Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health. The development of a vaccine is urgently needed for the prevention and control of COVID-19. Here, we report the pilot-scale production of an inactivated SARS-CoV-2 vaccine candidate (BBIBP-CorV) that induces high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and nonhuman primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. Two-dose immunizations using 2 µg/dose of BBIBP-CorV provided highly efficient protection against SARS-CoV-2 intratracheal challenge in rhesus macaques, without detectable antibody-dependent enhancement of infection. In addition, BBIBP-CorV exhibits efficient productivity and good genetic stability for vaccine manufacture. These results support the further evaluation of BBIBP-CorV in a clinical trial.

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.

CenterNet-Saccade: Enhancing Sonar Object Detection with Lightweight Global Feature Extraction.

Sonar imaging technology is widely used in the field of marine and underwater monitoring because sound waves can be transmitted in elastic media, such as the atmosphere and seawater, without much interference. In underwater object detection, due to the unique characteristics of the monitored sonar image, and since the target in an image is often accompanied by its own shadow, we can use the relative relationship between the shadow and the target for detection. To make use of shadow-information-aided detection and realize accurate real-time detection in sonar images, we put forward a network based on a lightweight module. By using the attention mechanism with a global receptive field, the network can make the target pay attention to the shadow information in the global environment, and because of its exquisite design, the computational time of the network is greatly reduced. Specifically, we design a ShuffleBlock model adapted to Hourglass to make the backbone network lighter. The concept of CNN dimension reduction is applied to MHSA to make it more efficient while paying attention to global features. Finally, CenterNet's unreasonable distribution method of positive and negative samples is improved. Simulation experiments were carried out using the proposed sonar object detection dataset. The experimental results further verify that our improved model has obvious advantages over many existing conventional deep learning models. Moreover, the real-time monitoring performance of our proposed model is more conducive to the implementation in the field of ocean monitoring.

An Aggregation-Induced Fluorescence Probe for Detection H2S and Its Application in Cell Imaging.

Monitoring hydrogen sulfide (H2S) in living organisms is very important because H2S acts as a regulator in many physiological and pathological processes. Upregulation of endogenous H2S concentration has been shown to be closely related to the occurrence and development of tumors, atherosclerosis, neurodegenerative diseases and diabetes. Herin, a novel fluorescent probe HND with aggregation-induced emission was designed. Impressively, HND exhibited a high selectivity, fast response (1 min) and low detection limit (0.61 µM) for H2S in PBS buffer (10 mM, pH = 7.42). Moreover, the reaction mechanism between HND and H2S was conducted by Job's plot, HR-MS, and DFT. In particular, HND was successfully employed to detect H2S in HeLa cells.

A Novel Coronavirus from Patients with Pneumonia in China, 2019.

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

Neutralizing antibody levels associated with injectable and aerosolized Ad5-nCoV boosters and BA.2 infection.

BACKGROUND: Several COVID-19 vaccines are in widespread use in China. Few data exist on comparative immunogenicity of different COVID-19 vaccines given as booster doses. We aimed to assess neutralizing antibody levels raised by injectable and inhaled aerosolized recombinant adenovirus type 5 (Ad5)-vectored COVID-19 vaccine as a heterologous booster after an inactivated COVID-19 vaccine two-dose primary series. METHODS: Using an open-label prospective cohort design, we recruited 136 individuals who had received inactivated vaccine primary series followed by either injectable or inhaled Ad5-vectored vaccine and measured neutralizing antibody titers against ancestral SARS-CoV-2 virus and Omicron BA.1 and BA.5 variants. We also measured neutralizing antibody levels in convalescent sera from 39 patients who recovered from Omicron BA.2 infection. RESULTS: Six months after primary series vaccination, neutralizing immunity against ancestral SARS-CoV-2 was low and neutralizing immunity against Omicron (B.1.1.529) was lower. Boosting with Ad5-vectored vaccines induced a high immune response against ancestral SARS-CoV-2. Neutralizing responses against Omicron BA.5 were ≥ 80% lower than against ancestral SARS-CoV-2 in sera from prime-boost subjects and in convalescent sera from survivors of Omicron BA.2 infection. Inhaled aerosolized Ad5-vectored vaccine was associated with greater neutralizing titers than injectable Ad5-vectored vaccine against ancestral and Omicron SARS-CoV-2 variants. CONCLUSIONS: These findings support the current strategy of heterologous boosting with injectable or inhaled Ad5-vectored SARS-CoV-2 vaccination of individuals primed with inactivated COVID-19 vaccine.

