Combination of novel oncolytic herpesvirus with paclitaxel as an efficient strategy for breast cancer therapy.

BACKGROUND: New strategies are needed to improve the treatment of patients with breast cancer (BC). Oncolytic virotherapy is a promising new tool for cancer treatment but still has a limited overall durable antitumor response. A novel replicable recombinant oncolytic herpes simplex virus type 1 called VG161 has been developed and has demonstrated antitumor effects in several cancers. Here, we explored the efficacy and the antitumor immune response of VG161 cotreatment with paclitaxel (PTX) which as a novel oncolytic viral immunotherapy for BC. METHODS: The antitumor effect of VG161 and PTX was confirmed in a BC xenograft mouse model. The immunostimulatory pathways were tested by RNA-seq and the remodeling of tumor microenvironment was detected by Flow cytometry analysis or Immunohistochemistry. Pulmonary lesions were analyzed by the EMT6-Luc BC model. RESULTS: In this report, we demonstrate that VG161 can significantly represses BC growth and elicit a robust antitumor immune response in a mouse model. The effect is amplified when combined with PTX treatment. The antitumor effect is associated with the infiltration of lymphoid cells, including CD4+ T cells, CD8+ T cells, and NK cells (expressing TNF and IFN-γ), and myeloid cells, including macrophages, myeloid-derived suppressor cells, and dendritic cell cells. Additionally, VG161 cotreatment with PTX showed a significant reduction in BC lung metastasis, which may result from the enhanced CD4+ and CD8+ T cell-mediated responses. CONCLUSIONS: The combination of PTX and VG161 is effective for repressing BC growth by inducing proinflammatory changes in the tumor microenvironment and reducing BC pulmonary metastasis. These data will provide a new strategy and valuable insight for oncolytic virus therapy applications in primary solid or metastatic BC tumors.

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine.

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants. In naïve animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccine's targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection against Delta and Omicron BA.1variants. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine-primed populations.

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Mental health and self-determination profiles of the diverse population of medical students in Malaysia during the COVID-19 pandemic.

INTRODUCTION: Medical schools throughout the world were forced to modify their programming during the COVID-19 pandemic. In Malaysia, virtual learning plans were implemented for non-clinical programming, while clinical posting modifications were designed to meet local SOPs. The prolonged enforcement of these modifications to undergraduate medical education will have affected student experiences, including well-being. Since these feelings can relate to perceived relatedness, autonomy, and competence, it is important to identify any potential factors that may lead to reduced intrinsic motivation in students. It is also important to consider how demographic features may contribute to student perspectives, which can be studied using the unique diversity represented by Malaysian students. METHODS: A quantitative survey was distributed to Malaysian medical students to assess their overall wellbeing, autonomy in educational decision making, student experiences, and position on changes to graduation timing. Intrinsic components were identified using Principal Component Analysis and were aligned with the three needs for self-determination, namely relatedness, autonomy, and competence. Finally, trends in responses for participants from various sub-populations were assessed using ANOVA testing. RESULTS: Responses were collected from 442 students representing 23 accredited Malaysian medical schools. Upon validation and reliability testing, eight components were identified with themes relating to: mental health, social concerns, communication, timing of modifications, depth of learning, and student-centred learning. Of these, gender was related to mental health, student-centred learning, and delayed graduation, while stage was related to student-centred learning and delayed graduation in addition to concerns about depth of learning and timing of modifications. Interestingly, ethnicity was related to differences in opinions about delayed graduation and income was related to social concerns. CONCLUSION: The results of this study indicate that, while students were satisfied in general with the content and delivery of their programmes given the circumstances, there is evidence to suggest negative effects on emotional wellbeing and expression of student voice, due to the modifications that were made. Additionally, these feelings related to the three motivational needs, suggesting that students were experiencing a dampened motivational profile during the pandemic. Further, motivational profiles were distinct between student sub-groups, providing insight for developing appropriate and inclusive accommodations moving forward.

Role of Human Antigen R (HuR) in the Regulation of Pulmonary ACE2 Expression.

Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is not known but may involve HuR, an RNA binding protein that increases protein expression by stabilizing mRNA. We hypothesized that HuR would increase ACE2 protein expression. We analyzed scRNA-seq data to profile ELAVL1 expression in distinct respiratory cell populations in COVID-19 and COPD patients. HuR expression and cellular localization was evaluated in COPD lung tissue by multiplex immunohistochemistry and in human lung cells by imaging flow cytometry. The regulation of ACE2 expression was evaluated using siRNA-mediated knockdown of HuR. There is a significant positive correlation between ELAVL1 and ACE2 in COPD cells. HuR cytoplasmic localization is higher in smoker and COPD lung tissue; there were also higher levels of cleaved HuR (CP-1). HuR binds to ACE2 mRNA but knockdown of HuR does not change ACE2 protein levels in primary human lung fibroblasts (HLFs). Our work is the first to investigate the association between ACE2 and HuR. Further investigation is needed to understand the mechanistic underpinning behind the regulation of ACE2 expression.

Children and Adolescents' Psychological Well-Being Became Worse in Heavily Hit Chinese Provinces during the COVID-19 Epidemic.

In light of the novel coronavirus's (COVID-19's) threat to public health worldwide, we sought to elucidate COVID-19's impacts on the mental health of children and adolescents in China. Through online self-report questionnaires, we aimed to discover the psychological effects of the pandemic and its associated risk factors for developing mental health symptoms in young people. We disseminated a mental health survey through online social media, WeChat, and QQ in the five Chinese provinces with the most confirmed cases of COVID-19 during the late stage of the country-wide lockdown. We used a self-made questionnaire that queried children and adolescents aged 6 to 18 on demographic information, psychological status, and other lifestyle and COVID-related variables. A total of 17,740 children and adolescents with valid survey data participated in the study. 10,022 (56.5%), 11,611 (65.5%), 10,697 (60.3%), 6868 (38.7%), and 6225 (35.1%) participants presented, respectively, more depressive, anxious, compulsive, inattentive, and sleep-related problems compared to before the outbreak of COVID-19. High school students reported a greater change in depression and anxiety than did middle school and primary school students. Despite the fact that very few children (0.1%) or their family members (0.1%) contracted the virus in this study, the psychological impact of the pandemic was clearly profound. Fathers' anxiety appeared to have the strongest influence on a children's psychological symptoms, explaining about 33% of variation in the child's overall symptoms. Other factors only explained less than 2% of the variance in symptoms once parents' anxiety was accounted for. The spread of COVID-19 significantly influenced the psychological state of children and adolescents in participants' view. It is clear that children and adolescents, particularly older adolescents, need mental health support during the pandemic. The risk factors we uncovered suggest that reducing fathers' anxiety is particularly critical to addressing young people's mental health disorders in this time.

Mental Health and Self-Determination Profiles of the Diverse Population of Medical Students in Malaysia During the COVID-19 Pandemic (preprint)

Introduction: Medical schools throughout the world were forced to modify their programming during the COVID-19 pandemic. In Malaysia, virtual learning plans were implemented for non-clinical programming, while clinical posting modifications were designed to meet local SOPs. The prolonged enforcement of these modifications to undergraduate medical education will have affected student experiences, including well-being. Since these feelings can relate to perceived relatedness, autonomy, and competence, it is important to identify any potential factors that may lead to reduced intrinsic motivation in students. It is also important to consider how demographic features may contribute to student perspectives, which can be studied using the unique diversity represented by Malaysian students. Methods: A quantitative survey was distributed to Malaysian medical students to assess their overall wellbeing, autonomy in educational decision making, student experiences, and position on changes to graduation timing. Intrinsic components were identified using Principal Component Analysis and were aligned with the three needs for self-determination, namely relatedness, autonomy, and competence. Finally, trends in responses for participants from various sub-populations were assessed using ANOVA testing. Results: Responses were collected from 442 students representing 23 accredited Malaysian medical schools. Upon validation and reliability testing, eight components were identified with themes relating to: mental health, social concerns, communication, timing of modifications, depth of learning, and student-centred learning. Of these, gender was related to mental health, student-centred learning, and delayed graduation, while stage was related to student-centred learning and delayed graduation in addition to concerns about depth of learning and timing of modifications. Interestingly, ethnicity was related to differences in opinions about delayed graduation and income was related to social concerns. Conclusion: The results of this study indicate that, while students were satisfied in general with the content and delivery of their programmes given the circumstances, there is evidence to suggest negative effects on emotional wellbeing, expression of student voice, due to the modifications that were made. Additionally, these feelings related to the three motivational needs, suggesting that students were experiencing a dampened motivational profile during the pandemic. Further, motivational profiles were distinct between student sub-groups, providing insight for developing appropriate and inclusive accommodations moving forward.

