Higher intracranial arterial pulsatility is associated with presumed imaging markers of the glymphatic system: An explorative study.

BACKGROUND: Arterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation of glymphatic clearance. However, whether intracranial arterial pulsatility is associated with glymphatic markers in humans has not yet been studied. METHODS: Seventy-three community participants were enrolled in the study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify the hemodynamic parameters including flow pulsatility index (PIflow) and area pulsatility index (PIarea) from 13 major intracerebral arterial segments. Three presumed neuroimaging markers of the glymphatic system were measured: including dilation of perivascular space (PVS), diffusivity along the perivascular space (ALPS), and volume fraction of free water (FW) in white matter. We explored the relationships between PIarea, PIflow, and the presumed glymphatic markers, controlling for related covariates. RESULTS: PIflow in the internal carotid artery (ICA) C2 segment (OR, 1.05; 95 % CI, 1.01-1.10, per 0.01 increase in PI) and C4 segment (OR, 1.05; 95 % CI, 1.01-1.09) was positively associated with the dilation of basal ganglia PVS, and PIflow in the ICA C4 segment (OR, 1.06, 95 % CI, 1.02-1.10) was correlated with the dilation of PVS in the white matter. ALPS was associated with PIflow in the basilar artery (ß, -0.273, p, 0.046) and PIarea in the ICA C2 (ß, -0.239, p, 0.041) and C7 segments (ß, -0.238, p, 0.037). CONCLUSIONS: Intracranial arterial pulsatility was associated with presumed neuroimaging markers of the glymphatic system, but the results were not consistent across different markers. Further studies are warranted to confirm these findings.

Small vessel disease and cognitive reserve oppositely modulate global network redundancy and cognitive function: A study in middle-to-old aged community participants.

Cerebral small vessel disease (SVD) can disrupt the global brain network and lead to cognitive impairment. Conversely, cognitive reserve (CR) can improve one's cognitive ability to handle damaging effects like SVD, partly by optimizing the brain network's organization. Understanding how SVD and CR collectively influence brain networks could be instrumental in preventing cognitive impairment. Recently, brain redundancy has emerged as a critical network protective metric, providing a nuanced perspective of changes in network organization. However, it remains unclear how SVD and CR affect global redundancy and subsequently cognitive function. Here, we included 121 community-dwelling participants who underwent neuropsychological assessments and a multimodal MRI examination. We visually examined common SVD imaging markers and assessed lifespan CR using the Cognitive Reserve Index Questionnaire. We quantified the global redundancy index (RI) based on the dynamic functional connectome. We then conducted multiple linear regressions to explore the specific cognitive domains related to RI and the associations of RI with SVD and CR. We also conducted mediation analyses to explore whether RI mediated the relationships between SVD, CR, and cognition. We found negative correlations of RI with the presence of microbleeds (MBs) and the SVD total score, and a positive correlation of RI with leisure activity-related CR (CRI-leisure). RI was positively correlated with memory and fully mediated the relationships between the MBs, CRI-leisure, and memory. Our study highlights the potential benefits of promoting leisure activities and keeping brain redundancy for memory preservation in older adults, especially those with SVD.

Lipid droplets-related Perilipin-3: potential immune checkpoint and oncogene in oral squamous cell carcinoma.

