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Abstract Purpose The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS). Methods The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses. Results A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97). Conclusions The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

Abstract Background Anxiety and depression are prevalent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, existing research has yielded conflicting findings regarding the effects of social frailty on anxiety and depression. The primary aim of this study is to validate the relationship between social frailty and social support with anxiety and depression in patients with acute exacerbations of COPD (AECOPD) and to investigate whether social support could explain the variations in prior study outcomes for patients with AECOPD. Methods Of the 315 patients hospitalized with AECOPD at the respiratory intensive care unit of a large tertiary care institution in Sichuan Province of China, between August 2022 and June 2023 who were surveyed, 306 were included in the analysis after excluding missing data. We conducted a logistic regression analysis to examine the associations of social frailty and social support with anxiety and depression and performed mediation analyses to examine whether social support mediates the relationship of social frailty with anxiety and depression. Results The logistic regression analysis revealed that social frailty did not associate anxiety or depression in patients with AECOPD. The mediation analysis supported this idea and indicated that while social frailty does not directly influence anxiety or depression, it can through social support. Conclusions The findings suggest that while social frailty may not directly impact anxiety or depression in patients with AECOPD, social support plays a crucial mediating role. Enhancing social support can indirectly alleviate anxiety and depression among these patients. Enhancing social support networks should thus be prioritized by healthcare providers and family members to improve mental health outcomes in this patient population.

Abstract DNA damage is a key factor affecting gametogenesis and embryo development. The integrity and stability of DNA are fundamental to a woman’s successful conception, embryonic development, pregnancy and the production of healthy offspring. Aging, reactive oxygen species, radiation therapy, and chemotherapy often induce oocyte DNA damage, diminished ovarian reserve, and infertility in women. With the increase of infertility population, there is an increasing need to study the relationship between infertility related diseases and DNA damage and repair. Researchers have tried various methods to reduce DNA damage in oocytes and enhance their DNA repair capabilities in an attempt to protect oocytes. In this review, we summarize recent advances in the DNA damage response mechanisms in infertility diseases such as PCOS, endometriosis, diminished ovarian reserve and hydrosalpinx, which has important implications for fertility preservation.

Abstract Background HIV-infected persons demonstrate notable disturbances in their intestinal microbiota; however, the impact of intestinal microbiota on HIV susceptibility in men who have sex with men (MSM), as well as the effects of HIV and antiretroviral therapy (ART) on their gut microbiota, remains under active study. Thus, our research focuses on clarifying the distinctions in intestinal microbiota composition among uninfected MSM and non-MSM healthy controls, investigating the alterations in early-stage intestinal microbial communities following HIV infection, and assessing how ART affects the intestinal microbiota. Methods This study enrolled four participant groups: uninfected MSM, Recent HIV-1 infection (RHI) MSM, MSM on ART, and non-MSM healthy controls, with 30 individuals in each group. We utilized 16S ribosomal DNA (16S rDNA) amplicon sequencing to analyze fecal microbiota and employed Luminex multiplex assays to measure plasma markers for microbial translocation (LBP, sCD14) and the inflammatory marker CRP. Findings Comparing uninfected MSM to non-MSM healthy controls, no substantial variances were observed in α and β diversity. Uninfected MSM had higher average relative abundances of Bacteroidetes, Prevotella, and Alloprevotella, while Bacteroides, Firmicutes, and Faecalibacterium had lower average relative abundances. MSM on ART had lower intestinal microbiota diversity than RHI MSM and uninfected MSM. In MSM on ART, Megasphaera and Fusobacterium increased, while Faecalibacterium and Roseburia decreased at genus level. Additionally, treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) led to significant alterations in intestinal microbiota diversity and composition compared to RHI MSM. The random forest model showed that HIV infection biomarkers effectively distinguished between newly diagnosed HIV-infected MSM and HIV-negative MSM, with an ROC AUC of 76.24% (95% CI: 61.17-91.31%). Conclusions MSM showed early intestinal microbiota imbalances after new HIV infection. MSM on ART experienced worsened dysbiosis, indicating a combined effect of HIV and ART. NNRTI-based treatment notably changed intestinal microbiota, suggesting a potential direct impact of NNRTI drugs on intestinal microbiota.

Abstract Background To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation. Conclusion Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.

