PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

DAB2IP inhibits glucose uptake by modulating HIF-1α ubiquitination under hypoxia in breast cancer.

Metabolic reprogramming has become increasingly important in tumor biology research. The glucose metabolic pathway is a major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor that acts as a scaffold protein to suppress tumor malignancy in breast cancer. Interestingly, DAB2IP has also been found to be a potential regulator of glucose uptake; however, the exact mechanism remains unclear. In this study, we found that DAB2IP inhibited glucose uptake under hypoxia conditions in breast cancer cells by suppressing HIF-1α signals. Mechanically, DAB2IP interacted with the E3 ubiquitin ligase STUB1 via its PER domain, thus triggering STUB1 mediated HIF-1α ubiquitylation and degradation, and inhibit glucose metabolism and tumor progression. Deleting the PER domain abrogated the DAB2IP-related inhibitory effects on glucose uptake, intracellular ATP production, and lactic acid production in breast cancer cells. These findings elucidate the biological roles of DAB2IP in cancer-related glucose metabolism as well as a novel mechanism by which STUB1-driven HIF-1α ubiquitylated degradation is regulated in breast cancer.

Impact of Memory T Cells on SARS-COV-2 Vaccine Response in Hematopoietic Stem Cell Transplant.

During the COVID-19 pandemic, hematopoietic stem cell transplant (HSCT) recipients faced an elevated mortality rate from SARS-CoV-2 infection, ranging between 10-40%. The SARS-CoV-2 mRNA vaccines are important tools in preventing severe disease, yet their efficacy in the post-transplant setting remains unclear, especially in patients subjected to myeloablative chemotherapy and immunosuppression. We evaluated the humoral and adaptive immune responses to the SARS-CoV-2 mRNA vaccination series in 42 HSCT recipients and 5 healthy controls. Peripheral blood mononuclear nuclear cells and serum were prospectively collected before and after each dose of the SARS-CoV-2 vaccine. Post-vaccination responses were assessed by measuring anti-spike IgG and nucleocapsid titers, and antigen specific T cell activity, before and after vaccination. In order to examine mechanisms behind a lack of response, pre-and post-vaccine samples were selected based on humoral and cellular responses for single-cell RNA sequencing with TCR and BCR sequencing. Our observations revealed that while all participants eventually mounted a humoral response, transplant recipients had defects in memory T cell populations that were associated with an absence of T cell response, some of which could be detected pre-vaccination.

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

Combination of Chest Computed Tomography Value and Clinical Laboratory Data for the Prognostic Risk Evaluation of Patients with COVID-19.

Objective: This study aims to investigate the independent prognostic factors of patients with coronavirus disease 2019 (COVID-19) and thereafter construct a related prognostic model. Methods: The subjects were screened following the COVID-19 diagnostic criteria. The independent prognostic factors were selected based on the indicators, including medical history, clinical manifestation, laboratory tests, imaging examination and clinical prognosis. Subsequently, we constructed a nomogram model to predict short-term prognosis. Results: Clinical information was obtained from 393 COVID-19 patients admitted to Zhongshan Hospital at Xiamen University between December 2022 and January 2023. The independent risk factors determined by Cox multivariate regression analysis included gender (OR: 0.355, 95% CI: 0.16~0.745), age (OR: 3.938, 95% CI: 1.221~15.9), pectoral muscle index (PMI, OR: 4.985, 95% CI: 2.336~11.443), pneumonia severity score (PSS, OR: 6.486, 95% CI: 2.082~21.416) and lactate dehydrogenase (LDH, OR: 3.857, 95% CI: 1.571~10.266). A short-term prognostic nomogram was developed based on the five independent risk factors above. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram model was 0.857. The calibration curve confirmed the outcomes of the prognostic model, which exhibited excellent consistency with the actual results. Conclusion: In summary, gender, age, pectoral muscle index, pneumonia severity score, and lactate dehydrogenase are all independent risk factors for COVID-19 mortality. Thus, the nomogram based on the above indicators can predict the risk of mortality in COVID-19 patients. This may have the potential of being clinical application in prognostic evaluation of COVID-19.

Toxicities associated with immune checkpoint inhibitors: a systematic study.