BACKGROUND: Lipid droplets (LDs) as major lipid storage organelles are recently reported to be innate immune hubs. Perilipin-3 (PLIN3) is indispensable for the formation and accumulation of LDs. Since cancer patients show dysregulated lipid metabolism, we aimed to elaborate the role of LDs-related PLIN3 in oral squamous cell carcinoma (OSCC). METHODS: PLIN3 expression patterns (n = 87), its immune-related landscape (n = 74) and association with B7-H2 (n = 51) were assessed by immunohistochemistry and flow cytometry. Real-time PCR, Western blot, Oil Red O assay, immunofluorescence, migration assay, spheroid-forming assay and flow cytometry were performed for function analysis. RESULTS: Spotted LDs-like PLIN3 staining was dominantly enriched in tumor cells than other cell types. PLIN3high tumor showed high proliferation index with metastasis potential, accompanied with less CD3+CD8+ T cells in peripheral blood and in situ tissue, conferring immunosuppressive microenvironment and shorter postoperative survival. Consistently, PLIN3 knockdown in tumor cells not only reduced LD deposits and tumor migration, but benefited for CD8+ T cells activation in co-culture system with decreased B7-H2. An OSCC subpopulation harbored PLIN3highB7-H2high tumor showed more T cells exhaustion, rendering higher risk of cancer-related death (95% CI 1.285-6.851). CONCLUSIONS: LDs marker PLIN3 may be a novel immunotherapeutic target in OSCC.

Transcriptomic and physiological analysis provide new insight into seed shattering mechanism in Pennisetum alopecuroides 'Liqiu'.

KEY MESSAGE: Through the histological, physiological, and transcriptome-level identification of the abscission zone of Pennisetum alopecuroides 'Liqiu', we explored the structure and the genes related to seed shattering, ultimately revealing the regulatory network of seed shattering in P. alopecuroides. Pennisetum alopecuroides is one of the most representative ornamental grass species of Pennisetum genus. It has unique inflorescence, elegant appearance, and strong stress tolerance. However, the shattering of seeds not only reduces the ornamental effect, but also hinders the seed production. In order to understand the potential mechanisms of seed shattering in P. alopecuroides, we conducted morphological, histological, physiological, and transcriptomic analyses on P. alopecuroides cv. 'Liqiu'. According to histological findings, the seed shattering of 'Liqiu' was determined by the abscission zone at the base of the pedicel. Correlation analysis showed that seed shattering was significantly correlated with cellulase, lignin, auxin, gibberellin, cytokinin and jasmonic acid. Through a combination of histological and physiological analyses, we observed the accumulation of cellulase and lignin during 'Liqiu' seed abscission. We used PacBio full-length transcriptome sequencing (SMRT) combined with next-generation sequencing (NGS) transcriptome technology to improve the transcriptome data of 'Liqiu'. Transcriptomics further identified many differential genes involved in cellulase, lignin and plant hormone-related pathways. This study will provide new insights into the research on the shattering mechanism of P. alopecuroides.

Retinoic acid mitigates the NSC319726-induced spermatogenesis dysfunction through cuproptosis-independent mechanisms.

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.

RNA pseudouridine modification in plants.

Pseudouridine is one of the well-known chemical modifications in various RNA species. Current advances to detect pseudouridine show that the pseudouridine landscape is dynamic and affects multiple cellular processes. Although our understanding of this post-transcriptional modification mainly depends on yeast and human models, the recent findings provide strong evidence for the critical role of pseudouridine in plants. Here, we review the current knowledge of pseudouridine in plant RNAs, including its synthesis, degradation, regulatory mechanisms, and functions. Moreover, we propose future areas of research on pseudouridine modification in plants.

Identification and characterization of cotton PHYTOCHROME-INTERACTING FACTORS in temperature-dependent flowering.

PHYTOCHROME INTERACTING FACTORS (PIFs) integrate light and temperature signs to control plant growth and development. However, little is known about PIFs in crop plants such as cotton. Here, we identified 68 PIF proteins and their coding genes from an allotetraploid and three diploid ancestors. Cotton PIFs contain typical ACTIVEPHYA-BINDING (APA) and ACTIVE PHYB-BINDING (APB) motifs by which they bind to phytochrome phyA and phyB, respectively, and have a BASIC HELIX-LOOP-HELIX (bHLH) domain and a nuclear localization sequence necessary for bHLH-type transcription factors. Bioinformatics analysis showed that the promoter of each PIF gene contains multiple cis-acting elements and that the evolution of cotton genomes probably underwent loss, recombination, and tandem replication. Further observations indicated that the sensitivity of cotton PIF expression to high temperature was significantly different from that to low temperature. We found that allotetraploid Gossypium hirsutum PIF4a (GhPIF4a) was induced by high temperature. GhPIF4a promotes flowering in cotton and Arabidopsis and binds to the promoter of GhFT (G. hirsutum FLOWERING LOCUS T), and binding increased with increasing temperature. Our work identifies the evolutionary and structural characteristics and functions of PIF family members in cotton.

