CD22 blockade aggravates EAE and its role in microglia polarization.

AIMS: Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease. Microglia are reportedly involved in the pathogenesis of MS. However, the key molecules that control the inflammatory activity of microglia in MS have not been identified. METHODS: Experimental autoimmune encephalomyelitis (EAE) mice were randomized into CD22 blockade and control groups. The expression levels of microglial CD22 were measured by flow cytometry, qRT-PCR, and immunofluorescence. The effects of CD22 blockade were examined via in vitro and in vivo studies. RESULTS: We detected increased expression of microglial CD22 in EAE mice. In addition, an in vitro study revealed that lipopolysaccharide upregulated the expression of CD22 in microglia and that CD22 blockade modulated microglial polarization. Moreover, an in vivo study demonstrated that CD22 blockade aggravated EAE in mice and promoted microglial M1 polarization. CONCLUSION: Collectively, our study indicates that CD22 may be protective against EAE and may play a critical role in the maintenance of immune homeostasis in EAE mice.

LncRNA SNHG5 adversely governs follicular growth in PCOS via miR-92a-3p/CDKN1C axis.

Small nucleolar RNA host genes (SNHGs) have been implicated in various biological processes, yet their involvement in polycystic ovary syndrome (PCOS) remains elusive. Specifically, SNHG5, a long non-coding RNA implicated in several human cancers, shows elevated expression in granulosa cells (GCs) of PCOS women and induces PCOS-like features when overexpressed in mice. In vitro, SNHG5 inhibits GC proliferation and induces apoptosis and cell-cycle arrest at G0/G1 phase, with RNA-seq indicating its impact on DNA replication and repair pathways. Mechanistically, SNHG5 acts as a competing endogenous RNA by binding to miR-92a-3p, leading to increased expression of target gene CDKN1C, which further suppresses GC proliferation and promotes apoptosis. These findings elucidate the crucial role of SNHG5 in the pathogenesis of PCOS and suggest a potential therapeutic target for this condition. Additional investigations such as large-scale clinical studies and functional assays are warranted to validate and expand upon these findings.

Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging combined with Texture Analysis in Predicting the Histological Grades of Rectal Adenocarcinoma.

PURPOSE: To evaluate the predictive value of 3.0T MRI Intravoxel Incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) combined with texture analysis (TA) in the histological grade of rectal adenocarcinoma. METHODS: Seventy-one patients with rectal adenocarcinoma confirmed by pathology after surgical resection were collected retrospectively. According to pathology, they were divided into a poorly differentiated group (n=23) and a moderately differentiated group (n=48). The IVIM-DWI parameters and TA characteristics of the two groups were compared, and a prediction model was constructed by multivariate logistic regression analysis. ROC curves were plotted for each individual and combined parameter. RESULTS: There were statistically significant differences in D and D* values between the two groups (P < 0.05). The three texture parameters SmallAreaEmphasis, Median, and Maximum had statistically significant differences between groups (P = 0.01, 0.004, 0.009, respectively). The logistic regression prediction model showed that D*, the median, and the maximum value were significant independent predictors, and the AUC of the regression prediction model was 0.860, which was significantly higher than other single parameters. CONCLUSION: 3.0T MRI IVIM-DWI parameters combined with TA can provide valuable information for predicting the histological grades of rectal adenocarcinoma one week before the operation.

Metabolome implies increased fatty acid utilization and histone methylation in the follicles from hyperandrogenic PCOS women.

