C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis.

C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a pre-metastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics.

ORAI2 is Important for the Development of Early-Stage Postirradiation Fibrosis in Salivary Glands.

PURPOSE: Although postirradiation hyposalivation significantly impairs patient quality of life, the underlying mechanisms driving radiation-induced salivary gland fibrosis and hyposalivation remain poorly understood. This study aims to explore the role of calcium-mediated signaling pathways in radiation-induced salivary gland fibrosis. METHODS AND MATERIALS: Primary human submandibular gland (SG) cells and C57BL/6J female mouse SGs were exposed to irradiation to model fibrosis development. Following 15 Gy irradiation exposure, RNA sequencing and bioinformatic analysis were conducted on mouse SGs. The effects of store-operated calcium entry (SOCE) inhibition using SKF96365 and YM58483 on fibrosis markers were assessed in vitro and in vivo. Additionally, the involvement of ORAI2 protein and the newly identified JNK/NFAT1/transforming growth factor ß1 (TGF-ß1) signaling axis in SG fibrosis was explored. RESULTS: We identified that the calcium release-activated calcium modulator ORAI2 was important in promoting early-stage postirradiation fibrosis in SGs. Calcium channel signaling was activated in both human patients and irradiated C57BL/6J female mice SGs. Inhibition of SOCE signaling effectively blocked fibrosis in an ORAI2-dependent manner 30 days after irradiation. Our mechanistic studies revealed a novel ORAI2/JNK/NFAT1 axis within the SOCE pathway critical in driving TGF-ß1-mediated fibrogenesis. Encouragingly, pharmacologic inhibition of NFAT1 significantly mitigated radiation-induced SG fibrosis and restored saliva flow to 84.61% of normal levels in treated mice 30 days after irradiation, without detectable side effects. CONCLUSIONS: Our findings highlight the significance of the ORAI2-mediated calcium signaling pathway, specifically via the ORAI2/JNK/NFAT1 axis, in promoting TGF-ß1 expression and contributing to the development of early-stage salivary gland fibrosis following irradiation exposure. Targeting the ORAI2/JNK/NFAT1 axis emerges as a promising therapeutic strategy to alleviate radiation-induced hyposalivation and fibrosis, potentially improving the quality of life for patients undergoing radiation therapy.

Cellular dynamics of tumor microenvironment driving immunotherapy resistance in non-small-cell lung carcinoma.

Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches.

Effect of immunochemotherapy infusion timing, sequence, and interval on prognosis of advanced esophageal cancer: A retrospective cohort study.

OBJECTIVE: The present study aims to explore the roles of infusion time, administration sequence and interval of immunochemotherapy (IO) in predicting overall survival (OS) in patients with locally advanced ESCC. METHODS: This multi-center retrospective study enrolled advanced ESCC who received IO between Nov 2019 and Nov 2021. Patients were divided into groups according to the three classifiers (IO infusion time, administration sequence, and infusion interval), and were further analyzed for the roles of these classifiers in predicting the prognosis of the ESCC patients. RESULTS: A total of 183 eligible patients with locally advanced ESCC were included in this study. Patients who received ≥ 75% of immunotherapy drug infusions after 12:00 h had better OS compared to those who received < 75% of immunotherapy drug infusions after 12:00 h in the 1:1 propensity score matching analysis (HRadjusted: 0.38, 95% CI: 0.17-0.82; P = 0.013). Cox proportional hazards regression revealed that ESCC patients with shorter infusion interval (< 3.3 h) had better OS (HRadjusted: 0.34, 95% CI: 0.15-0.76; P = 0.008). CONCLUSION: For patients with ESCC, the OS is significantly better when immunotherapy was administered after 12:00 h. A shorter infusion interval (< 3.3 hours) on the same-day immunochemotherapy could lead to a better prognosis.

Investigating the Interrelationships Among Mental Health, Substance Use Disorders, and Suicidal Ideation Among Lesbian, Gay, and Bisexual Adults in the United States: Population-Based Statewide Survey Study.

