"Moderate" adjuvant chemotherapy-induced leukopenia is beneficial for survival of patients with early breast cancer: a retrospective study.

BACKGROUND: The association between chemotherapy-induced leukopenia (CIL) and survival for patients with early breast cancer (EBC) is not known. We investigated the relationship between different grades of CIL and survival in patients with EBC receiving adjuvant chemotherapy. METHODS: A total of 442 patients with EBC receiving a regimen containing an anthracycline (A) and taxane (T) were included into our analysis. Survival analyses were undertaken using Kaplan-Meier curves. The P-value was calculated using the log rank test. Subgroup analysis was conducted to investigate the correlation of CIL grade and survival based on the clinicopathological characteristics of patients. Afterwards, univariate and multivariate analyses screened out independent prognostic factors to construct a prognostic model, the robustness of which was verified. RESULTS: Patients with EBC who experienced grade 2-4 ("moderate" and "severe") CIL were associated with longer overall survival (OS) than those with grade 0-1 (mild) CIL (P = 0.021). Compared with patients with mild CIL, OS was longer in patients with severe CIL (P = 0.029). Patients who suffered from moderate CIL tended to have longer OS than those with mild CIL (P = 0.082). Nevertheless, there was no distinguishable difference in OS between moderate- or severe-CIL groups. Subgroup analysis revealed that patients with moderate CIL had longer OS than those with mild CIL among patients who were premenstrual, or with human epidermal growth factor receptor 2-positive (HER2+), > 3 lymph nodes with metastases, a tumor diameter > 5 cm. A prognostic model based on menstrual status, N stage, and CIL grade showed satisfactory robustness. CONCLUSION: The grade of CIL was strongly associated with the prognosis among patients with EBC who received a regimen containing both anthracyclines and taxanes. Patients with a "moderate" CIL grade tended to have better survival outcomes.

Suppressive Monocytes Impair MAIT Cells Response via IL-10 in Patients with Severe COVID-19.

Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe COVID-19, the number of HLA-DRlow/- monocytes was significantly increased, but that of mucosal-associated invariant T (MAIT) cells was greatly reduced. MAIT cells were highly activated but functionally impaired in response to Escherichia coli and IL-12/IL-18 stimulation in patients with severe COVID-19, especially those with microbial coinfection. Single-cell transcriptome analysis revealed that IFN-stimulated genes were significantly upregulated in peripheral MAIT cells and monocytes from patients with severe COVID-19. IFN-α pretreatment suppressed MAIT cells' response to E. coli by triggering high levels of IL-10 production by HLA-DRlow/--suppressive monocytes. Blocking IFN-α or IL-10 receptors rescued MAIT cell function in patients with severe COVID-19. Moreover, plasma from patients with severe COVID-19 inhibited HLA-DR expression by monocytes through IL-10. These data indicate a unique pattern of immune dysregulation in severe COVID-19, which is characterized by enrichment of suppressive HLA-DRlow/- monocytes associated with functional impairment of MAIT cells through the IFN/IL-10 pathway.

Comprehensive Analysis of the Pectate Lyase Gene Family and the Role of FaPL1 in Strawberry Softening.

Fruit softening is a crucial factor that controls shelf life and commercial value. Pectate lyase (PL) has a major role in strawberry fruit softening. However, the PL gene family in strawberry has not been comprehensively analyzed. In this study, 65 FaPL genes were identified in the octoploid strawberry genome. Subcellular localization prediction indicated that FaPLs are mostly localized to the extracellular and cytoplasmic spaces. Duplication event analysis suggested that FaPL gene family expansion is mainly driven by whole genome or segmental duplication. The FaPL family members were classified into six groups according to the phylogenetic analysis. Among them, FaPL1, 3, 5, 20, 25, 42, and 57 had gradually increased expressions during strawberry fruit development and ripening and higher expression levels in the fruits with less firmness than that in firmer fruit. This result suggested that these members are involved in strawberry softening. Furthermore, overexpression of FaPL1 significantly reduced the fruit firmness, ascorbic acid (AsA), and malondialdehyde (MDA) content but obviously increased the anthocyanins, soluble proteins, and titratable acidity (TA), while it had no apparent effects on flavonoids, phenolics, and soluble sugar content. These findings provide basic information on the FaPL gene family for further functional research and indicate that FaPL1 plays a vital role in strawberry fruit softening.

A genome-wide survey of copy number variations reveals an asymmetric evolution of duplicated genes in rice.

