Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

Association of COVID-19 and Lung Cancer: Short-Term and Long-Term Interactions.

Background: COVID-19 has been ravaging the globe for more than three years. Due to systemic immunosuppression of anti-tumor therapy, application of chemotherapy and adverse effects of surgery, the short- and long-term prognosis of cancer patients to COVID-19 are of significant concern. Method: This research included three parts of data. The first part of the data came from the public database that covered Veneto residents. The second part of the data included participants in Guangzhou. The third part of the data was used for MR analysis. We assessed the associations by logistic, linear or Cox regression when appropriate. Result: Lung cancer patients with COVID-19 had shorter progression-free survival (PFS) after COVID-19 (Model II: HR: 3.28, 95% CI: 1.6~6.72; Model III: HR: 3.39, 95% CI: 1.45~7.95), compared with lung cancer patients without COVID-19. Targeted therapy patients recovered from SARS-CoV-2 infection more quickly (Model I: ß: -0.58, 95% CI: -0.75~-0.41; Model II: ß: -0.59, 95% CI: -0.76~-0.41; Model III: ß: -0.57; 95% CI: -0.75~-0.40). Conclusions: PFS in lung cancer patients is shortened by COVID-19. The outcome of COVID-19 in lung cancer patients was not significantly different from that of the healthy population. In lung cancer patients, targeted therapy patients had a better outcome of COVID-19, while chemotherapy patients had the worst.

Discovering Innate Driver Variants for Risk Assessment of Early Colorectal Cancer Metastasis.

Metastasis is the main fatal cause of colorectal cancer (CRC). Although enormous efforts have been made to date to identify biomarkers associated with metastasis, there is still a huge gap to translate these efforts into effective clinical applications due to the poor consistency of biomarkers in dealing with the genetic heterogeneity of CRCs. In this study, a small cohort of eight CRC patients was recruited, from whom we collected cancer, paracancer, and normal tissues simultaneously and performed whole-exome sequencing. Given the exomes, a novel statistical parameter LIP was introduced to quantitatively measure the local invasion power for every somatic and germline mutation, whereby we affirmed that the innate germline mutations instead of somatic mutations might serve as the major driving force in promoting local invasion. Furthermore, via bioinformatic analyses of big data derived from the public zone, we identified ten potential driver variants that likely urged the local invasion of tumor cells into nearby tissue. Of them, six corresponding genes were new to CRC metastasis. In addition, a metastasis resister variant was also identified. Based on these eleven variants, we constructed a logistic regression model for rapid risk assessment of early metastasis, which was also deployed as an online server, AmetaRisk (http://www.bio-add.org/AmetaRisk). In summary, we made a valuable attempt in this study to exome-wide explore the genetic driving force to local invasion, which provides new insights into the mechanistic understanding of metastasis. Furthermore, the risk assessment model can assist in prioritizing therapeutic regimens in clinics and discovering new drug targets, and thus substantially increase the survival rate of CRC patients.

Transcriptome analysis of the gills of Eriocheir sinensis provide novel insights into the molecular mechanisms of the pH stress response.

Eriocheir sinensis is an important economic species in China, which is easily affected by pH changes. However, the molecular mechanism of the pH stress response in E. sinensis is still unclear. Therefore, this study aimed to examine the molecular response mechanism of E. sinensis based on pH variation surveillance, histopathological evaluation and transcriptomic analyses. Firstly, pH variation surveillance showed that E. sinensis could actively regulate the pH of its environment. Meanwhile, the histopathological evaluation suggested that pH stress seriously damaged the gills, especially at high pH. Finally, transcriptome analysis showed that the expression of genes related to ion transport, immune stress, and energy metabolism significantly changed. Many genes played an important role in the pH response of E. sinensis, such as carbonic anhydrase (CA), mitochondrial proton/calcium exchanger protein (LETM1), recombinant sodium/hydrogen exchanger 3 (SLC9A3/NHE3), heat shock protein 90 alpha family class a member (HSP90A), alkylglycerone phosphate synthase (AGPS), succinate-CoA ligase ADP-forming subunit beta (LSC2), and superoxide dismutase (SOD). Our study revealed the molecular response mechanism of E. sinensis in response to pH stress, thus providing a basis for further research on the molecular mechanism of response to pH stress in aquatic animals.

The effects of ammonia stress exposure on protein degradation, immune response, degradation of nitrogen-containing compounds and energy metabolism of Chinese mitten crab.

