Promising therapeutic targets for ischemic stroke identified from plasma and cerebrospinal fluid proteomes: a multicenter Mendelian randomization study.

BACKGROUND: Ischemic stroke (IS) is more common every year, the condition is serious, and have a poor prognosis. New, efficient, and safe therapeutic targets are desperately needed as early treatment especially prevention and reperfusion is the key to lowering the occurrence of poorer prognosis. Generally circulating proteins are attractive therapeutic targets, this study aims to identify potential pharmacological targets among plasma and cerebrospinal fluid (CSF) proteins for the prevention and treatment of IS using a multicenter Mendelian randomization (MR) approach. METHODS: First, the genetic instruments of 734 plasma and 151 CSF proteins were assessed for causative connections with IS from MEGASTROKE consortium by MR to identify prospective therapeutic targets. Then, for additional validation, plasma proteins from the deCODE consortium and the Fenland consortium, as well as IS GWAS data from the FinnGen cohort, the ISGC consortium and UK biobank, were employed. A thorough evaluation of the aforementioned possible pharmacological targets was carried out using meta-analysis. The robustness of MR results was then confirmed through sensitivity analysis using several techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Finally, methods like Protein-Protein Interaction (PPI) Networking were utilized to investigate the relationship between putative drug targets and therapeutic agents. RESULTS: The authors discovered three proteins that may function as promising therapeutic targets for IS and meet the Bonferroni correction ( P <0.05/885=5.65×10 -5 ). Prekallikrein (OR=0.41, 95% CI: 0.27-0.63, P =3.61×10 -5 ), a protein found in CSF, has a 10-fold protective impact in IS, while the plasma proteins SWAP70 (OR=0.85, 95% CI: 0.80-0.91, P =1.64×10 -6 ) and MMP-12 (OR=0.92, 95% CI: 0.89-0.95, P =4.49×10 -6 ) of each SD play a protective role in IS. Prekallikrein, MMP-12, SWAP70 was replicated in the FinnGen cohort and ISGC database. MMP-12 (OR=0.93, 95% CI: 0.91-0.94, P <0.001), SWAP70 (OR=0.92, 95% CI: 0.90-0.94, P <0.001), and prekallikrein (OR=0.53, 95% CI: 0.33-0.72, P <0.001) may all be viable targets for IS, according to the combined meta-analysis results. Additionally, no evidence of reverse causality was identified, and Bayesian colocalization revealed MMP-12 (PPH 4 =0.995), SWAP70 (PPH 4 =0.987), and prekallikrein (PPH 4 =0.894) shared the same variant with IS, supporting the robustness of the aforementioned causation. Prekallikrein and MMP-12 were associated with the target protein of the current treatment of IS. Among them, Lanadelumab, a new drug whose target protein is a prekallikrein, may be a promising new drug for the treatment of IS. CONCLUSION: The prekallikrein, MMP-12, and SWAP70 are causally associated with the risk of IS. Moreover, MMP-12 and prekallikrein may be treated as promising therapeutic targets for medical intervention of IS.

Characterization the prognosis role and effects of snoRNAs in melanoma patients.

Melanoma is a melanocyte-derived malignant cancer and is known for its early metastasis and high mortality rates. It is a highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, and the identification of reliable diagnostic and prognostic markers is crucial for improving patient outcomes. In the search for biomarkers, various types of RNAs have been discovered and recognized as reliable prognostic markers. Among these, small nucleolar RNAs (snoRNAs) have emerged as a promising avenue for studying early diagnosis and prognostic markers in tumours due to their widespread presence in tissues, tumour specificity and stability. In our study, we analysed snoRNAs data from melanoma samples in the TCGA-SKCM cohort and developed a prognostic model comprising 12 snoRNAs (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 and AC004839). This model exhibited unique prognostic accuracy and demonstrated a significant correlation with the immune infiltration tumour microenvironment. Additionally, analysis of the GSE213145 dataset, which explored the sensitivity and resistance of immune checkpoint inhibitors, further supported the potential of snoRNAs as prognostic markers for immunotherapy. Overall, our study contributes reliable prognostic and immune-related biomarkers for melanoma patients. These findings can offer valuable insights for the future discovery of novel melanoma treatment strategies and hold promise for improving clinical outcomes in melanoma patients.