BACKGROUND: Copy number variations (CNVs) are an important type of structural variations in the genome that usually affect gene expression levels by gene dosage effect. Understanding CNVs as part of genome evolution may provide insights into the genetic basis of important agricultural traits and contribute to the crop breeding in the future. While available methods to detect CNVs utilizing next-generation sequencing technology have helped shed light on prevalence and effects of CNVs, the complexity of crop genomes poses a major challenge and requires development of additional tools. RESULTS: Here, we generated genomic and transcriptomic data of 93 rice (Oryza sativa L.) accessions and developed a comprehensive pipeline to call CNVs in this large-scale dataset. We analyzed the correlation between CNVs and gene expression levels and found that approximately 13% of the identified genes showed a significant correlation between their expression levels and copy numbers. Further analysis showed that about 36% of duplicate pairs were involved in pseudogenetic events while only 5% of them showed functional differentiation. Moreover, the offspring copy mainly contributed to the expression levels and seemed more likely to become a pseudogene, whereas the parent copy tended to maintain the function of ancestral gene. CONCLUSION: We provide a high-accuracy CNV dataset that will contribute to functional genomics studies and molecular breeding in rice. We also showed that gene dosage effect of CNVs in rice is not exponential or linear. Our work demonstrates that the evolution of duplicated genes is asymmetric in both expression levels and gene fates, shedding a new insight into the evolution of duplicated genes.

The local efficacy and influencing factors of ultrasound-guided percutaneous microwave ablation in colorectal liver metastases: a review of a 4-year experience at a single center.

PURPOSE: To investigate the clinical effectiveness and safety of ultrasound (US)-guided percutaneous microwave ablation (MWA) for colorectal liver metastasis (CRLM) and evaluate the influencing factors of local efficacy. METHODS: From January 2013 to January 2017, 137 CRLM patients accepting US-guided percutaneous MWA were included. The 2450-MHz microwave ablation system and a cooled-shaft antenna were used. All patients were regularly followed up for at least 6 months. Technical success, complete ablation, local tumor progression (LTP), complications and side effects were assessed. Logistic regression analysis was used to identify the independent prognostic factors for LTP. RESULTS: In total, 411 lesions (mean diameter 15.4 ± 7.2 mm, range 5-67 mm) were treated. Complete ablation was achieved in 99.27% (408/411) of lesions and 97.81% (134/137) of patients. LTP occurred in 5.35% (22/411) of lesions and 16.06% (22/137) of patients. LTP was more likely to occur in lesions larger than 3 cm in diameter (OR: 14.71; p < .001; 95% CI: 3.7 3-57.92), near a large vascular structure (OR: 7.04; p < .001; 95% CI: 2.41-20.60), near the diaphragm (OR: 4.02; p = .049; 95% CI: 1.05-16.11) and in patients with no response to chemotherapy before MWA (OR: 3.25; p = .032; 95% CI: 1.14-15.30). MWA was well tolerated, with a major complication rate of 3.65%, a minor complication rate of 8.03% and a mortality rate of 0%. Fever and pain were the most common side effects after MWA. CONCLUSIONS: US-guided percutaneous MWA of CRLM is a safe and effective method that is expected to become a routine treatment for local tumor control of CRLM.

[Comparison of four surgical procedures for the treatment of varicocele].

Objective: To compare the clinical effects of inguinal varicocelectomy, Palomo varicocelectomy,laparoscopic varicocelectomy, and microscopic varicocelectomy in the treatment of varicocele. Methods: We retrospectively analyzed the pre- and post-operative clinical data about 318 cases of varicocele,108 treated by inguinal varicocelectomy,84 by Palomo varicocelectomy,68 by laparoscopic varicocelectomy, and 58 by microscopic varicocelectomy. We compared the operation time, hospital stay, pre- and post-operative sperm concentration and progressive motility, incidence of complications, rate of recurrence, and rate of sperm quality improvement among the four groups. Results: The operation times for the inguinal, Palomo, laparoscopic, and microscopic varicocelectomy procedures were(50. 3 ± 13. 9),(70. 4 ± 14. 3),(35. 1 ± 11. 1),and(65. 3 ± 13. 2) min, respectively, significantly shorter for the laparoscopic strategy than for the other three( P < 0. 05). The lengths of hospital stay of the four groups of patients were(6. 3 ± 1. 6),(5. 7 ± 1. 5),(4. 3 ± 1. 4),and(3. 4 ± 1. 3) d, respectively, remarkably shorter in the microscopic group than in the other three( P < 0. 05). The microscopic group also showed a significantly lower rate of postoperative complications, incidence of spermatic vein reflux, and recurrence( P < 0. 05) and higher rates of improvement in postoperative sperm concentration and progressive motility than the other three groups( P < 0. 05). Conclusion: Microscopic varicocelectomy is superior to inguinal,Palomo and laparoscopic varicocelectomy procedures in the treatment of varicocele for its lower incidence of complications, higher rate of sperm quality improvement,and shorter length of hospital stay. It is therefore more suitable to be applied in community hospitals.