BACKGROUND: The Chinese mitten crab is one of the most economically important crabs that are widely farmed in China. Ammonia, which is a main physiological challenge for crab culture, grows rapidly in the intensive culture system over time, but little information is available with Chinese mitten crab on the molecular mechanisms. METHODS AND RESULTS: Therefore, to understand the mechanism of response to ammonia stress in Eriocheir japonica sinensis, comparative transcriptome analysis was used to identify the key genes and pathways in hepatopancreas challenged with ammonia stress (325.07 mg/L NH4Cl). By sequencing the transcriptome hepatopancreas of E. j. sinensis treated with ammonia, 366,472 unigenes were obtained and annotated into several public libraries for later analyses. Subsequently, 1775 differentially expressed genes (DEGs) were identified according to comparative transcriptome analysis, of which 307 were up-regulated and 1468 were down-regulated. According to the DEGs of GO and KEGG enrichment analyses, we focused on four aspects of significant enrichment in this study: protein degradation, immune response, degradation of nitrogen-containing compounds and energy metabolism. The genes involved in protein degradation and energy metabolism process showed a significant decrease which was consisting of overall biological activity of E. j. sinensis decreased. In addition, five genes involved in high concentration of ammonia were discovered and validated by qRT-PCR. CONCLUSIONS: This study will help us understand the molecular mechanisms of E. j. sinensis under high ammonia exposure and provide valuable information to the future research of other crabs with ammonia exposure.

Therapeutic Interventions of Gut-Brain Axis as Novel Strategies for Treatment of Alcohol Use Disorder Associated Cognitive and Mood Dysfunction.

Alcohol use disorders (AUD) is characterized by persistent or intermittent alcohol cravings and compulsive drinking. The functional changes in the central nervous system (CNS) after alcohol consumption are alcohol-associated cognitive impairment and mood disorders, which are major health issues reported in AUDs. Studies have shown that transferring the intestinal microbiota from AUDs patients to germ-free animals causes learning and memory dysfunction, depression and anxiety-like behavior, indicating the vital role of intestinal microbiota in development of neuropsychiatric disorders in AUD. Intestinal flora composition of AUD patients are significantly different from normal people, suggesting that intestinal flora imbalance orchestrate the development of neuropsychiatric disorders in AUD. Studies suggests that gut microbiome links bidirectional signaling network of the enteric nervous system (ENS) to central nervous system (CNS), forming gut-microbe-brain axis (brain-gut axis). In this review, we discussed pathogenesis and possible treatment of AUD-induced cognitive deficits, anxiety, and depression disorders. Further, we described the mechanism of intestinal flora imbalance and dysfunction of hippocampus-amygdala-frontal cortex (gut-limbic circuit system dysfunction). Therefore, we postulate therapeutic interventions of gut-brain axis as novel strategies for treatment of AUD-induced neuropsychiatric disorders.

High-Quality Genome Sequence Resource of a Rice False Smut Fungus Ustilaginoidea virens Isolate, UV-FJ-1.

Ustilaginoidea virens is the fungal pathogen causing rice false smut, resulting in not only yield lost but also grain pollution with toxic mycotoxins. Here we deployed PacBio Sequel II HIFI-read sequencing technology to generate a near-complete genome assembly for the U. virens isolate UV-FJ-1 (38.48 Mb), which was isolated from Fujian province, China. The genome assembly contains 116 contigs with N50 of 0.65 Mb and a maximum length of 2.10 Mb, and the genome completeness is ≥98% assessed by benchmarking universal single-copy orthologs (BUSCOs) and the mapping rate of Illumina short reads. Excluding 35.78% repeat sequences, we identified a total of 7,164 protein-coding genes, of which 5,818 were functionally annotated and 223 encode putative effector proteins. Moreover, 21 secondary metabolite biosynthesis gene clusters were found in UV-FJ-1 genome. Taken together, this high-quality genome assembly and gene annotation resource will provide a better insight for characterizing the biological and pathogenic mechanisms of U. virens.

Comparative transcriptome analysis of the gills of Procambarus clarkii provide novel insights into the response mechanism of ammonia stress tolerance.

Procambarus clarkii is an important model crustacean organism in many researches. Ammonia nitrogen is one of common contaminants in aquatic environment, influencing the health of aquatic organisms. The primary objective of this study was to investigate molecular mechanisms on ammonia stress in gills of P. clarkii to provide new insights into the strategies of aquatic animals in responding to high concentration of ammonia in the environment. Procambarus clarkii were randomly assigned into two groups (ammonia stress group, AG; control group, CG), and gill samples were dependently excised from AG and CG. Then response mechanisms on ammonia stress were investigated based on transcriptome data of P. clarkii. 9237 differentially expressed genes were identified in ammonia stress group. The genes of ion transport enzymes (NKA and SLC6A5S) were significantly up-regulated. Whereas the immune-related genes (e.g. MAP3K7, HSP70, HSP90A, CTSF, CTSL1, CHI and CTL4) and pathways were significantly up-regulated, which played an important role in reacting to ammonia stress. Procambarus clarkii may enhance immune defense to counteract ammonia toxicity by the up-regulation of immune-related genes and signaling pathways. The activities of ion transport enzymes are changed to mobilise signal transduction and ion channel regulation for adapting to ammonia environment. These previous key genes play an important role in resistance to ammonia stress to better prepare for survival in high concentration of ammonia.