Well-balanced metabolism is essential for the high-quality of oocytes, and metabolic fluctuations of follicular microenvironment potentially encourage functional changes in follicle cells, ultimately impacting the developmental potential of oocytes. Here, the global metabolomic profiles of follicular fluid from PCOS women with ovarian hyperandrogenism and nonhyperandrogenism were depicted by untargeted metabolome and transcriptome. In parallel, functional methods were employed to evaluate the possible impact of dysregulated metabolites on oocyte and embryo development. Our findings demonstrated that PCOS women exhibited distinct metabolic features in follicles, such as the increase in fatty acid utilization and the downregulation in amino acid metabolism. And intrafollicular androgen levels were positively correlated with contents of multiple fatty acids, suggesting androgen as one of the contributing factors to the metabolic abnormalities in PCOS follicles. Moreover, we further demonstrated that elevated levels of α-linolenic acid and H3K27me3 could hinder oocyte maturation, fertilization, and early embryo development. Hopefully, our data serve as a broad resource on the metabolic abnormalities of PCOS follicles, and advances in the relevant knowledge will allow the identification of biomarkers that predict the progression of PCOS and its poor pregnancy outcomes.

A combined analysis of multi-omics data reveals the prognostic values and immunotherapy response of LAG3 in human cancers.

Lymphocyte-activation gene 3 (LAG3) is a highly anticipated immune checkpoint in the context of cancer, exerting regulatory control over immune cell proliferation and function to reinforce the advancement of cancers. However, the comprehensive functional analysis of LAG3 across various cancer types remains undisclosed; thus, this study aims to investigate the pan-cancer expression profile of LAG3. We have investigated the expression profile, prognostic significance, and genetic alterations of LAG3 in various cancers while elucidating its characteristic in immune response regulation. Our findings demonstrated that elevated LAG3 expression is significantly associated with favorable prognosis in patients with cutaneous melanoma (SKCM), and it may be a potential biomarker for SKCM. Furthermore, multiple immune algorithms have highlighted the important regulatory role of LAG3 for the tumor-infiltrating immune cells including CD8 + T cells, B cells, dendritic cells (DCs), macrophages, and natural killer (NK) cells. We also examined the distribution of LAG3 at the single-cell level and explored its functional significance. A comprehensive and systematic analysis of LAG3 would facilitate a comprehensive evaluation of LAG3 in cancer biology and provide valuable insights for cancer management.

Effects of ensiling sugarcane tops with bacteria-enzyme inoculants on growth performance, nutrient digestibility, and the associated rumen microbiome in beef cattle.

Major challenges when ensiling sugarcane tops include fermentation that results in high quantities of alcohol and decrease in nutrient digestibility due to the accumulation of fiber components. Increased efforts to apply bacteria-enzyme inoculants in silage have the potential to improve nutrient digestibility. This study aimed to evaluate the effects of ensiling sugarcane tops with bacteria-enzyme inoculants or mixed bacterial inoculants on growth performance, nutrient digestibility, and rumen microbiome in beef cattle. Chopped sugarcane tops were ensiled in plastic bags for 60 d after application of 1) no inoculant (control check, CK); 2) bacteria-enzyme inoculants containing Pediococcus acidilactici, Saccharomyces cerevisiae, cellulase, and xylanase (T1, viable colony-forming units of each bacterial strain ≥108 CFU/g; enzyme activity of each enzyme ≥200 U/g); or 3) mixed bacterial inoculants containing Lactobacillus plantarum, Bacillus subtilis, and Aspergillus oryzae (T2, viable colony-forming units of each bacterial strain ≥107 CFU/g). Silages were fed to eighteen Holstein bull calves (n = 6/treatment) weighing 163.83 ±â€…7.13 kg to determine intake in a 49-d experimental period. The results showed that beef cattle-fed T1 silage or T2 silage had a significantly higher (P < 0.05) average daily gain than those fed CK silage, but the difference in dry matter intake was not significant (P > 0.05). The apparent digestibility of crude protein (CP) and acid detergent fiber (ADF) were higher (P < 0.05) for beef cattle-fed T1 silage or T2 silage than for those fed CK silage. The rumen bacterial community of beef cattle-fed T1 silage or T2 silage had a tendency to increase (P > 0.05) abundance of Firmicutes and Rikenellaceae_RC9_gut_group than those fed CK silage. Rumen fungal communities of beef cattle-fed T1 or T2 silage had a tendency to increase (P > 0.05) abundance of Mortierellomycota and of Mortierella than those fed CK silage. Spearman's rank correlation coefficient showed that the apparent digestibility of ADF for beef cattle was positively correlated with unclassified_p_Ascomycota of the fungal genera (P < 0.05). Neocalimastigomycota of the fungal phyla was strongly positively correlated with the apparent digestibility of neutral detergent fiber (NDF) (P < 0.05). Ruminococcus was positively correlated with the apparent digestibility of CP (P < 0.05). It was concluded that both T1 and T2 improved the growth performance of beef cattle by improving the ruminal apparent digestibility of CP and ADF, and had no significant impact on major rumen microbial communities in beef cattle.