The pleiotropic enhancer enh9 promotes cell proliferation and migration in non-small cell lung cancer via ERMP1 and PD-L1.

Enhancers, cis-acting DNA elements for transcriptional regulation, are important regulators of cell identity and disease. However, of the hundreds of thousands of enhancers annotated in the human genome, only a few have been studied for their regulatory mechanisms and functions in cancer progression and therapeutic resistance. Here, we report the pleiotropy of one enhancer (named enh9) in both cell proliferation and migration in non-small cell lung cancer (NSCLC) cells. By integrating multi-genomic data, ERMP1 and PD-L1 were screened out as potential targets of enh9. CUT&Tag sequencing demonstrated that enh9 was involved in the genomic interactions between the transcription factor RELA and the promoters of ERMP1 and PD-L1. In addition, ERMP1 and PD-L1 were validated to be involved in cell proliferation and migration, respectively. Our study fully elucidated the function and transcriptional regulation mechanisms of enh9 in NSCLC. The exploration on enhancers is promising to provide new insights for cancer diagnosis and therapy.

Clinical outcomes of pomalidomide-based and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma: A real-world cohort study in China.

BACKGROUND: Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real-world studies. METHODS: This retrospective cohort study included 140 RRMM patients treated with Pom-based or Dara-based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023. RESULTS: The overall response rates (ORR) for Pom-based (n = 48), Dara-based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression-free survival (PFS) was 5.7 months (95% CI: 5.0-6.5) for the Pom-based group, 10.5 months (5.2-15.8) for the Dara-based group, and 6.7 months (4.0-9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double-refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara-based regimens over Pom-based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara-based and DPd regimens (Pom-based 39.6% vs. Dara-based 64.7% vs. DPd 70.8%, p = 0.009). CONCLUSIONS: In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy.

The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8.

Replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is mediated by a complex of non-structural proteins (NSPs), of which NSP7 and NSP8 serve as subunits and play a key role in promoting the activity of RNA-dependent RNA polymerase (RdRp) of NSP12. However, the stability of subunits of the RdRp complex has rarely been reported. Here, we found that NSP8 was degraded by the proteasome in host cells, and identified tripartite motif containing 22 (TRIM22) as its E3 ligase. The interferon (IFN) signaling pathway was activated upon viral invasion into host cells, and TRIM22 expression increased. TRIM22 interacted with NSP8 and ubiquitinated it at Lys97 via K48-type ubiquitination. TRIM22 overexpression significantly reduced viral RNA and protein levels. Knockdown of TRIM22 enhanced viral replication. This study provides a new explanation for treating patients suffering from SARS-CoV-2 with IFNs and new possibilities for drug development targeting the interaction between NSP8 and TRIM22.IMPORTANCENon-structural proteins (NSPs) play a crucial role in the replication of severe acute respiratory syndrome coronavirus 2, facilitating virus amplification and propagation. In this study, we conducted a comprehensive investigation into the stability of all subunits comprising the RNA-dependent RNA polymerase complex. Notably, our results reveal for the first time that NSP8 is a relatively unstable protein, which is found to be readily recognized and degraded by the proteasome. This degradation process is mediated by the host E3 ligase tripartite motif containing 22 (TRIM22), which is also a member of the interferon stimulated gene (ISG) family. Our study elucidates a novel mechanism of antiviral effect of TRIM22, which utilizes its own E3 ubiquitin ligase activity to hinder viral replication by inducing ubiquitination and subsequent degradation of NSP8. These findings provide new ideas for the development of novel therapeutic strategies. In addition, the conserved property of NSP8 raises the possibility of developing broad antiviral drugs targeting the TRIM22-NSP8 interaction.

Modification of maternally defined H3K4me3 regulates the inviability of interspecific Xenopus hybrids.