Clinical outcomes and toxicities of locally advanced esophageal squamous cell carcinoma patients treated with early thoracic radiation therapy after induction chemotherapy.

OBJECTIVE: The purpose of this study was to compare the clinical outcomes and toxicities between induction chemotherapy (IC) + chemo-radiotherapy (CRT) and CRT alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC), to explore the appropriate thoracic radiotherapy (TRT) timing after IC and to identify prognostic factors. METHODS: 450 ESCC patients were included from September 2011 to December 2020, 238 of whom received IC/CRT. Propensity score matching was performed to balance potential confounders between the two groups. Multivariate Cox regression analysis was used to identify the independent prognostic factors. RESULTS: Patients who received IC/CRT experienced improved overall survival (OS) (38.5 vs. 28.8 months) and progression-free survival (PFS) (41.0 vs. 22.0 months) before matching, with similar results after matching. In the IC/CRT group, early TRT had more favorable survival than late TRT both matching before and after. In subgroup analysis, early TRT combination concurrent chemotherapy had better OS and PFS than late TRT combination concurrent chemotherapy. In addition, early TRT had better survival benefits regardless of the N stage. Notably, the IC/CRT group and early TRT group had manageable toxicities reaction compared with CRT alone group and the late TRT group. The nomogram was developed to predict the OS and PFS based on multivariate analysis results. The C-index was 0.743 and 0.722, respectively. CONCLUSION: IC/CRT and early TRT could yield satisfactory clinical outcomes and controllable toxicities in locally advanced ESCC. The IC plus early concurrent CRT might be a promising treatment strategy for improving further survival in ESCC.

A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR.

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).

Analysis of the RNA Editing Sites and Orthologous Gene Function of Transcriptome and Chloroplast Genomes in the Evolution of Five Deutzia Species.

In this study, the chloroplast genomes and transcriptomes of five Deutzia genus species were sequenced, characterized, combined, and analyzed. A phylogenetic tree was constructed, including 32 other chloroplast genome sequences of Hydrangeoideae species. The results showed that the five Deutzia chloroplast genomes were typical circular genomes 156,860-157,025 bp in length, with 37.58-37.6% GC content. Repeat analysis showed that the Deutzia species had 41-45 scattered repeats and 199-201 simple sequence repeats. Comparative genomic and pi analyses indicated that the genomes are conservative and that the gene structures are stable. According to the phylogenetic tree, Deutzia species appear to be closely related to Kirengeshoma palmata and Philadelphus. By combining chloroplast genomic and transcriptomic analyses, 29-31 RNA editing events and 163-194 orthologous genes were identified. The ndh, rpo, rps, and atp genes had the most editing sites, and all RNA editing events were of the C-to-U type. Most of the orthologous genes were annotated to the chloroplast, mitochondria, and nucleus, with functions including energy production and conversion, translation, and protein transport. Genes related to the biosynthesis of monoterpenoids and flavonoids were also identified from the transcriptome of Deutzia spp. Our results will contribute to further studies of the genomic information and potential uses of the Deutzia spp.

Combination analysis of single-molecule long-read and Illumina sequencing provides insights into the anthocyanin accumulation mechanism in an ornamental grass, Pennisetum setaceum cv. Rubrum.