Comprehensive analysis of cuproptosis-related long non-coding RNAs in prognosis, immune microenvironment infiltration and chemotherapy response of hepatocellular carcinoma.

The objective of this study is to explore the relationship between cuproptosis-related long noncoding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). RNA-seq data, including lncRNAs and related clinical information of HCC patients, were downloaded from The Cancer Genome Atlas database. A signature composed 3 cuproptosis-related lncRNAs was constructed by LASSO analysis, and HCC patients were classified into high- and low-risk groups. Patients in the high-risk group had a poorer prognosis compared with the low-risk group. Univariate Cox and multivariate Cox regression analyses confirmed that the signature model was an independent risk factor compared to other clinical biomarkers. Furthermore, gene set enrichment analysis indicated that metabolism-related pathways were enriched in low-risk group, including drug metabolism, and fatty acid metabolism. Further research demonstrated that there were markedly differences in drug response between the high- and low-risk group. Immune related analysis showed that the most type of immune cells and immunological function in the high-risk group were different with the risk-group. Finally, TP53 mutation rate and the tumor mutational burden in the high-risk group were higher compared with the low-risk group. In conclusion, we constructed a prognostic signature based on the expression of cuproptosis-related lncRNAs to predict HCC patients' prognosis, drug response and immune microenvironment, and further research will be conducted to uncover the mechanisms.

The romantic history of signaling pathway discovery in cell death: an updated review.

Cell death is a fundamental physiological process in all living organisms. Processes such as embryonic development, organ formation, tissue growth, organismal immunity, and drug response are accompanied by cell death. In recent years with the development of electron microscopy as well as biological techniques, especially the discovery of novel death modes such as ferroptosis, cuprotosis, alkaliptosis, oxeiptosis, and disulfidptosis, researchers have been promoted to have a deeper understanding of cell death modes. In this systematic review, we examined the current understanding of modes of cell death, including the recently discovered novel death modes. Our analysis highlights the common and unique pathways of these death modes, as well as their impact on surrounding cells and the organism as a whole. Our aim was to provide a comprehensive overview of the current state of research on cell death, with a focus on identifying gaps in our knowledge and opportunities for future investigation. We also presented a new insight for macroscopic intracellular survival patterns, namely that intracellular molecular homeostasis is central to the balance of different cell death modes, and this viewpoint can be well justified by the signaling crosstalk of different death modes. These concepts can facilitate the future research about cell death in clinical diagnosis, drug development, and therapeutic modalities.

Exploring the Causality of Type 1 Diabetes and Stroke Risk: A Mendelian Randomization Study and Meta-analysis.

Type II diabetes was causally related to stroke, which is a risk factor for stroke. However, the causal relationship between type I diabetes(T1D) and stroke, especially its subtypes, remains unclear. To determine whether T1D has a genetic causal link to stroke and its subtypes, we undertook this mendelian randomization (MR) study. The genome-wide association studies (GWAS) of T1D was the source of exposure. The outcomes were strokes and their subtypes, including ischemic stroke (IS), small vessel stroke (SVS), cardioembolic stroke (CES), large artery atherosclerosis stroke (LAS), intracerebral hemorrhage (ICH), lobar intracerebral hemorrhage (LICH), and non-lobar intracerebral hemorrhage (NLICH). We used outcome GWAS conducted by ISGC consortium for the initial phase and GWAS from MEGASTROKE consortium as the data for the replication phase to confirm the causal association. Besides, we conducted a meta-analysis of the causal association from ISGC and MEGASTROKE databases to confirm robust causality. Inverse-variance weighting (IVW) was utilized as the primary method to estimate the causality between T1D and stroke. The Cochran's Q test and the MR-PRESSO global test were used to examine the sensitivity. We discovered the causal relationship between T1D and SVS (OR = 1.17, 95% CI: 1.07-1.28, p = 6.0 × 10- 4), CES (OR = 1.11, 95%CI: 1.03-1.21, p = 0.0080) in initial stage. The replication phase validated T1D has a causal relationship with SVS (OR = 1.12, 95% CI: 1.06-1.18, p = 4.0 × 10- 5), but not with stroke and other subtypes. The meta-analysis of initial and replication stage again supported the causal link between T1D and SVS (OR = 1.13, 95% CI: 1.08-1.18, p < 0.05). However, no causal relationship was found between T1D and other stroke subtypes. The sensitivity analysis also supported the robust of these results. In conclusion, T1D was causally associated with SVS, but not with other subtypes of stroke. More investigation is needed to understand the underlying biology mechanism.