Identification of putative ingestion-related olfactory receptor genes in the Chinese mitten crab (Eriocheir japonica sinensis).

BACKGROUND: Olfaction plays a central role in mating, spawning, obtaining food and escaping predators, which is essential for survival and reproduction of animals. The nature of the olfactory perception in crabs, which is a major group of crustaceans, has remained elusive. OBJECTIVE: This project aims to explore the molecular mechanism of olfaction in crabs and further improve our understanding of olfactory perception in crustaceans. METHODS: The olfactory receptors and ingestion-related gene expression in Eriocheir japonica sinensis were studied by transcriptomic techniques. The de novo assembly, annotation and functional evaluation were performed with bioinformatics tools. RESULTS: A series of chemosensory receptors associated with olfaction were identified including 33 EsIRs, 24 EsIGluRs, 58 EsVIGluRs, 1 EsOR and 1 EsGC-D. We found IRs were key odorant receptors demonstrating a specific species evolutionary trend in crustaceans. Furthermore, we identified ORs in E. j. sinensis and Litopenaeus vannamei. The incomplete EsOR and LvOR1 structures implied that ORs exist in crustaceans, and may have been degenerated or even lost in the olfactory evolutionary process. In addition, comparative transcriptome analysises demonstrated two possible olfactory transduction pathways of E. j. sinensis: the cGMP-mediated olfactory pathway related to vegetable odor molecules and the cAMP-mediated olfactory pathway related to meat odor molecules. The above results were consistent with its omnivorous ingestion of E. j. sinensis. CONCLUSIONS: Our study revealed the unique olfactory molecular mechanism of omnivorous crabs and provided valuable information for further functional research on the chemoreception mechanisms in crustaceans.

Comparative transcriptome analysis of the gills of Cardisoma armatum provides novel insights into the terrestrial adaptive related mechanism of air exposure stress.

Cardisoma armatum is a typical member of the Gecarcinidae which show significant behavioral, morphological, physiological, and/or biochemical adaptations permitting extended activities on the land. The special gills (branchiostegal lung) of C. armatum play an important role in maintaining osmotic pressure balance and obtaining oxygen to adapt to the terrestrial environment. However, adaptive molecular mechanisms responding to air exposure in C. armatum are still poorly understood. In this study, transcriptomic analysis and histological analysis were conducted on the gills to test adaptive capabilities over 8 h between the aerial exposure (AE) and the water immersion (WI) group. Differentially expressed genes (DEGs) related to terrestrial adaptation were categorized into four broad categories: ion transport, acid-base balance, energy metabolism and immune response. This is the first research to reveal the molecular mechanism of terrestrial adaptation in C. armatum, and will provide new insight into the molecular genetic basis of terrestrial adaptation in crabs.

Evolution of digestive enzyme genes associated with dietary diversity of crabs.

Crabs feed on a wide range of items and display diverse feeding strategies. The primary objective of this study was to investigate 10 digestive enzyme genes in representative crabs to provide insights into the genetic basis of feeding habits among crab functional groups. Crabs were classified into three groups based on their feeding habits: herbivores (HV), omnivores (OV), and carnivores (CV). To test whether crabs' feeding adaptations matched adaptive evolution of digestive enzyme genes, we examined the 10 digestive enzyme genes of 12 crab species based on hepatopancreas transcriptome data. Each of the digestive enzyme genes was compared to orthologous sequences using both nucleotide- (i.e., PAML and Datamonkey) and protein-level (i.e., TreeSAAP) approaches. Positive selection genes were detected in HV crabs (AMYA, APN, and MGAM) and CV crabs (APN, CPB, PNLIP, RISC, TRY, and XPD). Additionally, a series of positive selection sites were localized in important functional regions of these digestive enzyme genes. This is the first study to characterize the molecular basis of crabs' digestive enzyme genes based on functional feeding group. Our data suggest that HV crabs have evolved an enhanced digestion capacity for carbohydrates, and CV crabs have acquired digestion capacity for proteins and lipids.

A case of 18p deletion syndrome after blepharoplasty.

