Safety and Efficacy of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Different Vaccines at Phase 3.

This systematic review and meta-analysis was conducted to compare the safety and efficacy of 2019 novel coronavirus disease (COVID-19) vaccines according to vaccine platform and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection severity. Articles published between 24 January 2020 and 30 May 2021 were retrieved via a PubMed and EMBASE search. A total of 12 reports on phase-3 clinical trials and observational studies of COVID-19 vaccines were included in the review. In terms of vaccine safety, mRNA vaccines showed more relevance to serious adverse events than viral vector and inactivated vaccines, but no solid evidence indicated that COVID-19 vaccines directly caused serious adverse events. Serious metabolic, musculoskeletal, immune-system, and renal disorders were more common among inactivated vaccine recipients, and serious gastrointestinal complications and infections were more common among viral vector and inactivated vaccine recipients. The occurrence of serious vessel disorders was more frequent in mRNA vaccines. In terms of efficacy, two mRNA vaccine doses conferred a lesser risk of SARS-COV-2 infection (odds ratio: 0.05; 95% confidence interval: 0.02-0.13) than did vaccination with viral vector and inactivated vaccines. All vaccines protected more against symptomatic than asymptomatic cases (risk ratio, 0.11 vs. 0.34), but reduced the risk of severe SARS-COV-2 infection. The COVID-19 vaccines assessed in this study are sufficiently safe and effective. The results indicate that two mRNA vaccine doses prevent SARS-COV-2 infection most effectively, but further research is needed due to the high degree of heterogeneity among studies in this sample. Interventions should be implemented continuously to reduce the risks of infection after one vaccine dose and asymptomatic infection.

A reliable detachable balloon that prevents abdominal cavity contamination during transrectal natural orifice transluminal endoscopic surgery.

OBJECTIVE: To evaluate the efficacy and safety of a detachable endoluminal balloon in the prevention of abdominal cavity contamination during transrectal natural orifice transluminal endoscopic surgery (NOTES). METHODS: The efficacy and safety of a detachable endoluminal balloon to maintain disinfection in the distal colon of the pigs were evaluated. The bacterial loads and colonic cleanliness were monitored. Additionally, the device was applied to another nine pigs that underwent a cholecystotomy by transrectal NOTES. Necropsy and pathological examination were performed after 28-day follow-up. RESULTS: All animals exposed to the device and one of the seven pigs not exposed to the device scored three points on the bowel cleanliness scale (P < 0.001). After 30 min bacterial loads of the test (with balloon occlusion) and control (without balloon occlusion) groups showed a significant difference (0.8 × 103 CFU/mL vs 186.8 × 103 CFU/mL, P < 0.01). Cholecystotomy by transrectal NOTES with the device was successfully performed. The mean intraperitoneal procedure time was 102.9 ± 37.7 min. There were no procedure-related adverse events. During the follow-up, all animals presented normal behavior and appetite. No peritoneal infection or adhesion was detected at autopsy. Cholecystotomy and rectal incision were histologically healed and no histological abnormalities were detected in the colon related to balloon placement. CONCLUSIONS: The detachable balloon provides a reliable solution for preventing peritoneal contamination during transluminal operations. The technique may assist in future transrectal NOTES.

Bortezomib protects against dextran sulfate sodium­induced ulcerative colitis in mice.

Bortezomib, a first­in­class proteasome inhibitor, is a standard method of treatment in multiple myeloma. In the present study, the therapeutic effect of bortezomib was evaluated in an ulcerative colitis model induced by dextran sulfate sodium (DSS) in mice, and the mechanism of action was also investigated. Mice were administered with 3% DSS drinking water for 7 consecutive days and then they were intraperitoneally treated with bortezomib (0.2, 0.6 or 1 mg/kg) for 1, 3 or 7 days. Mice in the control group and the DSS group were provided the same volume of PBS, respectively. Body weight, stool characteristics and hematochezia were observed. Serum levels of tumor necrosis factor­α (TNF­α), C­reactive protein (CRP), albumin (ALB) and colonic activity of superoxide dismutase (SOD) were evaluated using specific kits. The expression of the transcription factor nuclear factor­κB (NF­κB) p65 gene and the DNA­binding activity of NF­κB protein were also evaluated. Administration of bortezomib attenuates colonic inflammation in mice. After 3 or 7 days of treatment, Disease Activity Index (DAI) as well as histological scores and NF­κB p65 protein expression were significantly reduced in mice treated with bortezomib at a dose of 0.6 or 1 mg/kg/day. Furthermore, it was also revealed that bortezomib was able to reduce serum levels of CRP and TNF­α caused by DSS and increase the level of ALB in serum and the activity of SOD in colonic tissues. These results demonstrated that bortezomib exerts a protective effect on DSS­induced colitis, and its underlying mechanisms are associated with the NF­κB gene inhibition that mitigates colon inflammatory responses in intestinal epithelial cells.