Potential preventive markers in the intracerebral hemorrhage process are revealed by serum untargeted metabolomics in mice using hypertensive cerebral microbleeds.

Hypertensive cerebral microbleeds (HCMB) may be the early stage of hypertensive intracerebral hemorrhage (HICH), which is a serious threat to health due to its high mortality and disability rates. The early clinical symptoms of HCMB may not be significant. Moreover, it is difficult to achieve early diagnosis and intervention for targeted prevention of HICH. Although hypertension (HTN) is a predisposition for HCMB, it remains unclear whether there is any difference between hypertensive patients with or without HCMB. Therefore, we carried out liquid chromatography-mass spectrometry (LC-MS) to analyze early biomarkers for HCMB in mice with hypertension and to lay the foundation for early prevention of HICH in hypertensive patients. In total, 18 C57 male mice were randomly divided into the HCMB (n = 6), HTN (n = 6), and control groups (CON, n = 6). Hematoxylin-eosin and diaminobenzidine staining were used to assess the reliability of the model. The metabolite expression level and sample category stability were tested using the displacement test of orthogonal partial least squares discriminant analysis (OPLS-DA). Significant differences in metabolites were screened out using variable importance in the projection (VIP > 1), which were determined using the OPLS-DA model and the P-value of the t-test (P < 0.05) combined with the nonparametric rank-sum test. With an area under the curve (AUC) > 0.85 and a P-value of 0.05, the receiver operating characteristic curve (ROC) was used to further screen the distinct metabolites of HCMB. Compared with the HTN and CON groups, the HCMB group had significantly higher blood pressure and lower average body weight (P < 0.05). Through untargeted LC-MS analysis, 93 distinct metabolites were identified in the HCMB (P < 0.05, VIP > 1) group. Among these potential biomarkers, six significantly decreased and eight significantly increased differential metabolites were found. Meanwhile, we found that the HCMB group had statistically distinct arginine and purine metabolism pathways (P < 0.05), and citrulline may be the most significant possible biomarker of HCMB (AUC > 0.85, P < 0.05). All of these potential biomarkers may serve as early biomarkers for HICH in hypertension.

Mendelian randomization study and meta-analysis exploring the causality of age at menarche and the risk of intracerebral hemorrhage and ischemic stroke.

BACKGROUND: The relationship between the age at menarche (AAM) and the risk of intracerebral hemorrhage (ICH) and ischemic stroke (IS) is still up for debate. The purpose of this study was to investigate potential causal connections between them. METHODS: Genome-wide association analysis (GWAS) of AAM conducted by the MRC-IEU consortium was utilized for association analyses of ICH and IS by two-sample Mendelian randomization (MR) study. AAM data of the within-family GWAS consortium were used as replication phase data to verify the causal relationship between each other. Inverse variance weighting (IVW) method was the primary method used in this MR study. For additional proof, the weighted median estimation, MR-Egger regression, MR-PRESSO test, and MR-Robust Adjusted Profile Score evaluation were performed. The Cochran's Q test and the MR-PRESSO global test were used, respectively, to examine the sensitivity and pleiotropy. Random effects meta-analysis was utilized to analyze the causal data from the two consortiums to further explore the causality between AAM and ICH, IS. RESULTS: We found that the AAM was causally linked with the risk of ICH (OR = 0.48, 95% CI: 0.28-0.80, p = 0.006). On the contrary, the causal effect from AAM to IS (OR = 0.98, 95% CI: 0.91-1.06, p = 0.64) has not been confirmed. For all subtypes of ICH, we found that nonlobar intracerebral hemorrhage (NLICH, OR = 0.41, 95% CI: 0.23-0.75, p = 0.004) but not lobar intracerebral hemorrhage (LICH, OR = 0.65, 95% CI: 0.34-1.24, p = 0.19) was associated with AAM without surprise. Similarly, we used the within-family GWAS consortium data to explore causality and found that AAM may reduce the risk of ICH (OR = 0.78, 95% CI: 0.72-0.86, p = 9.5 × 10-8 ) and NLICH (OR = 0.68, 95% CI: 0.61-0.75, p = 3.4 × 10-13 ) by IVW methods, but is not related to IS (OR = 0.97, 95% CI: 0.93-1.02, p = 0.26). These findings are further supported by the meta-analysis. Both Cochran's Q test and the MR-PRESSO global test failed to detect the presence of sensitivity. CONCLUSION: AAM and ICH, particularly NLICH, are causally related, but not LICH, IS, or its subtypes in European population.