Increasing evidence suggests that interspecific hybridization is crucial to speciation. However, chromatin incompatibility during interspecific hybridization often renders this process. Genomic imbalances such as chromosomal DNA loss and rearrangements leading to infertility have been commonly noted in hybrids. The mechanism underlying reproductive isolation of interspecific hybridization remains elusive. Here, we identified that modification of maternally defined H3K4me3 in Xenopus laevis and Xenopus tropicalis hybrids determines the different fates of the two types of hybrids as te×ls with developmental arrest and viable le×ts. Transcriptomics highlighted that the P53 pathway was overactivated, and the Wnt signaling pathway was suppressed in te×ls hybrids. Moreover, the lack of maternal H3K4me3 in te×ls disturbed the balance of gene expression between the L and S subgenomes in this hybrid. Attenuation of p53 can postpone the arrested development of te×ls. Our study suggests an additional model of reproductive isolation based on modifications of maternally defined H3K4me3.

Interferon stimulated immune profile changes in a humanized mouse model of HBV infection.

The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.

Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies.

BACKGROUND/AIMS: Absence of curative treatment creates urgent need for new strategies for unresectable hepatoma. Based on former discoveries of good liver cell compatibility, safety and tumour-specific inhibition of hydroxyapatite nanoparticles (nHAP), this work tries to make nHAP serve as gene vector in the hepatoma-targeted trans-arterial embolization (TAE) gene therapy to elevate and synergize the therapeutic efficacy of TAE and target gene therapy. METHOD: Following dosage and ratio optimization, polypolex formed by surface modified nHAP and p53 expressing plasmid was applied in vitro for human hepatoma HePG2 cell, and then in vivo for rabbit hepatic VX2 tumour by injection of polypolex/lipodoil emulsion to the hepatic artery in a tumour-target manner. RESULTS: In vitro, the polypolex transfected only about 5% HepG2 cells, but can elevate the inhibition of its growth and apoptosis in a much more degree while keeping safe to the normal hepatocyte line, L02. In vivo, the emulsion, with better dispersion than the polypolex and more specific tumour-target than lipiodol, mediated specific 4% p53 expression and antitumoural nanoparticle retention in the target tumour site, also significantly reduced tumour growth and prolonged the animal survival times more than the lipiodol (P < 0.05). CONCLUSIONS: In all, this new treatment based on nHAP can enhance therapeutic effect of HCC safely both in vitro and in vivo.

High-sodium intake aggravates myocardial injuries induced by aldosterone via oxidative stress in Sprague-Dawley rats.

AIM: To evaluate the effects of aldosterone with or without high sodium intake on blood pressure, myocardial structure and left ventricular function in rats, and to investigate the mechanisms underlying the effects. METHODS: Eight-week-old male Sprague-Dawley rats were randomly divided into 3 groups: (1) control (CON) group fed a normal sodium diet, (2) aldosterone (ALD) group receiving aldosterone infusion and a normal sodium diet, and (3) high sodium plus aldosterone (HS-ALD) group receiving 1% NaCl diet in conjunction with aldosterone infusion. Aldosterone was administered through continuously subcutaneous infusion with osmotic minipump at the rate of 0.75 µg/h for 8 weeks. The myocardium structure was observed using transthoracic echocardiography and transmission electron microscopy. The collagen deposition in left ventricle was evaluated with Masson's trichrome staining. The expression of IL-18, p22phox, and p47phox proteins was examined using Western blot analysis. RESULTS: The systolic blood pressure in the ALD and HS-ALD groups was significantly higher than that in the CON group after 2-week treatment. But the blood pressure showed no significant difference between the HS-ALD and ALD groups. The left ventricular hypertrophy, myocardial collagen deposition and oxidative stress were predominantly found in the HS-ALD and ALD group. Furthermore, the breakdown of myocardial structure and oxidative stress were more apparent in the HS-ALD group as compared with those in the ALD group. CONCLUSION: Long-term infusion of aldosterone results in hypertension and profibrotic cardiovascular responses in rats fed a normal sodium diet, which were mediated by oxidative stress. High-sodium intake could aggravate myocardial injuries induced by aldosterone.

Spike-mediated ACE2 down-regulation was involved in the pathogenesis of SARS-CoV-2 infection.

The ongoing global pandemic of Coronavirus disease 2019 (COVID-19) poses a serious threat to human health, with patients reportedly suffering from thrombus, vascular injury and coagulation in addition to acute and diffuse lung injury and respiratory diseases. Angiotensin converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 entry, is also an important regulator of renin-angiotensin system (RAS) homeostasis, which plays an unsettled role in the pathogenesis of COVID-19. Here, we demonstrated that SARS-CoV-2 Spike protein activated intracellular signals to degrade ACE2 mRNA. The decrease of ACE2 and higher level of angiotensin (Ang) II were verified in COVID-19 patients. High dose of Ang II induced pulmonary artery endothelial cell death in vitro, which was also observed in the lung of COVID-19 patients. Our finding indicates that the downregulation of ACE2 potentially links COVID-19 to the imbalance of RAS.

