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Background: Cathepsin L, a lysosomal enzyme, participates in diverse physiological processes. Recombinant Trichinella spiralis cathepsin L domains (rTsCatL2) exhibited natural cysteine protease activity and hydrolyzed host immunoglobulin and extracellular matrix proteins in vitro, but its functions in larval invasion are unknown. The aim of this study was to explore its functions in T. spiralis invasion of the host's intestinal epithelial cells. Methodology/principal findings: RNAi significantly suppressed the expression of TsCatL mRNA and protein with TsCatL specific siRNA-302. T. spiralis larval invasion of Caco-2 cells was reduced by 39.87% and 38.36%, respectively, when anti-TsCatL2 serum and siRNA-302 were used. Mice challenged with siRNA-302-treated muscle larvae (ML) exhibited a substantial reduction in intestinal infective larvae, adult worm, and ML burden compared to the PBS group, with reductions of 44.37%, 47.57%, and 57.06%, respectively. The development and fecundity of the females from the mice infected with siRNA-302-treated ML was significantly inhibited. After incubation of rTsCatL2 with Caco-2 cells, immunofluorescence test showed that the rTsCatL2 gradually entered into the cells, altered the localization of cellular tight junction proteins (claudin 1, occludin and zo-1), adhesion junction protein (e-cadherin) and extracellular matrix protein (laminin), and intercellular junctions were lost. Western blot showed a 58.65% reduction in claudin 1 expression in Caco-2 cells treated with rTsCatL2. Co-IP showed that rTsCatL2 interacted with laminin and collagen I but not with claudin 1, e-cadherin, occludin and fibronectin in Caco-2 cells. Moreover, rTsCatL2 disrupted the intestinal epithelial barrier by inducing cellular autophagy. Conclusions: rTsCatL2 disrupts the intestinal epithelial barrier and facilitates T. spiralis larval invasion. Author summary: Trichinosis is a severe zoonotic disease that affects humans by eating raw or semi-raw meat products containing T. spiralis larvae. The intestinal mucosal barrier is the initial defense against T. spiralis infection and the main point of contact between the host and the parasite. Beyond the mechanical action, the protease released by the worm are essential for T. spiralis invasion of the host small intestine. Cathepsins play a crucial role in the migration of Fasciola hepatica and the invasion of Schistosoma japonicum, essential for their parasitism in the host. Nevertheless, the specific functions of T. spiralis cathepsin L during the worm's invasion of the intestinal mucosa remain unexplored. In this study, the TsCatL gene was silenced using siRNA, which inhibited worm invasion of Caco-2 cells, impaired worm development, and decreased female fertility. Incubation of rTsCatL2 with Caco-2 cells resulted in the translocation of cell tight junction proteins (claudin 1, occludin and zo-1), adhesion junction protein (e-cadherin) and extracellular matrix protein (laminin) into the cytoplasm or the nucleus, a reduction in claudin 1 expression and cellular autophagy, leading to disruption of the intestinal epithelial barrier. This study provides a novel target for developing anti-trichinosis vaccines and drugs. [ABSTRACT FROM AUTHOR]