BACKGROUND: Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)-related toxicities, is estimated to be between 0.3 and 1.3%. OBJECTIVE: This systematic review aimed to investigate cancer patients' susceptibility to toxicities associated with PD-1/PD-L1 inhibitors and establish a clinically relevant landscape of side effects of PD-1/PD-L1 inhibitors. DATA SOURCES: Relevant publications from PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) between 2014 and 2019. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We searched randomized controlled trials (RCTs) reporting treatment-related toxicities associated with PD-1 and PD-L1 inhibitors in the treatment of cancers. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. A total of 29 RCTs, incorporating 8576 patients, met the eligibility criteria. STUDY APPRAISAL AND SYNTHESIS METHODS: We calculated the pooled relative risks and corresponding 95% CIs using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on cancer type, toxicity grade (severity), system and organ, treatment regimens in the intervention arm and the control arm, PD-1/PD-L1 inhibitor drug type, and cancer type. RESULTS: A total of 11 categories (e.g. endocrine toxicity), and 39 toxicity types (e.g. hyperthyroidism) were identified. For toxicities at any grade, those treated with PD-1/PD-L1 inhibitors were at lower risks for gastrointestinal toxicity, hematologic toxicity, and treatment event leading to discontinuation; and were at higher risks for respiratory toxicity (all P <0.05). Those treated with PD-1/PD-L1 inhibitors were at lower risks for fatigue, asthenia, and peripheral edema and were at higher risks for pyrexia, cough, dyspnea, pneumonitis, and pruritus. LIMITATIONS: The present research is a meta-analysis at the study level rather than at the patient level; insights on risk factors associated with the development of toxicities cannot be found in our study. There was a possible overlap in Common Terminology Criteria for Adverse Events (CTCAE) definitions which prevents understanding the true rates of specific toxicities. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations. SYSTEMATIC REVIEW REGISTRATION NUMBER: We registered the research protocol with PROSPERO (registration number CRD42019135113).

Comparison of GLIM and PG-SGA for predicting clinical outcomes of patients with esophageal squamous carcinoma resection.

Introduction: Objective: to determine the validity of the Global Leadership Initiative on Malnutrition (GLIM) against the Patient Generated-Subjective Global Assessment (PG-SGA) as a gold standard tool in malnutrition diagnosis, and to assess the impact of malnutrition diagnosed using GLIM and PG-SGA on the clinical outcomes of patients with esophageal squamous carcinoma (ESCC) resection. Methods: we prospectively analyzed 182 patients with ESCC who underwent radical esophagectomy. Preoperative malnutrition was diagnosed using GLIM and PG-SGA, and the postoperative clinical outcomes, including postoperative complications, postoperative chest tube indwelling time, length of stay and total hospitalization cost, were recorded. The association between the prevalence of malnutrition defined by the two tools and postoperative clinical outcomes was evaluated. Results: among the 182 ESCC patients, the incidence of malnutrition before surgery was 58.2 % and 48.4 % defined by PG-SGA and GLIM, respectively. GLIM and PG-SGA had good consistency in nutritional assessment of ESCC patients (k = 0.628, p < 0.001). Malnourished patients had higher TNM stages and older ages (all p < 0.05). Patients with malnutrition as assessed by PG-SGA and GLIM had a higher incidence of postoperative complications, a longer indwelling time of chest tube after esophagectomy, longer hospital length of stay, and higher hospitalization costs than patients with good nutrition (p < 0.001). Comparing the predictive efficiency of postoperative complications, the sensitivity of PG-SGA- and GLIM-defined malnutrition were 81.6 % and 79.6 %, the specificity were 50.4 % and 63.2 %, the Youden index were 0.320 and 0.428, and the Kappa value were 0.110 and 0.130, respectively. The areas under ROC curve of PG-SGA- and GLIM-defined malnutrition and postoperative complications were 0.660 and 0.714, respectively. Conclusions: this study indicates the effectiveness of malnutrition diagnosed according to GLIM and PG-SGA in predicting postoperative clinical outcomes among patients with ESCC. Compared with PG-SGA, GLIM criteria can better predict postoperative complications of ESCC. Follow-up analysis of postoperative long-term survival is needed to explore the association between different assessment tools and postoperative long-term clinical outcomes.