OBJECTIVE: The deletion of the short arm of chromosome 18 is thought to be one of the rare chromosomal aberrations. Here, we report a case to review this disease. CASE REPORT: The proband is a five-and-a-half-year-old girl who has had phenotypes manifested mainly by ptosis, broad face, broad neck with low posterior hairline, mental retardation, short stature, and other malformations. Chromosomal analysis for her mother showed a normal karyotype. Her father and younger brother were phenotypically normal. RESULT: Phenotypical features were quite similar throughout other cases and in accordance with the usual phenotype of del(18p) suggested within the same cases and among the del(18p) cases described. She underwent blepharoplasty, which improved her appearance. CONCLUSION: 18p deletion syndrome is diagnosed by gene analysis. Plastic surgeries for improving the appearance might be an option for these patients.

Effects of neurotrophin 3 on interdigestive migrating motor complex in rats with acute liver injury / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the effects of neurotrophin 3(NT-3)on interdigestive migrating motor complex (MMC) in rats with D-galactosamine induced acute liver injury.</p><p><b>METHODS</b>Twenty-four specific pathogen-free purebred rats were equally randomized into control and acute liver injury groups. The control group was injected with equal volume of normal saline via tail vein. Acute liver injury model of the rats was induced by D-galactosamine injection via the tail vein in the acute liver injury group. And the indexes of interdigestive MMC before and after NT-3 injection were recorded by a polygraph and analyzed in model group. The serum NT-3 concentration was assayed in the two groups.</p><p><b>RESULTS</b>There were no significant changes of gastrointestinal MMC cycle and jejunal phase I MMC after NT-3 injection. Compared with the acute liver injury rats before NT-3 injection , the antral phases I, III and IV MMC were significantly prolonged [(577.44 ± 248.60)s vs (343.58 ± 227.30) s, (80.94 ± 21.15) s vs (24.76 ± 7.41) s, (405.69 ± 131.34) s vs (191.67 ± 128.15) s, P < 0.05] and the phase II MMC was shortened [ (883.94 ± 488.50) s vs (1519.00 ± 831.14) s, P < 0.05] in the acute liver injury group. The duodenal phases I, III and IV MMC were significantly prolonged [ (557.63 ± 335.14) s vs (309.46 ± 220.22) s,(75.91 ± 15.75) s vs (31.15 ± 13.67) s, (423.38 ± 135.22) s vs (209.77 ± 123.83) s, P < 0.05] and MMC II phase was shortened [ (748.81 ± 579.69) s vs (1535.86 ± 930.50) s, P < 0.05] in the acute liver injury rats. In addition, the jejunal MMC III and MMC IV phase was significantly prolonged [ (86.58 ± 23.40) s vs (31.41 ± 16.09) s,(385.18 ± 110.02) s vs (220.59 ± 159.30) s, P < 0.05] and phase II MMC was shortened [ (876.89 ± 652.01) s vs (1870.89 ± 1010.35) s, P < 0.05 ] in the acute liver injury rats. The serum NT-3 level was significantly higher in model group than in control group.</p><p><b>CONCLUSION</b>NT-3 could enhance the gastrointestinal motility in acute liver injury rats.</p>

[Clinical experiment of cytokines induced killer cells for treatment of benzene poisoning].

OBJECTIVE: To assess the reaction of cytokines induced killer (CIK) cells treatment in hematopoietic injury at different levels on patients with benzene poisoning and seek a novel, safe and effective immunotherapy for benzene poisoning. METHODS: CIK cells were in vitro activated by interleukin-2 (IL-2) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) from the peripheral blood mononuclear cells (PBMC). Thirty-two patients with benzene poisoning were treated with CIK cells. Nineteen patients with mild or moderate benzene poisoning in the control group were treated with VitB4, batilol, leucogen, inosine and stanozolol. The results for treatment of 12 patients with aplastic anemia induced by severe benzene poisoning (the efficacy rate and the case fatality rate) were analyzed. The change of T-lymphocyte subset analyzed by flow cytometry was also observed before and after treatment. RESULTS: For mild or moderate benzene poisoning, the increase of WBC and RLT in CIK group was higher than that in the control group (P < 0.05). The CD(4)/CD(8) levels were significantly increased after CIK treatment. And for severe benzene poisoning, the effective rate of the CIK group was 91.7% and the mortality rate was 0%. CONCLUSION: CIK treatment is safe and effective for hematopoietic injury caused by benzene poisoning. The mechanism may be related with the immune modulation of CIK treatment on immunodeficiency of patients with benzene poisoning.

Application of RAPD Molecular Marker to Edible Fungi / 中国生物工程杂志

RAPD molecular marker was widely applied to the studies of edible fungi due to it’s simplicity , rapidity and economy. The principle of RAPD molecular marker and its applications to edible fungi were summarized. The applications of RAPD to edible fungi were introduced in species and parental strain identification,genetic diversity, gene clone, gene isolation and the construction of gene linkage map. RAPD molecular marker provids a powerful tool for the studies of edible fungi.