Protection of cultured human hepatocytes from hydrogen peroxide­induced apoptosis by relaxin­3.

Previous studies have suggested that hepatocyte apoptosis may be a fundamental underlying mechanism of liver injury and diseases, such as liver fibrosis. Relaxin­3 has been reported to have anti­fibrotic actions in the heart and to attenuate isoproterenol­induced myocardial injury; however, the beneficial role of relaxin­3 on hepatocyte apoptosis remains to be elucidated. The aim of the present study was to explore the role and possible mechanisms of relaxin­3 through hydrogen peroxide (H2O2)­induced apoptosis in primary human hepatocytes. Cells were treated with relaxin­3 and then cell viability, morphological features, the presence of cleaved caspases as well as the levels of endoplasmic reticulum stress (ERS) protein markers and autophagy markers were evaluated. The H2O2 group showed significantly decreased cell viability, increased apoptosis as well as upregulation of caspases (cleaved caspase­3, ­8 and ­9) and ERS protein markers compared with those of the control group. However, cells treated with relaxin­3 (10 ng/ml) demonstrated improved cell viability, reduced apoptosis and decreased expression of cleaved caspases and ERS markers. However, the expression of autophagy markers remained unchanged following H2O2­induced apoptosis and relaxin­3 treatment. In conclusion, relaxin­3 was shown to protect hepatocytes from H2O2­induced apoptosis via downregulation of cleaved caspase­8 and ­9, as well as inhibition of the ERS pathway.

Functional mechanism of the enhancement of 5-fluorouracil sensitivity by TUSC4 in colon cancer cells.

5-Fluorouracil (5-FU) is the chemotherapeutic drug of choice for the treatment of metastatic colorectal cancer (CRC). Tumor suppressor candidate 4 (TUSC4), also referred to as nitrogen permease regulator-like 2 (NPRL2), is located at chromosome 3p21.3 and expressed in numerous normal tissues, including the heart, liver, skeletal muscle, kidney, and pancreas. The aim of the present study was to investigate the functional mechanism by which TUSC4 affects sensitivity to 5-FU and to determine its clinical significance in CRC. The results of the present study demonstrated that TUSC4 overexpression increases the sensitivity of HCT116 cells to 5-FU. The IC50 of 5-FU was reduced in cells transduced with TUSC4 compared with negative control (NC) cells, and the effect of TUSC4 on 5-FU sensitivity was time dependent. Following TUSC4 transduction in HCT116 cells, a proportion of the cells were arrested in the G1 phase of the cell cycle, and a reduction in the S phase population was observed. Flow cytometry analysis revealed that TUSC4 transduction and 5-FU treatment increased apoptosis compared with NC cells. The mechanism through which TUSC4 overexpression enhances 5-FU sensitivity involves the downregulation of the function of the PI3K/Akt/mTOR network. Furthermore, 5-FU upregulated caspase-3 and caspase-9, promoting apoptosis in TUSC4-overexpressing cells compared with cells that were transduced with TUSC4 or treated with 5-FU and NC cells. The findings of the present study indicate that TUSC4 has potential as a biomarker for the prediction of the response to 5-FU and prognosis in patients with colorectal cancer and other types of human cancer. TUSC4 may also act as a molecular therapeutic agent for enhancing the patient's response to 5-FU treatment.

Endostar, a novel human recombinant endostatin, attenuates liver fibrosis in CCl4-induced mice.

