The impact of short-term exposure to meteorological factors on the risk of death from hypertension and its major complications: a time series analysis based on Hefei, China.

OBJECTIVES: This study aimed to reveal the short-term impact of meteorological factors on the mortality risk in hypertensive patients, providing a scientific foundation for formulating pertinent prevention and control policies. METHODS: In this research, meteorological factor data and daily death data of hypertensive patients in Hefei City from 2015 to 2018 were integrated. Time series analysis was performed using distributed lag nonlinear model (DLNM) and generalized additive model (GAM). Furthermore, we conducted stratified analysis based on gender and age. Relative risk (RR) combined with 95% confidence interval (95% CI) was used to represent the mortality risk of single day and cumulative day in hypertensive patients. RESULTS: Single-day lag results indicated that high daily mean temperature (T mean) (75th percentile, 24.9 °C) and low diurnal temperature range (DTR) (25th percentile, 4.20 °C) levels were identified as risk factors for death in hypertensive patients (maximum effective RR values were 1.144 and 1.122, respectively). Extremely high levels of relative humidity (RH) (95th percentile, 94.29%) reduced the risk of death (RR value was 0.893). The stratified results showed that the elderly and female populations are more susceptible to low DTR levels, whereas extremely high levels of RH have a more significant protective effect on both populations. CONCLUSION: Overall, we found that exposure to low DTR and high T mean environments increases the risk of death for hypertensive patients, while exposure to extremely high RH environments significantly reduces the risk of death for hypertensive patients. These findings contribute valuable insights for shaping targeted prevention and control strategies.

Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis.

Metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer-derived metabolic and non-metabolic factors, is an emerging aspect of cancer-host interaction. We show that in normal and cancer-associated fibroblasts, breast cancer-secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer-derived miR-105 and miR-204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re-feeding, 13 C-arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer-derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations.

Spatial-temporal-demographic and virological changes of hand, foot and mouth disease incidence after vaccination in a vulnerable region of China.

BACKGROUND: The enterovirus 71 (EV-A71) vaccine has been used in Hefei for several years, and the epidemiological significance of vaccination in this area is unclear. We aims to explore the spatial-temporal-demographic and virological changes of hand, foot and mouth disease (HFMD) after vaccination in China. METHODS: The data for HFMD from 2012 to 2020 were downloaded with the help of HFMD reporting system of Hefei Center for Disease Control and Prevention and combined with the EV-A71 vaccination status in Hefei. The study defined the period between 2012 to 2016 as the pre-vaccination period and explored the effect of vaccination on the incidence of HFMD by comparing the changes of HFMD before and after vaccination in terms of spatial, temporal, demographic and virological aspects. RESULTS: During the study period, a higher incidence occurred in urban area and the random distribution changed to a slight cluster after vaccination. HFMD incidence had inconsistent seasonality over years, with one or two incidence peaks in varying years. The morbidity decreased from 215.22/105 in 2012-2016 to 179.81/105 in 2017-2020 (p < 0.001). Boys, 0-4 years old children and Scattered children were more susceptible to HFMD compared with the others, the proportions decreased after vaccination except in Scattered children. The main pathogenic enterovirus gradually changed from EV-A71 to Other Enteroviruses, especially coxsackieviruses A6 (CV-A6) after the implementation of EV-A71 vaccination. CONCLUSIONS: The EV-A71 vaccine was effective in reducing the incidence of HFMD and changing the spatial, temporal, demographic, and virological characteristic. These changes should be considered during the vaccination implementation to further reduce the disease burden of HFMD.

Genetic manipulation of primary human natural killer cells to investigate the functional and oncogenic roles of PRDM1.