Background: During the early stages of Trichinella spiralis infection, macrophages predominantly undergo polarization to the M1-like phenotype, causing the host's inflammatory response and resistance against T. spiralis infection. As the disease progresses, the number of M2-type macrophages gradually increases, contributing to tissue repair processes within the host. While cysteine protease overexpression is typically associated with inflammation, the specific role of T. spiralis cathepsin L (TsCatL) in mediating macrophage polarization remains unknown. The aim of this study was to assess the killing effect of macrophage polarization mediated by recombinant T. spiralis cathepsin L domains (rTsCatL2) on newborn larvae (NBL). Methods: rTsCatL2 was expressed in Escherichia coli strain BL21. Polarization of the rTsCatL2-induced RAW264.7 cells was analyzed by enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), western blot, immunofluorescence and flow cytometry. The effect of JSH-23, an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), on rTsCatL2-induced M1 polarization investigated. Cytotoxic effects of polarized macrophages on NBL were observed using in vitro killing assays. Results: Following the co-incubation of rTsCatL2 with RAW264.7 murine macrophage cells, qPCR and ELISA revealed increased transcription and secretion levels of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α) in macrophages. Western blot analysis showed a significant increase in iNOS protein expression, while the expression level of arginase-1 protein remained unchanged. Flow cytometry revealed a substantial increase in the number of CD86-labeled macrophages. The western blot results also indicated that rTsCatL2 increased the expression levels of phospho-NF-κB and phospho-nuclear factor-κB inhibitor alpha (IκB-α) proteins in a dose-dependent manner, while immunofluorescence revealed that rTsCatL2 induced nuclear translocation of the p65 subunit of NF-κB (NF-κB p65) protein in macrophages. The inhibitory effect of JSH-23 suppressed and abrogated the effect of rTsCatL2 in promoting M1 macrophage polarization. rTsCatL2 mediated polarization of macrophages to the M1-like phenotype and enhanced macrophage adhesion and antibody-dependent cell-mediated cytotoxicity (ADCC) killing of NBL. Conclusions: The results indicated that rTsCatL2 induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of NBL. This study provides a further understanding of the interaction mechanism between T. spiralis and the host. [ABSTRACT FROM AUTHOR]

Purpose: To compare the long-term clinical and radiological results of meniscal allograft transplantation (MAT) for discoid lateral meniscus (DLM) patients with MAT for non-discoid lateral meniscus patients and meniscectomy (ME) for DLM patients and, thus, to determine whether DLM patients are suitable candidates for MAT. Methods: Eight MAT cases in DLM patients were identified (discoid MAT group), six MAT cases in non-discoid lateral meniscus patients (non-discoid MAT group) and ten total meniscectomy cases in DLM patients (discoid ME group) were matched as controls. Subjective evaluations, postoperative radiography and magnetic resonance imaging (MRI) were conducted at 5 years and 10–14 years, respectively. Joint degeneration was evaluated by the Kellgren–Lawrance (KL) grade and joint space width (JSW). MRI with T2 mapping sequences was used to quantitatively evaluate degeneration of the joint cartilage and shrinkage of the allografts. Student's t test was used to compare quantitative variables and the Mann‒Whitney U test was used to compare categorical variables. Results: There was no difference in Lysholm, IKDC, Tegner or VAS scores amongst the discoid MAT, non-discoid MAT and discoid ME groups at the final follow-up. No revision surgery was performed in any MAT patient. The JSW narrowing in the discoid MAT group was better than that in the discoid ME group (0.8 ± 0.4 mm vs. 2.1 ± 1.3 mm, p = 0.012) and worse than that in the non-discoid MAT group (0.1 ± 0.1 mm, p = 0.003). The KL progression of the discoid MAT group was less than that of the discoid ME group (1.3 ± 0.7 vs. 2.3 ± 0.9, p = 0.034). The discoid ME group had worse cartilage lesion progression than the discoid MAT and non-discoid MAT groups. The allograft width of the DLM patients shrank more than that of the non-discoid patients at the meniscus midbody (3.6 ± 0.9 mm vs. 6.2 ± 1.9 mm, p = 0.015). Conclusion: Compared to meniscectomy, MAT achieved similar long-term symptom relief and superior chondroprotection in discoid meniscus patients. Despite more graft shrinkage, the outcomes of MAT in discoid meniscus patients were comparable to those in non-discoid meniscus patients. Therefore, DLM patients may be suitable candidates for MAT procedures. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

The article discusses the role of apolipoprotein b mRNA editing enzyme catalytic-polypeptide-like proteins 3 (APOBEC3) enzymes in autoimmune diseases. Topics include possible involvement of hA3 enzymes in disorders, genetic variants and methylation CpG sites linking APOBEC3 enzymes to autoimmune diseases, and how integrated dissection of data on genetic, epigenetic and gene expression levels would facilitate the elucidation of the underlying mechanisms.

