Αρχειοθήκη ιστολογίου

Κυριακή 11 Δεκεμβρίου 2022

Transcriptomic reveals the ferroptosis features of host response in a mouse model of Zika virus infection

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Abstract

Background

Zika virus (ZIKV) is a neurotropic flavivirus. The outbreak of ZIKV in 2016 created a global health emergency. However, the underlying pathogenic mechanisms remain elusive.

Methods

We investigated the host response features of in vivo replication in a mouse model of ZIKV infection, by performing a series of transcriptomic and bioinformatic analyses of ZIKV and mock-infected brain tissue.

Results

Tissue damage, inflammatory cells infiltration and high viral replication were observed in the brain tissue of ZIKV infected mice. RNA-Seq of the brain indicated the activation of ferroptosis pathways. Enrichment analysis of ferroptosis regulators revealed their involvement in pathways such as mineral absorption, fatty acid biosynthesis, fatty acid degradation, PPAR signaling pathway, peroxidase and adipokinesine signalling pathway. We then identified 12 interacted hub ferroptosis regulators (CYBB, HMOX1, CP, SAT1, TF, SLC39A14, FTL, LPCAT3, FTH1, SLC3A2, TP53 and SLC40A1) that were related to the differential expression of CD8+ T cells, microglia and monocytes. CYBB, HMOX1, SALT and SLAC40A1 were selected as potential biomarkers of ZIKV infection. Finally, we validated our results using RT-qPCR and outside available datasets.

Conclusions

For the first time, we proposed a possible mechanism of ferroptosis in brain tissue infected by ZIKV in mice and identified the four key ferroptosis regulators.

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Establishment of a diverse head and neck squamous cancer cell bank using conditional reprogramming culture methods

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Abstract

Most laboratory models of head and neck squamous cell cancer (HNSCC) rely on established immortalized cell lines, which carry inherent bias due to selection and clonality. We established a robust panel of HNSCC tumor cultures using a "conditional reprogramming" (CR) method, which utilizes a rho kinase inhibitor (Y-27632) and co-culture with irradiated fibroblast (J2 strain) feeder cells to support indefinite tumor cell survival. Sixteen CR cultures were successfully generated from 19 consecutively enrolled ethnically and racially diverse patients with HNSCC at a tertiary care center in the Bronx, NY. Of the 16 CR cultures, 9/16 were derived from oral cavity, 4/16 were derived from oropharynx, and 3/16 were from laryngeal carcinomas. Short tandem repeat (STR) profiling was used to validate culture against patient tumor tissue DNA. All CR cultures expressed ΔNp63 and cytokeratin 5/6, which are markers of squamous identity. Human papilloma virus (HPV) testing was assessed utiliz ing clinical p16 staining on primary tumors, RT-PCR of HPV16/18 specific viral oncogenes E6 and E7 in RNA extracted from tumor samples, and HPV DNA sequencing. Three of 4 oropharyngeal tumors were p16 and HPV-positive and maintained HPV in culture. CR cultures were able to establish three-dimensional spheroid and murine flank and orthotopic tongue models. CR methods can be readily applied to all HNSCC tumors regardless of patient characteristics, disease site, and molecular background, providing a translational research model that properly includes patient and tumor diversity.

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Avian influenza A virus H7N9 in China, a role reversal from reassortment receptor to the donator

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Abstract

Reassortment can introduce one or more gene segments of influenza A viruses (IAVs) into another, resulting in novel subtypes. Since 2013, a new outbreak of human highly pathogenic avian influenza has emerged in the Yangtze River Delta (YRD) and South-Central regions of China. In this study, using Anhui province as an example, we discuss the possible impact of H7N9 IAVs on future influenza epidemics through a series of gene reassortment events. Sixty-one human H7N9 isolates were obtained from five outbreaks in Anhui province from 2013–2019. Bioinformatics analyses revealed that all of them were characterized by low pathogenicity and high human or mammalian tropism and have introduced novel avian influenza A virus (AIV) subtypes such as H7N2, H7N6, H9N9, H5N6, H6N6, and H10N6 through gene reassortment. In reassortment events, Anhui isolates may donate one or more segments of HA, NA, and the six internal protein-coding genes for the novel subtype AIVs. Our study revealed that H7N9, H9N2, and H5N1 can serve as stable and persistent gene pools for AIVs in the YRD and South-Central regions of China. Novel AIV subtypes might be generated continuously by reassortment. These AIVs may have obtained human-type receptor-binding abilities from their donors and prefer binding to them, which can cause human epidemics through accidental spillover infections. Facing the continual threat of emerging avian influenza, constant monitoring of AIVs should be conducted closely for agricultural and public health.

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Gimap5 promoted RSV degradation through interaction with M6PR

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Abstract

Backgroud

Respiratory Syncytial Virus (RSV) is one of the main pathogens of viral pneumonia and bronchiolitis in infants and young children and a life threatening diseases among infants and young children. GTPases of the immune-associated protein family (GIMAP) are a new family members of immune-associated GTPases. In recent years, much attention has been paid to the function of the GIMAP family in coping with infection and stress. Gimap5 is a member of the GIMAP family, which may be correlated with anti-infectious immunity.