A prophylactic effect of aluminium-based adjuvants against respiratory viruses via priming local innate immunity.

Infection caused by respiratory viruses can lead to a severe respiratory disease and even death. Vaccination is the most effective way to prevent the disease, but it cannot be quickly applied when facing an emerging infectious disease. Here, we demonstrated that immunization with an aluminium-zinc hybrid particulate adjuvant (FH-001) alone, bearing great resemblance in morphology with commonly used aluminium-based adjuvants in vaccines, could quickly induce mice to generate a broadly protective immune response to resist the lethal challenge of influenza B viruses. Furthermore, a multi-omics-based analysis revealed that the alveolar macrophage and type I interferon pathway, rather than adaptive immunity and type II interferon pathway, were essential for the observed prophylactic effect of FH-001. More importantly, a similar protective effect was observed against influenza A virus strain A/Shanghai/02/2013(H7N9), A/California/04/2009(H1N1) and respiratory syncytial virus. Therefore, we introduced here a new and promising strategy that can be quickly applied during the outbreak of emerging respiratory viruses.

Vascular endothelial dysfunction in patients with newly diagnosed type 2 diabetes and effects of 2-year and 5-year multifactorial intervention.

OBJECTIVES: Investigate short- and long-term effect of multifactorial intervention on endothelial dysfunction in patients with newly diagnosed type 2 diabetes. BACKGROUND: Whether multifactorial intervention reduces cardiovascular risk in type 2 diabetes is largely controversial, partially because of lack of reliable method for endothelial dysfunction detection. Using high-resolution ultrasonographical flow-mediated vasodilatation (FMD), we completed a 5-year randomized prospective intervention trial in patients with newly diagnosed type 2 diabetes. We have studied the effect of multifactorial intervention therapy on their endothelial dysfunction. METHODS: One hundred eight patients with newly diagnosed type 2 diabetes, and 83 healthy subjects received measurement of brachial artery FMD and endothelium-independent dilatation (EID). Diabetic patients were assigned into four groups, treated with: (A) hypoglycemic and antihypertensive agents, (B) hypoglycemic, antihypertensive and lipid-lowering agents, (C) hypoglycemic, antihypertensive and lipid-lowering agents, and vitamin E, and (D) hypoglycemic, antihypertensive and lipid-lowering agents, and compound salvia tablets. Both FMD and EID were remeasured after 24- and 60-month treatment. RESULTS: FMD in diabetic patients was significantly lower than those in healthy subjects. After 24-month treatment, there was no FMD change. However, FMD improved significantly after 60-month treatment. The differences between 24- and 60-month are also significant. EID did not change significantly after both 24- and 60-month treatments. CONCLUSIONS: (1) FMD-detectable endothelial dysfunction exists in newly diagnosed type 2 diabetic patients. (2) Reverse of endothelial function occurs only after long-term (60-month) multifactorial intervention. (3) FMD could potentially help early identification, stratification, and treatment of endothelial dysfunction in type 2 diabetic patients.

Fibrinogen-to-Albumin Ratio is Associated with All-Cause Mortality in Cancer Patients.

BACKGROUND: Past studies have identified fibrinogen-to-albumin ratio (FAR) as a novel prognostic immune biomarker in various diseases. Here, we investigated the prognostic value of FAR in all combined cancer mortality. METHODS: We extracted patient data from the Multiparameter Intelligent Monitoring in Intensive Care Database III. FAR was measured prior to hospital admission. Only first admission data from each patient were used. Baseline data were extracted within 24 h after admission. The clinical endpoints were 90- and 365-day all-cause cancer mortality. Cox proportional hazards models and subgroup analyses were used to determine the relationship between FAR and these clinical endpoints. RESULTS: A total of 652 eligible patients were enrolled. Upon adjusting for age and gender, multivariate analysis revealed correlation between higher FAR values and increased risk of all-cause mortality. After adjusting for more confounding factors, higher FAR values significantly correlated with 90- and 365-day all-cause mortality relative to low FAR values (tertile 3 vs tertile 1: HR, 95% CI: 1.65, 1.15-2.39; 1.52, 1.10-2.10). CONCLUSION: Our findings indicate that FAR may predict the risk of cancer mortality and is an independent prognostic indicator of all-cause mortality in cancer patients.