PubMed, ScienceDirect, Cochrane, Embase, Scopus, China National Knowledge Infrastructure (CNKI), Chinese Weipu, and Wanfang databases were searched to evaluate the effects of probiotics supplements on gastric cancer‐related inflammatory factors. Parallel randomized controlled trials (RCTs) assessing the effects of prebiotics supplement on gastric cancer patients were included in the review. Compared with routine nutrition, meta‐analysis shows that probiotics supplements reduce gastric cancer‐related inflammation levels by mostly increasing the levels of cluster of differentiation 4+ and greatly reducing the levels of interleukin‐6. Probiotics supplements can control the inflammatory response in cancer patients and may be a potential approach for controlling inflammatory levels in the patients. However, a larger population is needed for further study because of a certain degree of heterogeneity in this review. Practical applications: The effects of probiotics (Bifidobacterium, Lactobacillus, and Streptococcus species) on the gastric cancer‐related inflammation were investigated.Probiotics can reduce gastric cancer‐related inflammation levels more effectively by increasing the levels of cluster of differentiation 4+ and greatly reducing the levels of interleukin‐6.The study provides some theoretical basis for controlling cancer‐related inflammation responses in the patients using probiotics. [ABSTRACT FROM AUTHOR]

Schematic representation of intrinsic apoptotic pathway induced by Sinularin relied on FOXO3 in prostate cancer cells. Sinularin upregulates FOXO3 via inhibiting the activity of AKT and ERK which phosphorylate FOXO3 at Ser253 and Ser294 respectively. Phosphorylation at these sites leads to FOXO3 binding to 14-3-3 protein, FOXO3 translocation to cytoplasm from nucleus, and subsequent ubiquitin–proteasome degradation. The upregulated FOXO3 increased its target PUMA, a pro-apoptotic protein belonging to the BH3 sub-family of Bcl-2 family. PUMA binds and antagonizes Bcl-2, then leads to mitochondrial outer membrane permeabilization and mitochondrial membrane potential collapses, promoting cytochrome c release and apoptosis. [Display omitted] Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin–proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin–proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin–proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer. [ABSTRACT FROM AUTHOR]

Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated gastric cancer entity, and very few patients transition to poorly differentiated tubular adenocarcinoma during progression. Gastric adenocarcinoma of the fundic gland originates from the mucosa of the gastric fundic gland, usually without chronic gastritis or intestinal metaplasia. Histologically, the tumor cells are closely arranged to form anastomosing tubular glands, and more than 95% of tumor cells differentiate towards chief cells. Most gastric adenocarcinoma of the fundic gland cases are characterized by submucosal involvement, but the tumor volume is usually small, with lymphatic and vascular invasion rarely observed. Therefore, endoscopic submucosal dissection can be an ideal treatment, leading to a favorable prognosis, and recurrence and metastasis of the disease are uncommon. [ABSTRACT FROM AUTHOR]

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003–2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23–5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28–4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer. [ABSTRACT FROM AUTHOR]

Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated gastric cancer entity, and very few patients transition to poorly differentiated tubular adenocarcinoma during progression. Gastric adenocarcinoma of the fundic gland originates from the mucosa of the gastric fundic gland, usually without chronic gastritis or intestinal metaplasia. Histologically, the tumor cells are closely arranged to form anastomosing tubular glands, and more than 95% of tumor cells differentiate towards chief cells. Most gastric adenocarcinoma of the fundic gland cases are characterized by submucosal involvement, but the tumor volume is usually small, with lymphatic and vascular invasion rarely observed. Therefore, endoscopic submucosal dissection can be an ideal treatment, leading to a favorable prognosis, and recurrence and metastasis of the disease are uncommon. [ABSTRACT FROM AUTHOR]