Introducción: Objetivo: determinar la validez de la iniciativa de Liderazgo Global sobre la Malnutrición (GLIM) frente a la Evaluación Global Subjetiva Generada por el Paciente (PG-SGA) como herramienta de referencia en el diagnóstico de la malnutrición y evaluar el impacto de la malnutrición diagnosticada usando GLIM y PG-SGA en los resultados clínicos de los pacientes con resección de carcinoma escamoso de esófago (CEE). Métodos: se analizaron prospectivamente 182 pacientes con CEE sometidos a esofagectomía radical. La desnutrición preoperatoria se diagnosticó utilizando GLIM y PG-SGA, y se registraron los resultados clínicos posoperatorios, incluyendo complicaciones posoperatorias, tiempo de permanencia del tubo torácico, posoperatorio, duración de la estancia y coste total de hospital. Se evaluó la asociación entre la prevalencia de desnutrición definida por las dos herramientas y los resultados clínicos postoperatorios. Resultados: entre 182 pacientes con CEE, la incidencia de desnutrición antes de la cirugía fue del 58,2 % y 48,4 % definida por PG-SGA y GLIM, respectivamente. GLIM y PG-SGA tuvieron buena consistencia en la evaluación nutricional de los pacientes con CEE (k = 0,628, p < 0,001). Los pacientes desnutridos presentaron estadios TNM más altos y edades mayores (todos p < 0,05). Los pacientes con desnutrición evaluada por PG-SGA y GLIM tuvieron una mayor incidencia de complicaciones posoperatorias, mayor tiempo de permanencia del tubo torácico después de la esofagectomía, mayor tiempo de hospitalización y mayores costos de hospitalización que los pacientes con buena nutrición (p < 0,001). Comparando la eficacia predictiva de las complicaciones posoperatorias, la sensibilidad de la desnutrición definida por PG-SGA y GPG fue del 81,6 % y 79,6 %; la especificidad, del 50,4 % y 63,2 %; el índice de Youden, del 0,320 y 0,428; y el valor de Kappa, de 0,110 y 0,130, respectivamente. Las áreas bajo la curva de ROC de la malnutrición definida por PG-SGA y GPG y las complicaciones postoperatorio fueron 0,660 y 0,714, respectivamente. Conclusiones: este estudio indica la eficacia de la desnutrición diagnosticada según GLIM y PG-SGA en la predicción de los resultados clínicos postoperatorios en pacientes con CEE. En comparación con PG-SGA, los criterios GLIM pueden predecir mejor las complicaciones posoperatorias del CEE. Es necesario realizar un análisis de seguimiento de la supervivencia posoperatoria a largo plazo para explorar la asociación entre las diferentes herramientas de evaluación y los resultados clínicos posoperatorios a largo plazo.

Proteomic Profiling of Cryoglobulinemia.

Objective: We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs). Methods: The tandem mass tag (TMT)-labeled serum quantitative proteomics approach was used to identify differentially expressed proteins between the CGE and DC groups. Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins. Biomarker candidates were validated in another cohort using the parallel reaction monitoring (PRM) method. Apolipoprotein A1 (APOA1), apolipoprotein CIII (APOC3), adiponectin, and proprotein convertase subtilisin/kexin type-9 (PCSK9), which represent key proteins involved in the cholesterol metabolism pathway, were further verified in an increased number of samples by enzyme-linked immunosorbent assay (ELISA). Results: A total of 1004 proteins were identified, of which 109 proteins were differentially expressed between the CGE and DC groups. These differentially expressed proteins were primarily involved in hepatic fibrosis/hepatic stellate cell activation and immune/inflammation-related pathways. In the disease and biofunction analysis, these proteins were mainly associated with the adhesion of blood cells, leukocyte migration, cholesterol transport, and transport of lipids. Twelve candidate biomarkers were validated by PRM-based proteomics, and proteins involved in the cholesterol metabolism pathway were further verified. APOA1, APOC3, adiponectin and PCSK9 concentrations were increased in CGE patients compared with healthy controls (P=0.0123, 0.1136, 0.5760, and 0.0019, respectively). Conclusion: This report describes the first application of a TMT-PRM-ELISA workflow to identify and validate CGE-specific biomarkers in serum. APOA1 and PCSK9 have been confirmed to be increased in CGE patients, demonstrating that proteins involved in cholesterol metabolism are also implicated in the development of CGE. These findings contribute to pathogenesis research and biomarker discovery in CGE.

SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulating the T cell regulatory gene networks post-transcriptionally, which are critical in response to type I interferon signaling for supporting thymocyte maturation. Here, we report SRSF1 also contributes to the determination of the CD8+ T cell fate. By specific ablation of SRSF1 in CD4+CD8+ double positive (DP) thymocytes, we found that SRSF1 deficiency impaired the maturation of late thymocytes and diminished the output of both CD4+ and CD8+ single positive T cells. Interestingly, the ratio of mature CD4+ to CD8+ cells was notably altered and more severe defects were exhibited in CD8+ lineage than those in CD4+ lineage, reflecting the specific function of SRSF1 in CD8+ T cell fate decision. Mechanistically, SRSF1-deficient cells downregulate their expression of Runx3, which is a crucial transcriptional regulator in sustaining CD8+ single positive (SP) thymocyte development and lineage choice. Moreover, forced expression of Runx3 partially rectified the defects in SRSF1-deficient CD8+ thymocyte maturation. Thus, our data uncovered the previous unknown role of SRSF1 in establishment of CD8+ cell identity.

Hypertension Induced by Combination Therapy of Cancer: A Systematic Review and Meta-Analysis of Global Clinical Trials.

Background: Nowadays, due to the limitation of single therapy, combination therapy for cancer treatments has become important strategy. With the advancement of research on cardiotoxicities induced by anti-cancer treatment, among which cancer treatment-induced hypertension is the most frequent case. However, due to the small sample size and the absence of comparison (single-arm study alone), these studies have limitations to produce a feasible conclusion. Therefore, it is necessary to carry out a meta-analysis focusing on hypertension caused by cancer combination therapy. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and CNKI, from database inception to November 31, 2020, with randomized controlled trials (RCTs) associated with hypertension induced by cancer combination drugs. The main endpoint of which was to assess the difference in the incidence of hypertension in cancer patients with monotherapy or combination therapy. We calculated the corresponding 95% confidence interval (95% CIs) according to the random effect model and evaluated the heterogeneity between different groups. Results: According to the preset specific inclusion and exclusion criteria, a total of 23 eligible RCTs have been included in the present meta-analysis, including 6,241 patients (Among them, 2872 patients were the control group and 3369 patients were the experimental group). The results showed that cancer patients with combination therapy led to a higher risk of hypertension (All-grade: RR 2.85, 95% CI 2.52∼3.22; 1∼2 grade: RR 2.43, 95% CI 2.10∼2.81; 3∼4 grade: RR 4.37, 95% CI 3.33∼5.72). Furthermore, compared with the control group who received or did not receive a placebo, there was a higher risk of grade 3-4 hypertension caused by cancer combination treatment. Conclusion: The present meta-analysis carries out a comprehensive analysis on the risk of patients suffering from hypertension in the process of multiple cancer combination therapies. Findings in our study support that the risk of hypertension may increase significantly in cancer patients with multiple cancer combination therapies. The outcomes of this meta-analysis may provide a reference value for clinical practice and may supply insights in reducing the incidence of hypertension caused by cancer combined treatment.

SRSF1 plays a critical role in invariant natural killer T cell development and function.

Invariant natural killer T (iNKT) cells are highly conserved innate-like T lymphocytes that originate from CD4+CD8+ double-positive (DP) thymocytes. Here, we report that serine/arginine splicing factor 1 (SRSF1) intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms. Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation, survival, and TCRα rearrangement. The transition from stage 0 to stage 1 of iNKT cells was substantially blocked, and the iNKT2 subset was notably diminished in SRSF1-deficient mice. SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation, including Myb, PLZF, Gata3, ICOS, and CD5. In particular, we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells. Strikingly, ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1. Furthermore, we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury upon α-GalCer and Con A induction. Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation, providing new clinical insights into iNKT-correlated disease.