A novel genome sequence of Jasminum sambac helps uncover the molecular mechanism underlying the accumulation of jasmonates.

Jasminum sambac is a well-known plant for its attractive and exceptional fragrance, the flowers of which are used to produce scented tea. Jasmonate (JA), an important plant hormone was first identified in Jasminum species. Jasmine plants contain abundant JA naturally, of which the molecular mechanisms of synthesis and accumulation are not clearly understood. Here, we report a telomere-to-telomere consensus assembly of a double-petal J. sambac genome along with two haplotype-resolved genomes. We found that gain-and-loss, positive selection, and allelic specific expression of aromatic volatile-related genes contributed to the stronger flower fragrance in double-petal J. sambac compared with single- and multi-petal jasmines. Through comprehensive comparative genomic, transcriptomic, and metabolomic analyses of double-petal J. sambac, we revealed the genetic basis of the production of aromatic volatiles and salicylic acid (SA), and the accumulation of JA under non-stress conditions. We identified several key genes associated with JA biosynthesis, and their non-stress related activities lead to extraordinarily high concentrations of JA in tissues. High JA synthesis coupled with low degradation in J. sambac results in accumulation of high JA under typical environmental conditions, similar to the accumulation mechanism of SA. This study offers important insights into the biology of J. sambac, and provides valuable genomic resources for further utilization of natural products.

MATRILINEAL, a sperm-specific phospholipase, triggers maize haploid induction.

Sexual reproduction in flowering plants involves double fertilization, the union of two sperm from pollen with two sex cells in the female embryo sac. Modern plant breeders increasingly seek to circumvent this process to produce doubled haploid individuals, which derive from the chromosome-doubled cells of the haploid gametophyte. Doubled haploid production fixes recombinant haploid genomes in inbred lines, shaving years off the breeding process. Costly, genotype-dependent tissue culture methods are used in many crops, while seed-based in vivo doubled haploid systems are rare in nature and difficult to manage in breeding programmes. The multi-billion-dollar maize hybrid seed business, however, is supported by industrial doubled haploid pipelines using intraspecific crosses to in vivo haploid inducer males derived from Stock 6, first reported in 1959 (ref. 5), followed by colchicine treatment. Despite decades of use, the mode of action remains controversial. Here we establish, through fine mapping, genome sequencing, genetic complementation, and gene editing, that haploid induction in maize (Zea mays) is triggered by a frame-shift mutation in MATRILINEAL (MTL), a pollen-specific phospholipase, and that novel edits in MTL lead to a 6.7% haploid induction rate (the percentage of haploid progeny versus total progeny). Wild-type MTL protein localizes exclusively to sperm cytoplasm, and pollen RNA-sequence profiling identifies a suite of pollen-specific genes overexpressed during haploid induction, some of which may mediate the formation of haploid seed. These findings highlight the importance of male gamete cytoplasmic components to reproductive success and male genome transmittance. Given the conservation of MTL in the cereals, this discovery may enable development of in vivo haploid induction systems to accelerate breeding in crop plants.

The First Human Infection Case of Macacine Alphaherpesvirus 1 Virus in China.

BACKGROUND: Macacine alphaherpesvirus 1 (BV) was first reported in the 1930s and only about 60 cases have been diagnosed since then. METHODS: A 53-year-old male who worked as a veterinary surgeon, developed a fever with nausea and vomiting in April 2021 in Beijing, China. Real-time polymerase chain reaction (PCR) and metagenomics Next Generation Sequencing (mNGS) were used for diagnosis. RESULTS: BV DNA was confirmed by mNGS and PCR. The case died 51 days after onset, due to the damage to the brain and spinal cord caused by a viral infection and hypoxic-ischemic encephalopathy. The typical BV inclusion bodies in the brain were found for the first time. CONCLUSIONS: Here we reported the first human infection case of BV in China. This fatal case highlights the potential threat of BV to occupational workers and the essential role of surveillance.