FGFR3 is one of the most frequently mutated genes in bladder cancer and a driver of an oncogenic dependency. Here we report that only the most common recurrent FGFR3 mutation, S249C (T C C → T G C), represents an APOBEC-type motif and is probably caused by the APOBEC-mediated mutagenic process, accounting for its over-representation. We observed significant enrichment of the APOBEC mutational signature and overexpression of AID / APOBEC gene family members in bladder tumors with S249C compared to tumors with other recurrent FGFR3 mutations. Analysis of replication fork directionality suggests that the coding strand of FGFR3 is predominantly replicated as a lagging strand template that could favor the formation of hairpin structures, facilitating mutagenic activity of APOBEC enzymes. In vitro APOBEC deamination assays confirmed S249 as an APOBEC target. We also found that the FGFR3 S249C mutation was common in three other cancer types with an APOBEC mutational signature, but rare in urothelial tumors without APOBEC mutagenesis and in two diseases probably related to aging. We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3 S249C, one of the most common mutations in bladder cancer. Knowledge about the etiology of this mutation will improve our understanding of the molecular mechanisms of bladder cancer. We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations, even within suboptimal motifs, such as in the case of FGFR3 S249C, one of the most common mutations in bladder cancer. Knowledge about the etiology of this mutation will improve our understanding of molecular mechanisms of bladder cancer. [ABSTRACT FROM AUTHOR]

Background. Refractory and relapsed multiple myeloma (RRMM) remains a clinical challenge. We compared the progression-free survival (PFS) of RRMM patients treated with lenalidomide and low dose dexamethasone plus elotuzumab or carfilzomib (ELD vs. CLD), using reconstructed individual patient data (IPD) based on two published trials reports. Methods. We extracted data of study-level characteristics from original trial reports. We evaluated the comparability between the two treatment groups in terms of baseline status. Digitization of PFS Kaplan-Meier curves, reconstruction of IPD data, and subsequent survival analysis were performed. Distribution of progression and death events over time was visualized as histograms and corresponding kernel density lines, and Kaplan-Meier survival curves were plotted. Hazard ratio (HR) and corresponding 95% confidence interval (95% CI) were calculated. Results. Significant difference in race and disease stage distribution was found (P < 0.0001). Higher proportion of white patients and patients with advanced disease in the carfilzomib group was identified. Survival analysis revealed better PFS in the carfilzomib group (elotuzumab group vs. carfilzomib group: HR = 1.36, 95% CI = [1.11-1.67]). Conclusion. The CLD regimen may result in better PFS as compared with the ELD regimen in RRMM patients. [ABSTRACT FROM AUTHOR]

Background. A possible association between the TACC3 rs798766 polymorphism and urinary bladder cancer risk has been indicated in published literature. We performed this meta-analysis as a synthesis of all relevant data to summarize currently available evidence and to provide estimation with increased precision. Methods. EMBASE, PubMed, Google Scholar, and Wanfang Data were searched. “rs798766” and “urinary bladder cancer” were used as the search terms. A total of 6 eligible studies were identified, in which 8194 cases and 50,165 controls were investigated. Meta-analysis was performed using extracted data. Subgroup analysis by ethnicity was also performed. Population attributable risk (PAR) was calculated. Results. We found a significant association between rs798766[T] and increased risk of bladder cancer, allelic[T] OR=1.27, 95%CI=1.20–1.33. Subgroup analysis by ethnicity revealed similar results, allelic[T] OR=1.24, 95%CI=1.17–1.32 in Caucasian subjects and allelic[T] OR=1.33, 95%CI=1.21–1.46 in Asian subjects. PAR based on pooled allelic ORs and the frequency of the risk allele in control subjects was 4.63% in the overall population and 3.92% in Asians and 4.36% in Caucasians. Conclusion. rs798766 is associated with increased risk of bladder cancer, and no ethnic difference was found. [ABSTRACT FROM AUTHOR]