Major challenges when ensiling sugarcane tops include fermentation that results in high quantities of alcohol and decrease in nutrient digestibility due to the accumulation of fiber components. Increased efforts to apply bacteria-enzyme inoculants in silage have the potential to improve nutrient digestibility. This study aimed to evaluate the effects of ensiling sugarcane tops with bacteria-enzyme inoculants or mixed bacterial inoculants on the growth performance, nutrient digestibility, and rumen microbiome in beef cattle. Chopped sugarcane tops were ensiled in plastic bags for 60 d after application of 1) no inoculant (control check, CK); 2) bacteria-enzyme inoculants (Pediococcus acidilactici, Saccharomyces cerevisiae, cellulase, and xylanase), termed treatment T1; or 3) mixed bacterial inoculants (Lactobacillus plantarum, Bacillus subtilis, and Aspergillus oryzae), termed treatment T2. Silages were fed to 18 Holstein bull calves (n = 6/treatment) weighing 163.83 ±â€…7.13 kg to determine intake in a 49-d experimental period. It was concluded that both T1 and T2 improved the growth performance of beef cattle by improving the ruminal apparent digestibility of crude protein and acid detergent fiber, and had no significant impact on major rumen microbial communities in beef cattle.

Geographic and Sociodemographic Variations in Prevalence of Mental Health Symptoms Among US Youths, 2022.

Objectives. To assess geographic and sociodemographic variations in prevalence of mental health symptoms among US youths. Methods. We analyzed data from the Household Pulse Survey, phases 3.5 and 3.6, between June 1 and November 14, 2022. The sample included 103 296 households with an estimated 190 017 youths younger than 18 years. We defined mental health symptoms based on parental responses and estimated prevalence by state and subgroups, including race/ethnicity, parental education, household income, housing tenure, household food sufficiency, and health insurance coverage. All analyses incorporated sampling weight. Results. An estimated 34.5% (95% confidence interval [CI] = 33.7%, 35.3%) of youths had parent-reported mental health symptoms. The prevalence of symptoms varied across states, ranging from 27.9% (95% CI = 23.8%, 32.0%) in Florida to 46.4% (95% CI = 41.9%, 50.9%) in New Hampshire. We observed variations by subgroup, with youths in households that did not pay rent reporting a prevalence of 43.8% (95% CI = 39.3%, 48.4%) and those experiencing food insufficiency reporting a prevalence of 56.0% (95% CI = 50.9%, 61.2%). Conclusions. There is an urgent need for attention to mental health challenges among youths, taking into account geographic and sociodemographic variations. (Am J Public Health. 2023;113(10):1116-1119. https://doi.org/10.2105/AJPH.2023.307355).

Large scale rice germplasm screening for identification of novel brown planthopper resistance sources.