Development and Validation of a Prognostic Gene Signature in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC), one of the most common urologic cancer types, has a relatively good prognosis. However, clinical diagnoses are mostly done during the medium or late stages, when mortality and recurrence rates are quite high. Therefore, it is important to perform real-time information tracking and dynamic prognosis analysis for these patients. We downloaded the RNA-seq data and corresponding clinical information of ccRCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 3,238 differentially expressed genes were identified between normal and ccRCC tissues. Through a series of Weighted Gene Co-expression Network, overall survival, immunohistochemical and the least absolute shrinkage selection operator (LASSO) analyses, seven prognosis-associated genes (AURKB, FOXM1, PTTG1, TOP2A, TACC3, CCNA2, and MELK) were screened. Their risk score signature was then constructed. Survival analysis showed that high-risk scores exhibited significantly worse overall survival outcomes than low-risk patients. Accuracy of this prognostic signature was confirmed by the receiver operating characteristic curve and was further validated using another cohort. Gene set enrichment analysis showed that some cancer-associated phenotypes were significantly prevalent in the high-risk group. Overall, these findings prove that this risk model can potentially improve individualized diagnostic and therapeutic strategies.

SRSF1 serves as a critical posttranscriptional regulator at the late stage of thymocyte development.

The underlying mechanisms of thymocyte maturation remain largely unknown. Here, we report that serine/arginine-rich splicing factor 1 (SRSF1) intrinsically regulates the late stage of thymocyte development. Conditional deletion of SRSF1 resulted in severe defects in maintenance of late thymocyte survival and a blockade of the transition of TCRßhiCD24+CD69+ immature to TCRßhiCD24-CD69- mature thymocytes, corresponding to a notable reduction of recent thymic emigrants and diminished periphery T cell pool. Mechanistically, SRSF1 regulates the gene networks involved in thymocyte differentiation, proliferation, apoptosis, and type I interferon signaling pathway to safeguard T cell intrathymic maturation. In particular, SRSF1 directly binds and regulates Irf7 and Il27ra expression via alternative splicing in response to type I interferon signaling. Moreover, forced expression of interferon regulatory factor 7 rectifies the defects in SRSF1-deficient thymocyte maturation via restoring expression of type I interferon-related genes. Thus, our work provides new insight on SRSF1-mediated posttranscriptional regulatory mechanism of thymocyte development.

Epidemiological and clinical characteristics of cancer patients with COVID-19: A systematic review and meta-analysis of global data.

There are minimal data regarding the prevalence of cancer in patients with coronavirus disease 2019 (COVID-19), as well as the incidence of severe illness and rate of mortality in COVID-19 patients with cancer. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched, from database inception to July 15, 2020, for studies of patients with COVID-19 that included information regarding comorbid cancer. In total, 109 eligible global studies were included in this systematic review. Ninety studies with 94,845 COVID-19 patients, among which 4106 exhibited comorbid cancer, were included in the meta-analysis regarding prevalence of comorbid cancer. Twenty-three studies with 71,969 COVID-19 patients, among which 4351 with comorbid cancer had severe illness or death, were included in the meta-analysis. The overall prevalence of cancer among COVID-19 patients was 0.07 (95% CI 0.05-0.09). The cancer prevalence in COVID-19 patients was higher in Europe (0.22, 95% CI 0.17-0.28) than in the Asia-Pacific region (0.04, 95% CI 0.03-0.06) or North America (0.05, 95% CI 0.04-0.06). The cancer prevalence in COVID-19 patients aged >60 years was 0.10 (95% CI 0.07-0.14), while the prevalence among patients aged ≤60 years was 0.05 (95% CI 0.03-0.06). The pooled prevalence of severe illness among COVID-19 patients with cancer was 0.34 (95% CI 0.26-0.42) and the pooled mortality rate of COVID-19 patients with cancer was 0.20 (95% CI 0.16-0.25). Pooled incidences of severe illness among COVID-19 patients with cancer from Asia Pacific, Europe, and North America were 0.38 (95% CI 0.24-0.52), 0.39 (95% CI 0.25-0.53), and 0.26 (95% CI 0.20-0.31), respectively; pooled mortality rates from the Asia-Pacific region, Europe, and North America were 0.17 (95% CI 0.10-0.24), 0.26 (95% CI 0.18-0.35), and 0.19 (95% CI 0.13-0.25), respectively.