Abstract Aims Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. Methods and results We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B−/− mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. Conclusions These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

Abstract Background The BOP (Bambusoideae, Oryzoideae, and Pooideae) clade of the Poaceae has a common ancestor, with similarities to the genomes of rice, Oryza sativa (2n = 24; genome size 389 Mb) and Brachypodium, Brachypodium distachyon (2n = 10; 271 Mb). We exploit chromosome-scale genome assemblies to show the nature of genomic expansion, structural variation, and chromosomal rearrangements from rice and Brachypodium, to diploids in the tribe Aveneae (e.g., Avena longiglumis, 2n = 2x = 14; 3,961 Mb assembled to 3,850 Mb in chromosomes). Results Most of the Avena chromosome arms show relatively uniform expansion over the 10-fold to 15-fold genome-size increase. Apart from non-coding sequence diversification and accumulation around the centromeres, blocks of genes are not interspersed with blocks of repeats, even in subterminal regions. As in the tribe Triticeae, blocks of conserved synteny are seen between the analyzed species with chromosome fusion, fission, and nesting (insertion) events showing deep evolutionary conservation of chromosome structure during genomic expansion. Unexpectedly, the terminal gene-rich chromosomal segments (representing about 50 Mb) show translocations between chromosomes during speciation, with homogenization of genome-specific repetitive elements within the tribe Aveneae. Newly-formed intergenomic translocations of similar extent are found in the hexaploid A. sativa. Conclusions The study provides insight into evolutionary mechanisms and speciation in the BOP clade, which is valuable for measurement of biodiversity, development of a clade-wide pangenome, and exploitation of genomic diversity through breeding programs in Poaceae.

Abstract Background Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice. Methods We generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r +/− microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r +/− mice and wild-type control littermates. Results We found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r +/− mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r +/− microglia. Treatment with minocycline could suppress the activation of Csf1r +/− microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r +/− mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r +/− mice. Conclusions Our study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

Abstract Background Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated. Results Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m3. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice. Conclusions These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

Abstract Protein ubiquitination is closely related to tumor occurrence and development. The specific role of ubiquitination in endometrial cancer remains largely unclear. Therefore, we constructed a novel endometrial cancer prognostic model based on ubiquitination-related genes. We extracted the expression matrices of ubiquitination-related genes from the Cancer Genome Atlas database, upon which we performed univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses to obtain 22 ubiquitination-related genes for the construction of the prognostic model. Survival, regression, clinical correlation, and principal component analyses were performed to assess the performance of the model. Drug sensitivity analysis was performed based on these ubiquitination-related genes. Finally, a prognostic nomogram was constructed based on the prognostic model to quantify patient outcomes. Survival, regression, clinical correlation, and principal component analyses revealed that the performance of the prognostic model was satisfactory. Drug sensitivity analysis provided a potential direction for the treatment of endometrial cancer. The prognostic nomogram could be used to effectively estimate the survival rate of patients with endometrial cancer. In summary, we constructed a new endometrial cancer prognostic model and identified 5 differentially expressed, prognosis-associated, ubiquitination-related genes. These 5 genes are potential diagnostic and treatment targets for endometrial cancer.

Abstract Background Biomarkers of DNA damage repair deficiency provide opportunities for personalized treatment with immunotherapy. However, there is limited research on the immune microenvironment of adeno-neuroendocrine prostate cancer (NEPC). In this study, we aimed to assess and describe the comprehensive clinicopathological manifestations of NEPC to improve diagnosis and predict prognosis. Methods A retrospective medical record review of 66 patients with prostate cancer (PCa) was performed. PCa samples from the 66 patients were analyzed using immunohistochemical staining for the detection of chromogranin, neural cell adhesion molecule 1, and synaptophysin. For tumor-associated immune microenvironment analysis, PD-L1, CD3, and CD8 were labeled in tissue slides. The effect of clinicopathological factors on the survival of patients with Adeno-NEPC was analyzed. Results Twenty patients presented with adeno-NEPC, whereas 46 presented with adeno-PCa. The median age of patients at PCa diagnosis was 67.86 ± 7.05 years (68.65 ± 7.23 years, adeno-NEPC; 67.52 ± 7.02 years, adeno-PCa). Eleven patients with adeno-NEPC underwent prostatectomy, whereas nine received primary androgen deprivation therapy (ADT). Additionally, 30 patients with adeno-PCa underwent prostatectomy, whereas 16 (34.8%) received primary ADT. There was a significant difference in overall survival between patients with adeno-NEPC and those with adeno-PCa (46.0 months vs. 65.0 months). There was also a significant difference in time from prostatectomy to biochemical recurrence between the groups of patients who underwent prostatectomy. Prostatectomy and normal lactate dehydrogenase levels were clinical factors that were significantly associated with better outcomes in patients with adeno-NEPC. Metastatic adeno-NEPC was associated with a higher programmed death ligand 1 (PD-L1) score (2–4) than localized PCa. The data showed that PD-L1 expression in adeno-NEPC may be negatively associated with that in CD8+ T cells. Conclusions Our study revealed clinicopathological manifestations of adeno-NEPC and some possible predictive factors significantly associated with better outcomes in patients with adeno-NEPC. These findings might be beneficial in the development of diagnostic strategies and customized treatment plans.