Rice (Oryza sativa L.) is a staple food crop globally. Brown planthopper (Nilaparvata lugens Stål, BPH) is the most destructive insect that threatens rice production annually. More than 40 BPH resistance genes have been identified so far, which provide valuable gene resources for marker-assisted breeding against BPH. However, it is still urgent to evaluate rice germplasms and to explore more new wide-spectrum BPH resistance genes to combat newly occurring virulent BPH populations. To this end, 560 germplasm accessions were collected from the International Rice Research Institute (IRRI), and their resistance to current BPH population of China was examined. A total of 105 highly resistant materials were identified. Molecular screening of BPH resistance genes in these rice germplasms was conducted by developing specific functional molecular markers of eight cloned resistance genes. Twenty-three resistant germplasms were found to contain none of the 8 cloned BPH resistance genes. These accessions also exhibited a variety of resistance mechanisms as indicated by an improved insect weight gain (WG) method, suggesting the existence of new resistance genes. One new BPH resistance gene, Bph44(t), was identified in rice accession IRGC 15344 and preliminarily mapped to a 0-2 Mb region on chromosome 4. This study systematically sorted out the corresponding relationships between BPH resistance genes and germplasm resources using a functional molecular marker system. Newly explored resistant germplasms will provide valualble donors for the identification of new resistance genes and BPH resistance breeding programs. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01416-x.

1,25-Dihydroxyvitamin D inhibits hepatic diacyglycerol accumulation and ameliorates metabolic dysfunction in polycystic ovary syndrome rat models.

Introduction: We aimed to evaluate the influence of 1,25-dihydroxyvitamin D (1,25(OH)2D) on metabolic dysfunction and elucidate its underlying mechanism using a rat model of polycystic ovary syndrome (PCOS). Methods: Twenty-four Sprague-Dawley rats were randomly divided into four groups: control group (CON, 2 ml/kg of oral 0.5% CMC), 1,25VD group (oral 0.5% CMC and 2.5 ug/kg intraperitoneal 1,25(OH)2D), PCOS group (1 mg/kg oral letrozole), PCOS+1,25VD group (1 mg/kg oral letrozole orally 2.5 ug/kg intraperitoneal 1,25(OH)2D). The treatments were administered for 8 weeks. Body weight, estrus cycle, insulin tolerance, and oral glucose tolerance of the rats in the different groups were assessed. The rats were euthanized at the 8th weeks, and plasma, ovarian, and liver samples were collected and analyzed. The hepatic lipid profile was characterized using HPLC/MRM. Results: Letrozole-induced PCOS rats exhibited increased weight, insulin resistance, postprandial glucose abnormalities, and dyslipidemia. Compared with the PCOS group rats, the PCOS+1,25VD group rats showed reduced body weight, increased sensitivity to insulin, decreased postprandial glucose, and elevated levels of high-density lipoprotein cholesterol. Moreover, abnormally increased liver concentrations of total diacylglycerol (DG) and DG species in the PCOS rats were reversed by treatment with 1,25(OH)2D. Additionally, hepatic DG and insulin sensitivity were correlated. Conclusion: 1,25(OH)2D inhibited hepatic DG accumulation and ameliorated metabolic dysfunction in PCOS rat models.

Sperm morphological abnormalities in autosomal dominant polycystic kidney disease are associated with the Hippo signaling pathway via PC1.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder mostly caused by mutations in PKD1 or PKD2 genes. Here, we report thirteen ADPKD males with infertility and investigated the sperm morphological defects associated with PC1 disruption. Methods: Targeted next-generation sequencing was performed to detect PKD1 variants in patients. Sperm morphology was observed by immunostaining and transmission electron microscopy, and the sperm motility was assessed using the computer-assisted sperm analysis system. The Hippo signaling pathway was analyzed with by quantitative reverse transcription polymerase chain reaction (qPCR) and western blotting in vitro. Results: The ADPKD patients were infertile and their sperm tails showed morphological abnormalities, including coiled flagella, absent central microtubules, and irregular peripheral doublets. In addition, the length of sperm flagella was shorter in patients than in controls of in in. In vitro, ciliogenesis was impaired in Pkd1-depleted mouse kidney tubule cells. The absence of PC1 resulted in a reduction of MST1 and LATS1, leading to nuclear accumulation of YAP/TAZ and consequently increased transcription of Aurka. which might promote HDAC6-mediated ciliary disassembly. Conclusion: Our results suggest the dysregulated Hippo signaling significantly contributes to ciliary abnormalities in and may be associated with flagellar defects in spermatozoa from ADPKD patients.