Extra-nodal natural killer/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive lymphoma, where the tumor suppressor gene (TSG) PRDM1 is frequently lost/inactivated. We employed two different CRISPR/Cas9 approaches to generate PRDM1-/- primary NK cells to study its role in NK-cell homeostasis. PRDM1-/- NK cells showed a marked increase in cloning efficiency, higher proliferation rate and less apoptosis compared with their wild type counterparts. Gene expression profiling demonstrated a marked enrichment in pathways associated with proliferation, cell cycle, MYC, MYB and TCR/NK signaling in PRDM1-/- NK cells, but pathways associated with normal cellular functions including cytotoxic functions were down-regulated, suggesting that the loss of PRDM1 shifted NK cells toward proliferation and survival rather than the performance of its normal functions. We were also able to further modify a PRDM1 deleted clone to introduce heterozygous deletions of common TSG in ENKTCL such as TP53, DDX3X, or PTPN6. We have established an in vitro model to elucidate the major pathways through which PRDM1 mediates its homeostatic control of NK-cells. This approach can be applied to the study of other relevant genetic lesions and oncogenic collaborations in lymphoma pathogenesis.

Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection.

Chimeric antigen receptor-T (CAR-T) cell therapy is a promising treatment for CD19+ B-cell malignancies. However, elimination of B cells by anti-CD19 CAR-T cells may lead to the reactivation of hepatitis B virus (HBV) and related hepatitis in patients with HBV infection. This study aims to evaluate the safety and efficacy of humanized anti-CD19 CAR-T (hCAR-T) therapy in B-cell malignancies with HBV infection. Twenty relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) patients with HBV infection were treated with hCAR-T therapy. Among them, five hepatitis B antigen-positive patients who received antiviral prophylaxis did not develop HBV reactivation, including two patients who received both hCAR-T and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 15 patients with resolved HBV infection, two received antiviral prophylaxis, and the other 13 did not experience HBV reactivation without antiviral prophylaxis. One patient with resolved HBV infection experienced HBV reactivation 6 months after hCAR-T therapy and sequential allo-HSCT. Moreover, HBV infection did not affect in vivo expansion of hCAR-T cells or increase the risk of severe cytokine release syndrome. In conclusion, hCAR-T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis.

Short-term effects of ambient temperature and pollutants on the mortality of respiratory diseases: A time-series analysis in Hefei, China.

BACKGROUND: The air pollution has become an important environmental health problem due to its adverse health effect. The objective of this study was to investigate the effects of ambient temperature and pollutants on mortality of respiratory diseases (RD) in Hefei, China, a typical inland city. METHODS: Nonlinear exposure-response dependencies and delayed effects of urban daily mean temperature (DMT) and pollutants were evaluated by distributed lag non-linear models (DLNM). To further explore this effect, different genders and ages were also examined by stratified analysis. RESULTS: A total of 12876 deaths from RD were collected from January 1, 2014 to December 31, 2018 in Hefei, China. There was a U-shaped correlation between DMT and RD mortality, and the RD mortality rised by 11.6% (95% CI: 2.2-22.0%) when the DMT was 35.8 °C (reference temperature is 20 °C). The results show that risk of death with short-term exposure to elevated concentrations of PM10 and SO2 was not significant. The maximum hysteresis and cumulative relative risk (RR) of RD mortality were 1.012 (95% CI: 1.003 ~ 1.021, lag 0 day) and 1.072 (95% CI: 1.014 ~1.133, lag 10 days) for each 10 µg/m3 augment in NO2; 1.005 (95% CI: 1.001-1.009, lag 0 day) and 1.027 (95% CI: 1.004-1.051, lag 10 days) for each 10 µg/m3 augment in O3; a negative association between CO exposure and the cumulative risk of death was observed (RR = 0.964, 95% CI: 0.935-0.993, lag 07 days). Subgroup analysis showed the effect of high temperatures, NO2, O3 and CO exposure was still statistically significant for the elderly and male. CONCLUSION: The present study found that short-term exposure to high temperature, NO2, O3 and CO were significantly associated with the risk of RD mortality and male as well as elderly are more susceptible to these factors.

Efficacy and safety of humanized anti-CD19-CAR-T therapy following intensive lymphodepleting chemotherapy for refractory/relapsed B acute lymphoblastic leukaemia.