Abstract Background Diabetes was commonly seen in chronic total occlusion (CTO) patients but data regarding the impact of successful percutaneous coronary intervention (PCI) on clinical outcome of CTO patients with diabetes was controversial. And importantly, no studies have compared quality of life (QOL) after CTO-PCI in patients with and without diabetes. Methods Consecutive patients undergoing elective CTO-PCI were prospectively enrolled from Apr. 2018 to May 2021. Patients were subdivided into 2 groups: Diabetes and No Diabetes. Detailed baseline characteristics, assessment of symptoms and QOL, angiographic and procedural details, in-hospital complications, and 1 month and 1 year follow-up data were collected. These data were analyzed accordingly for risk predictors of clinical outcome in patients who have diabetes and received successful CTO-PCI. Results A total of 1076 patients underwent CTO-PCI attempts. Diabetes was present in 374 (34.76%) patients, who had more hypertension, previous PCI and stroke. Regarding the coronary lesions, diabetic patients suffered more LCX lesion, multivessel disease, number of lesions per patient, blunt stump, calcification and higher J-CTO score (p 0.05). Number of lesions per patient was an independent risk factor of MACE and all-cause mortality (p 0.05). Conclusions Successful CTO-PCI could represent an effective strategy improving clinical outcome, symptoms and QOL in CTO patients with diabetes.

Abstract Background Metastasis is critical for endometrial cancer (EC) progression and prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) can operate as independent functional entities. However, the functional regulatory mechanisms of circRNAs in EC remain unclear. Methods The levels of circESRP1, miR-874-3p, and CPEB4 mRNA in EC tissues and cells were determined by qRT-PCR. Sanger sequencing, PCR with divergent primers, an actinomycin D assay, and RNase R treatment were applied to verify the circular properties. Fluorescence in situ hybridization (FISH) and nuclear-cytoplasmic fractionation were used to determine the localization of circESRP1. CCK-8, EdU incorporation, colony formation, Transwell, and wound healing assays were applied to assess the effects of circESRP1 on cell proliferation, migration, and invasion. The mutual regulatory mechanism of ceRNAs was investigated using dual-luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP), and Western blot assays. The biological effects were further validated in vivo in nude mouse xenograft models. Results circESRP1 was highly expressed in EC tissues and cells and was mainly localized in the cytoplasm. Silencing circESRP1 inhibited the proliferation, migration, and invasion of EC cells in vitro and in vivo; however, overexpression of circESRP1 had the opposite effects. Mechanistically, circESRP1 sponged miR-874-3p to upregulate CPEB4 expression and ultimately contribute to EC cell proliferation and metastasis. Furthermore, circESRP1 regulated tumour growth in xenograft models. Conclusions CircESRP1 can interact with miR-874-3p to regulate EMT in endometrial cancer via the miR-874-3p/CPEB4 axis. CircESRP1 may serve as a promising therapeutic target for endometrial cancer.

Abstract Background Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population. Methods Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts. Results Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway. Conclusions Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.

Abstract Background Globally, endometrial cancer is the fourth most common malignant tumor in women and the number of women being diagnosed is increasing. Tumor progression is strongly related to the cell survival-promoting functions of autophagy. We explored the relationship between endometrial cancer prognoses and the expression of autophagy genes using human autophagy databases. Methods The Cancer Genome Atlas was used to identify autophagy related genes (ARGs) that were differentially expressed in endometrial cancer tissue compared to healthy endometrial tissue. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were referenced to identify important biological functions and signaling pathways related to these differentially expressed ARGs. A prognostic model for endometrial cancer was constructed using univariate and multivariate Cox, and Least Absolute Shrinkage and Selection Operator regression analysis. Endometrial cancer patients were divided into high- and low-risk groups according to risk scores. Survival and receiver operating characteristic (ROC) curves were plotted for these patients to assess the accuracy of the prognostic model. Using immunohistochemistry the protein levels of the genes associated with risk were assessed. Results We determined 37 ARGs were differentially expressed between endometrial cancer and healthy tissues. These genes were enriched in the biological processes and signaling pathways related to autophagy. Four ARGs (CDKN2A, PTK6, ERBB2 and BIRC5) were selected to establish a prognostic model of endometrial cancer. Kaplan–Meier survival analysis suggested that high-risk groups have significantly shorter survival times than low-risk groups. The area under the ROC curve indicated that the prognostic model for survival prediction was relatively accurate. Immunohistochemistry suggested that among the four ARGs the protein levels of CDKN2A, PTK6, ERBB2, and BIRC5 were higher in endometrial cancer than healthy endometrial tissue. Conclusions Our prognostic model assessing four ARGs (CDKN2A, PTK6, ERBB2, and BIRC5) suggested their potential as independent predictive biomarkers and therapeutic targets for endometrial cancer.