METTL3-mediated m6A modification of lnc KCNQ1OT1 promotes doxorubicin resistance in breast cancer by regulating miR-103a-3p/MDR1 axis.

Doxorubicin (DOX) resistance in breast cancer (BC) poses a huge challenge for the therapeutic effect on BC. Lnc KCNQ1OT1 play crucial roles in chemotherapy resistance. However, the role and mechanism of lnc KCNQ1OT1 in DOX resistance BC have not been investigated, which merits further exploration. Based on MCF-7 and MDA-MB-231 cells, MCF-7/DOX and MDA-MB-231/DOX cells were established using gradient concentrations of DOX. IC50 values and cell viability were determined using MTT. Cell proliferation was investigated by colony formation. Flow cytometry was performed to examine cell apoptosis and cell cycle. Gene expression was examined using qRT-PCR and western blot. The interactions among METTL3, lnc KCNQ1OT1, miR-103a-3p, and MDR1 were validated with MeRIP-qPCR, RIP, and dual-luciferase reporter gene assays. The results showed that Lnc KCNQ1OT1 was highly expressed in DOX-resistant BC cells, and lnc KCNQ1OT1 depletion could enhance DOX sensitivity in BC cells and DOX-resistant BC cells. Besides, lnc KCNQ1OT1 was modulated by MELLT3 in the manner of m6A modification. MiR-103a-3p could interact with lnc KCNQ1OT1 and MDR1. Overexpression of MDR1 abolished the impacts of lnc KCNQ1OT1 depletion on DOX resistance in BC. In conclusion, our results unveiled that in BC cells and DOX-resistant BC cells, lnc KCNQ1OT1 could be mediated by METTL3 through m6A modification to elevate and stabilize its expression, further inhibiting miR-103a-3p/MDR1 axis to promote DOX resistance, which might provide novel thought to overcome DOX resistance in BC.

Integrated single-cell and bulk RNA sequencing analysis identifies a cancer-associated fibroblast-related gene signature for predicting survival and therapy in gastric cancer.

As the dominant component of the tumor microenvironment, cancer-associated fibroblasts (CAFs), play a vital role in tumor progression. An increasing number of studies have confirmed that CAFs are involved in almost every aspect of tumors including tumorigenesis, metabolism, invasion, metastasis and drug resistance, and CAFs provide an attractive therapeutic target. This study aimed to explore the feature genes of CAFs for potential therapeutic targets and reliable prediction of prognosis in patients with gastric cancer (GC). Bioinformatic analysis was utilized to identify the feature genes of CAFs in GC by performing an integrated analysis of single-cell and transcriptome RNA sequencing using R software. Based on these feature genes, a CAF-related gene signature was constructed for prognostic prediction by LASSO. Simultaneously, survival analysis and nomogram were performed to validate the prognostic predictive value of this gene signature, and qRT-PCR and immunohistochemical staining verified the expression of the feature genes of CAFs. In addition, small molecular drugs for gene therapy of CAF-related gene signatures in GC patients were identified using the connectivity map (CMAP) database. A combination of nine CAF-related genes was constructed to characterize the prognosis of GC, and the prognostic potential and differential expression of the gene signature were initially validated. Additionally, three small molecular drugs were deduced to have anticancer properties on GC progression. By integrating single-cell and bulk RNA sequencing analyses, a novel gene signature of CAFs was constructed. The results provide a positive impact on future research and clinical studies involving CAFs for GC.

Comparison of State-of-the-Art Neural Network Survival Models with the Pooled Cohort Equations for Cardiovascular Disease Risk Prediction.

