Comparison of the clinical characteristics and mortalities of severe COVID-19 patients between pre- and post-menopause women and age-matched men.

The mortality rate of young female COVID-19 patients is reported to be lower than that of young males but no significant difference in mortality was found between female and male COVID-19 patients aged over 65 years, and the underlying mechanism is unknown. We retrospectively analyzed clinical characteristics and outcomes of severely ill pre- and post-menopausal COVID-19 patients and compared with age-matched males. Of the 459 patients included, 141 aged ≤55, among whom 19 died (16 males vs. 3 females, p<0.005). While for patients >55 years (n=318), 115 died (47 females vs. 68 males, p=0.149). In patients ≤55 years old, the levels of NLR, median LDH, median c-reactive protein and procalcitonin were significantly higher while the median lymphocyte count and LCR were lower in male than in female (all p<0.0001). In patients over 55, these biochemical parameters were far away from related normal/reference values in the vast majority of these patients in both genders which were in contrast to that seen in the young group. It is concluded that the mortality of severely ill pre-menopausal but not post-menopausal COVID-19 female patients is lower than age-matched male. Our findings support the notion that estrogen plays a beneficial role in combating COVID-19.

Mechanisms and Clinical Trials of Hepatocellular Carcinoma Immunotherapy.

Hepatocellular carcinoma (HCC), one of the most common and lethal tumors worldwide, is usually not diagnosed until the disease is advanced, which results in ineffective intervention and unfavorable prognosis. Small molecule targeted drugs of HCC, such as sorafenib, provided only about 2.8 months of survival benefit, partially due to cancer stem cell resistance. There is an urgent need for the development of new treatment strategies for HCC. Tumor immunotherapies, including immune check point inhibitors, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb), have shown significant potential. It is known that the expression level of glypican-3 (GPC3) was significantly increased in HCC compared with normal liver tissues. A bispecific antibody (GPC3-S-Fabs) was reported to recruit NK cells to target GPC3 positive cancer cells. Besides, bispecific T-cell Engagers (BiTE), including GPC3/CD3, an aptamer TLS11a/CD3 and EpCAM/CD3, were recently reported to efficiently eliminate HCC cells. It is known that immune checkpoint proteins programmed death-1 (PD-1) binding by programmed cell death-ligand 1 (PD-L1) activates immune checkpoints of T cells. Anti-PD-1 antibody was reported to suppress HCC progression. Furthermore, GPC3-based HCC immunotherapy has been shown to be a curative approach to prolong the survival time of patients with HCC in clinically trials. Besides, the vascular endothelial growth factor (VEGF) inhibitor may inhibit the migration, invasion and angiogenesis of HCC. Here we review the cutting-edge progresses on mechanisms and clinical trials of HCC immunotherapy, which may have significant implication in our understanding of HCC and its immunotherapy.

Cell­cell fusion as an important mechanism of tumor metastasis (Review).

Cell­cell fusion is a dynamic biological phenomenon, which plays an important role in various physiological processes, such as tissue regeneration. Similarly, normal cells, particularly bone marrow­derived cells (BMDCs), may attempt to fuse with cancer cells to rescue them. The rescue may fail, but the fused cells end up gaining the motility traits of BMDCs and become metastatic due to the resulting genomic instability. In fact, cell­cell fusion was demonstrated to occur in vivo in cancer and was revealed to promote tumor metastasis. However, its existence and role may be underestimated, and has not been widely acknowledged. In the present review, the milestones in cell fusion research were highlighted, the evidence for cell­cell fusion in vitro and in vivo in cancer was evaluated, and the current understanding of the molecular mechanisms by which cell­cell fusion occurs was summarized, to emphasize their important role in tumor metastasis. The summary provided in the present review may promote further study into this process and result in novel discoveries of strategies for future treatment of tumor metastasis.

Astragalus polysaccharide has a protective effect on hematopoiesis in an irradiated mouse model and decreases apoptosis in megakaryocytes.