Background: APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods: We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results: We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. Conclusions: Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Characterizing the heterogeneity of individual cognitive aging from a mitochondrial perspective. • Comprehensively assessing brain resilience through genetic metrics. • Individuals' levels of brain resilience were comprehensively measured by eight pathological characteristics. • The performance of PRS models could be efficiently improved by incorporating mitochondria-related loci. • Significant implications for the prevention and intervention of Alzheimer's disease. Identification of high-risk people for Alzheimer's disease (AD) is critical for prognosis and early management. Longitudinal epidemiologic studies have observed heterogeneity in the brain and cognitive aging. Brain resilience was described as above-expected cognitive function. The "resilience" framework has been shown to correlate with individual characteristics such as genetic factors and age. Besides, accumulative evidence has confirmed the association of mitochondria with the pathogenesis of AD. However, it is challenging to assess resilience through genetic metrics, in particular incorporating mitochondria-associated loci. In this paper, we first demonstrated that polygenic risk scores (PRS) could characterize individuals' resilience levels. Then, we indicated that mitochondria-associated loci could improve the performance of PRSs, providing more reliable measurements for the prevention and diagnosis of AD. The discovery (N = 1,550) and independent validation samples (N = 2,090) were used to construct nine types of PRSs containing mitochondria-related loci (PRSMT) from both biological and statistical aspects and combined them with known AD risk loci derived from genome-wide association studies (GWAS). Individuals' levels of brain resilience were comprehensively measured by linear regression models using eight pathological characteristics. It was found that PRSs could characterize brain resilience levels (e.g., Pearson correlation test P min = 7.96 × 10 - 9 ). Moreover, the performance of PRS models could be efficiently improved by incorporating a small number of mitochondria-related loci (e.g., Pearson correlation test P improved from 1.41 × 10 - 3 to 6.09 × 10 - 6 ). PRSs' ability to characterize brain resilience was validated. More importantly, by incorporating some mitochondria-related loci, the performance of PRSs in measuring brain resilience could be significantly improved. Our findings imply that mitochondria may play an important role in brain resilience, and targeting mitochondria may open a new door to AD prevention and therapy. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the leading cause of dementia, with its prevalence increasing as the global population ages. AD is a multifactorial and intricate neurodegenerative disease with pathological changes varying from person to person. Because the mechanism of AD is highly controversial, effective treatments remain a distant prospect. Currently, one of the most promising hypotheses posits mitochondrial dysfunction as an early event in AD diagnosis and a potential therapeutic target. Objective: Here, we adopted a systems medicine strategy to explore the mitochondria-related mechanisms of AD. Then, its implications for discovering nutrients combatting the disease were demonstrated. Methods: We employed conditional mutual information (CMI) to construct AD gene dependency networks. Furthermore, the GeneRank algorithm was applied to prioritize the gene importance of AD patients and identify potential anti-AD nutrients targeting crucial genes. Results: The results suggested that two highly interconnected networks of mitochondrial ribosomal proteins (MRPs) play an important role in the regulation of AD pathology. The close association between mitochondrial ribosome dysfunction and AD was identified. Additionally, we proposed seven nutrients with potential preventive and ameliorative effects on AD, five of which have been supported by experimental reports. Conclusions: Our study explored the important regulatory role of MRP genes in AD, which has significant implications for AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Abstract Bodyweight loss and rumen microbial dysfunction of grazing sheep was a challenge for the sheep production industry during cold season, which were considered to correlated with under-roughage-feeding. Alfalfa is a good roughage supplementary for ruminants, which can improve grazing sheep bodyweight-loss and rumen microbial dysfunction during grass-withering period. This study evaluated the effects of alfalfa hay supplementary change dietary non-fibrous carbohydrate/neutral detergent fiber (NFC/NDF) ratios on rumen fermentation and microbial function of Gansu alpine fine wool sheep during extreme cold season. 120 ewes (3–4 yrs) with an average body weight of 28.71 ± 1.22 kg were allocated randomly into three treatments, and fed NFC/NDF of 1.92 (H group), 1.11 (M group), and 0.68 (L group), respectively. This study was conducted for 107 d, including 7 d of adaption to the diets. The rumen fermentation parameters and microbial characteristics were measured after the end of feeding trials. The results showed that the concentrations of sheep body weight, nitrogen components (Total-N, Soluble protein-N and Ammonia-N), blood biochemical indices (LDH, BUN and CHO) and ruminal volatile fatty acids (TVFA and propionate) significantly increased with an increase in the proportion of NFC/NDF ratios (p < .05), and the acetate and acetate/propionat ratio presented a contrary decreasing trend (p < .05). A total of 1018 OTUs were obtained with 97% consistency. Ruminococcus, Ruminococcaceae and Prevotella were observed as the predominant phyla in ruminal fluid microbiota. Higher NFC/NDF ratios with Alfalfa supplementary increased the richness and diversity of ruminal fluid microbiota, and decreased ruminal fluid microbiota beta-diversity. Using clusters of orthologous groups (COG), the ruminal fluid microbiota of alfalfa supplementary feeding showed low immune pathway and high carbohydrate metabolism pathway. In summary, the study suggested that there was an increasing tendency in dietary NFC/NDF ratio of 1.92 in body weight, ruminal fermentation, microbial community composition and fermentation characteristics through developing alfalfa supplementary system. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer is one of the most common cancers worldwide. The most important known cause of bladder cancer is tobacco smoking. Several genetic variations are also linked to the risk of developing bladder cancer. In this study, we focused on how smoking behavior interacts with genes to affect bladder cancer risk using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr). The COBLAnCE cohort comprises approximately 1700 bladder cancer patients with available smoking and genetic information. We identified new chromosomal regions (specifically, genes located at 4q22.1, 12p13.1, and 16p13.3) of which variations may interact with smoking behavior in relation to bladder cancer risk. These findings need to be replicated in other studies. Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies. [ABSTRACT FROM AUTHOR]

