Human males absent on the first (hMOF), a human ortholog of the Drosophila MOF protein, is responsible for histone H4 lysine 16 (H4K16) acetylation in human cells. The depletion of hMOF leads to a global reduction in histone H4K16 acetylation in human cells, genomic instability, cell cycle defects, reduced transcription of certain genes, defective DNA damage repair and early embryonic lethality. Studies have shown that abnormal hMOF gene expression is involved in a number of primary cancers. The present study examined the involvement of hMOF expression and histone H4K16 acetylation in clinically diagnosed primary ovarian cancer tissues. Clinically diagnosed frozen primary ovarian cancer tissues were used for polymerase chain reaction (PCR), quantitative PCR (qPCR), western blotting and immunohistochemical staining approaches. A PCR analysis of mRNA expression in 47 samples revealed a downregulation of hMOF mRNA in 81% of patients, whereas only 13% of patients demonstrated upregulation. qPCR was used to validate the frequent downregulation of hMOF expression in the primary ovarian cancer tissues. As expected, the analysis of hMOF expression in 57 samples revealed that hMOF mRNA expression was significantly downregulated (>2-fold decrease) in 65% of patients, while a <2-fold reduction of hMOF was observed in 10.5% of patients. Furthermore, the expression of hMOF-regulated human leukocyte antigen (HLA) complex 5, (HCP5), was also found to be downregulated in >87% of patients with a decrease in hMOF. hMOF and its regulated gene, HCP5, are frequently downregulated in human ovarian cancer, suggesting that hMOF may be involved in the pathogenesis of the disease.

Renal fibrosis, a pathological hallmark of chronic kidney disease (CKD), is associated with dysregulated lipid metabolism, leading to ectopic lipid deposition and tubular lipotoxicity. This highlights the importance of lipophagy, a selective autophagic process that clears lipid droplets. Fucoidan (FPS), a sulfated polysaccharide, has demonstrated renoprotective potential, but whether it alleviates renal fibrosis by restoring lipophagy remains unclear. We investigated this hypothesis using an adenine/Western diet-induced CKD mouse model (FPS, 100 or 200 mg·kg-1·d-1) and TGF-β1/palmitic acid-stimulated HK-2 cells (FPS, 100-400 μg/mL). FPS improved renal function, ameliorated systemic and intrarenal lipid metabolic disturbances, reduced renal lipid deposition, and attenuated tubular injury and interstitial fibrosis. Mechanistically, FPS restored lipophagy-related processes, with increased Beclin1/Atg5/LC3-II and Rab7, reduced p62 accumulation, enhanced ATGL-LC3 and LD-autophagosome/lysosome co-localization, and improved GFP-mRFP-LC3 autophagic flux, accompanied by reduced LD burden. These effects were similar to those of AdipoRon and were attenuated by chloroquine, indicating sensitivity to lysosome-dependent degradation. FPS enhanced fatty acid oxidation and mitochondrial homeostasis. At the signaling level, FPS was associated with SIRT1 upregulation, FoxO1 deacetylation, and ATGL induction, while ATGL silencing diminished improvements in lipophagy-related processes, LD clearance, fatty acid oxidation, and fibrotic phenotypes. As a translational supplement, public CKD datasets with a type 2 diabetes mellitus and diabetic kidney disease (DKD) cohort supported ATGL downregulation and its association with renal dysfunction and lipid abnormalities. Moreover, serum ATGL showed moderate DKD discrimination (AUC 0.789, 95% CI 0.716-0.863). Collectively, these findings support a mechanistic link between FPS-responsive SIRT1/FoxO1/ATGL-associated lipophagy regulation and the attenuation of CKD-associated fibrosis.