Decreasing hepatic fibrosis remains one of the major therapeutic challenges in hepatology. The present study aims to evaluate the effect of Endostar on both CCl4-induced liver fibrosis in mice and a hepatic stellate cell (HSC) line. Two main models were studied: (i) a liver fibrosis model was induced in BALB/c mice using CCl4 by intraperitoneal injection for six weeks. Six animal groups were studied: group 1: normal animals; group 2: CCl4-induced liver fibrosis; group 3: CCl4 + Endostar 20 mg/kg/d, six weeks; group 4: CCl4 + Endostar 10 mg/kg/d, six weeks; group 5: CCl4 + Endostar 20 mg/kg/d, four weeks; group 6: CCl4 + Endostar 10 mg/kg/d, four weeks corresponded to different Endostar doses and duration of administration. Liver fibrosis was evaluated by histopathological staining and liver hydroxyproline content. Expressions of collagen type I, α-smooth muscle actin (α-SMA), TGF-ß1 and VEGFR were measured by real-time polymerase chain reaction (PCR). (ii) A liver cell model. HSC-T6 cells were cultured with or without Endostar for 12 h or 24 h. Expressions of collagen type I, α-SMA, and TGF-ß1 were measured by real-time PCR. Collagen I and transforming growth factor ß1 (TGF-ß1) contents in cell supernatant were measured by enzyme-linked immunosorbent assay. As compared to the group without Endostar, liver fibrosis scores and hydroxyproline content were decreased in both Endostar groups (P < 0.05). Moreover, Endostar inhibited the hepatic expression of α-SMA, TGF-ß1, Collagen-1, VEGFR1, and VEGFR2 mRNA (P < 0.05). In the HSC-T6 cell line model, Endostar profoundly inhibited the expression of α-SMA, Collagen-1, and TGF-ß1 mRNA. Expressions of Collagen-1 and TGF-ß1 protein were decreased in the Endostar group as compared to the normal controls in the supernatant of HSC-T6 cells (P < 0.05). Endostar decreased both liver fibrosis in CCl4-induced mice and collagen synthesis in HSCs in vitro. Therefore, this recombinant human endostatin is a promising compound for counteracting liver fibrosis.

Relationship between tumor and peripheral blood NPRL2 mRNA levels in patients with colorectal adenoma and colorectal cancer.

NPRL2 is a tumor suppressor gene involved in the progression of human cancer. The present study investigated whether NPRL2 expression correlates with colorectal cancer (CRC) progression. Colorectal tissue and peripheral blood samples were obtained from 62 patients with CRC, 38 patients with colorectal adenomas and 51 normal controls. NPRL2 mRNA levels in tissue samples and blood were measured using quantitative real-time PCR. NPRL2 protein expression was determined by immunohistochemistry. NPRL2 protein expression in CRCs was significantly lower than in the adenomas or normal colorectal tissue. NPRL2 mRNA expression was significantly decreased in adenomas compared with normal controls (P<0.0001) and it was further decreased in colorectal tumors compared with adenomas (P<0.0001). NPRL2 mRNA levels expression correlated with tumor stage. In addition, NPRL2 mRNA levels in the blood correlated with the levels detected in tumors. Furthermore, receiver operating characteristic (ROC) analysis showed that NPRL2 expression in blood could distinguish colorectal adenomas and CRCs from normal controls. NPRL2 mRNA expression in CRC tumor tissues and peripheral blood correlated with colorectal tumor progression. Based on our findings, we can conclude that NPRL2 mRNA blood levels could be a potentially useful marker for the detection of early stage adenomas and CRCs.

[Wnt/b-catenin signaling pathway affects the protein expressions of caspase-3, XIAP and Grp-78 in hepatocellular carcinoma].

To investigate the relationship and significance of Wnt/b-catenin signaling pathway with caspase-3, XIAP, HSP27and Grp-78. The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against b-catenin. After 72 and 96 h, protein was extracted and the protein expressions of b-catenin, caspase-3, XIAP, Grp-78 and HSP27 were detected by Western blot. b-catenin protein expression was inhibited at both time points and the expression at 96 h was higher than that at 72 h (F = 160.72, P is less than to 0.01). Interestingly, Caspase-3 protein expression was decreased at 72 h and increased to normal at 96 h (F = 136.10, P is less than to 0.01), while p-caspase-3 protein expression increased at 72 h and decreased to normal at 96 h (F = 98.65, P is less than to 0.01). XIAP protein expression decreased at 72 h (F = 37.29, P is less than to 0.01) and increased at 96 h. Grp-78 protein expression increased at 72 h and decreased to normal at 96 h ( F = 58.72, P is less than to 0.01). HSP27 protein expression showed no change following transfection ( F = 1.91, P is more than to 0.05). Wnt/b-catenin signaling pathway is related to the protein expressions of caspase-3, XIAP and Grp-78, but not related to HSP27 protein expression in HCC. Wnt/b-catenin signaling pathway may participate in the regulation of HCC apoptosis, proliferation and differentiation through affecting these factors.

STAT3 and beta-catenin signaling pathway may affect GSK-3beta expression in hepatocellular carcinoma.