KEY MESSAGE: Combination analysis of single-molecule long-read and Illumina sequencing provide full-length transcriptome information and shed new light on the anthocyanin accumulation mechanism of Pennisetum setaceum cv. 'Rubrum'. Pennisetum setaceum cv. 'Rubrum' is an ornamental grass with purple leaves widely used in landscaping. However, the current next-generation sequencing (NGS) transcriptome information of this species is not satisfactory due to the difficulties in obtaining full-length transcripts. Furthermore, the molecular mechanisms of anthocyanin accumulation in P. setaceum have not been thoroughly studied. In this study, we used PacBio full-length transcriptome sequencing (SMRT) combined with NGS technology to build and improve the transcriptomic datasets and reveal the molecular mechanism of anthocyanin accumulation in P. setaceum cv. 'Rubrum'. Therefore, 280,413 full-length non-chimeric reads sequences were obtained using the SMRT technology. We obtained 97,450 high-quality non-redundant transcripts and identified 5352 alternative splicing events. In addition, 93,066 open reading frames (ORFs), including 57,457 full ORFs and 2910 long non-coding RNA (lncRNAs) were screened out. Furthermore, 10,795 differentially expressed genes were identified using NGS. We also explored key genes, synthesis pathways, and detected lncRNA involved in anthocyanin accumulation, providing new insights into anthocyanin accumulation in P. setaceum cv. 'Rubrum'. To our best knowledge, we provided the full-length transcriptome information of P. setaceum cv. 'Rubrum' for the first time. The results of this study will provide baseline information for gene function studies and pave the way for future P. setaceum cv. 'Rubrum' breeding projects.

Single-molecule long-read sequencing analysis improves genome annotation and sheds new light on the transcripts and splice isoforms of Zoysia japonica.

BACKGROUND: Zoysia japonica is an important warm-season turfgrass used worldwide. Although the draft genome sequence and a vast amount of next-generation sequencing data have been published, the current genome annotation and complete mRNA structure remain incomplete. Therefore, to analyze the full-length transcriptome of Z. japonica, we used the PacBio single-molecule long-read sequencing method in this study. RESULTS: First, we generated 37,056 high-confidence non-redundant transcripts from 16,005 gene loci. Next, 32,948 novel transcripts, 913 novel gene loci, 8035 transcription factors, 89 long non-coding RNAs, and 254 fusion transcripts were identified. Furthermore, 15,675 alternative splicing events and 5325 alternative polyadenylation sites were detected. In addition, using bioinformatics analysis, the underlying transcriptional mechanism of senescence was explored based on the revised reference transcriptome. CONCLUSION: This study provides a full-length reference transcriptome of Z. japonica using PacBio single-molecule long-read sequencing for the first time. These results contribute to our knowledge of the transcriptome and improve the knowledge of the reference genome of Z. japonica. This will also facilitate genetic engineering projects using Z. japonica.

Optimal adaptive promising zone designs.

We develop optimal decision rules for sample size re-estimation in two-stage adaptive group sequential clinical trials. It is usual for the initial sample size specification of such trials to be adequate to detect a realistic treatment effect δa with good power, but not sufficient to detect the smallest clinically meaningful treatment effect δmin . Moreover it is difficult for the sponsors of such trials to make the up-front commitment needed to adequately power a study to detect δmin . It is easier to justify increasing the sample size if the interim data enter a so-called "promising zone" that ensures with high probability that the trial will succeed. We have considered promising zone designs that optimize unconditional power and promising zone designs that optimize conditional power and have discussed the tension that exists between these two objectives. Where there is reluctance to base the sample size re-estimation rule on the parameter δmin we propose a Bayesian option whereby a prior distribution is assigned to the unknown treatment effect δ , which is then integrated out of the objective function with respect to its posterior distribution at the interim analysis.

A simulation-based comparison of estimation methods for adaptive and classical group sequential clinical trials.