Background: Although immunotherapy is effective in improving the clinical outcomes of patients with bladder cancer (BC), it is only effective in a small percentage of patients. Intercellular crosstalk in the tumor microenvironment strongly influences patient response to immunotherapy, while the crosstalk patterns of plasma cells (PCs) as endogenous antibody-producing cells remain unknown. Here, we aimed to explore the heterogeneity of PCs and their potential crosstalk patterns with BC tumor cells. Methods: Crosstalk patterns between PCs and tumor cells were revealed by performing integrated bulk and single-cell RNA sequencing (RNA-seq) and spatial transcriptome data analysis. A risk model was constructed based on ligand/receptor to quantify crosstalk patterns by stepwise regression Cox analysis. Results: Based on cell infiltration scores inferred from bulk RNA-seq data (n = 728), we found that high infiltration of PCs was associated with better overall survival (OS) and response to immunotherapy in BC. Further single-cell transcriptome analysis (n = 8; 41,894 filtered cells) identified two dominant types of PCs, IgG1 and IgA1 PCs. Signal transduction from tumor cells of specific states (stress-like and hypoxia-like tumor cells) to PCs, for example, via the LAMB3/CD44 and ANGPTL4/SDC1 ligand/receptor pairs, was validated by spatial transcriptome analysis and associated with poorer OS as well as nonresponse to immunotherapy. More importantly, a ligand/receptor pair-based risk model was constructed and showed excellent performance in predicting patient survival and immunotherapy response. Conclusions: PCs are an important component of the tumor microenvironment, and their crosstalk with tumor cells influences clinical outcomes and response to immunotherapies in BC patients. [ABSTRACT FROM AUTHOR]

By developing a transgenic mouse model, we demonstrated that gain-of-function mutations of FGFR3 receptor initiate luminal bladder cancer (BCa) formation and favor BCa male sex bias, potentially through FGFR3-dependent estrogen receptor (ESR1) downregulation. Patients with early-stage BCa could thus potentially benefit from FGFR3 targeting. Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3 -mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3 –driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3 -mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions. [ABSTRACT FROM AUTHOR]