Huangqi, the dried root of Radix Astragali, is an essential herb in Traditional Chinese Medicine and has been used to promote hematopoiesis for centuries. Astragalus polysaccharide (ASPS), the bioactive compound of Huangqi, serves a crucial role in hematopoiesis. The aim of the present study was to investigate the hematopoietic effects, in particular the thrombopoietic effects, and the molecular mechanisms of ASPS using an irradiation­induced myelosuppressive mouse model. Colony­forming unit assays, flow cytometric analysis of apoptosis, ELISAs, Giemsa staining and western blotting were performed to determine the hematopoietic and anti­apoptotic effects of ASPS. The results demonstrated that ASPS enhanced the recovery of red blood cells at day 21 following treatment, as well as platelets and white blood cells at day 14. In addition, ASPS promoted colony formation in all lineages (megakaryocytes, granulocyte monocytes, erythroid cells and fibroblasts). The morphological study of the bone marrow demonstrated that tri­lineage hematopoiesis was preserved in the ASPS­ and thrombopoietin (TPO)­treated groups compared with the control group. The overall cellularity (mean total cell count/area) of the ASPS­treated group was similar to that of the TPO­treated group. Additionally, in vitro experiments indicated that treatment with 100 µg/ml ASPS exhibited the maximum effect on colony formation. ASPS attenuated cell apoptosis in megakaryocytic cells via inhibiting the mitochondrial caspase­3 signaling pathway. In conclusion, ASPS promoted hematopoiesis in irradiated myelosuppressive mice possibly via enhancing hematopoietic stem/progenitor cell proliferation and inhibiting megakaryocytes apoptosis.

Melatonin protects against apoptosis of megakaryocytic cells via its receptors and the AKT/mitochondrial/caspase pathway.

Clinical studies have shown that melatonin lowers the frequency of thrombocytopenia in patients with cancer undergoing radiotherapy or chemotherapy. Here, we investigated the mechanisms by which melatonin promotes platelet formation and survival. Our results show that melatonin exerted protective effects on serum-free induced apoptosis of CHRF megakaryocytes (MKs). Melatonin promoted the formation of MK colony forming units (CFUs) in a dose-dependent manner. Using doxorubicin-treated CHRF cells, we found that melatonin rescued G2/M cell cycle arrest and cell apoptosis induced by doxorubicin. The expression of p-AKT was increased by melatonin treatment, an effect that was abolished by melatonin receptor blocker. In addition, we demonstrated that melatonin enhanced the recovery of platelets in an irradiated mouse model. Megakaryopoiesis was largely preserved in melatonin-treated mice. We obtained the same results in vivo from bone marrow histology and CFU-MK formation assays. Melatonin may exert these protective effects by directly stimulating megakaryopoiesis and inhibiting megakaryocyte apoptosis through activation of its receptors and AKT signaling.

c-Mpl and TPO expression in the human central nervous system neurons inhibits neuronal apoptosis.

Thrombopoietin (TPO) is a growth factor for the megakaryocytic/platelet lineage. In this study, we investigated the expression of TPO and its receptor, c-Mpl, in the human central nervous system (CNS) and their roles after a neural insult. Our results demonstrate that both TPO and c-Mpl are expressed in the neurons of the human CNS. TPO was also detected in human cerebrospinal fluid. TPO was found to be neuroprotective in hypoxic-ischemic neonatal rat brain models. In these rat models, treatment with TPO reduced brain damage and improved sensorimotor functions. In addition, TPO promoted C17.2 cell proliferation through activation of the PI3K/Akt signaling pathway. Via the Bcl-2/BAX signaling pathway, TPO exerted an antiapoptotic effect by suppressing mitochondrial membrane potentials. Taken together, our results indicate that TPO is neuroprotective in the CNS.

Analysis and assessment of the no-slip and slip boundary conditions for the discrete unified gas kinetic scheme.

The discrete unified gas kinetic scheme (DUGKS) with a force term is a finite volume solver for the Boltzmann equation. Unlike the standard lattice Boltzmann method (LBM), DUGKS can be applied on nonuniform grids. For both the LBM and DUGKS, the boundary conditions need to be processed through the density distribution function. So researchers introduced the boundary conditions from the LBM frame into the DUGKS. However, the accuracy of these boundary conditions in the DUGKS has not been studied thoroughly. Through strict theoretical deduction, we find that the bounce-back (BB) scheme leads to a different dependence of the numerical error term in the DUGKS as compared to the LBM. The error term is influenced by the relaxation time and the body force. And it can be reduced by lowering the kinetic viscosity. Unlike the BB scheme, the nonequilibrium bounce-back scheme has the ability to implement real no-slip boundary condition. Furthermore, two slip boundary conditions incorporated with Navier's slip model are introduced from the LBM framework into the DUGKS. The tangential momentum change-based (TMAC) scheme can be used directly in the DUGKS because it generates no numerical error term in the DUGKS. For the combination of the bounce-back and specular reflection schemes (BSR), the relation between the slip length and the combination parameter should be modified in accordance with the numerical error term. Analysis shows that the TMAC scheme can simulate a wider range of slip length than the BSR scheme. Numerical simulations of the Couette flow and the Poiseuille flow confirm our theoretical analysis.