Statistical methods for controlling the type-I error of hypothesis tests in adaptive group sequential clinical trials are well established and well understood. However, methods for obtaining statistically valid point estimates and confidence intervals for adaptive designs are not as well established or as well understood. At the end of an adaptive trial, one may calculate the repeated confidence interval (RCI), which provides conservative coverage of δ , or the backward image confidence interval (BWCI), which provides exact coverage of δ and is an extension of the stagewise adjusted confidence interval (SWCI, used in classical group sequential designs). The BWCI can also provide a median unbiased estimate (MUE) of δ . There is a need to better understand the coverage and possible biases associated with these methods. We conducted a simulation study exploring parameter estimation following sample size reestimation based on testing methods with strong control of type-I error. Generally, the BWCI provided exact coverage, the naïve CI provided inconsistent coverage, and the RCI provided conservative coverage. Additionally, we note considerable asymmetry in the coverage from above/from below for the RCI, although we did not see any instance where the 95% RCI excluded the true parameter more than 2.5% on either side. At the end of an adaptive group sequential trial, we strongly recommend the use of the BWCI (and associated MUE), with the RCI computed during interim looks; the naïve CI should be avoided. These results and conclusions also hold true for classical group sequential designs.

Combined transcriptome and proteome analysis provides insights into anthocyanin accumulation in the leaves of red-leaved poplars.

KEY MESSAGE: Anthocyanin was highly accumulated in the leaves of red-leaved poplars; Many structural genes involved in anthocyanin synthesis were significantly up-regulated in 'Quanhong' and 'Xuanhong'; TTG2, HYH, and HY5 may be directly involved in the regulation of anthocyanin synthesis in both red-leaved poplars. The red-leaved poplar cultivars 'Quanhong' and 'Xuanhong' are bud mutations of Populus deltoides cv. 'Zhonglin 2025'. These cultivars are valued for their beautiful shape, lack of flying catkins, and ornamental leaf colors. However, the understanding of the molecular mechanism of anthocyanin accumulation in the leaves of red-leaved poplars is still unclear. Here, we profiled the changes of pigment content, transcriptome and proteome expression in the leaves of three poplar cultivars and the results showed that the ratios of anthocyanin to total chlorophyll in both red-leaved poplars were higher than that in 'Zhonglin 2025', indicating that the anthocyanin was highly accumulated in the leaves of red-leaved poplars. Based on the results of combined transcriptome and proteome analysis, 15 and 11 differentially expressed genes/proteins involved in anthocyanin synthesis were screened in 'Quanhong' and 'Xuanhong', respectively, indicating that the two red-leaved poplar cultivars have slightly different patterns of regulating anthocyanin biosynthesis. Among the 120 transcription factors, 3 (HY5, HYH, and TTG2), may be directly involved in the regulation of anthocyanin synthesis in both red-leaved poplars. This study screens the candidate genes involved in anthocyanin accumulation in the leaves of red-leaved poplars and lays a foundation for further exploring the molecular mechanism of leaf red coloration in red-leaved poplars.

The development of SSR markers based on RNA-sequencing and its validation between and within Carex L. species.

BACKGROUND: Carex L. is one of the largest genera in the Cyperaceae family and an important vascular plant in the ecosystem. However, the genetic background of Carex is complex and the classification is not clear. In order to investigate the gene function annotation of Carex, RNA-sequencing analysis was performed. Simple sequence repeats (SSRs) were generated based on the Illumina data and then were utilized to investigate the genetic characteristics of the 79 Carex germplasms. RESULTS: In this study, 36,403 unigenes with a total length of 41,724,615 bp were obtained and annotated based on GO, KOG, KEGG, NR databases. The results provide a theoretical basis for gene function exploration. Out of 8776 SSRs, 96 pairs of primers were randomly selected. One hundred eighty polymorphic bands were amplified with a polymorphism rate of 100% based on 42 pairs of primers with higher polymorphism levels. The average band number was 4.3 per primer, the average distance value was 0.548, and the polymorphic information content was ranged from 0.133 to 0.494. The number of observed alleles (Na), effective alleles (Ne), Nei's (1973) gene diversity (H), and the Shannon information index (I) were 2.000, 1.376, 0.243, and 0.391, respectively. NJ clustering divided into three groups and the accessions from New Zealand showed a similar genetic attribute and clustered into one group. UPGMA and PCoA analysis also revealed the same result. The analysis of molecular variance (AMOVA) revealed a superior genetic diversity within accessions than between accessions based on geographic origin cluster and NJ cluster. What's more, the fingerprints of 79 Carex species are established in this study. Different combinations of primer pairs can be used to identify multiple Carex at one time, which overcomes the difficulties of traditional identification methods. CONCLUSIONS: The transcriptomic analysis shed new light on the function categories from the annotated genes and will facilitate future gene functional studies. The genetic characteristics analysis indicated that gene flow was extensive among 79 Carex species. These markers can be used to investigate the evolutionary history of Carex and related species, as well as to serve as a guide in future breeding projects.