BACKGROUND: The Pooled Cohort Equations (PCEs) are race- and sex-specific Cox proportional hazards (PH)-based models used for 10-year atherosclerotic cardiovascular disease (ASCVD) risk prediction with acceptable discrimination. In recent years, neural network models have gained increasing popularity with their success in image recognition and text classification. Various survival neural network models have been proposed by combining survival analysis and neural network architecture to take advantage of the strengths from both. However, the performance of these survival neural network models compared to each other and to PCEs in ASCVD prediction is unknown. METHODS: In this study, we used 6 cohorts from the Lifetime Risk Pooling Project (with 5 cohorts as training/internal validation and one cohort as external validation) and compared the performance of the PCEs in 10-year ASCVD risk prediction with an all two-way interactions Cox PH model (Cox PH-TWI) and three state-of-the-art neural network survival models including Nnet-survival, Deepsurv, and Cox-nnet. For all the models, we used the same 7 covariates as used in the PCEs. We fitted each of the aforementioned models in white females, white males, black females, and black males, respectively. We evaluated models' internal and external discrimination power and calibration. RESULTS: The training/internal validation sample comprised 23216 individuals. The average age at baseline was 57.8 years old (SD = 9.6); 16% developed ASCVD during average follow-up of 10.50 (SD = 3.02) years. Based on 10 × 10 cross-validation, the method that had the highest C-statistics was Deepsurv (0.7371) for white males, Deepsurv and Cox PH-TWI (0.7972) for white females, PCE (0.6981) for black males, and Deepsurv (0.7886) for black females. In the external validation dataset, Deepsurv (0.7032), Cox-nnet (0.7282), PCE (0.6811), and Deepsurv (0.7316) had the highest C-statistics for white male, white female, black male, and black female population, respectively. Calibration plots showed that in 10 × 10 validation, all models had good calibration in all race and sex groups. In external validation, all models overestimated the risk for 10-year ASCVD. CONCLUSIONS: We demonstrated the use of the state-of-the-art neural network survival models in ASCVD risk prediction. Neural network survival models had similar if not superior discrimination and calibration compared to PCEs.

Associations Between Asthma and Polycystic Ovary Syndrome: Current Perspectives.

A potential correlation between polycystic ovary syndrome (PCOS) and asthma, used to be identified as diseases originating from two independent systems, has been supported by increasing evidence. From an epidemiological perspective, mounting studies have confirmed that women suffering from PCOS exhibit increased susceptibility to asthma. Meanwhile, PCOS and asthma seem to share several mutual pathological conditions, such as metabolic disorders, hormonal fluctuation, proinflammatory state, etc. Here, we further elucidate the correlation between asthma and PCOS by focusing on the internal common pathophysiology and adverse influences on women's health. Understanding the internal connection between PCOS and asthma may shed light on developing new prevention and control strategies to fight against these conditions.

Intestinal fibrosis classification in patients with Crohn's disease using CT enterography-based deep learning: comparisons with radiomics and radiologists.

OBJECTIVES: Accurate evaluation of bowel fibrosis in patients with Crohn's disease (CD) remains challenging. Computed tomography enterography (CTE)-based radiomics enables the assessment of bowel fibrosis; however, it has some deficiencies. We aimed to develop and validate a CTE-based deep learning model (DLM) for characterizing bowel fibrosis more efficiently. METHODS: We enrolled 312 bowel segments of 235 CD patients (median age, 33 years old) from three hospitals in this retrospective study. A training cohort and test cohort 1 were recruited from center 1, while test cohort 2 from centers 2 and 3. All patients performed CTE within 3 months before surgery. The histological fibrosis was semi-quantitatively assessed. A DLM was constructed in the training cohort based on a 3D deep convolutional neural network with 10-fold cross-validation, and external independent validation was conducted on the test cohorts. The radiomics model (RM) was developed with 4 selected radiomics features extracted from CTE images by using logistic regression. The evaluation of CTE images was performed by two radiologists. DeLong's test and a non-inferiority test were used to compare the models' performance. RESULTS: DLM distinguished none-mild from moderate-severe bowel fibrosis with an area under the receiver operator characteristic curve (AUC) of 0.828 in the training cohort and 0.811, 0.808, and 0.839 in the total test cohort, test cohorts 1 and 2, respectively. In the total test cohort, DLM achieved better performance than two radiologists (*1 AUC = 0.579, *2 AUC = 0.646; both p < 0.05) and was not inferior to RM (AUC = 0.813, p < 0.05). The total processing time for DLM was much shorter than that of RM (p < 0.001). CONCLUSION: DLM is better than radiologists in diagnosing intestinal fibrosis on CTE in patients with CD and not inferior to RM; furthermore, it is more time-saving compared to RM. KEY POINTS: • Question Could computed tomography enterography (CTE)-based deep learning model (DLM) accurately distinguish intestinal fibrosis severity in patients with Crohn's disease (CD)? • Findings In this cross-sectional study that included 235 patients with CD, DLM achieved better performance than that of two radiologists' interpretation and was not inferior to RM with significant differences and much shorter processing time. • Meaning This DLM may accurately distinguish the degree of intestinal fibrosis in patients with CD and guide gastroenterologists to formulate individualized treatment strategies for those with bowel strictures.