Characteristics, source apportionment and health risks of ambient VOCs during high ozone period at an urban site in central plain, China.

On 3rd to May 24, 2018, volatile organic compound (VOC) samples were collected four times a day by using stainless steel canisters at an urban site in Zhengzhou, China. The concentrations, compositions, sources, ozone (O3) formation potential (OFP), and health risk assessment of VOCs were discussed based on the measurements of 103 VOC species. Results show that the average mixing ratio of VOCs was 29.11 ± 15.33 ppbv, and the dominant components comprised oxygenated VOCs (OVOCs) and alkanes, followed by halocarbons, alkenes, aromatics, and a sulfide. Various groups of VOCs had typical diurnal variation characteristics. Alkenes, alkanes, and aromatics contributed most to the OFP. Five sources identified by the positive matrix factorization model revealed solvent utilization as the largest contributor, followed by industrial production, long-lived and secondary species, vehicular emission, and biogenic emission. Solvent utilization and vehicular emission were important sources to OFP. During O3 episode days, the mixing ratios of alkanes, alkenes, halocarbons, OVOCs, aromatics, and TVOCs decreased to varying degrees; the source contribution of solvent utilization decreased significantly while industrial production showed the opposite trend. VOC species and sources posed no non-carcinogenic risk while five species and all sources except for biogenic emission had carcinogenic risks to exposed population. Industrial emission was the largest contributor to both non-carcinogenic and carcinogenic risks. These results will help to provide some references for O3 pollution research and prevention and control of pollution sources.

[Clinical effects of qianggan capsule on the liver tissue pathology and PDGF-BB, TGF-beta1, TIMP-1, and MMP-1 factors in patients with chronic hepatitis B].

OBJECTIVE: To study the therapeutic efficacy of Qianggan Capsule (QC) in treating patients Seventy pa-with chronic hepatitis B fibrosis from the pathological aspect and serum fibrosis markers. METHODS: patients with chronic hepatitis B were randomly assigned to two groups, the treated group (45 cases) and the control group (25 cases). QC was given to patients in the treated group, while glucurone and compound vitamin B were given to those in the control group. The therapeutic course for both groups was 6 months. The therapeutic effect was assessed by determination of fibrosis markers including serum levels of platelet-derived growth factor-BB (PDGF-BB), transforming growth factor beta 1 (TGF-beta1), matrix metalloproteinases-1 (MMP-1), tissue inhibitors of metalloproteinases-1 (TIMP-1) and serum levels of alanine transaminase (ALT), total bilirubin (TBIL), albumin (ALB), and prothrombin time (PT) were completed 1 month before treatment and at the end of the trial respectively. RESULTS: (1) Serum levels of ALT, TBIL, PT decreased obviously and the serum ALB level obviously increased in both groups (all P<0.05), showing no significant difference between the two groups (P>0.05). (2) Hepatic fibrosis markers: Serum levels of PDGF-BB, TGF-1P3, and TIMP-1 significantly decreased, and serum MMP-1 level markedly increased in the treated group more than before treatment (all P<0.05). No significant difference was shown between before and after treatment in each index of the control group (P>0.05). Serum levels of PDGF-BB, TGF-beta1, and TIMP-1 were obviously lower and the serum MMP-1 level was obviously higher in the treated group than in the control group after treatment (all P<0.05). (3) Hepatic histopathological results: The hepatic inflammatory necrosis activity and the hepatic fibrosis degree in the treated group were significantly improved (P<0.05), with the total effective rate of the hepatic necrosis activity improvement being 40.00% and that of the hepatic fibrosis degree being 57.78%. But there was no obvious improvement in the hepatic inflammatory necrosis activity or the hepatic fibrosis degree in the control group (P>0.05). CONCLUSIONS: QC could effectively improve serological indices and pathological indices of chronic hepatitis B fibrosis patients, showing better therapeutic effect in reversing hepatic fibrosis and alleviating hepatic inflammatory necrosis.