BACKGROUND: Mental health disparities have been documented among lesbian, gay, and bisexual (LGB) adults in the United States. Substance use disorders and suicidal ideation have been identified as important health concerns for this population. However, the interrelationships among these factors are not well understood. OBJECTIVE: This study aims to investigate the interrelationships among mental health, substance use disorders, and suicidal ideation among LGB adults in the United States using a population-based statewide survey. METHODS: Our study was an observational cross-sectional analysis, and the data for this study were collected from a sample of LGB adults who participated in the statewide survey. The survey collected information on mental health, substance use disorders, and suicidal ideation using validated measures. Descriptive statistics and inferential data analysis were conducted to explore the interrelationships among these factors. RESULTS: The results showed that LGB adults who reported higher levels of depression and drug abuse and dependence also reported higher levels of suicidal tendency and mental illness. Inferential data analysis using χ2 tests revealed significant differences in depression score (χ22=458.241; P<.001), drug abuse and dependence score (χ22=226.946; P<.001), suicidal tendency score (χ22=67.795; P<.001), and mental illness score (χ22=363.722; P<.001) among the 3 sexual identity groups. Inferential data analysis showed significant associations between sexual identity and mental health outcomes, with bisexual individuals reporting the highest levels of depression, drug abuse and dependence, suicidal tendency, and mental illness. CONCLUSIONS: This study provides important insights into the interrelationships among mental health, substance use disorders, and suicidal ideation among LGB adults in the United States. The findings underscore the need for targeted interventions and research aimed at addressing the mental health needs of sexual minority populations. Future research should aim to better understand the underlying mechanisms driving these disparities and develop culturally sensitive and tailored interventions that meet the unique needs of LGB individuals. Reducing stigma and discrimination against sexual minority populations is also crucial to improving their mental health outcomes.

CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GC), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-offunction experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Protocol to study immunodynamics in the tumor microenvironment using a tyramide signal amplification-based immunofluorescent multiplex panel.

Immunodynamics in the tumor microenvironment can be precisely examined by using multiple antigen identification approaches. Here, we present a protocol for capturing expression levels of multiple target proteins in the same specimen at single-cell resolution using a tyramide signal amplification-based immunofluorescent multiplexing system. We describe steps for tumor tissue microarray preparation, multiplex immunohistochemistry staining, image acquisition, and quantification. This protocol can quantify immune cells in tissues from patients or experimental disease models at a protein level. For complete details on the use and execution of this protocol, please refer to Chung et al. (2023),1 Tang et al. (2022),2 and Tang et al. (2022).3.

Societal discrimination and mental health among transgender athletes: a systematic review and Meta-analysis.

BACKGROUND: Discrimination and inequality have been identified as significant problems faced by transgender individuals in sports participation. However, uncertainties remain regarding the effectiveness of interventions aimed at promoting equality. OBJECTIVES: This systematic review and meta-analysis aimed to examine the experiences of transgender athletes in sports, focusing on mental health issues and factors contributing to inequality among transgender and other sexual minorities. METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched 10 electronic databases, including PubMed, Google Scholar, and Web of Science, to identify eligible studies published between 2005 and 2022. The search yielded 1430 articles, of which only 12 studies met the inclusion criteria for this review. RESULTS: The meta-analysis of the 12 studies included in this review revealed that transgender athletes faced social discrimination and inequality in sports participation, resulting in mental health problems and higher rates of suicide. From a cohort of 21,565 participants in the studies, 7152 (33%) were subjected to discrimination in sports participation and healthcare, with a rate of 0.61 (95% confidence interval [CI]: 0.35, 0.81). However, transgender athletes who felt welcomed and embraced by their respective teams accounted for 0.39 (95% CI: 0.19, 0.65). These results indicated significant differences between how transgender athletes are treated in healthcare settings and when participating in sports. CONCLUSION: The study findings underscore the need for policies, cultural research, and interventions to address discrimination and inequality faced by transgender athletes in sports participation. Promoting equality and safeguarding the rights of transgender athletes can mitigate the risk of mental health problems and increase physical activity among sexual minorities.

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage-Myofibroblast Transition in Non-Small-Cell Lung Carcinoma.

Macrophage-myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro-tumoral cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC) in a TGF-ß1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor-associated macrophage at single-cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT-specific TGF-ß1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT-derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage-specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage-specific genetic deletion and systemic pharmacological inhibition of TGF-ß1/Smad3/Runx1 signaling effectively prevent MMT-driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.

Advance in Targeted Cancer Therapy and Mechanisms of Resistance.

Drug resistance remains one of the important clinical challenges, making cancer one of the leading causes of death worldwide [...].