In recent years, graphene has shown great application prospects in tunable microwave devices due to its tunable conductivity. However, the electromagnetic (EM) properties of graphene, especially the dynamic tunning characteristics, are largely dependent on experimental results, and thus are unable to be effectively predicted according to growth parameters, which causes great difficulties in the design of graphene-based tunable microwave devices. In this work, we systematically explored the impact of chemical vapor deposition (CVD) parameters on the dynamic tunning range of graphene. Firstly, through improving the existing waveguide method, the dynamic tunning range of graphene can be measured more accurately. Secondly, a direct mathematical model between growth parameters and the tunning range of graphene is established. Through this, one can easily obtain needed growth parameters for the desired tunning range of graphene. As a verification, a frequency tunable absorber prototype is designed and tested. The good agreement between simulation and experimental results shows the reliability of our mathematic model in the rapid design of graphene-based tunable microwave devices. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the long-term clinical and radiological outcomes between the immediate and delayed meniscus allograft transplantation (MAT). Methods: Nine menisci were transplanted immediately after total meniscectomy (immediate group, IM), and 10 menisci were delayed transplanted in patients with the median of 35 months (range 9–92 months) after total meniscectomy (delayed group, DE). Patient's subjective clinical outcomes including VAS, IKDC, Lysholm and Tegner scores as well as muscle strength measures were compared. Joint degeneration was evaluated by both radiographs to assess joint space width narrowing, Kellegren–Lawrence (KL) grade and MRI with T2 mapping sequences to quantitatively analyze both cartilage and meniscal allograft degeneration. Results: The median follow-up time was 10.8 years (range 10–14 years). The IKDC (IM vs DE, 89.8 vs 80.9, n.s.) and Lysholm scores (IM vs DE, 87.7 vs 78.0, n.s.) were close in two groups, while the IM group showed slightly lower VAS (IM vs DE, 0.2 vs 1.5, p = 0.031), higher Tegner score (IM vs DE, 7 vs 3.5 p = 0.021) and better quadriceps muscle strength. The IM group had less joint space narrowing (IM vs DE, 0.35 mm vs 0.71 mm, n.s.), less KL grade progression (IM vs DE, 0.6 vs 1.7, p = 0.041) on radiographs and less chondral lesions development on MRIs (Cartilage Degeneration Index, IM vs DE, 252 vs 2038, p = 0.025). All meniscal grafts exhibited degeneration by showing grade 3 signal on MRI, and 4 (4/9) in the IM group and 8 (8/10) cases in the DE group. The T2 value of cartilage and meniscal allograft in the IM group was close to that of the healthy control and was significantly lower than that of the DE group. Conclusion: Compared to the conventional delayed MAT, the immediate MAT achieved better cartilage and meniscus protection in the long-term, while its superiority in patient-reported outcomes was limited. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the highly homologous sequences of theanine synthetase genes and glutamine synthetase genes of tea plant, speculate their evolutionary relationship, predict their structures, natures, functions and differences of enzyme active sites, and then to provide a basis for CsTS genes function studies of tea. Two gene sequences logged on NCBI were cloned, the expression of enzymes activities was verificated through HPLC and LC-MS and phylogenetic analysis was implemented within the searching result. The expression of enzymes in E. coli suggested CsTS and CsGS had different catalytic activities although their high homology. The primary and secondary protein structures of CsTS and CsGS were analyzed and the result showed that there was no significant difference between them, but the third protein structure analysis by homology modeling in the catalytic sites showed three differences in the catalytic sites, which could lead to the difference of enzyme activity. In this research, CsTS gene sequences were firstly identified as the members of GS gene family through phylogenetic analysis. According to cellular localization prediction, CsTS should belong to cytoplasmic GS(GS1), for its kinship close to grape, upland cotton, rubber tree, arabidopsis etc. [ABSTRACT FROM AUTHOR]