AR pathway-independent prostate cancer (ARIPC), particularly neuroendocrine prostate cancer (NEPC), represents one of the most lethal states of metastatic castration-resistant prostate cancer. However, how fatty acid synthesis (FAS) is organized in ARIPC and whether distinct lipogenic states shape neuroendocrine lineage transdifferentiation remain unclear. By integrating single-cell and bulk transcriptomic analyses of mCRPC cohorts, we identify NEPC as a fatty-acid-synthesis-low state associated with poor survival. Within this context, fatty acid synthase (FASN) emerges as a key indicator and functional contributor to lipogenic activity. FASN depletion suppresses lipogenesis while increasing NEPC-associated programs, migration, and metastatic colonization. We further identify FGFRL1 as the FGF family member most consistently associated with fatty acid synthesis activity in ARIPC. FGFRL1 depletion reduces FASN expression and relative free fatty-acid content, while targeted GC-MS supports broader fatty-acid remodeling and fluorescent uptake assays show increased exogenous fatty-acid uptake. FASN restoration partially restores relative free fatty-acid content and attenuates NEPC-associated and migratory phenotypes. Directional perturbation, rescue, AKT phosphorylation, and co-immunoprecipitation analyses further support the functional FGFRL1-FASN relationship. ONECUT2 is prioritized as a candidate downstream transcriptional regulator whose expression correlates with the neuroendocrine program. Together, these findings support an FGFRL1-FASN metabolic axis that regulates neuroendocrine lineage transdifferentiation and metastatic progression in ARIPC.

Enveloped virus invasion relies on spike glycoprotein-mediated membrane fusion. Cholesterol that serves crucial roles in modulating protein conformations and membrane properties, plays an essential role in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry. However, the precise regulatory mechanism of cholesterol in SARS-CoV-2 fusion remains unknown. Here, using an in vitro vesicle-vesicle content mixing assay, we demonstrated that the addition of cholesterol enhanced SARS-CoV-2 spike-mediated vesicle-vesicle fusion, with this enhancement being dependent on the C-terminal cytoplasmic domain of spike. Further single-vesicle analyses demonstrate this enhancement primarily stems from increased docking probability, with cholesterol exerting mild effect on fusion probabilities. In the cell-based membrane fusion assay, cholesterol depletion from spike containing membrane significantly reduces syncytia formation and SARS-CoV-2 pseudovirus infection, indicating its modulatory role in this process. Using structured illumination microscopy (SIM) based super-resolution imaging and single-molecule photobleaching microscopy, we demonstrated that spike proteins tended to form into an oligomeric cluster in the presence of cholesterol, likely through the interaction between cholesterol and palmitoylated cysteine rich region (CRR) in the C-terminus of spike. Last, substitution of residues of CRR with alanine in the C-terminus of spike abolished both the cholesterol-induced spike clustering and the cholesterol-dependent enhancement of vesicle docking. Taken together, our results suggest that cholesterol may induce the oligomerization of spike through specific interactions with its CRR, with this structural clustering critically mediating viral docking to host cell membranes, thereby promoting the subsequent membrane fusion and viral entry processes.

Background:Olaparib has demonstrated therapeutic potential in treating metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations, especially BRCA2. However, resistance to PARP inhibition remains a significant clinical hurdle. Recent evidence suggests frequent activation of fibroblast growth factor receptor 1 (FGFR1) signaling in mCRPC, yet its impact on DNA repair regulation is poorly understood. This study aimed to investigate whether FGFR1 signaling modulates BRCA2 expression and contributes to PARP inhibitor resistance. Methods:We performed integrative transcriptomic analyses of multiple mCRPC datasets to examine the correlation between FGFR1 and BRCA2 expression. Functional assays including genetic knockdown, pharmacological inhibition, and overexpression studies were conducted in DU145 and PC3 cells. In vitro and in vivo models were employed to evaluate the impact of FGFR1 modulation on olaparib sensitivity, apoptosis, and proliferation. Gene set enrichment analysis (GSEA) was used to identify FGFR1-associated pathways. Western blotting and pathway inhibition experiments were used to dissect the underlying mechanism. Results:In this study, integrative transcriptomic analyses of multiple mCRPC datasets revealed a strong positive correlation between FGFR1 and BRCA2 expression. Functional assays in DU145 cells, which exhibit high FGFR1 and BRCA2 levels, demonstrated that genetic knockdown or pharmacological inhibition of FGFR1 (via PD173074) markedly reduced BRCA2 expression. FGFR1 inhibition significantly enhanced olaparib sensitivity by promoting apoptosis and suppressing cell proliferation both in vitro and in vivo. Gene set enrichment analyses stratified by BRCA2 levels converged on MAPK as the predominant FGFR1-downstream pathway linked to BRCA2. Mechanistically, FGFR1 functions as an upstream regulator of BRCA2, contributing to sustained HRR activity and attenuated response to PARP inhibition. Complementarily, transient FGFR1 overexpression in PC3 elevated phosphorylated-ERK and BRCA2, whereas MAPK inhibition blunted phosphorylated-ERK and attenuated BRCA2 induction, supporting an FGFR1-MAPK/ERK-BRCA2 axis. Conclusions:Together, these data reveal an FGFR1-driven, MAPK-dependent mechanism that sustains BRCA2 and attenuates PARP-inhibitor activity, nominate FGFR1 status as a candidate biomarker of PARP-inhibitor responsiveness, and support biomarker-guided co-targeting of FGFR1 and PARP in BRCA2-dependent mCRPC.

SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi–Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.

Coronaviruses employ various strategies for survival, among which the activation of endogenous or exogenous apoptosis stands out, with viral proteins playing a pivotal role. Notably, highly pathogenic coronaviruses such as SARS-CoV-2, SARS-CoV, and MERS-CoV exhibit a greater array of non-structural proteins compared to low-pathogenic strains, facilitating their ability to induce apoptosis via multiple pathways. Moreover, these viral proteins are adept at dampening host immune responses, thereby bolstering viral replication and persistence. This review delves into the intricate interplay between highly pathogenic coronaviruses and apoptosis, systematically elucidating the molecular mechanisms underpinning apoptosis induction by viral proteins. Furthermore, it explores the potential therapeutic avenues stemming from apoptosis inhibition as antiviral agents and the utilization of apoptosis-inducing viral proteins as therapeutic modalities. These insights not only shed light on viral pathogenesis but also offer novel perspectives for cancer therapy.

Stimulatorof interferon genes (STING) is an intracellular sensor of cyclic dinucleotides involved in the innate immune response against pathogen- or self-derived DNA. For years, interferon (IFN) induction of cyclic GMP-AMP synthase (cGAS)-STING has been considered as a canonical pattern defending the host from viral invasion. The mechanism of the cGAS-STING-IFN pathway has been well-illustrated. However, other signalling cascades driven by cGAS-STING have emerged in recent years and some of them have been found to possess antiviral ability independent of IFN. Here, we summarize the current progress on cGAS-STING-mediated nonclassic antiviral activities with an emphasis on the nuclear factor-kappa B and autophagy pathways, which are the most-studied pathways. In addition, we briefly present the primordial function of the cGAS-STING pathway in primitive species to show the importance of IFN-unrelated antiviral activity from an evolutionary angle. Finally, we discuss open questions that need to be solved for further exploitation of this field.

Abstract Background Dysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC). Methods Multiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored. Results A novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P < 0.0001). The prognostic model’s accuracy was additionally confirmed by employing time-dependent Receiver Operating Characteristic (ROC) curves and conducting Decision Curve Analysis (DCA). High-risk patients were found to correlate with advanced clinical stages, specific tumor microenvironment subtypes, and distinct morphologies. ESTIMATE analysis demonstrated a significant inverse relationship between increased immune, stromal, and ESTIMATE scores and lowered risk score. Immune analysis indicated a negative correlation between high-risk score and the abundance of most tumor-infiltrating immune cells, including dendritic cells, CD8+ T cells, CD4+ T cells, and B cells. This correlation extended to immune checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, and BTLA. The protein expression patterns of selected genes in clinical NPC samples were validated through immunohistochemistry. Conclusion This study presents a prognostic model utilizing IMRGs in NPC, which could assist in assessing patient prognosis and provide insights into new therapeutic targets for NPC.