Mitigating Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: Ameliorating Sexual Function and Psychological Well-Being in Older Men.

This study aimed to investigate the prevalence of lower urinary tract symptoms (LUTS) in older men (N= 3056) with benign prostatic hyperplasia (BPH) and its effects on their sexual function and mental health. Descriptive, correlation, and regression analyses were used to explore the relationships between prostate and lower urinary tract health and psychological well-being. Better prostate and lower urinary tract health positively affected psychological well-being, and sexual function also had a positive influence. LUTS have an adverse impact on sexual function and mental health. Early intervention is crucial for mitigating the negative impact of LUTS on the quality of life in older men. Addressing prostate and lower urinary tract health issues through appropriate interventions may improve psychological well-being. Health care professionals must consider the adverse effects of BPH and LUTS on sexual function and mental health, and implement interventions to enhance the overall quality of life in older men.

Tumour-associated macrophages: versatile players in the tumour microenvironment.

Tumour-Associated Macrophages (TAMs) are one of the pivotal components of the tumour microenvironment. Their roles in the cancer immunity are complicated, both pro-tumour and anti-cancer activities are reported, including not only angiogenesis, extracellular matrix remodeling, immunosuppression, drug resistance but also phagocytosis and tumour regression. Interestingly, TAMs are highly dynamic and versatile in solid tumours. They show anti-cancer or pro-tumour activities, and interplay between the tumour microenvironment and cancer stem cells and under specific conditions. In addition to the classic M1/M2 phenotypes, a number of novel dedifferentiation phenomena of TAMs are discovered due to the advanced single-cell technology, e.g., macrophage-myofibroblast transition (MMT) and macrophage-neuron transition (MNT). More importantly, emerging information demonstrated the potential of TAMs on cancer immunotherapy, suggesting by the therapeutic efficiency of the checkpoint inhibitors and chimeric antigen receptor engineered cells based on macrophages. Here, we summarized the latest discoveries of TAMs from basic and translational research and discussed their clinical relevance and therapeutic potential for solid cancers.

Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ.

Transforming growth factor-ß (TGF-ß)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.

Needs and experiences of cancer care in patients' perspectives among the lesbian, gay, bisexual, transgender and queer community: a systematic review.

Individuals within the Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ) community who are diagnosed with cancer experience inequitable treatment in healthcare systems worldwide, resulting in dissatisfaction, communication challenges with healthcare providers, and a deep sense of disappointment. Stigma, discrimination, and perceived homophobia further heighten the risk of psychological and attitudinal disorders, including depression and suicidal tendencies, among LGBTQ cancer patients. To comprehensively assess the discrimination faced by LGBTQ cancer patients and gain deeper insights into their needs and experiences, we conducted a systematic review following PRISMA guidelines. We searched for relevant articles using specific keywords in reputable databases such as PubMed, Google Scholar, and PsycINFO. We rigorously evaluated article quality using the CASP (Critical Appraisal Skills Programme) checklist. From a total of 75 eligible studies, we carefully selected 14 studies, specifically examining LGBTQ cancer patients who were currently undergoing or had previously undergone cancer treatment. The studies revealed various factors, including unmet needs related to anxiety and depression, instances of discrimination, disparities in care, and inadequate support systems. A majority of patients expressed dissatisfaction with their cancer care and continued to encounter discrimination and disparities throughout their treatment journeys. Consequently, this led to heightened levels of anxiety, stress, depression, and negative perceptions of healthcare providers. Based on these findings, we recommend providing specialized training to social workers and healthcare providers. This training will equip them with the necessary skills and knowledge to deliver culturally sensitive care tailored to the unique needs of LGBTQ cancer patients. By addressing discrimination, reducing disparities, and fostering an inclusive environment, healthcare professionals can strive to ensure that LGBTQ cancer patients receive the care they deserve.

Promotion effect of TGF-ß-Zfp423-ApoD pathway on lip sensory recovery after nerve sacrifice caused by nerve collateral compensation.