Methods

RT-qPCR, Western blot and indirect immunofluorescence (IFA) were used to detect the expression of Gimap5, M6PR and IGF1R(the major RSV receptor). Transmission electron microscopy (TEM) was used to detect the degradation of RSV in Gimap5-overexpressed or -silent cell lines. Computer virtual screening was used to screen small molecule compounds targeting Gimap5 and the anti-RSV effects were explored through in vivo and in vitro experiments.

Results

GIMAP5 and M6PR were significantly down-regulated after RSV infection. Gimap5 accelerated RSV degradation in lysosomes by interacting with M6PR, and further prevented RSV invasion by down-regulating the expression of RSV surface receptor IGF1R. Three small molecule compounds targeting Gimap5 were confirmed to be the agonists of Gimap5. The three compounds effectively inhibited RSV infection and RSV-induced complications.

Conclusion

Gimap5 promotes the degradation of RSV and its receptor through interacting with M6PR. Gimap5 agonists can effectively reduce RSV infection and RSV-induced complication in vivo and in vitro, which provides a new choice for the treatment of RSV.

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Efficacy and safety of camrelizumab plus apatinib compared to apatinib monotherapy as third‐line or above therapy for metastatic colorectal cancer patients: A retrospective cohort study

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Efficacy and safety of camrelizumab plus apatinib compared to apatinib monotherapy as third-line or above therapy for metastatic colorectal cancer patients: A retrospective cohort study

This study aimed to investigate the treatment efficacy and safety of camrelizumab (programmed cell death protein-1 (PD-1) inhibitor) plus apatinib as third-line or above therapy in metastatic colorectal cancer (mCRC) patients. Totally, 64 unresectable mCRC patients receiving camrelizumab plus apatinib (N = 31) and apatinib (N = 33) were retrospectively enrolled. It was found that disease control rate and objective response rate (ORR) were increased in camrelizumab plus apatinib group compared to apatinib group, but ORR did not achieve statistical significance. Besides, the median (95% confidence interval [CI]) progressive-free survival (PFS) and overall survival (OS) were 6.9 (3.7–10.1) and 11.5 (7.7–15.3) months in camrelizumab plus apatinib group, as well as 3.6 (1.7–5.5) and 6.7 (5.0–8.4) months in apatinib group. Additionally, PFS and OS were prolonged in camrelizumab plus apatinib group compared with apatinib group. The incidence of a dverse events did not differ between groups. Conclusively, camrelizumab (PD-1 inhibitor) plus apatinib achieves a better treatment efficacy than apatinib as third-line or above therapy with a good safety profile in mCRC patients.


Abstract

What Is Known and Objective

Programmed cell death protein-1 (PD-1) inhibitors synergize apatinib for anti-tumour effect by regulating tumour microenvironment, vascular endothelial growth factor, hypoxia condition, immune response, etc. This study aimed to investigate the treatment efficacy and safety of camrelizumab (PD-1 inhibitor) plus apatinib as third-line or above therapy in metastatic colorectal cancer (mCRC) patients.

Methods

Totally, 64 unresectable mCRC patients receiving camrelizumab plus apatinib (N = 31) and apatinib (N = 33) were retrospectively enrolled.

Results

Disease control rate (80.6% vs. 57.6%) (P = 0.047) was elevated in camrelizumab plus apatinib group compared to apatinib group; however, objective response rate (22.6% vs. 6.1%) (P = 0.078) only showed an increasing trend but did not achieve statistical significance. Besides, the median (95% confidence interval [CI]) progressive-free survival (PFS) and overall survival (OS) were 6.9 (3.7–10.1) and 11.5 (7.7–15.3) months in camrelizumab plus apatinib group; meanwhile, the median (95% CI) PFS and OS were 3.6 (1.7–5.5) and 6.7 (5.0–8.4) months in the apatinib group. Additionally, PFS (P = 0.017) and OS (P = 0.006) were prolonged in camrelizumab plus apatinib group compared with apatinib group, which was confirmed by further multivariate Cox's proportional hazards regression analysis (hazard ratio [HR] = 0.340, P < 0.001 for PFS; HR = 0.271, P < 0.001 for OS). Th e incidence of total, grade 1–2, and grade 3–4 adverse events did not differ between groups (all P > 0.05).

Conclusion

Camrelizumab (PD-1 inhibitor) plus apatinib achieves a better treatment efficacy than apatinib as third-line or above therapy with a good safety profile in mCRC patients.
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Evaluation the efficacy and safety of N‐acetylcysteine inhalation spray in controlling the symptoms of patients with COVID‐19: An open‐label randomized controlled clinical trial

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

The aim of this study was to evaluate the effect and safety of N-acetylcysteine (NAC) inhalation spray in the treatment of patients with coronavirus disease 2019 (COVID-19).

Methods

This randomized controlled clinical trial study was conducted on patients with COVID-19. Eligible patients (n=250) were randomly allocated into the intervention group (routine treatment + NAC inhaler spray one puff per 12 hours, for 7 days) or the control group who received routine treatment alone. Clinical features, hemodynamic, hematological, biochemical parameters and patient outcomes were assessed and compared before and after treatment.