Illuminating the potential causality of serum level of matrix metalloproteinases and the occurrence of cardiovascular and cerebrovascular diseases: a Mendelian randomization study.

BACKGROUND: It is still not clear that whether the expression levels of matrix metalloproteinases (MMPs) family are associated with cardiovascular and cerebrovascular diseases (CCDs) in genetic level. We explored the causal role of 12 members of MMPs in CCDs with mendelian randomization (MR) method to facilitate further exploring the underlying mechanisms. METHODS: The relationship between MMPs and CCDs including intracerebral hemorrhage (ICH), hypertension, coronary heart disease (CHD), atrial fibrillation (AF), and outstanding risk factors of type II diabetes were determined with the inverse variance-weighted (IVW) method. The sensitivity analyses including MR-Egger regression, weighted median estimation, and MR pleiotropy residual sum and outlier were utilized to test the robustness of the results generated from the MR method. RESULTS: We found that a higher serum level of MMP-12 was related to a lower risk of ICH (OR = 0.8287, 95% CI: 0.7526-0.9125, p = 0.00013), but not hypertension, CHD, type II diabetes or AF. And our study also revealed that a higher serum level of MMP-8 could result in a lower risk of hypertension (OR = 0.9976, 95% CI: 0.9964-0.9988, p = 0.00012) and AF (OR = 0.9851, 95% CI: 0.9741-0.9963, p = 0.0092), but not ICH, CHD or type II diabetes. All other members of MMPs other than MMP-8 and MMP-12 showed no statistical association with CCDs according to this study. Sensitivity analyses confirmed the reliability of our results. CONCLUSIONS: We provided statistical evidences for a potential causal relationship between MMP-12 and ICH, as well as MMP-8 and hypertension, while other MMPs showed weaker association with CCDs. The underlying mechanisms need to be established in the future.

JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens.

Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies.

The high morbidity, mortality, and disability rates associated with cerebrovascular disease (CeVD) pose a severe danger to human health. Gut bacteria significantly affect the onset, progression, and prognosis of CeVD. Gut microbes play a critical role in gut-brain interactions, and the gut-brain axis is essential for communication in CeVD. The reflection of changes in the gut and brain caused by gut bacteria makes it possible to investigate early warning biomarkers and potential treatment targets. We primarily discussed the following three levels of brain-gut interactions in a systematic review of the connections between gut microbiota and several cerebrovascular conditions, including ischemic stroke, intracerebral hemorrhage, intracranial aneurysm, cerebral small vessel disease, and cerebral cavernous hemangioma. First, we studied the gut microbes in conjunction with CeVD and examined alterations in the core microbiota. This enabled us to identify the focus of gut microbes and determine the focus for CeVD prevention and treatment. Second, we discussed the pathological mechanisms underlying the involvement of gut microbes in CeVD occurrence and development, including immune-mediated inflammatory responses, variations in intestinal barrier function, and reciprocal effects of microbial metabolites. Finally, based on the aforementioned proven mechanisms, we assessed the effectiveness and potential applications of the current therapies, such as dietary intervention, fecal bacterial transplantation, traditional Chinese medicine, and antibiotic therapy.