Association of the malnutrition-inflammation score with physical function and functional disability in elderly patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: To describe nutritional status and inflammation of elderly patients with chronic kidney disease and to confirm the association between a Malnutrition-Inflammation Score and physical func-tion and functional disability. METHODS AND STUDY DESIGN: A total of 221 chronic kidney disease patients (aged ≥60 years) were included. A Malnutrition-Inflammation Score was used to assess malnutrition and inflammation. Physical function was assessed using the SF-12. Functional status was evaluated using basic activities of daily living and instrumental activities of daily living. RESULTS: Thirty percent of participants had a Malnutrition-Inflammation Score ≥6, which denoted poor nutritional status. Participants with a Malnutrition-Inflammation Score ≥6 had decreased concentration of hemoglobin, albumin, prealbumin, handgrip strength and walking speed and increased concentration of inflammatory markers, including CRP, IL-6 and fibrinogen. Physical function and physical component summary were lower and basic activities of daily living dependence and instrumental activities of daily living dependence were higher among patients with higher Malnutrition-Inflammation Score than those with a lower Malnutrition-Inflammation Score. The Malnutrition-Inflammation Score was an independent risk factor for physical function and instrumental activities of daily living dependence. CONCLUSIONS: The elderly chronic kidney disease patients with a high Malnutrition-Inflammation Score had a decreased physical function and an increased risk of functional instrumental activities of daily living dependence.

Interplay of Helicobacter pylori, fibroblasts, and cancer cells induces fibroblast activation and serpin E1 expression by cancer cells to promote gastric tumorigenesis.

BACKGROUND: Helicobacter pylori (H. pylori) can disrupt the tight junctions between gastric epithelial cells and penetrate the intercellular spaces acting on epithelial cells, normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs), but their interaction in gastric cancer tumorigenesis and progression remains unclear. METHODS: Primary CAFs and NFs were isolated from paired gastric cancer tissues and adjacent normal tissues and identified by immunofluorescence staining and western blot analysis for FSP-1, α-SMA, FAP, and vimentin expression. RNA-sequencing was used to compare the transcriptomes between CAFs and NFs. The expressions of FAP, lumican, and α-SMA, human cytokine array, and Transwell assay were used to assess the transformation of NFs to CAFs. CCK-8 assay, colony formation, flow cytometry, Transwell assay, and nude mouse xenograft model were used to determine the effects of Serpin E1 on cell proliferation and metastasis in vitro and in vivo. Finally, Serpin E1 and/or FAP expression was measured in H. pylori-infected gerbil gastric mucosa and human gastric cancer tissues. RESULTS: Gastric CAFs are inflammatory CAFs with α-SMAlowFAPhighlumicanhigh. The interplay of H. pylori, fibroblasts, and cancer cells promotes the transition of NFs to CAFs by inducing cytokine release, especially Serpin E1. Long-term H. pylori infection and CAFs induce Serpin E1 expression in gerbil gastric tissues and human gastric cancer cells. Serpin E1 overexpression enhances the growth, migration, invasion of gastric cancer cells in vitro, and xenograft tumor growth in nude mice via inducing angiogenesis. Serpin E1 and FAP were highly expressed in cancer cells and CAFs of gastric cancer tissues, respectively, and a good correlation was observed between their expression. Higher Serpin E1 expression is negatively associated with the overall survival of patients with gastric cancer. CONCLUSIONS: The interplay of H. pylori, fibroblasts, and cancer cells induced Serpin E1 expression to promote the activation of NFs to CAFs and gastric carcinogenesis. Targeting Serpin E1 will provide a promising therapeutic strategy for gastric cancer by disrupting the interaction between H. pylori, CAFs, and gastric cancer cells.

Total neoadjuvant therapy for locally advanced gastric cancer and esophagogastric junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase II clinical trial.