Cellular infections by DNA viruses trigger innate immune responses mediated by DNA sensors. The cyclic GMP–AMP synthase (cGAS)‐stimulator of interferon gene (STING) signaling pathway has been identified as a DNA‐sensing pathway that activates interferons in response to viral infection and, thus, mediates host defense against viruses. Previous studies have identified oncogenes E7 and E1A of the DNA tumor viruses, human papillomavirus 18 (HPV18) and adenovirus, respectively, as inhibitors of the cGAS‐STING pathway. However, the function of STING in infected cells and the mechanism by which HPV18 E7 antagonizes STING‐induced Interferon beta production remain unknown. We report that HPV18 E7 selectively antagonizes STING‐triggered nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) activation but not IRF3 activation. HPV18 E7 binds to STING in a region critical for NF‐κB activation and blocks the nuclear accumulation of p65. Moreover, E7 inhibition of STING‐triggered NF‐κB activation is related to HPV pathogenicity but not E7–Rb binding. HPV18 E7, severe acute respiratory syndrome coronavirus‐2 open reading frame 3a, human immunodeficiency virus‐2 viral protein X, and Kaposi's sarcoma‐associated herpesvirus KSHV viral interferon regulatory factor 1 selectively inhibited STING‐triggered NF‐κB or IRF3 activation, suggesting a convergent evolution among these viruses toward antagonizing host innate immunity. Collectively, selective suppression of the cGAS‐STING pathway by viral proteins is likely to be a key pathogenic determinant, making it a promising target for treating oncogenic virus‐induced tumor diseases.

Recognizing aberrant cytoplasmic double‐stranded DNA and stimulating innate immunity is essential for the host's defense against viruses and tumors. Cyclic GMP–AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that synthesizes the second messenger 2′3′‐cGAMP and subsequently activates stimulator of interferon genes (STING)‐mediated activation of TANK‐binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and the production of type I interferon (IFN‐I). Both the cGAS–STING‐mediated IFN‐I antiviral defense and the countermeasures developed by diverse viruses have been extensively studied. However, recent studies have revealed a convergent evolutionary feature of severe acute respiratory syndrome coronavirus 2 and human immunodeficiency virus (HIV) viral proteins in terms of the selective regulation of cGAS–STING‐mediated nuclear factor‐κB (NF‐κB) signaling without any effect on cGAS–STING‐mediated TBK1/IRF3 activation and IFN production. The potential beneficial effect of this cGAS–STING‐mediated, NF‐κB‐dependent antiviral effect, and the possible detrimental effect of IFN‐I in the pathogenesis of coronavirus disease 2019 and HIV infection deserve more attention and future investigation.

Substantial improvement in prognosis among metastatic renal cell carcinoma (mRCC) patients has been achieved, owing to the rapid development and utilization of immunotherapy. In particular, immune checkpoint inhibitors (ICIs) have been considered the backbone of systemic therapy for patients with mRCC alongside multi-targeted tyrosine kinase inhibitors (TKIs) in the latest clinical practice guidelines. However, controversies and challenges in optimal individualized treatment regarding immunotherapy remains still About 2/3 of the patients presented non-response or acquired resistance to ICIs. Besides, immune-related toxicities, namely immune-related adverse events, are still elusive and life-threatening. Thus, reliable biomarkers to predict immunotherapeutic outcomes for mRCC patients are needed urgently. Tumor microenvironment (TME), consisting of immune cells, vasculature, signaling molecules, and extracellular matrix and regulates tumor immune surveillance and immunological evasion through complex interplay, plays a critical role in tumor immune escape and consequently manipulates the efficacy of immunotherapy. Various studied have identified the different TME components are significantly associated with the outcome of mRCC patients receiving immunotherapy, making them potential valuable biomarkers in therapeutic guidance. The present review aims to summarize the latest evidence on the associations between the components of TME including immune cells, cytokines and extracellular matrix, and the therapeutic responses among mRCC patients with ICI-based treatment. We further discuss the feasibility and limitation of these components as biomarkers.

Innate immunity represents one of the main host responses to viral infection.1-3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.