Associations of Sperm mtDNA Copy Number, DNA Fragmentation Index, and Reactive Oxygen Species With Clinical Outcomes in ART Treatments.

Recent studies have suggested that sperm mitochondrial DNA copy number (mtDNA-CN), DNA fragmentation index (DFI), and reactive oxygen species (ROS) content are crucial to sperm function. However, the associations between these measurements and embryo development and pregnancy outcomes in assisted reproductive technology (ART) remain unclear. Semen samples were collected from 401 participants, and seminal quality, parameters of sperm concentration, motility, and morphology were analyzed by a computer-assisted sperm analysis system. DFI, mtDNA-CN, and ROS levels were measured using sperm chromatin structure assay, real-time quantitative polymerase chain reaction, and ROS assay, respectively. Among the participants, 126 couples underwent ART treatments, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and 79 of the couples had embryos transferred. In 401 semen samples, elevated mtDNA-CN and DFI were associated with poor seminal quality. In 126 ART couples, only mtDNA-CN was negatively correlated with the fertilization rate, but this correlation was not significant after adjusting for male age, female age, seminal quality, ART strategy, number of retrieved oocytes, controlled stimulation protocols, and cycle rank. Regarding pregnancy outcomes, sperm mtDNA-CN, ROS, and DFI were not associated with the clinical pregnancy rate or live birth rate in 79 transferred cases. In conclusion, increased mtDNA-CN and DFI in sperm jointly contributed to poor seminal quality, but sperm mtDNA-CN, ROS, and DFI were not associated with clinical outcomes in ART.

Identification of a Novel Glycosyltransferase Prognostic Signature in Hepatocellular Carcinoma Based on LASSO Algorithm.

Although many prognostic models have been developed to help determine personalized prognoses and treatments, the predictive efficiency of these prognostic models in hepatocellular carcinoma (HCC), which is a highly heterogeneous malignancy, is less than ideal. Recently, aberrant glycosylation has been demonstrated to universally participate in tumour initiation and progression, suggesting that dysregulation of glycosyltransferases can serve as novel cancer biomarkers. In this study, a total of 568 RNA-sequencing datasets of HCC from the TCGA database and ICGC database were analysed and integrated via bioinformatic methods. LASSO regression analysis was applied to construct a prognostic signature. Kaplan-Meier survival, ROC curve, nomogram, and univariate and multivariate Cox regression analyses were performed to assess the predictive efficiency of the prognostic signature. GSEA and the "CIBERSORT" R package were utilized to further discover the potential biological mechanism of the prognostic signature. Meanwhile, the differential expression of the prognostic signature was verified by western blot, qRT-PCR and immunohistochemical staining derived from the HPA. Ultimately, we constructed a prognostic signature in HCC based on a combination of six glycosyltransferases, whose prognostic value was evaluated and validated successfully in the testing cohort and the validation cohort. The prognostic signature was identified as an independent unfavourable prognostic factor for OS, and a nomogram including the risk score was established and showed the good performance in predicting OS. Further analysis of the underlying mechanism revealed that the prognostic signature may be potentially associated with metabolic disorders and tumour-infiltrating immune cells.

mFOLFOXIRI with or without bevacizumab for conversion therapy of RAS/BRAF/PIK3CA mutant unresectable colorectal liver metastases: the FORBES non-randomized phase II trial.