A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Genetic and Clinical Factors Associated with Opioid Response in Chinese Han Patients with Cancer Pain: An Exploratory Cross-Sectional Study.

INTRODUCTION: Studies have shown that genetic variation and environmental factors are associated with individual differences in therapeutic efficacy and side effects of opioids. However, the focus of these studies has been on a single factor of single-nucleotide polymorphisms (SNPs) or haplotypes, for which results have rarely been validated. For complex traits, such as cancer pain and opioid response, interactions between multiple genetic variation and environmental factors need to be considered to explain the opioid individual differences. METHODS: We conducted an exploratory two-stage cross-sectional study with 1027 Chinese patients who were taking strong opioid medications for their cancer pain, and genotyped 110 SNPs to explore the association of SNPs, haplotypes, gene-gene and gene-environment interactions with opioid dose, pain relief, and opioid-induced constipation. RESULTS: Due to the failure to meet Benjamini-Hochberg criteria in the discovery stage or to be validated in replication stage, no association was found between SNPs, haplotypes, paired SNP-SNP interactions or multi-dimensional gene-gene interactions and opioid response. However, for gene-environment interactions, optimal models have been constructed in all phenotypes of opioid response. CONCLUSIONS: This study reveals for the first time that construction of multidimensional gene-environment interactions enables better interpretations of the effect of genetic variation and environmental factors on the opioid response in patients with cancer pain. TRIAL REGISTRATION: Chictr.org.cn, identifier, ChiCTR2000033576.

Childhood Obesity and Risk of Stroke: A Mendelian Randomisation Analysis.

Background: The causal relationship between childhood obesity and stroke remains unclear. Our objective was to elucidate the causal relationship between childhood obesity and the risk of stroke and its subtypes by performing Mendelian randomisation (MR) analyses. Methods: Genetic instruments for childhood obesity were obtained from a genome-wide association study (GWAS) of 13,848 European participants. Summary level data for stroke, intracerebral haemorrhage, ischaemic stroke (IS), and its subtypes were evaluated using the MEGASTROKE GWAS dataset, which included 446,696 European adults. Inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and MR-Robust Adjusted Profile Score were applied in this MR analysis. The leave-one-out sensitivity test, MR-PRESSO Global test, and Cochran's Q test were conducted to confirm the accuracy and robustness of our results. Results: Genetic evaluations revealed that childhood obesity was associated with a higher risk of stroke (OR = 1.04, 95%CI: 1.01-1.07, p = 0.005) and IS (OR = 1.05, 95%CI: 1.02-1.08, p = 0.003), but not with intracerebral haemorrhage (ICH, OR = 0.93, 95%CI: 0.80-1.09, p = 0.39). In the subtype analysis, childhood obesity was also associated with large artery stroke (LAS, OR = 1.12, 95%CI: 1.02-1.22, p = 0.016) but not with cardioembolic stroke (OR = 1.06, 95%CI: 0.96-1.18, p = 0.21) and small vessel stroke (OR = 1.06, 95%CI: 0.98-1.15, p = 0.17). These results were stable in the sensitivity analysis and remained significant after Bonferroni correction. Conclusion: Our study provides evidence that childhood obesity is associated with a higher risk of stroke, IS, and LAS. The prevention of stroke, especially IS and LAS, should be promoted in populations with childhood obesity.

Deciphering the Irregular Risk of Stroke Increased by Obesity Classes: A Stratified Mendelian Randomization Study.