Cancer cells, including those of prostate cancer (PCa), often hijack intrinsic cell signaling to reprogram their metabolism. Part of this reprogramming includes the activation of de novo synthesis of fatty acids that not only serve as building blocks for membrane synthesis but also as energy sources for cell proliferation. However, how de novo fatty acid synthesis contributes to PCa progression is still poorly understood. Herein, by mining public datasets, we discovered that the expression of acetyl-CoA carboxylase alpha (ACACA), which encodes acetyl-CoA carboxylase 1 (ACC1), was highly expressed in human PCa. In addition, patients with high ACACA expression had a short disease-free survival time. We also reported that depletion of ACACA reduced de novo fatty acid synthesis and PI3K/AKT signaling in the human castration-resistant PCa (CRPC) cell lines DU145 and PC3. Furthermore, depletion of ACACA downregulates mitochondrial beta-oxidation, resulting in mitochondrial dysfunction, a reduction in ATP production, an imbalanced NADP+/NADPhydrogen(H) ratio, increased reactive oxygen species, and therefore apoptosis. Reduced exogenous fatty acids by depleting lipid or lowering serum supplementation exacerbated both shRNA depletion and pharmacological inhibition of ACACA-induced apoptosis in vitro. Collectively, our results suggest that inhibition of ectopic ACACA, together with suppression of exogenous fatty acid uptake, can be a novel strategy for treating currently incurable CRPC.

Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS-STING-mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS-CoV-2 infection, responsible for the COVID-19 pandemic, triggers cGAS-STING activation. cGAS-STING activation can trigger IRF3-Type I interferon (IFN) and autophagy-mediated antiviral activity. Although viral evasion of STING-triggered IFN-mediated antiviral function has been well studied, studies concerning viral evasion of STING-triggered autophagy-mediated antiviral function are scarce. In the present study, we have discovered that SARS-CoV-2 ORF3a is a unique viral protein that can interact with STING and disrupt the STING-LC3 interaction, thus blocking cGAS-STING-induced autophagy but not IRF3-Type I IFN induction. This novel function of ORF3a, distinct from targeting autophagosome-lysosome fusion, is a selective inhibition of STING-triggered autophagy to facilitate viral replication. We have also found that activation of bat STING can induce autophagy and antiviral activity despite its defect in IFN induction. Furthermore, ORF3a from bat coronaviruses can block bat STING-triggered autophagy and antiviral function. Interestingly, the ability to inhibit STING-induced autophagy appears to be an acquired function of SARS-CoV-2 ORF3a, since SARS-CoV ORF3a lacks this function. Taken together, these discoveries identify ORF3a as a potential target for intervention against COVID-19.

Immune infiltration in Prostate Cancer (PCa) was reported to be strongly associated with clinical outcomes. However, previous research could not elucidate the diversity of different immune cell types that contribute to the functioning of the immune response system. In the present study, the CIBERSORT method was employed to evaluate the relative proportions of immune cell profiling in PCa samples, adjacent tumor samples and normal samples. Three types of molecular classification were identified in tumor samples using the 'CancerSubtypes' package of the R software. Each subtype had specific molecular and clinical characteristics. In addition, functional enrichment was analyzed in each subtype. The submap and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were also used to predict clinical response to the immune checkpoint blockade. Moreover, the Genomics of Drug Sensitivity in Cancer (GDSC) database was employed to screen for potential chemotherapeutic targets for the treatment of PCa. The results showed that Cluster I was associated with advanced PCa and was more likely to respond to immunotherapy. The findings demonstrated that differences in immune responses may be important drivers of PCa progression and response to treatment. Therefore, this comprehensive assessment of the 22 immune cell types in the PCa Tumor Environment (TEM) provides insights on the mechanisms of tumor response to immunotherapy and may help clinicians explore the development of new drugs.

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

Background Growing evidence demonstrated that dietary protein intake may be a risk factor for prostate cancer and elevate the level of prostate-specific antigen (PSA). However, proof for the correlation between dietary protein intake and PSA in American adults without prostate tumor history is limited. Our goal was to investigate the association of dietary protein intake with PSA using the National Health and Nutrition Examination Survey (NHANES) (2003–2010) database. Methods After the screening, 6403 participants were included in the study. The interested independent is the dietary protein intake, and the dependent variable is PSA levels, the covariates included demographic, dietary, biological data, and physical examination variables. A weighted linear model and a weighted linear regression model were used to examine the distribution of variables in the covariate differences between the different independent groups according to quartiles. Four models were used to survey the association between dietary protein intake and PSA. We also attempted to find a nonlinear relationship between dietary protein intake and PSA using the GAM model and the penalty spline method and further solved the nonlinear problem using weighted two-piecewise linear model. Results The weighted multivariate linear regression analysis demonstrated that dietary protein intake was not independently associated with PSA levels after adjusting potential confounders (β = 0.015, 95%CI:-0.024, 0.055). However, we found the non-linear relationship between dietary protein intake and PSA, whose point was 18.18 g (per 10 g change). The magnitude and confidence intervals for the left and right inflection points are − 0.03 (− 0.09, 0.02) and 0.22 (0.07, 0.36), respectively. On the right side of the inflection point, one gram of increment in protein intake was associated with increased PSA levels by 0.22 (log2 transformation: 0.22, 95%CI: 0.07, 0.36). Conclusions After adjusting for potential covariates, the non-linear correlation between dietary protein intake and PSA was observed. When dietary protein intake exceeded the threshold of 181.8 g, dietary protein intake was positively correlated with elevated PSA levels.