Exploring the role of monocyte chemoattractant protein-1 in fibroblast-like synovial cells in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease with persistent synovitis. In the present study, the impact of monocyte chemoattractant protein-1 (MCP-1) was explored to determine methods for the diagnosis and treatment of RA. METHODS: First, fibroblast-like synoviocytes (FLSs) were obtained from a collagen-induced rat RA model. Next, MCP-1-overexpression plasmid and small interfering RNA were transfected into human and rat FLSs. Cell Counting Kit-8 (CCK-8), Transwell migration and flow cytometry assays were used to analyze cell proliferation, migration and apoptosis of FLSs following MCP-1 transfections, respectively. Furthermore, western blotting was used to analyze the expression levels of p-P38, p-PI3K, PI3K, CD31, VEGF, TNF-α and IL-ß in FLSs following MCP-1 transfection. In addition, reverse transcription-quantitative PCR and ELISAs were used to analyze the expression levels of C-reactive protein (CRP), estrogen receptor, MCP-1 and pentraxin-3 in patients with clinical RA, followed by correlation analysis of clinical data. Finally, expression validation, diagnostic and protein-protein interaction (PPI) network analysis of MCP-1 were performed. RESULTS: MCP-1 promoted FLS proliferation and migration, and affected the apoptosis of FLSs. In addition, the expression levels of p-P38, p-PI3K, PI3K, CD31, VEGF, TNF-α and IL-ß were also affected by MCP-1. In patients with clinical RA, the expression level of MCP-1 was increased. Moreover, CRP expression level was significantly up-regulated in RA. Clinically, MCP-1 was strongly correlated with tender joint count, swollen joint count, visual analog scale for general health and disease activity score 28 (DAS28)-MCP-1, and was moderately correlated with DAS28 and DAS28-CRP. PPI analysis showed that MCP-1 mainly interacted with other inflammatory cytokines. CONCLUSION: In conclusion, MCP-1 may play a significant regulatory role in RA, and could be used as a measurement index of clinical RA activity.

Quasispecies of SARS-CoV-2 revealed by single nucleotide polymorphisms (SNPs) analysis.

New SARS-CoV-2 mutants have been continuously indentified with enhanced transmission ever since its outbreak in early 2020. As an RNA virus, SARS-CoV-2 has a high mutation rate due to the low fidelity of RNA polymerase. To study the single nucleotide polymorphisms (SNPs) dynamics of SARS-CoV-2, 158 SNPs with high confidence were identified by deep meta-transcriptomic sequencing, and the most common SNP type was C > T. Analyses of intra-host population diversity revealed that intra-host quasispecies' composition varies with time during the early onset of symptoms, which implicates viral evolution during infection. Network analysis of co-occurring SNPs revealed the most abundant non-synonymous SNP 22,638 in the S glycoprotein RBD region and 28,144 in the ORF8 region. Furthermore, SARS-CoV-2 variations differ in an individual's respiratory tissue (nose, throat, BALF, or sputum), suggesting independent compartmentalization of SARS-CoV-2 populations in patients. The positive selection analysis of the SARS-CoV-2 genome uncovered the positive selected amino acid G251V on ORF3a. Alternative allele frequency spectrum (AAFS) of all variants revealed that ORF8 could bear alternate alleles with high frequency. Overall, the results show the quasispecies' profile of SARS-CoV-2 in the respiratory tract in the first two months after the outbreak.

Dysregulated hematopoiesis in bone marrow marks severe COVID-19.

Severe coronavirus disease 2019 (COVID-19) is often indicated by lymphopenia and increased myelopoiesis; however, the underlying mechanism is still unclear, especially the alteration of hematopoiesis. It is important to explore to what extent and how hematopoietic stem cells contribute to the impairment of peripheral lymphoid and myeloid compartments in COVID-19 patients. In this study, we used single-cell RNA sequencing to assess bone marrow mononuclear cells from COVID-19 patients with peripheral blood mononuclear cells as control. The results showed that the hematopoietic stem cells in these patients were mainly in the G1 phase and prone to apoptosis, with immune activation and anti-viral responses. Importantly, a significant accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors in severe cases were identified, along with the up-regulation of transcription factors (such as SPI1, LMO4, ETS2, FLI1, and GATA2) that are important for the hematopoietic stem cell or multipotent progenitor to differentiate into downstream progenitors. Our results indicate a dysregulated hematopoiesis in patients with severe COVID-19.