BACKGROUND: Gastric cancer ranks high in terms of morbidity and mortality worldwide. Multimodal therapy is therefore essential for locally advanced gastric cancer. Recent studies have demonstrated that both perioperative chemotherapy and neoadjuvant chemoradiotherapy can improve the prognosis of patients. However, the completion rate of chemotherapy after surgery remains low, which may affect survival. Thus, identifying the best way to combine radiotherapy, chemotherapy and surgery is important. The aim of this study was to explore the toxicity and efficacy of the total neoadjuvant therapy modality for locally advanced gastric cancer. METHODS: This study will be a prospective, multicenter, single-arm, phase II clinical trial. Patients diagnosed with locally advanced (stage cT3-4 and cN positive, AJCC 8th) gastric cancer and gastroesophageal junction adenocarcinoma will be enrolled. Patients will initially receive radiotherapy (95% planned target volume: 45 Gy/25 f) and concurrent chemotherapy (S-1: 40-60 mg twice a day) followed by six cycles of consolidated chemotherapy (SOX, consisting of S-1 and oxaliplatin) and surgery. The primary objective will assess pathological complete response; the secondary objectives will include toxicities assessing surgical complications, the tumor downstaging rate and the R0 resection rate. DISCUSSION: Investigation of total neoadjuvant therapy in gastric cancer is limited. The goal of this trial is to explore the efficacy and toxicity of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04062058, August 20, 2019).

Comparison of sleep quality among puerperal women before and during the COVID-19 pandemic: a cross-sectional survey in Lanzhou, China.

PURPOSE: Few studies have yet examined sleep quality among puerperal women during the coronavirus disease 2019 (COVID-19) pandemic. This cross-sectional study aimed to compare the sleep quality of puerperal women before and during the COVID-19 pandemic in Lanzhou, China. The study exploreed the factors that affect sleep quality among puerperal women. METHODS: The study population comprised puerperal women who went to the obstetric department of the Gansu Provincial Maternity and Childcare Hospital on the 42nd day after childbirth. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Data were collected by doctors in the obstetric department before the COVID-19 pandemic (Oct.-Dec. 2019) and during the COVID-19 pandemic (Feb.-Apr. 2020) in China. Multiple linear regressions were used to examine the association between the sleep quality of puerperal women and COVID-19 and to identify factors that affect the total PSQI scores. RESULTS: In 2019, 546 puerperal women were assessed compared with 655 who were assessed in 2020. Compared with before COVID-19, the total PSQI scores of puerperal women improved during the COVID-19 pandemic. In addition, the influencing factors of sleep quality among puerperal women were the pandemic itself, age, conception method, and postpartum depression (PPD). CONCLUSIONS: In contrast with other studies, there was no evidence for worsening sleep quality of puerperal women during the COVID-19 pandemic in Lanzhou, China. Puerperal women who underwent assisted pregnancy or developed PPD were more likely to experience poor sleep quality.

The number of cycles of adjuvant chemotherapy in stage III and high-risk stage II rectal cancer: a nomogram and recursive partitioning analysis.

OBJECTIVE: The prognostic role of the number of cycles of adjuvant chemotherapy (ACT) after total mesorectal excision in stage III and high-risk stage II rectal cancer is unknown. As a result of this, our study was designed to assess the effect of the number of cycles of ACT on the prediction of cancer-specific survival. METHODS: Four hundred patients that were diagnosed as stage III and high-risk stage II rectal cancer from January 2012 to January 2018 and who had received total mesorectal excision were enrolled in this study. A nomogram incorporating the number of cycles of ACT was also developed in this study. For internal validation, the bootstrap method was used and the consistency index was used to evaluate the accuracy of the model. The patients were stratified into risk groups according to their tumor characteristics by recursive partitioning analysis. RESULTS: We found that the risk of death was decreased by 26% (HR = 0.74, 95% CI: 0.61-0.89, P = 0.0016) with each increasing ACT cycle. The N stage, positive lymph node ratio (PLNR), carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, and the number of cycles of ACT were chosen and entered into the nomogram model. Recursive partitioning analysis-based risk stratification revealed a significant difference in the prognosis in rectal cancer patients with high-risk, intermediate-risk, and low-risk (3-year cancer-specific survival: 0.246 vs. 0.795 vs. 0.968, P < 0.0001). Seven or more cycles of ACT yielded better survival in patients with PLNR ≥ 0.28 but not in patients with PLNR < 0.28. CONCLUSION: In conclusion, the nomogram prognosis model based on the number of cycles of ACT predicted individual prognosis in rectal cancer patients who had undergone total mesorectal excision. These findings further showed that in patients with PLNR ≥ 0.28, no fewer than 7 cycles of ACT are needed to significantly reduce the patient's risk of death.