BACKGROUND/AIMS: To study the correlation and significance of beta-catenin, STAT3 and GSK-3beta signaling pathway in hepatocellular carcinoma (HCC). METHODOLOGY: The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against 8-catenin or STAT3. After 72 and 96h, protein was extracted and the protein expression of beta-catenin, STAT3, and GSK-3beta was detected by Western blot analysis. RESULTS: After siRNA directed against beta-catenin was transfected into HepG2 cells, beta-catenin protein expression was decreased at 72 and 96h, GSK-3beta and p-GSK-3beta protein expression increased gradually at 72 and 96h, and STAT3 protein expression showed no change following transfection. After siRNA directed against STAT3 was transfected into HepG2 cells, STAT3 protein expression was decreased at 72 and 96h and beta-catenin, GSK-3beta and p-GSK-3beta protein expression all increased at 72h and decreased at 96 h after transfection. CONCLUSION: In HCC, the beta-catenin signaling pathway may regulate GSK-3beta protein expression and the STAT3 signaling pathway may regulate beta-catenin and GSK-3beta protein expression, thereby playing key roles during HCC genesis and development.

Esophageal and gastric cardia cancers on 4238 Chinese patients residing in municipal and rural regions: a histopathological comparison during 24-year period.

BACKGROUND: Nutrition deficiencies or poverty traditionally have been recognized to be related with increased risk for esophageal cancer (EC) in rural regions at junction of Henan, Hebei, and Shanxi provinces in northern China--the highest incidence area for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Since the 1980s, economic and nutrition condition in these areas have been improved greatly. However, the histopathological types, staging pattern, and occurrence of ESCC and GCA, especially for esophageal adenocarcinoma (EAC), which have been rarely examined in the Chinese population during the past decades in these areas have not been well characterized to date. METHODS: Yearly diagnosed new esophageal cancer (ESCC and EAC) and GCA patients from Beijing Tongren Hospital (in municipal low-risk region) and Cixian People Hospital (in rural high-risk region) during 24-year period (1982-2005) were studied retrospectively. Only local resident patients with surgical resection were included. Age at diagnosis, tumor stage and site, and histopathological pattern were recorded for each patient from the tumor registry database in these hospitals. RESULTS AND CONCLUSIONS: This study demonstrated that the common ESCC sites were different in municipal (chiefly in lower third of the esophagus) and in rural (chiefly in middle third of the esophagus) regions. The peak age of ESCC, EAC, and GCA patients in rural region was 10 years younger than in municipal region. Eighty-six percent of ESCC and 90% of GCA in municipal region were diagnosed at middle and advanced stage; similarly, more than 95% of ESCC and GCA in rural region were diagnosed at middle and advanced stage during the 24-year study period. An increasing tendency in number of yearly diagnosed new patients with ESCC and GCA was observed in municipal region, but not in rural region. However, an increasing tendency for EAC was observed both in municipal and rural regions during the past 24-year period. The present results demonstrate the difference in municipal and rural regions of ESCC, ECA, and GCA in histopathological types, and suggest that there may be different etiological factors involved in esophageal and gastric cardia carcinogenesis in these different areas.

A probiotic treatment containing Lactobacillus, Bifidobacterium and Enterococcus improves IBS symptoms in an open label trial.

OBJECTIVE: To evaluate the efficacy and safety of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules in treatment of irritable bowel syndrome. METHODS: Eighty-five patients [male 32, female 53; age (45.31+/-11.72) years] were given live combined Bifidobacterium, Lactobacillus and Enterococcus capsules 1260 mg/d t.i.d.x4 weeks. Syndrome scales were used to evaluate the efficacy in gastrointestinal syndrome. Fecal flora was also measured before and after the treatment. Six bacteria were cultured and the colony forming units were counted in stool. SPSS was used for data analysis. RESULTS: Seventy-four patients finished the follow-up. No side-effect was found. For treatment of irritable bowel syndrome, the effective rate of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules was 56.8% in the second week, 74.3% in the fourth week and 73.0% in the sixth week. Single symptom was improved, especially in abdominal pain and stool character. The probiotica containing live combined Bifidobacterium, Lactobacillus and Enterococcus could increase bifidobacterium count (P<0.01) and lactobacillus count (P<0.05); decrease bacteroides count (P<0.05) and enterococci count (P<0.01); No obvious changes were observed in clostridium difficile colonitis and enterobacteriaceae (P>0.05). CONCLUSION: The result of the study indicated that the administration of live combined Bifidobacterium, Lactobacillus and Enterococcus improved the symptom of irritable bowel syndrome and that there was a gradual increase of this effect. Thereafter conditions remained stable for 2 weeks. That improvement may be associated with alterations in gastrointestinal flora.