Prognostic value of SEC61G in lung adenocarcinoma: a comprehensive study based on bioinformatics and in vitro validation.

BACKGROUND: Studies have shown that the Sec61 gamma subunit (SEC61G) is overexpressed in several tumors and could serve as a potential prognostic marker. However, the correlation between SEC61G and lung adenocarcinoma (LUAD) remains unclear. In the current study, we aimed to demonstrate the prognostic value and potential biological function of the SEC61G gene in LUAD. METHODS: Public datasets were used for SEC61G expression analyses. The prognostic value of SEC61G in LUAD was investigated using the Kaplan-Meier survival and Cox analyses. The correlation between the methylation level of SEC61G and its mRNA expression was evaluated via cBioPortal. Additionally, MethSurv was used to determine the prognostic value of the SEC61G methylation levels in LUAD. Functional enrichment analysis was conducted to explore the potential mechanism of SEC61G. Also, single sample GSEA (ssGSEA) and TIMER online tool were applied to identify the correlation between SEC61G and immune filtration. Furthermore, cell functional experiments were conducted to verify the biological behavior of SEC61G in lung adenocarcinoma cells (LAC). RESULTS: SEC61G was upregulated in pan-cancers, including LUAD. High SEC61G expression was significantly correlated with worse prognosis in LUAD patients. Multivariate analysis demonstrated that high SEC61G expression was an independent prognostic factor in the TCGA cohort. (HR = 1.760 95% CI: 1.297-2.388, p < 0.001). The methylation level of SEC61G negatively correlated with the SEC61G expression (R = - 0.290, p < 0.001), and patients with low SEC61G methylation had worse overall survival. (p = 0.0014). Proliferation-associated terms such as cell cycle and cell division were significantly enriched in GO and KEGG analysis. Vitro experiments demonstrated that knockdown of SEC61G resulted in decreased cell proliferation, invasion and facilitated apoptosis in LAC. GSEA analysis found that SEC61G expression was associated with the E2F targets. Moreover, SEC61G expression was negatively correlated with the immune cell infiltration including CD4+ T cell, CD8+ T cell, B cell, macrophage, neutrophil, and dendritic cell. CONCLUSION: Our study indicated that overexpression of SEC61G was significantly associated with poor prognosis of LUAD patients and the malignant phenotypes of LUAD cells, suggesting that it could be a novel prognostic biomarker and potential therapeutic target of LUAD.

Targeting the microRNAs in exosome: A potential therapeutic strategy for alleviation of diabetes-related cardiovascular complication.

Diabetes-related cardiovascular disease (CVD) is a global health issue that causes thousands of people's death around the world annually. Diabetes-related CVD is still prevailing despite the progression being made in its diagnosis and treatment. Therefore it is urgent to find therapeutic strategies.to prevent it. MicroRNA (miRNA) is a single-stranded non-coding RNA involved in the process of post-transcriptional control of gene expression in eukaryotes. A large number of literatures reveal that miRNAs are implicated in diabetes-related CVD. The increase of miRNAs in exosomes may promote the occurrence and development of diabetes-related cardiovascular complication. However, some other studies identify that miRNAs in exosomes are supposed to be involved in cardiac regeneration and confer cardiac protection effect. Therefore, targeting the miRNA in exosome is regarded as a potent therapeutic measure to alleviate diabetes-related CVD. In this article, we review current knowledge about the role of exosomal miRNAs in diabetes-related cardiovascular complication, such as coronary heart disease, Peripheral artery disease, stroke, diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy. Exosomal miRNAs are considered to be central regulators of diabetes-Related CVD and provide a therapeutic tool for diagnosis and treatment of diabetes-related cardiovascular complication.

