Disrupting the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how HSCs sustain their quiescent ...state and avoid type I interferon (IFN)-mediated exhaustion remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly expressed in the nucleus of long-term (LT)-HSCs. Cia-cGAS deficiency in mice caused elevated expression of type I IFNs in bone marrow and led to decreased numbers of dormant LT-HSCs. Under homeostatic conditions, cia-cGAS bound DNA sensor cGAS in the nucleus to block its synthase activity, thereby protecting dormant LT-HSCs from cGAS-mediated exhaustion. Moreover, cia-cGAS harbored a stronger binding affinity to cGAS than self-DNA did and consequently suppressed cGAS-mediated production of type I IFNs in LT-HSCs. Our findings reveal a mechanism by which cia-cGAS inhibits nuclear cGAS by blocking its enzymatic activity and preventing cGAS from recognizing self-DNA to maintain host homeostasis.
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•Cia-cGAS deficiency leads to elevated type I IFNs in LT-HSCs•Cia-cGAS binds to cGAS and inactivates the enzymatic activity of cGAS in LT-HSCs•Cia-cGAS protects dormant HSCs from cGAS-mediated exhaustion•Cia-cGAS is a potent suppressor of cGAS-mediated recognition and autoimmune response
Disrupting the balance between self-renewal and differentiation of HSCs leads to severe pathologic consequences. Xia et al. identify a circular RNA cia-cGAS that is highly expressed in the nucleus of LT-HSCs. Under homeostatic conditions, cia-cGAS binds DNA sensor cGAS to block its synthase activity, protecting dormant LT-HSCs from cGAS-mediated exhaustion.
Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential ...prognostic and therapeutic biomarkers in PRCC2.
A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker.
PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%).
TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.
Objective
Serine palmitoyltransferase, long chain base subunit 1 (SPTLC1) catalyzes the first step in sphingolipid synthesis and has been implicated in the progression of various cancers. However, ...its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we investigated the expression and prognostic value of SPTLC1 in ccRCC.
Methods
Three ccRCC patient cohorts were studied. ccRCC and adjacent normal kidney tissue samples were obtained from 183 patients at the Fudan University Shanghai Cancer Center (FUSCC) and subjected to immunohistochemical staining and quantitative reverse‐transcription polymerase chain reaction to evaluate SPTLC1 protein and messenger RNA (mRNA) expression. Two validation cohorts consisting of mRNA and clinicopathological data sets from patients with ccRCC were obtained from the Cancer Genome Atlas (TCGA, n = 429) and Oncomine (n = 178) databases. Associations between low and high SPTLC1 mRNA and protein expression and survival were evaluated using the Kaplan‐Meier method and log‐rank test. Independent prognostic factors were identified using univariate and multivariate Cox regression analysis.
Results
SPTLC1 mRNA or protein were expressed at significantly lower levels in ccRCC tissues compared with normal kidney tissues in all three patient cohorts (P < .001). Low SPTLC1 expression was significantly associated with shorter overall survival in the FUSCC (P = .041) and Oncomine (P < .001) cohorts, and was significantly associated with shorter overall survival (P < .0001) and progression‐free survival (P < .001) in the TCGA cohort. Bioinformatics analysis identified 10 genes significantly coregulated with SPTLC1 in ccRCC, most of which contributed to sphingomyelin metabolism (SPTLC2, SPTLC3, SPTSSA, SPTSSB, ORMDL1, ORMDL2, ORMDL3, ZDHHC9, GOLGA7B, and KDSR). Functional enrichment analysis predicted that SPTLC1 and its network play significant roles in inflammatory, hypoxia, and interferon gamma responses, and in allograft rejection pathways.
Conclusion
Low SPTLC1 expression is significantly associated with disease progression and poor survival in patients with ccRCC, suggesting that SPTLC1 may function as a tumor suppressor. Thus, SPTLC1 could be a potential new biomarker and/or therapeutic target for ccRCC.
Serine palmitoyltransferase, long chain base subunit 1 (SPTLC1) involves in sphingolipid metabolism pathway and suppresses the progression of various tumors. However, the role of SPTLC1 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aims to identify the expression of SPTLC1 in ccRCC and clarify its prognostic value in patients with ccRCC.
Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) are expressed in a variety of tumors. Activation of the PDGF/PDGFR signaling pathway is associated with cancer proliferation, ...metastasis, invasion, and angiogenesis through modulating multiple downstream pathways, including phosphatidylinositol 3 kinase/protein kinase B pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Therefore, targeting PDGF/PDGFR signaling pathway has been demonstrated to be an effective strategy for cancer therapy, and accordingly, some great progress has been made in this field in the past few decades. This review will focus on the PDGF isoforms and their binding with the related PDGFRs, the PDGF/PDGFR signaling and regulation, and especially present strategies and inhibitors developed for cancer therapy, and the related clinical benefits and side effects.
BackgroundTertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically ...comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated.MethodsImmunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration.ResultsInfiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p<0.001) and overall survival (OS, p=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (p=0.02) and OS (p=0.021). These findings were further validated in an external validation set of 105 patients with ccRCC. Notably, the presence of mature TLS (namely secondary follicle-like TLS, with CD23+ germinal center) was significantly associated with better clinical outcomes in patients with ccRCC. Furthermore, novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC (area under the curve >0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME.ConclusionThis study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.
BackgroundDual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted ...receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented.MethodsPatients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTotally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1–28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension.ConclusionsCamrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination.Trial registration numberNCT03827837.
Tracking the final fate of subducting carbon is crucial to understanding global carbon cycles and climate changes in the history of the Earth. Available geochemical tracers such as carbon isotopes ...are apt to identify recycled organic carbon but usually insufficient to discriminate between primordial carbon in the mantle and carbon derived from recycled carbonate sediments. In the past decade, magnesium and zinc isotope systematics have been proposed as novel proxies for subducting carbon owing to the noticeable isotopic offsets between carbonate sediments and the mantle (i.e., δ26Mgcarbonate < δ26Mgmantle; δ66Zncarbonate > δ66Znmantle). Nonetheless, isotopic effects induced by subduction-zone processes and crystal-melt differentiation may obscure the information of Mg and Zn isotopic compositions of mantle-derived magmas. In this paper we firstly discuss how these processes modify the Mg and Zn isotopic systematics of mantle-derived magmas. Based on the fact that different carbonate species (calcite, dolomite, and magnesite) possess distinct Mg and Zn contents and their stabilities in subduction zones vary with pressure, we then develop the two isotope systematics as tools to track the final storage depth of subducting carbon. We test this application by collating available Mg and Zn isotopic compositions of ultramafic xenoliths and basaltic lavas sourced from various mantle depths. The lack of light Mg and heavy Zn isotopic anomalies of global arc lavas supports experimental and theoretical prediction that the dissolved carbonate species in the sub-arc mantle−if any−is dominated by calcium-rich carbonate. The findings of pervasive low-δ26Mg and high-δ66Zn ultramafic xenoliths and basaltic lavas sourced from the sub-continental lithospheric mantle (SCLM) suggest that the SCLM is an important storage of subducting carbon via metasomatism by dolomite that can be substantially dissolved by supercritical fluids at depths of >160 km. Intraplate alkali basalts with low δ26Mg and high δ66Zn are commonly restricted to the regions with stagnant slabs at depths of ~410–660 km, suggesting that the mantle transition zone is another global storage of subducting carbon composed mainly of Mg-rich carbonates. Overall, observations on mantle-derived rocks, with Mg and Zn isotopes as the tracers, indicate that a significant flux of Earth's surface carbon has survived the arc regime and been recycled into the deeper mantle. Future studies that explore a quantitative relationship between Mg-Zn isotopic ratios and the flux of subducting carbon will further promote the application of the paired isotopic proxies.
•Factors obscuring the interpretation of Mg and Zn isotopic data of mantle-derived rocks or magmas were reviewed.•Developing Mg and Zn isotopes as novel proxies for the storage depths of subducting carbonates in the mantle.•Test this application using available Mg and Zn isotope data of natural samples from various mantle depths.•A significant flux of Earth's surface carbon have survived the arc regime and been recycled into the deeper mantle.
Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples ...and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease‐free survival (DFS) and overall survival (OS). Kaplan‐Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein‐protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.
Increasing findings suggest that eukaryotic Rad50 may serve a vital role in homologous recombinational repair of DNA damage, while the prognostic value of Rad50 in prostate cancer (PCa) remained unclear. This study reveals that elevated Rad50 expression is significantly correlated with cancer progression and poor survival in patients with PCa. These data suggest that Rad50 may act as an oncoprotein and a promising prognostic marker for patients with PCa.
An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration ...of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-β1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-β1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation.
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•ILCregs exist in mouse and human intestines•ILCregs contribute to the resolution of innate intestinal inflammation•ILCregs suppress the activation of ILC1s and ILC3s via secretion of IL-10•Autocrine TGF-β1 is required for the expansion of ILCregs during inflammation
A subpopulation of innate lymphoid cells, called ILCregs, are found to have a regulatory role in intestinal homeostasis and innate immune defenses akin to Treg cells.
Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many ...immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients.
A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes.
Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways.
Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.
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