METTL3-dependent m6A modification programs T follicular helper cell differentiation.

T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m6A-miCLIP-seq shows the 3' UTR of Tcf7 mRNA is subjected to METTL3-dependent m6A modification. Loss of METTL3 or mutation of the Tcf7 3' UTR m6A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.

The kinase PDK1 is critical for promoting T follicular helper cell differentiation.

The kinase PDK1 is a crucial regulator for immune cell development by connecting PI3K to downstream AKT signaling. However, the roles of PDK1 in CD4+ T cell differentiation, especially in T follicular helper (Tfh) cell, remain obscure. Here we reported PDK1 intrinsically promotes the Tfh cell differentiation and germinal center responses upon acute infection by using conditional knockout mice. PDK1 deficiency in T cells caused severe defects in both early differentiation and late maintenance of Tfh cells. The expression of key Tfh regulators was remarkably downregulated in PDK1-deficient Tfh cells, including Tcf7, Bcl6, Icos, and Cxcr5. Mechanistically, ablation of PDK1 led to impaired phosphorylation of AKT and defective activation of mTORC1, resulting in substantially reduced expression of Hif1α and p-STAT3. Meanwhile, decreased p-AKT also suppresses mTORC2-associated GSK3ß activity in PDK1-deficient Tfh cells. These integrated effects contributed to the dramatical reduced expression of TCF1 and ultimately impaired the Tfh cell differentiation.

Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells.

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution.

Tcf-1 (encoded by Tcf7) not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy. However, the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood. In this study, Tcf7fl/fl mice were crossed with Vav-cre, Lck-cre, or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC, DN2-DN3, or DP stage, respectively. The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models. Interestingly, consistent with Tcf7-/- mice, Tcf7fl/flVav-cre mice developed aggressive T cell lymphoma within 45 weeks, but no tumors were generated in Tcf7fl/flLck-cre or Tcf7fl/flCd4-cre mice. Single-cell RNA-seq (ScRNA-seq) indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters (C1, C2, and C3) and DN2-DN3 cells into three clusters (C4, C5, and C6). Moreover, Tcf-1 deficiency redirects bifurcation among divergent cell fates, and clusters C1 and C4 exhibit high potential for leukemic transformation. Mechanistically, we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes, including Myb, Mycn, Runx1, and Lyl1 in the DN1 phase and Lef1, Id2, Dtx1, Fyn, Bcl11b, and Zfp36l2 in the DN2-DN3 phase. The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis. Thus, we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation, providing new insights and evidence for clinical trials on T-ALL leukemia.

YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7.

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/ß-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/ß-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. SIGNIFICANCE: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2651/F1.large.jpg.

Prevalence of metabolic syndrome among ethnic groups in China.

BACKGROUND: Metabolic syndrome (MetS) is common in China, which has a multi-ethnic population of 1·3 billion. We set out to determine the prevalence of MetS and its components in different ethnic groups. METHODS: This nationwide cross-sectional survey involved 24,796 participants from eight ethnicities in six provinces in China from 2008 to 2011. MetS was defined using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Results were analysed using SPSS version 22·0 in 2018. Logistic regression was used for deriving odds ratios and 95% confidence intervals of risk factors for the MetS. RESULTS: The prevalence of MetS increased with age from 3·60% to 21·68%. After age standardization, the prevalence of MetS, in descending order, was 35·42% (Korean), 22·82% (Hui), 19·80% (Han), 13·72% (Miao), 12·90% (Tujia), 12·04% (Li), 11·61% (Mongolian), 6·17% (Tibetan). Korean ethnicity was associated with a higher prevalence in five components of MetS, while Tibetan ethnicity was associated with lower prevalence except decreased HDL cholesterol. Logistic regression analyses showed that age, drinking and being non-Tibetan were associated with a higher risk of MetS. CONCLUSIONS: Within one country, albeit a large one, the prevalence of MetS can vary greatly. Chinese of Korean ethnicity had a much higher prevalence than Tibetan ethnicity. Measures to tackle MetS should be tailored to the ethnic groups within a population.