molecular mechanisms underlying aggressive phenotypes of ATC and provide promisingly diagnostic biomarkers and therapeutic targets.

Efficacy of compound aluminum sulfate injection as a monotherapeutic regimen in non-muscle invasive bladder cancer patients: a retrospective single-arm cohort study.

Background: Compound aluminum sulfate injection (CASI) originated from a Chinese traditional medicine, "Kuzhiye", and has been used in treating non-muscle invasive bladder cancer (NMIBC). Previous studies suggested that CASI was a potential monotherapeutic drug for NMIBC. However, the efficacy and safety of CASI in the treatment of NMIBC, as well as the long-term recurrence after treatment, need to be further evaluated. Methods: A multicenter retrospective single-arm cohort study was conducted. From 2006 to 2009, 101 patients (74 men and 27 women, aged 58.9±11.9 years) with T1 or benign NMIBC were enrolled. Each patient was directly injected with CASI through catheter needle into the root of NMIBC. Vital signs, electrocardiography, blood count, blood biochemistry, and urine analysis were re-examined on day 2 and day 14 after CASI injection, together with a cystoscopic examination 4 weeks after CASI treatment was performed for all patients to assess the clinical activity and safety of CASI. To study long-term efficacy, patients in center 2 were followed up for recurrence with a median follow-up time of 13.8 years. Results: For the 101 patients enrolled in this study, demographic characteristics in the 3 centers showed no significant differences. After CASI, 2 patients showed administration site-dependent, but not dose-dependent, increase in their aluminum concentration in 24 hours without obvious abnormality in blood biochemistry. The overall effective rate was 97.03%, including complete tumor necrosis in 94 patients. Treatment-related adverse events occurred in 20 patients (19.80%), including 9 drug-related and 11 cystoscopy-related adverse events (AEs). All AEs were endurable and disappeared within 2 weeks without any treatment. The maximum tolerated single dose of CASI was 21 mL. Among the 43 patients at center 2, 3 patients were excluded because they changed to other treatment regimen. As of April 2022, of the 40 patients enrolled, 22 had no recurrence and 7 relapsed. The follow-up time was 2-16.2 years. The other 11 patients were lost to follow up. Conclusions: CASI may be an effective and safe option for the treatment of NMIBC and is expected to be a potential monotherapy regimen for NMIBC.

Recurrent Laryngeal Nerve with Loss of Signal During Monitored Thyroidectomy: Percentage Reduction in Sum of the Amplitude of Left and Right Channel.

PURPOSE: The prognostication for the injured recurrent laryngeal nerve (RLN) with incomplete loss of signal (LOS) and its function outcome have not been well unified. A warning criterion was proposed to predict RLN injury during monitored thyroidectomy. METHODS: A retrospective review of prospectively collected data from consecutive 357 patients with 560 nerves at risk was conducted. Vocal cords mobility with laryngoscope was performed preoperatively, on the second day, and once a month postoperatively until complete recovery. Different cutoff values of the percentage reduction in sum of the amplitude of left and right channel at the end of the surgery, for postoperative vocal cord paralysis (VCP) prediction were compared. RESULTS: Percentage reduction in sum of the amplitude of left and right channel at the end of operation ranged from 30.2 to 63.6% in 27 nerves with incomplete LOS (absolute amplitude value of final R2 > 100 µV with reduction > 50% of R1). Seven (1.25%) nerves experienced transient postoperative VCP, in which one nerve with postoperative VCP showed no amplitude reduction. The positive predictive value of VCP for the sum amplitude reduction exceeding 30, 40, 50, and 60% was 22.2, 40, 85.7, and 100%, respectively. Accuracy was 96.1, 98.2, 99.6, 99.4%, respectively. CONCLUSION: Percentage reduction in sum of the amplitude of left and right channel is a meaningful method to improve the accuracy of VCP prediction. When the sum amplitude reduction ≥ 50%, surgeons should consider the possibility of postoperative VCP and correct some surgical maneuvers.

The origins of resident macrophages in mammary gland influence the tumorigenesis of breast cancer.

Macrophage is the important sentinel cell type of innate immune system, and bridge with the adaptive immune response via antigen presentation. Tissue-resident macrophages are universal in almost all organs and play essential roles in maintaining specific organ homeostasis, inflammation responses, and disease genesis, including tumorigenesis. Macrophage is generally divided into two extreme statuses, M1 and M2, with sophisticated continuous subtypes due to different stimuli and microenvironments. Tumor-associated macrophage (TAM) is regarded as the key factor related to the prognosis, staging, classification, and treatment strategy of various cancers. However, emerging evidence indicated potential opposite functions of TAM in different tumor models. Recent studies found that different originated resident macrophages show notably different profiles in the same tissue niche. More evidence pointed out that the strategies to repolarize the subtypes of TAM or resident macrophages are valuable in carcinoma treatments. In the breast cancer model, studies pointed that macrophages located differently in histology show obvious different cell markers and functions. In this review, we will illustrate the profiles of resident macrophages in breast cancer with various aspects, including origination, polarization, tumoricidal activity, tumorigenesis, and the factors that could regulate the functions of macrophages.

The initial expression alterations occurring to transcription factors during the formation of breast cancer: Evidence from bioinformatics.