Effects of three fluid resuscitation methods on apoptosis of visceral organs in rats with hemorrhagic shock.

OBJECTIVE: To observe the effects of three fluid resuscitation methods on apoptosis of visceral organs in rats with hemorrhagic shock. METHODS: A model of rat with severe hemorrhagic shock and active bleeding was established in 32 SD (Sprague-Dawley) rats. The rats were randomly divided into control group, no fluid resuscitation group (NF group), controlled fluid resuscitation group (NS40 group) and rapid large scale fluid resuscitation group (NS80 group). Each group contained 8 rats. The curative effects were compared. At the same time, the apoptosis in liver, kidney, lung and small intestinal mucosa of survivors after hemorrhage and resuscitation was detected by light microscopy in HE (hematoxylin and eosin) stained tissue sections, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). RESULTS: The survival rate of early fluid resuscitation (14/16) was markedly higher than that of NF group (3/8). There was some apoptosis in liver, kidney, lung and small intestinal mucosa of all survivors. Compared with NF and NS40 groups, the apoptosis of liver, kidney and small intestinal mucosa of NS80 group was obviously increased. CONCLUSIONS: Among three fluid resuscitation methods, controlled fluid resuscitation can obviously improve the early survival rate and the apoptosis of liver, kidney and small intestinal mucosa in rats with severe and uncontrolled hemorrhagic shock, and may benefit improvement of prognosis.

Trial of a novel endoscopic tattooing biopsy forceps on animal model.

AIM: To tattoo gastric mucosa with a novel medical device which could be used to monitor and follow-up gastric mucosal lesions. METHODS: Combining endoscopic biopsy with sclerotherapy injection, we designed a new device that could perform biopsy and injection simultaneously. We performed endoscopies on a pig by using a novel endoscope tattoo biopsy forceps for 15 mo. At the same time, we used two-step method combining sclerotherapy injection needle with endoscopic biopsy. The acuity, inflammation and duration of endoscopy were compared between two methods. RESULTS: Compared with the old two-step method, although the inflammation induced by our new device was similar, the duration of procedure was markedly decreased and the acuity of tattooing was better than the old two-step method. All characteristics of the novel device complied with national safety guidelines. Follow-up gastroscopy after 15 mo showed the stained site with injection of 1:100 0.5 mL of India ink was still markedly visible with little inflammatory reaction. CONCLUSION: Endoscopic tattooing biopsy forceps can be widely used in monitoring precancerous lesions. Its safety and effectiveness has been established in animals.

Intestinal microecology and quality of life in irritable bowel syndrome patients.

AIM: It has been noticed that gastroenteritis or dysentery plays a role in pathogenesis of irritable bowel syndrome (IBS), and antibiotics can increase functional abdominal symptoms, both of which may be partly due to intestinal flora disorders. This study was to determine the change of gut flora of IBS, a cluster of abdominal symptoms. Because of the chronic course and frequent occurrence of the disease, IBS patients suffered much from it. So the quality of life (Qol) of IBS patients was also evaluated in this study. METHODS: Twenty-five Rome II criteria-positive IBS patients were recruited, and 25 age and gender-matched healthy volunteers were accepted as control. The fecal flora, including Lactobacillus, Bifidobacterium, Bacteroides, C. perfringens Enterobacteriacea and Enterococus, were analyzed quantitatively and qualitatively. We also calculated the ratio of Bifidobacterium to Enterobacteriaceae (B/E ratio) in both IBS patients and controls. In both groups, the data were further analyzed based on age difference, and comparisons were made between the younger and elder subgroups. We also evaluated the quality of life (QoL) of IBS patients and the control group using the Chinese version of SF-36 health questionnaire. RESULTS: In IBS patients, the number of fecal Bifidobacterium was significantly decreased and that of Enterobacteriaceae was significantly increased compared with that in healthy controls (both P<0.05). The mean microbial colonization resistance (CR) of the bowel in IBS patients was smaller than 1, making a significant difference compared with that in control which was more than 1 (P<0.01). There was no significant difference in gut flora between two subgroups. While in control, the elder subgroup presented more Enterobacteriacea than the younger one (P<0.05). Compared with the control group, IBS patients had significantly lower scores on all SF-36 scales, with the exception of physical functioning. However, there was no significant correlation between quality of life and enteric symptoms in IBS patients. CONCLUSION: There are intestinal flora disorders in IBS patients, which may be involved in triggering the IBS-like symptoms. IBS patients experience significant impairment in QoL, however, the impairment is not caused directly by enteric symptoms.