Facile fabrication of phenylenediamine residue derived N, O co-doped hierarchical hyperporous carbon for high-efficient chloroxylenol removal

The chloroxylenol (PCMX) has shown well virucidal efficacy against COVID-19, but the large-scale utilization of which will undoubtedly pose extra environmental threaten. In the present study, the recycled industrial phenylenediamine residue was used and an integrated strategy of “carbonization-casting-activation” using super low-dose of activator and templates was established to achieve in-situ N/O co-doping and facile synthesis of a kind of hierarchical hyperporous carbons (HHPC). The sample of HHPC-1.25-0.5 obtained with activator and template to residue of 1.25 and 0.5 respectively shows super-high specific surface area of 3602 m2/g and volume of 2.81 cm3/g and demonstrates remarkable adsorption capacity of 1475 mg/g for PCMX in batch and of 1148 mg/g in dynamic column adsorption test. In addition, the HHPC-1.25-0.5 exhibits excellent reusability and tolerance for PCMX adsorption under various ionic backgrounds and real water matrix conditions. The combined physio-chemistry characterization, kinetic study and DFT calculation reveal that the enhanced high performances originate from the hierarchical pore structure and strong electrostatic interaction between PCMX and surface rich pyridinic-N and carbonyl groups.

A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes' interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19.

Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19.

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications are not known. Using computational analysis with experimental data, we report that idiopathic pulmonary fibrosis (IPF)- and chronic obstructive pulmonary disease (COPD)-derived lung fibroblasts express higher levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is antifibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far has received relatively little attention in the context of COVID-19.

[Clinical efficacy of Matrine and Sodium Chloride Injection in treatment of 40 cases of COVID-19].

In this paper, we analyzed medical records of 40 patients with coronavirus disease 2019(COVID-19), in order to explore the clinical efficacy of Matrine and Sodium Chloride Injection in the treatment of COVID-19. The investigation was based on the results of a previous animal test, which was aimed to investigate and confirme the clinical efficacy of Matrine and Sodium Chloride Injection in the treatment of COVID-19. The animal test demonstrated that Matrine and Sodium Chloride Injection has a significant therapeutic effect on the human coronavirus pneumonia for the model mice. The lung inhibition index reached up to 86.86%. The evaluation was conducted on 40 confirmed cases of COVID-19 treated at Jingzhou Hospital of Infectious Disease(Chest Hospital) of Hubei Pro-vince from January 30~(th) to March 21~(th), 2020. In these cases, patients were treated with other integrated Chinese and Western medicines regimens in the recommended Matrine and Sodium Chloride Injection diagnosis and treatment regimen. The clinical manifestations, laboratory data, nucleic acid clearance time, and imaging data were compared and analyzed before and after treatment. After administration with Matrine and Sodium Chloride Injection, the clinical symptoms of 40 cases were alleviated markedly, and their blood analysis and biochemical indexes returned to normal. The lung CT showed more than 50% of lesion absorption rate, and the viral nucleic acid test showed the average clearance time of patients was 16.6 days, and the average length of hospital stay was 25.9 days. After administration with Matrine and Sodium Chloride Injection, the symptoms of cough and fatigue were alleviated significantly, and the appetite was significantly improved compared with before, especially for patients with gastrointestinal symptoms. Additionally, laboratory indicators, especially absolute value and ratio of lymphocytes and CRP were significantly alleviated. According to the chest CT for short-term review, the absorption of lung lesions was faster than before, especially for grid-like and fibrotic lesions. Compared with antiviral drugs, such as Abidol and Kriging, the nucleic acid clearance time was significantly shorter than the cases treated with Matrine and Sodium Chloride Injection. The clinical effective rate of 40 cases was 100.0%. We believed that Matrine and Sodium Chloride Injection have a good clinical effect in the treatment of COVID-19, and suggested increasing the clinical application and further conducting large-sample-size cli-nical verification.