Chinese expert recommendations on management of hepatocellular carcinoma during COVID-19 pandemic: a nationwide multicenter survey.

BACKGROUND: This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic. METHODS: A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic. RESULTS: 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the "face-to-face" visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC. DISCUSSION: During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery.

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

BACKGROUND: In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. METHODS: We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. FINDINGS: The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. INTERPRETATION: 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. FUNDING: National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells.

Effect of the duration of the capecitabine regimen following colon cancer surgery in an elderly population: a retrospective cohort study.

BACKGROUND: Only 50-70% of elderly colon cancer patients could complete the recommended 6 months of postoperative chemotherapy. It is unknown whether a shorter duration of postoperative capecitabine-alone chemotherapy would compromise survival. We thus conducted this study to analyze the association between postoperative chemotherapy duration of a capecitabine-alone regimen and cancer-specific survival (CSS) and disease-free survival (DFS) of surgery-treated elderly colon cancer patients. METHODS: We performed a retrospective cohort study of surgically treated stage III and high-risk stage II colon cancer patients aged ≥ 70 treated at two medical centers. Cox proportional hazard regression models were utilized to calculate crude and adjusted hazard ratios (HRs). The nonlinear relationship between postoperative chemotherapy duration and survival was analyzed through restricted cubic spline regression analysis, and the threshold effect was calculated by the two-piecewise Cox proportional hazard model. RESULTS: A total of 1217 surgery-treated colon cancer patients between August 1, 2013, and September 1, 2019, were reviewed, and 257 stage III and high-risk stage II patients aged ≥ 70 were enrolled. Postoperative chemotherapy with capecitabine was administered to 114 patients, and 143 patients only received surgery. As the duration of chemotherapy increased by 1 week, the risk of cancer-specific death was reduced by 11% (HR = 0.89, 95% confidence interval (CI) 0.82-0.96), and the risk of recurrence was reduced by 10% (HR = 0.90, 0.82-0.96). Nonlinearity exploration suggested a threshold effect of capecitabine duration on CSS in stage III disease. The HR for death was 0.79 (95% CI, 0.68-0.92) with duration ≤ 16 weeks and 1.34 (95% CI, 0.91-1.97) with duration > 16 weeks. CONCLUSIONS: The postoperative capecitabine duration was significantly associated with a decrease in death risk and recurrence risk in elderly colon cancer patients. However, the threshold effect of capecitabine duration on survival suggests that short-term chemotherapy may improve survival in elderly stage III colon cancer patients.

High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses.

Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.IMPORTANCE Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.

Design, synthesis and structure-activity relationship studies of novel partial FXR agonists for the treatment of fatty liver.

Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, while there is still no medicine available. Farnesoid X receptor (FXR) is considered as a potential target for the treatment of NAFLD, and there are several FXR agonists reached in clinical trials. Based on better safety, industry and academia are pursuing development of the partial FXR agonists. To extend the chemical space of existing partial FXR agonists, we performed a structure-activity relationship study based on previously reported partial agonist 1 by using bioisosteric strategy. All of these efforts resulted in the identification of novel partial FXR agonist 13, which revealed the best agonistic activity in this series. Notably, compound 13 significantly alleviated the hepatic steatosis and hepatic function index in methionine-choline deficient (MCD) induced db/db mice, a classical nonalcoholic steatohepatitis (NASH) model widely used in preclinical evaluation. These results suggested that partial FXR agonist 13 might be a promising lead compound worthy further researches.