Background: To investigate the relationship between different classes of obesity and stroke, we conducted a stratified Mendelian randomization (MR) study. Methods: The body mass index (BMI) data of 263,407 Europeans with three classes of obesity (obesity class I, 30 kg/m2 ≤ BMI < 35 kg/m2; obesity class II, 35 kg/m2 ≤ BMI < 40 kg/m2; obesity class III, 40 kg/m2 ≤ BMI) were extracted from the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary-level data of stroke and its subtypes [ischemic stroke (IS) and intracerebral hemorrhage (ICH)] were obtained from the genome-wide association study (GWAS) meta-analysis, which was performed by the MEGASTROKE consortium. MR methods were used to identify the causal relationships. Results: The MR analysis revealed that both obesity class I [odds ratio (OR) = 1.08, 95% CI: 1.05-1.12, p = 1.0 × 10-5] and obesity class II (OR = 1.06, 95% CI: 1.03-1.09, p = 1 × 10-4) were significantly positively related to IS, while obesity class III was not (OR = 1.01, 95% CI: 0.96-1.06, p = 0.65). In contrast to IS, there was no class of obesity associated with ICH risk. Further examination of the relationship between obesity classification and IS subtypes revealed that certain degrees of obesity were related to large artery stroke (LAS) (OR = 1.14, 95% CI: 1.04-1.24, p = 2.8 × 10-3 for class I; OR = 1.08, 95% CI: 1.01-1.16, p = 0.002 for class II) and cardioembolic stroke (CES) (OR = 1.11, 95% CI: 1.02-1.20, p = 0.02 for class I; OR = 1.08, 95% CI: 1.02-1.15, p = 0.007 for class II). Conclusions: A higher risk of IS, but not ICH, could be linked to obesity classes I and II. A strong association between LAS and CES and obesity was observed among all IS subtypes in the obese population.

Complex analysis of the personalized pharmacotherapy in the management of COVID-19 patients and suggestions for applications of predictive, preventive, and personalized medicine attitude.

AIMS: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. METHODS: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. RESULTS: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. CONCLUSION: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

Vertical field enhancement of a spot-size converter using a nanopixel waveguide and window structure.

Spot-size converter (SSC) is an essential building block for integrated photonic circuits applied as a mode transformer between optical components. One typical issue for SSC is the difficulty of broadening the vertical field profile. Herein, we propose a nanopixel SSC (1 × 2 µm2) with changing hole size and density. Unlike a typical SSC, this configuration controls both the lateral and vertical field profiles relatively easily by enhancing the nanopixel density. A vertical field expansion of 1.21 µm was obtained by enhancing the nanopixel density. In addition, we designed the optical field in the lateral direction using deep neural network (DNN)-based learning to realize a perfect circular spot for high coupling efficiency that reached -3 dB at λ0 = 1.572 µm when the optical field aspect ratio was adjusted to 1 after training for 200 epochs. Furthermore, the vertical expansion was increased from 1.21 to 4.9 µm and the coupling efficiency from -3 to -0.41 dB by combining it a silicon dioxide window structure (5 × 15 × 10 µm3). The 1-dB operating bandwidth of the designed SSC structure is 100 nm (1.5-1.6 µm), while fabrication tolerance of the nanopixels and window structure length for the designed SSC structure are ±15 nm and ±250 nm when the coupling efficiency drops by 1 dB.

A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family.

PURPOSE: In order to clarify which variants of the MMR gene could provide current "healthy" members in affected families a more accurate risk assessment or predictive testing. PATIENTS AND METHODS: One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing. RESULTS: A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro. CONCLUSION: We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.

The role of CSDE1 in translational reprogramming and human diseases.

CSDE1 (cold shock domain containing E1) plays a key role in translational reprogramming, which determines the fate of a number of RNAs during biological processes. Interestingly, the role of CSDE1 is bidirectional. It not only promotes and represses the translation of RNAs but also increases and decreases the abundance of RNAs. However, the mechanisms underlying this phenomenon are still unknown. In this review, we propose a "protein-RNA connector" model to explain this bidirectional role and depict its three versions: sequential connection, mutual connection and facilitating connection. As described in this molecular model, CSDE1 binds to RNAs and cooperates with other protein regulators. CSDE1 connects with different RNAs and their regulators for different purposes. The triple complex of CSDE1, a regulator and an RNA reprograms translation in different directions for each transcript. Meanwhile, a number of recent studies have found important roles for CSDE1 in human diseases. This model will help us to understand the role of CSDE1 in translational reprogramming and human diseases. Video Abstract.