Background: The aim of this non-randomized single-center phase II trial was to prospectively assess the clinical efficacy of triplet chemotherapy with modified 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (mFOLFOXIRI) plus bevacizumab as conversion therapy for initially unresectable rat sarcoma viral oncogene homolog (RAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/phosphatidylinositol-3 kinase catalytic alpha (PIK3CA) mutant colorectal liver-limited metastases (CRLMs). Methods: Patients with RAS/BRAF/PIK3CA mutant initially unresectable CRLMs were recruited at a ratio of 2:1 to receive mFOLFOXIRI plus bevacizumab (experimental group) or mFOLFOXIRI alone (control group). The rate of patients attaining no evidence of disease (NED) was the primary endpoint. The secondary endpoints included objective response rate (ORR), depth of tumor response (DpR), secondary resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: The rate of NED achieved was 40.7% and 30.8%, respectively, in the experimental (n=54) and control groups (n=26); the adjusted odds ratio was 4.519 [95% confidence interval (CI): 1.247-16.375, P=0.022]. The ORR was 77.4% in the experimental group and 60.0% in the control group (P=0.112). The median DpR was significantly greater in the experimental group (45.6% vs. 34.9%, P=0.041). The median PFS was 12.6 months in the experimental group and 9.1 months in the control group [adjusted hazard ratio (HR): 0.584, 95% CI: 0.304-1.121, P=0.106]. Median OS was prolonged in the experimental group compared with the control group (42.6 vs. 35.3 months, adjusted HR: 0.443, 95% CI: 0.195-1.006, P=0.052). Thirty patients (55.6%) in the experimental group and 16 (61.5%) in the control group experienced grade 3/4 adverse events. Conclusions: We observed that the combination of mFOLFOXIRI and bevacizumab increased the rate of clinical NED and showed a trend toward improved survival compared with mFOLFOXIRI alone. This could represent a conversion therapy option for fit patients with initially unresectable RAS/BRAF/PIK3CA mutant CRLMs.

Circulating Innate Lymphoid Cells Exhibit Distinctive Distribution During Normal Pregnancy.

Over the past decades, the investigation of innate lymphoid cells (ILCs) has revealed their significance in successful pregnancy. Sex hormones, such as estradiol and progesterone, show specific changes during pregnancy and modulate both adaptive and innate immune systems. ILC subset distribution in peripheral blood of pregnant women and its potential association with sex hormone levels have not been well revealed. Peripheral blood was obtained from healthy non-pregnant, early-pregnant, and late-pregnant women. Radioimmunoassay was performed to measure plasma estradiol and progesterone levels. The levels of type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), type 3 ILCs (ILC3s), and total ILCs as well as estrogen and progesterone receptors of ILC2s in peripheral blood were analyzed using flow cytometry. The proportion of total ILCs and distribution of ILC subsets in peripheral blood changed dynamically during pregnancy. Compared to non-pregnant women, late-pregnant women displayed significantly higher proportion of circulating ILCs, among which ILC2s accounted for the majority in late-pregnant women while a smaller part in others, and ILC3s displayed the opposite. Plasma estradiol and progesterone levels elevated while pregnancy proceeded and the expression of their receptors in ILC2s increased consisted with the proportion of circulating ILC2s. Our work first observed the existence of progesterone receptors in human circulating ILC2s and revealed the distribution pattern of circulating ILC subsets and their interrelation with plasma sex hormone levels during pregnancy. Our results suggested that the estradiol and progesterone levels might partly influence the distribution of circulating ILC subsets and implied the interplay between circulating ILCs and pregnancy.