Resection of oral and maxillofacial tumors is often accompanied by the inferior alveolar nerve neurectomy, resulting in abnormal sensation in lower lip. It is generally believed that spontaneous sensory recovery in this nerve injury is difficult. However, during our follow-up, patients with inferior alveolar nerve sacrifice showed different degrees of lower lip sensory recovery. In this study, a prospective cohort study was conducted to demonstrate this phenomenon and analyze the factors influencing sensory recovery. A mental nerve transection model of Thy1-YFP mice and tissue clearing technique were used to explore possible mechanisms in this process. Gene silencing and overexpression experiments were then conducted to detect the changes in cell morphology and molecular markers. In our follow-up, 75% of patients with unilateral inferior alveolar nerve neurectomy had complete sensory recovery of the lower lip 12 months postoperatively. Patients with younger age, malignant tumors, and preservation of ipsilateral buccal and lingual nerves had a shorter recovery time. The buccal nerve collateral sprouting compensation was observed in the lower lip tissue of Thy1-YFP mice. ApoD was demonstrated to be involved in axon growth and peripheral nerve sensory recovery in the animal model. TGF-ß inhibited the expression of STAT3 and the transcription of ApoD in Schwann cells through Zfp423. Overall, after sacrificing the inferior alveolar nerve, the collateral compensation of the ipsilateral buccal nerve could innervate the sensation. And this process was regulated by TGF-ß-Zfp423-ApoD pathway.

Transforming growth factor-ß signaling: from tumor microenvironment to anticancer therapy.

Transforming growth factor-ß (TGF-ß) signaling is an important pathway for promoting the pathogenesis of inflammatory diseases, including cancer. The roles of TGF-ß signaling are heterogeneous and versatile in cancer development and progression, both anticancer and protumoral actions are reported. Interestingly, increasing evidence suggests that TGF-ß enhances disease progression and drug resistance via immune-modulatory actions in the tumor microenvironment (TME) of solid tumors. A better understanding of its regulatory mechanisms in the TME at the molecular level can facilitate the development of precision medicine to block the protumoral actions of TGF-ß in the TME. Here, the latest information about the regulatory mechanisms and translational research of TGF-ß signaling in the TME for therapeutic development had been summarized.

New insights into fibrotic signaling in renal cell carcinoma.

Fibrotic signaling plays a pivotal role in the development and progression of solid cancers including renal cell carcinoma (RCC). Intratumoral fibrosis (ITF) and pseudo-capsule (PC) fibrosis are significantly correlated to the disease progression of renal cell carcinoma. Targeting classic fibrotic signaling processes such as TGF-ß signaling and epithelial-to-mesenchymal transition (EMT) shows promising antitumor effects both preclinically and clinically. Therefore, a better understanding of the pathogenic mechanisms of fibrotic signaling in renal cell carcinoma at molecular resolution can facilitate the development of precision therapies against solid cancers. In this review, we systematically summarized the latest updates on fibrotic signaling, from clinical correlation and molecular mechanisms to its therapeutic strategies for renal cell carcinoma. Importantly, we examined the reported fibrotic signaling on the human renal cell carcinoma dataset at the transcriptome level with single-cell resolution to assess its translational potential in the clinic.

Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma.

Neutrophils are dynamic with their phenotype and function shaped by the microenvironment, such as the N1 antitumor and N2 pro-tumor states within the tumor microenvironment (TME), but its regulation remains undefined. Here we examine TGF-ß1/Smad3 signaling in tumor-associated neutrophils (TANs) in non-small cell lung carcinoma (NSCLC) patients. Smad3 activation in N2 TANs is negatively correlate with the N1 population and patient survival. In experimental lung carcinoma, TANs switch from a predominant N2 state in wild-type mice to an N1 state in Smad3-KO mice which associate with enhanced neutrophil infiltration and tumor regression. Neutrophil depletion abrogates the N1 anticancer phenotype in Smad3-KO mice, while adoptive transfer of Smad3-KO neutrophils reproduces this protective effect in wild-type mice. Single-cell analysis uncovers a TAN subset showing a mature N1 phenotype in Smad3-KO TME, whereas wild-type TANs mainly retain an immature N2 state due to Smad3. Mechanistically, TME-induced Smad3 target genes related to cell fate determination to preserve the N2 state of TAN. Importantly, genetic deletion and pharmaceutical inhibition of Smad3 enhance the anticancer capacity of neutrophils against NSCLC via promoting their N1 maturation. Thus, our work suggests that Smad3 signaling in neutrophils may represent a therapeutic target for cancer immunotherapy.

Novel TCF21high pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix.

OBJECTIVE: Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. DESIGN: TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21-knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. RESULTS: Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21high TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21high TPCs. CONCLUSION: This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.