Results

The mortality rate was significantly higher in the control group than in the intervention group (39.2% vs 3.2%, P<0.001). Significant differences were found between the two groups (intervention and control, respectively) for white blood cell count (6.2 vs 7.8, P<0.001), hemoglobin (12.3 vs 13.3, P=0.002), C-reactive protein (CRP: 6 vs 11.5, P<0.0001) and aspartate aminotransferase (AST: 32 vs 25.5, P<0.0001). No differences were seen for hospital length of stay (11.98±3.61 vs 11.81±3.52, P=0.814) or the requirement for ICU admission (7.2% vs 11.2%, P=0.274).

Conclusions

NAC was beneficial in reducing the mortality rate in patients with COVID-19 and inflammatory parameters, and a reduction in the development of severe respiratory failure; however, it did not affect the length of hospital stay or the need for ICU admission. Data on the effectiveness of NAC for SARS-CoV-2 is limited and further research is required.

Clinical Trial Registration

This study Registered at Iranian Registry of Clinical Trials (IRCT20080901001165N55) dated 23-05-2020.

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Mendelian randomization suggests a potential causal effect of eosinophil count on influenza vaccination responsiveness

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Currently, the clinical factors affecting immune responses to influenza vaccines have not been systematically explored. The mechanism of low responsiveness to influenza vaccination (LRIV) is complicated and not thoroughly elucidated. Thus, we integrate our in-house genome-wide association studies (GWAS) analysis result of LRIV (N = 111, Ncase [Low Responders] = 34, Ncontrol [Responders] = 77) with the GWAS summary of 10 blood-based biomarkers (sample size ranging from 62,076 to 108,794) deposited in BioBank Japan (BBJ) to comprehensively explore the shared genetics between LRIV and blood-based biomarkers to investigate the causal relationships between blood-based biomarkers and LRIV by Mendelian randomization (MR). The applications of four MR approaches (inverse-variance-weighted (IVW), weighted median, weighted mode, and generalized summary-data-based Mendelian randomization (GSMR)) suggested that the genetically instrumented LRIV was associated with decreased eosinophil count (� � = -5.517 to -4.422, p-value = 0.004 to 0.039). Finally, we conclude that the low level of eosinophil count is a suggestive risk factor for LRIV.

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The prognostic significance of hematogones in childhood B‐cell acute lymphoblastic leukemia

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

Recent studies have demonstrated hematogones (HGs) expansion to be associated with favorable outcomes in hematological diseases, especially in patients with acute myeloid leukemia and patients undergoing hematopoietic stem cell transplantation. Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. As of now, minimal residual disease (MRD) remains the most compelling independent prognostic factor in childhood ALL. There is need for more prognostic tools for evaluating relapse risk.

Procedure

The goal of this study was to assess the prognostic value of HGs on relapse-free survival (RFS) and overall survival (OS) in childhood ALL. In this prospective cohort study, a total of 122 subjects with definitive diagnosis of precursor B lymphoblastic leukemia were evaluated. Flow cytometric HG detection was performed in bone marrow aspirates after induction and consolidation therapy.

Results

The median follow-up period of patients was 35.5 ± 9.4 (SD) months. Patients who had at least 1.0% HGs had a significantly better RFS (p = .023). Moreover, univariate and multivariate analyses confirmed that positive HGs were independently associated with longer RFS (unadjusted model: hazard ratio = 0.33, 95% CI = 0.12–0.91, p = .031; adjusted model: hazard ratio = 0.30, 95% CI = 0.11–0.82, p = .020).

Conclusions

Along with the role of MRD, our study shows the significance of HGs as an independent prognostic factor. The results indicate the independent prognostic value of HGs on RFS after adjustment for other prognostic factors, and can be beneficial for risk stratification and treatment modifications amongst pediatric B-cell ALL patients.
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Duration of antibiotic treatment for acute graft pyelonephritis: What's the standard of care?

alexandrossfakianakis shared this article with you from Inoreader
Duration of antibiotic treatment for acute graft pyelonephritis: What's the standard of care?


Abstract

Background

Limited evidence is available to inform the duration of antibiotic treatment in kidney transplant recipients with bacterial acute graft pyelonephritis. Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation suggest a 14–21 day duration.

Methods

A four-question survey was constructed to determine the current standard of practice for the duration of treatment for acute graft pyelonephritis. The survey was distributed among members of the Infectious Diseases and the Kidney Pancreas Communities of Practice of the American Society of Transplantation.

Results

Among 144 survey respondents, 87 (60%) were infectious disease physicians, and 36 (25%) were transplant nephrologists. Although most (55%) respondents preferred a 14-day duration, a spread between 7 and 28 days was observed. Goals of treatment and drivers for longer duration differed between infectious disease physicians and transplant nephrologists.

Conclusions

Although most respondents prefer a 14-day duration of treatment for acute graft pyelonephritis, a wide range of responses was seen between 7 and 28 days. More evidence is needed to inform optimal treatment duration in this common infectious complication after transplantation.

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