We studied the efficacy and safety of humanized CAR-T therapy following intensive chemotherapy for refractory/relapsed (R/R) acute lymphoblastic leukaemia (B-ALL). Twenty-three patients with R/R B-ALL were pretreated with intensive chemotherapy (fludarabine combined with medium-dose cytarabine) 12 days before CAR-T therapy. Adverse events (AEs), curative effects, infection indicators and cytokine release syndrome (CRS) were monitored. Each of the 23 patients received a dose of 1·0 × 106 cells/kg CAR-T cell infusion on day 0. After 14 days, 19 patients (82·61%) achieved complete response (CR) or CR with incomplete count recovery. No survival benefit was achieved with consolidative haematopoietic stem-cell transplantation (HSCT), with a median follow-up of 14·0 months (range, 1·5-21·0 months). The notable AEs were grade 1-2 CRS in 18 patients, while the other five patients were grade 3 CRS. No patients died of CRS. Only one patient died of respiratory failure due to cytomegalovirus infection 24 days after infusion. The proportion of leukaemic cells in bone marrow on infusion day and the peaks of IL-6, TNF-α and IL-8 levels were correlated with CRS levels. A lower disease burden was achieved by intensive lymphodepleting chemotherapy, and the subsequent CAR-T therapy had a high response and manageable toxicity. Trial registration: The patients were enrolled in a clinical trial of ChiCTR-ONN-16009862, and ChiCTR1800019622.

Effects of air pollutants on occurrences of influenza-like illness and laboratory-confirmed influenza in Hefei, China.

Accumulating evidence suggests that air pollution is a risk factor for adverse respiratory and cardiovascular health outcomes. However, the different impacts of exposure to air pollutants on influenza virus activity and influenza-like illness (ILI) have not been well documented in epidemiological studies. We examined the association between air pollutants of particular matters < 2.5 µm (PM2.5), particular matters < 10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and influenza occurrences in Hefei, China, from December 2013 to December 2015 by generalized Poisson additive regression models. The result suggested that PM2.5 and PM10 had similar effects on clinical ILI and influenza incidence. PM10 was negatively associated with clinical ILI (relative risk (RR) 0.980, 95% confidence interval (CI) 0.974-0.987), while PM2.5 were positively associated with clinical ILI (RR 1.040; 95% CI 1.032-1.049). RRs for the laboratory-confirmed cases of influenza were 0.813 (95% CI, 0.755-0.875) for PM10 and 1.216 (95% CI, 1.134-1.304) for PM2.5. Nevertheless, the impacts of SO2 and NO2 on ILI and influenza were distinct. SO2 had significant influence on laboratory-confirmed influenza and had no significant linear relationship with ILI. NO2 was negatively correlated with influenza but had no obvious effect on clinical ILI cases. The present study contributes novel evidence on understanding of the effects of various air pollutants on influenza activities, and these findings can be useful and important for the development of influenza surveillance and early warning systems.

Polarized Secretion of Extracellular Vesicles by Mammary Epithelia.

Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia.

Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts.

BACKGROUND: Bone is one of the most frequent metastatic sites of advanced breast cancer. Current therapeutic agents aim to inhibit osteoclast-mediated bone resorption but only have palliative effects. During normal bone remodeling, the balance between bone resorption and osteoblast-mediated bone formation is essential for bone homeostasis. One major function of osteoblast during bone formation is to secrete type I procollagen, which will then be processed before being crosslinked and deposited into the bone matrix. METHODS: Small RNA sequencing and quantitative real-time PCR were used to detect miRNA levels in patient blood samples and in the cell lysates as well as extracellular vesicles of parental and bone-tropic MDA-MB-231 breast cancer cells. The effects of cancer cell-derived extracellular vesicles isolated by ultracentrifugation and carrying varying levels of miR-218 were examined in osteoblasts by quantitative real-time PCR, Western blot analysis, and P1NP bone formation marker analysis. Cancer cells overexpressing miR-218 were examined by transcriptome profiling through RNA sequencing to identify intrinsic genes and pathways influenced by miR-218. RESULTS: We show that circulating miR-218 is associated with breast cancer bone metastasis. Cancer-secreted miR-218 directly downregulates type I collagen in osteoblasts, whereas intracellular miR-218 in breast cancer cells regulates the expression of inhibin ß subunits. Increased cancer secretion of inhibin ßA results in elevated Timp3 expression in osteoblasts and the subsequent repression of procollagen processing during osteoblast differentiation. CONCLUSIONS: Here we identify a twofold function of cancer-derived miR-218, whose levels in the blood are associated with breast cancer metastasis to the bone, in the regulation of type I collagen deposition by osteoblasts. The adaptation of the bone niche mediated by miR-218 might further tilt the balance towards osteolysis, thereby facilitating other mechanisms to promote bone metastasis.

Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells.

Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites.

AIM: Benzothiophene compounds are selective estrogen receptor modulators (SERMs), which are recently found to activate antioxidant signaling. In this study the molecular mechanisms of antioxidant signaling activation by benzothiophene compound BC-1 were investigated. METHODS: HepG2 cells were stably transfected with antioxidant response element (ARE)-luciferase reporter (HepG2-ARE cells). The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in HepG2-ARE cells was suppressed using siRNA. The metabolites of BC-1 in rat liver microsome incubation were analyzed using LC-UV and LC-MS. RESULTS: Addition of BC-1 (5 µmol/L) in HepG2-ARE cells resulted in a 17-fold increase of ARE-luciferase activity. Pretreatment with the estrogen receptor agonist E2 (5 µmol/L) or antagonist ICI 182,780 (5 µmol/L) did not affect BC-1-induced ARE-luciferase activity. However, transfection of the cells with anti-Nrf2 siRNA suppressed this effect by 79%. Addition of BC-1 in rat microsome incubation resulted in formation of di-quinone methides and o-quinones, followed by formation of GSH conjugates. BC-1 analogues with hydrogen (BC-2) or fluorine (BC-3) at the 4' position did not form the di-quinone methides. Both BC-2 and BC-3 showed comparable estrogenic activity with BC-1, but did not induce ARE-luciferase activity in HepG2-ARE cells. CONCLUSION: Benzothiophene compound BC-1 activates ARE signaling via reactive metabolite formation that is independent of estrogen receptors.

Effect of Ultraviolet-B Radiating Drosophila melanogaster as Host on the Quality of Trichopria drosophilae, a Pupal Parasitoid of Drosophila suzukii.

The pupal parasitoid, Trichopria drosophilae Perkins (Hymenoptera: Diapriidae), is an ectoparasitoid of the genus Drosophila with great potential for application in biological control based on its excellent control efficiency for Drosophila suzukii Matsumura (Diptera: Drosophilidae), and it has has even been commercialized by biofactories. Due to its characteristics of short life cycle, large number of offspring, easy rearing, rapid reproduction, and low cost, Drosophila melanogaster (Diptera: Drosophilidae) is currently being utilized as a host to mass produce T. drosophilae. To simplify the mass rearing process and omit the separation of hosts and parasitoids, ultraviolet-B (UVB) was used as an irradiation source to irradiate D. melanogaster pupae, and the effects on T. drosophilae were studied. The results showed that UVB radiation significantly reduces host emergence and affects the duration of parasitoid development (female: F0 increased from 21.50 to 25.80, F1 from 23.10 to 26.10; male: F0 decreased from 17.00 to 14.10, F1 from 17.20 to 14.70), which has great significance for the separation of hosts and parasitoids as well as of females and males. Of the various studied conditions, UVB irradiation was ideal when the host was supplied with parasitoids for 6 h. The selection test results showed that the female-to-male ratio of emerging parasitoids in this treatment was highest at 3.47. The no-selection test resulted in the highest rates of parasitization and parasitoid emergence rate, maximized inhibition of host development, and allowed the omission of the separation step. Finally, the results of the semi-field test showed that the parasitoids bred in this treatment could search for their hosts normally and could therefore be directly applied in the biological control of Drosophila pests in the field.

The Effect of Cuelure on Attracting and Feeding Behavior in Zeugodacus tau (Walker) (Diptera: Tephritidae).

As a vital pest control strategy, trapping plays an important role in the system of monitoring, catching and killing fruit flies. Cuelure (4-(4-acetoxyphenyl)-2-butanone, CL) is a male lure that attracts Zeugodacus tau and also stimulates feeding in this species. In this study, the attraction of Z. tau to CL and its subsequent feeding behavior were investigated. Under the significant influence of age and time of day, the attraction of CL to Z. tau was found to be optimal when flies were 14 days old, and the number of flies trapped increased with trapping duration. It was determined that consumption can improve the mating success and female adult fertility of Z. tau. After the observation period, the mating success rate of flies that ingested CL was significantly higher than that of the control group and was maintained at a higher level. It was found that parental consumption of CL could accelerate the development of eggs and larvae, resulting in increased pupation and emergence rates. The results of this study will further clarify the dynamic relationship between pest and lure, and provide a research basis for navigating the integrated management of Z. tau in the field.

Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.

Transcriptome analysis of sex-biased gene expression in the spotted-wing Drosophila, Drosophila suzukii (Matsumura).

Sexual dimorphism occurs widely throughout insects and has profound influences on evolutionary path. Sex-biased genes are considered to account for most of phenotypic differences between sexes. In order to explore the sex-biased genes potentially associated with sexual dimorphism and sexual development in Drosophila suzukii, a major devastating and invasive crop pest, we conducted whole-organism transcriptome profiling and sex-biased gene expression analysis on adults of both sexes. We identified transcripts of genes involved in several sex-specific physiological and functional processes, including transcripts involved in sex determination, reproduction, olfaction, and innate immune signals. A total of 11,360 differentially expressed genes were identified in the comparison, and 1,957 differentially expressed genes were female-biased and 4,231 differentially expressed genes were male-biased. The pathway predominantly enriched for differentially expressed genes was related to spliceosome, which might reflect the differences in the alternative splicing mechanism between males and females. Twenty-two sex determination and 16 sex-related reproduction genes were identified, and expression pattern analysis revealed that the majority of genes were differentially expressed between sexes. Additionally, the differences in sex-specific olfactory and immune processes were analyzed and the sex-biased expression of these genes may play important roles in pheromone and odor detection, and immune response. As a valuable dataset, our sex-specific transcriptomic data can significantly contribute to the fundamental elucidation of the molecular mechanisms of sexual dimorphism in fruit flies, and may provide candidate genes potentially useful for the development of genetic sexing strains, an important tool for sterile insect technique applications against this economically important species.

Highly Prevalent SARS-CoV-2 Antigenemia in COVID-19 Patients.

Background: Many issues, such as severity assessment and antibody responses, remain to be answered eagerly for evaluation and understanding of COVID-19. Immune lesion is one of key pathogenesis of the disease. It would be helpful to understand the disease if an investigation on antigenemia and association was conducted in the patients with SARS-CoV-2 infection. Methods: A total of 156 patients admitted to the First People's Hospital of Hefei or Anhui Provincial Hospital on January to February 2020 were involved in this study. SARS-CoV-2 nucleocapsid (NP) antigen, specific IgM/IgG antibodies, and RNA were detected in sequential sera from three COVID-19 patients, and additional 153 COVID-19 patients by means of NP-antigen capture enzyme-linked immunosorbent assay, colloidal gold quick diagnosis, and real-time RT-PCR, respectively. The clinical types of COVID-19 patients were classified into asymptomatic, mild, moderate, severe, and critical, following on the Chinese guideline of COVID-19 diagnosis and treatment. The demographic and clinical data of patients were obtained for comparable analysis. Results: NP antigen was detected in 5 of 20 sequential sera collected from three COVID-19 patients with typically clinical symptoms, and 60.13% (92/153) expanded samples collected within 17 days after illness onset. No SARS-CoV-2 RNA segment was detected in these sera. The NP positive proportion reached a peak (84.85%, 28/33) on 6 to 8 days after illness onset. Both NP concentration and positive proportion were increased with the increase of clinical severity of COVID-19. Compared to NP negative patients, NP positive patients had older age [years, medians (interquartile ranges (IQR)), 49 (6) vs. 31 (11)], lower positive proportion of NP specific IgM [27.17% (25/92) vs. 59.02% (36/61)], and IgG [21.74% (20/92) vs. 59.02% (36/61)] antibodies, and longer duration [days, medians (IQR), 24 (10) vs. 21 (13)] from illness to recovery. Conclusions: SARS-CoV-2 NP antigenemia occurred in COVID-19, and presented highly prevalent at early stage of the disease. The antigenemia was related to clinical severity of the disease, and may be responsible for the delay of detectable SARS-Cov-2 IgM.

Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma.

Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.