Early argatroban and antiplatelet combination therapy in acute non-lacunar single subcortical infarct associated with mild intracranial atherosclerosis.

BACKGROUND: Patients with acute non-lacunar single subcortical infarct (SSI) associated with mild intracranial atherosclerosis (ICAS) have a relatively high incidence of early neurological deterioration (END), resulting in unfavorable functional outcomes. Whether the early administration of argatroban and aspirin or clopidogrel within 6-12 h after symptom onset is effective and safe in these patients is unknown. METHODS: A review of the stroke database of Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University and Qingdao Center Hospital, Qingdao University Medical College in China was undertaken from May 2017 to January 2020 to identify all patients with non-lacunar SSI caused by ICAS within 6-12 h of symptom onset based on MRI screening. Patients were divided into two groups, one comprising those who received argatroban and mono antiplatelet therapy with aspirin or clopidogrel on admission (argatroban group), and the other those who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel during hospitalization (DAPT group). The primary outcome was recovery by 90 days after stroke based on a modified Rankin scale (mRS) score (0 to 1). The secondary outcome was END incidence within 120 h of admission. Safety outcomes were intracranial hemorrhage (ICH) and major extracranial bleeding. The probability of clinical benefit (mRS score 0-1 at 90 days) was estimated using multivariable logistic regression analysis. RESULTS: A total of 304 acute non-lacunar SSI associated with mild ICAS patients were analyzed. At 90 days, 101 (74.2%) patients in the argatroban group and 80 (47.6%) in the DAPT group had an mRS score that improved from 0 to 1 (P < 0.001). The relative risk (95% credible interval) for an mRS score improving from 0 to 1 in the argatroban group was 1.50 (1.05-2.70). END occurred in 10 (7.3%) patients in the argatroban group compared with 37 (22.0%) in the DAPT group (P < 0.001). No patients experienced symptomatic hemorrhagic transformation. CONCLUSIONS: Early combined administration of argatroban and an antiplatelet agent (aspirin or clopidogrel) may be beneficial for patients with non-lacunar SSI associated with mild ICAS identified by MRI screening and may attenuate progressive neurological deficits. TRIAL REGISTRATION: Our study is a retrospectively registered trial.

Early predictors and screening tool developing for severe patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a declared global pandemic, causing a lot of death. How to quickly screen risk population for severe patients is essential for decreasing the mortality. Many of the predictors might not be available in all hospitals, so it is necessary to develop a simpler screening tool with predictors which can be easily obtained for wide wise. METHODS: This retrospective study included all the 813 confirmed cases diagnosed with COVID-19 before March 2nd, 2020 in a city of Hubei Province in China. Data of the COVID-19 patients including clinical and epidemiological features were collected through Chinese Disease Control and Prevention Information System. Predictors were selected by logistic regression, and then categorized to four different level risk factors. A screening tool for severe patient with COVID-19 was developed and tested by ROC curve. RESULTS: Seven early predictors for severe patients with COVID-19 were selected, including chronic kidney disease (OR 14.7), age above 60 (OR 5.6), lymphocyte count less than < 0.8 × 109 per L (OR 2.5), Neutrophil to Lymphocyte Ratio larger than 4.7 (OR 2.2), high fever with temperature ≥ 38.5℃ (OR 2.2), male (OR 2.2), cardiovascular related diseases (OR 2.0). The Area Under the ROC Curve of the screening tool developed by above seven predictors was 0.798 (95% CI 0.747-0.849), and its best cut-off value is > 4.5, with sensitivity 72.0% and specificity 75.3%. CONCLUSIONS: This newly developed screening tool can be a good choice for early prediction and alert for severe case especially in the condition of overload health service.