BACKGROUND: Breast cancer (BC) is the leading malignancy among women worldwide. AIM: This work aimed to present a comprehensively bioinformatic analysis of gene expression profiles and to identify the hub genes during BC tumorigenesis, providing potential biomarkers and targets for the diagnosis and therapy of BC. MATERIALS & METHODS: In this study, multiple public databases, bioinformatics approaches, and online analytical tools were employed and the real-time reverse transcription polymerase chain reaction was implemented. RESULTS: First, we identified 10, 107, and 3869 differentially expressed genes (DEGs) from three gene expression datasets (GSE9574, GSE15852, and GSE42568, covering normal, para-cancerous, and BC samples, respectively), and investigated different biological functions and pathways involved. Then, we screened out 8, 16, and 29 module genes from these DEGs, respectively. Next, 10 candidate genes were determined through expression and survival analyses. We noted that seven candidate genes JUN, FOS, FOSB, EGR1, ZFP36, CFD, and PPARG were downregulated in BC compared to normal tissues and lower expressed in aggressive types of BC (basal, HER2+ , and luminal B), TP53 mutation group, younger patients, higher stage BC, and lymph node metastasis BC, while CD27, PSMB9, and SELL were upregulated. The present study discovered that the expression levels of these candidate genes were correlated with the infiltration of immune cells (CD8+ T cell, macrophage, natural killer [NK] cell, and cancer-associated fibroblast) in BC, as well as biomarkers of immune cells and immune checkpoints. We also revealed that promoter methylation, amplification, and deep deletion might contribute to the abnormal expressions of candidate genes. Moreover, we illustrated downstream-targeted genes of JUN, FOS, FOSB, EGR1, and ZFP36 and demonstrated that these targeted genes were involved in "positive regulation of cell death", "pathways in cancer", "PI3K-Akt signaling pathway", and so on. DISCUSSION & CONCLUSION: We presented differential gene expression profiles among normal, para-cancerous, and BC tissues and further identified candidate genes that might contribute to tumorigenesis and progression of BC, as potential diagnostic and prognostic targets for BC patients.

High Expression of CEMIP Correlates Poor Prognosis and the Tumur Microenvironment in Breast Cancer as a Promisingly Prognostic Biomarker.

Cell migration-inducing hyaluronidase 1 (CEMIP), a Wnt-related protein and also known as KIAA1199, is implicated in the process of metastatic colonization in a variety of malignant tumors, including breast cancer (BC), which is one of the most frequently diagnosed tumors in women worldwide. In this study, multiple public databases, online analytical tools, and bioinformatics approaches were applied to explore the expression levels, regulatory mechanisms, and biological functions of CEMIP in BC. We illustrated that CEMIP was highly expressed in various kinds of carcinomas, including BC, especially advanced subtypes, and predicted less favorable prognosis (negatively associated with overall survival) in BC patients, which might be an independent prognostic factor. Then, we revealed that the mutation and high expression of CEMIP might lead to it as an oncogene. We also demonstrated that TP53 mutation, DNA hypo-methylation, and the expression changes of three potential upstream transcription factors (EZH2, EGR1, and JUN) of CEMIP were likely to cause the hyperexpression of CEMIP in BC. Moreover, our findings suggested that CEMIP might exert its carcinogenic roles in the tumor microenvironment via participation in the extracellular matrix formation, increasing cancer-associated fibroblast (CAF), M2 macrophage, and neutrophil infiltration and decreasing CD8+ T cell infiltration. In summary, our study provided more solid evidence for CEMIP as a prognostic and metastatic biomarker and a potential therapeutic target in BC. Of course, these findings also need more confirmations of basic experiments and further clinical trials in the future.

USP12 promotes CD4+ T cell responses through deubiquitinating and stabilizing BCL10.

Deubiquitinases (DUBs) regulate diverse biological processes and represent a novel class of drug targets. However, the biological function of only a small fraction of DUBs, especially in adaptive immune response regulation, is well-defined. In this study, we identified DUB ubiquitin-specific peptidase 12 (USP12) as a critical regulator of CD4+ T cell activation. USP12 plays an intrinsic role in promoting the CD4+ T cell phenotype, including differentiation, activation, and proliferation. Although USP12-deficient CD4+ T cells protected mice from autoimmune diseases, the immune response against bacterial infection was subdued. USP12 stabilized B cell lymphoma/leukemia 10 (BCL10) by deubiquitinating, and thereby activated the NF-κB signaling pathway. Interestingly, this USP12 regulatory mechanism was identified in CD4+ T cells, but not in CD8+ T cells. Our study results showed that USP12 activated CD4+ T cell signaling, and targeting USP12 might help develop therapeutic interventions for treating inflammatory diseases or pathogen infections.

Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis.

Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64hiMHCIIlo and CD64loMHCIIhi macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.

Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine-1-phosphate in a sphingosine-1-phosphate lyase-dependent manner.

Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti-inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti-inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine-1-phosphate (S1P) in a S1P lyase (SPL)-dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro-inflammatory cytokines by suppressing nuclear factor-κB and mitogen-activated protein kinases signalling pathways. Furthermore, vitamin B6-reduced accumulation of S1P by promoting SPL activity. The anti-inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti-inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.