Abstract Background CNAP monitor is a continuous and noninvasive blood pressure (BP) measurement device that can be used in intraoperative monitoring. But whether its accuracy changes with age and its detectability of hypertension and hypotension are still unclear. This study was to investigate the agreement of CNAP and invasive arterial pressure (IAP) in different age groups, and the ability of CNAP to detect hypertension and hypotension. Methods This observational study enrolled 48 Chinese patients undergoing surgery under general anaesthesia, including 25 relatively old patients (age between 50 and 70) and 23 relatively young patients (age between 18 and 49). IAP was monitored at the radial artery and CNAP was applied on the opposite arm simultaneously. Paired BP data in the entire surgery were recorded, and analyzed with Bland Altman plot and Spearman correlation. The ratio of the hypertension and hypotension episodes detected by IAP and CNAP was analyzed using chi-square test. Results 7990 valid paired BP data were analyzed, wherein 4186 data were from 25 relatively old patients, and the other data were from 23 relatively young patients. Bias (SD) for relatively old patients was: systolic BP (SBP): − 6.5 (18.6) mm Hg; diastolic BP (DBP): 9.3 (7.8) mmHg; and mean BP (MBP): 4.2 (9.5) mm Hg. Bias (SD) for relatively young patients was: SBP: − 6.2 (12.1) mm Hg; DBP: 10.6 (6.9) mmHg; and MBP: 4.8 (7.3) mm Hg. The correlation between CNAP and IAP was higher in MBP than those in SBP and DBP, and it decreased with the increase of age. Comparing to IAP, CNAP tended to miss reporting a high SBP, low DBP and low MBP, and misinform a low SBP, high DBP and high MBP. Conclusion CNAP showed acceptable agreement with IAP in MBP for all age groups, but reduced agreement with IAP in SBP and DBP, especially for relatively old patients. Ability of CNAP to detect hypertension and hypotension episodes was weaker than IAP. Therefore, CNAP monitor is suitable for young patients and hemodynamically stable surgery, but may not be recommended for old patients with arteriosclerosis and diabetes or surgeries expecting to have fluctuating blood pressure.

Abstract Background Finding peptides with high binding affinity to Class I major histocompatibility complex (MHC-I) attracts intensive research, and it serves a crucial part of developing a better vaccine for precision medicine. Traditional methods cost highly for designing such peptides. The advancement of computational approaches reduces the cost of new drug discovery dramatically. Compared with flourishing computational drug discovery area, the immunology area lacks tools focused on in silico design for the peptides with high binding affinity. Attributed to the ever-expanding amount of MHC-peptides binding data, it enables the tremendous influx of deep learning techniques for modeling MHC-peptides binding. To leverage the availability of these data, it is of great significance to find MHC-peptides binding specificities. The binding motifs are one of the key components to decide the MHC-peptides combination, which generally refer to a combination of some certain amino acids at certain sites which highly contribute to the binding affinity. Result In this work, we propose the Motif Activation Mapping (MAM) network for MHC-I and peptides binding to extract motifs from peptides. Then, we substitute amino acid randomly according to the motifs for generating peptides with high affinity. We demonstrated the MAM network could extract motifs which are the features of peptides of highly binding affinities, as well as generate peptides with high-affinities; that is, 0.859 for HLA-A*0201, 0.75 for HLA-A*0206, 0.92 for HLA-B*2702, 0.9 for HLA-A*6802 and 0.839 for Mamu-A1*001:01. Besides, its binding prediction result reaches the state of the art. The experiment also reveals the network is appropriate for most MHC-I with transfer learning. Conclusions We design the MAM network to extract the motifs from MHC-peptides binding through prediction, which are proved to generate the peptides with high binding affinity successfully. The new peptides preserve the motifs but vary in sequences.

Abstract Background The purpose of this study was to screen the critical genes for future diagnosis and treatment of colon cancer by bioinformatics method. Methods In this study, we used bioinformatics approaches to identify gene alteration that contribute to colon cancer progression via analysis of TCGA RNA sequencing data and other publicly GEO microarray data. The Random forest survival model was used to screen gene sets related to the prognosis in DEGs. Gene ontology and KEGG pathway enrichment analysis were performed to determine the potential function of DEGs. Results We identified versican (VCAN), a member of the aggrecan/versican proteoglycan family, as a key regulator in human colon cancer development and progression involved in cell adhesion, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Interestingly, we found that VCAN is highly over-expressed in colon cancer and increased expression of VCAN was associated with the progression of colon cancer. High VCAN levels also predict shorter overall survival of colon cancer patients. Furthermore, in vitro assays of silencing VCAN inhibit HCT116 cell proliferation and invasion. Conclusions These data demonstrated VCAN were associated with tumorigenesis and may be as biomarker for identification of the pathological grade of colon cancer.