BACKGROUND AND OBJECTIVES:Previous study has reported phosphorus intake is associated prostate cancer (PCa), but the association between phosphorus intake and serum prostate specific antigen (PSA) levels hasn't been reported in non-history of PCa population. Therefore, we performed a secondary data analysis based on existing data from the public Nutrition Examination Survey (NHANES) (2003-2010) database.METHODS AND STUDY DESIGN:Totally 6403 participants were selected from NHANES (2003-2010) database. The interested independent and dependent variables were considered as dietary phosphorus intake and PSA level, respectively. Covariates included demographic data, dietary data, physical examination data, and comorbidities. Weighted linear regression and generalized additive models were used to addressing the linear and non-linear link of phosphorus intake to PSA level.RESULTS:Linear association between phosphorus intake and PSA was not detected [β=0.016 (95% Confidence Interval (CI) -0.012, 0.045)]. But we found an existing nonlinearity. By the recursive algorithm, the inflection point was 1151 mg. On the left side of the inflection point, we did not find the correlation between dietary phosphorus intake (per 100 change) and PSA level [β=-0.04 (95% CI -0.11, 0.02), p=0.2155], while dietary phosphorus intake (per 100 change) positively associated with PSA [β=0.05 (95% CI 0.01, 0.09) p=0.0293] on the right side of inflection point.CONCLUSIONS:There is a non-linear correlation between dietary phosphorus intake and PSA. Dietary phosphorus intake was positively associated with increased PSA when dietary phosphorus intake is beyond 1151 mg after adjusting other covariates. Over 1151 mg per day dietary phosphorus intake may be the risk factor for PSA increasing.

Background: Immune infiltration of head and neck cancer (HNC) highly correlated with the patient's prognosis. However, previous studies failed to explain the diversity of different cell types that make up the function of the immune response system. The aim of the study was to uncover the differences in immune phenotypes of the tumor microenvironment (TME) between HNC adjacent tumor tissues and tumor tissues using CIBERSORT method and explore their therapeutic implications. Method: In current work, we employed the CIBERSORT method to evaluate the relative proportions of immune cell profiling in 11 paired HNC and adjacent samples, and analyzed the correlation between immune cell infiltration and clinical information. The tumor-infiltrating immune cells of TCGA HNC cohort was analyzed for the first time. The fractions of LM22 immune cells were imputed to determine the correlation between each immune cell subpopulation and survival and response to chemotherapy. Three types of molecular classification were identified via “CancerSubtypes” R-package. The functional enrichment was analyzed in each subtype. Results: The profiles of immune infiltration in TCGA HNC cohort significantly vary between paired cancer and para-cancerous tissue and the variation could reflect the individual difference. Total Macrophage, Macrophages M0 and NK cells resting were elevated in HNC tissues, while total T cells, total B cells, T cells CD8, B cell navie, T cell follicular helper, NK cells activated, Monocyte and Mast cells resting were decreased when compared to paracancerous tissues. Among each cell immune subtype, T cells regulatory Tregs, B cells naïve, T cells follicular helper, and T cells CD4 memory activated was significantly associated with HNC survival. Three clusters were observed via Cancer Subtypes R-package. Each cancer subtype has a specific molecular classification and subtype-specific immune cell characterization. Conclusions: Our data suggest a difference in immune response may be an important driver of HNC progression and response to treatment. The deconvolution algorithm of gene expression microarray data by CIBERSOFT provides useful information about the immune cell composition of HNC patients.