The heterogeneity and the complex cellular architecture have a crucial effect on breast cancer progression and response to treatment. However, deciphering the neoplastic subtypes and their spatial organization is still challenging. Here, we combine single-nucleus RNA sequencing (snRNA-seq) with a microarray-based spatial transcriptomics (ST) to identify cell populations and their spatial distribution in breast cancer tissues. Malignant cells are clustered into distinct subpopulations. These cell clusters not only have diverse features, origins and functions, but also emerge to the crosstalk within subtypes. Furthermore, we find that these subclusters are mapped in distinct tissue regions, where discrepant enrichment of stromal cell types are observed. We also inferred the abundance of these tumorous subpopulations by deconvolution of large breast cancer RNA-seq cohorts, revealing differential association with patient survival and therapeutic response. Our study provides a novel insight for the cellular architecture of breast cancer and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a common malignant solid tumor that is characterized by high hypoxia. The transcription of genes associated with hypoxia affects tumor occurrence and development. Long non-coding RNAs (lncRNAs) have been reported to play important roles in cancer development. In this study, we screened for differentially expressed ncRNAs (non-coding RNA) and mRNAs between hypoxia-inducible factor-1 (HIF-1α) knockdown GC cells and scrambled GC cells. Microarray data revealed that HIF-1α regulated the expression of LINC01355 (Hypoxia Yield Proliferation Associated LncRNA, HYPAL). HYPAL was found to be significantly upregulated in GC cells and tissues and was correlated with poor GC prognosis. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays revealed that HIF-1α promoted HYPAL expression by binding the promoter region. A regulatory network for the competing endogenous RNA (ceRNA) was constructed using bioinformatics tools. Mechanistic studies revealed that HYPAL acted as a ceRNA of miR-431-5p to regulate CDK14 expression. Carcinogenic effects of HYPAL were evaluated in vitro and in vivo. The HIF-1α/HYPAL/miR-431-5p/CDK14 (Cyclin-dependent kinase 14) axis activated the Wnt/β-catenin signaling pathway and induced GC cell proliferation while inhibiting apoptosis. In conclusion, HYPAL is a potential molecular target for GC therapy. [ABSTRACT FROM AUTHOR]

Background: The long-term chondroprotective effect of meniscal allograft transplant (MAT) and its superiority over meniscectomy have rarely been reported. Hypothesis: MAT would reduce osteoarthritis (OA) progression when compared with the meniscus-deficient knee. Graft extrusion distance would strongly affect the chondroprotective effect of the MAT. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 17 knees receiving MAT were followed up as the MAT group. The MAT group was further divided into the nonextrusion subgroup (n = 9) and the extrusion subgroup (n = 8) according to 3-mm extrusion on the magnetic resonance imaging (MRI) coronal section. A further 26 consecutive patients receiving meniscectomy in the same period were followed up as the ME group. The healthy control group consisted of healthy contralateral legs chosen from the MAT and ME groups (n = 27). Joint space width (JSW) narrowing was measured on radiographs. Three-dimensional MRI with a T2 mapping sequence was used to quantitatively analyze cartilage degeneration and meniscal allograft extrusion in 5 directions (0°, 45°, 90°, 135°, and 180°). The cartilage degeneration index (CDI) was calculated according to the size and degree of the chondral lesions on MRI scans. The correlation between the CDI increase and the extrusion distance was analyzed. Results: The mean follow-up time was 11.3 years (range, 10-14 years). The MAT group had moderate superiority in chondral protection with less JSW narrowing (0.58 ± 0.66 mm) and CDI increase (1132 ± 1589) compared with the ME group (JSW narrowing: 1.26 ± 1.13 mm, P =.025; CDI increase: 2182 ± 1958, P =.079). The JSW narrowing (0.71 ± 0.80 mm; P =.186) and CDI increase (2004 ± 1965; P =.830) of the extrusion subgroup were close to those of the ME group, demonstrating that a 3-mm extrusion led to complete loss of the meniscal chondroprotective effect. The nonextrusion group had significantly less JSW narrowing (0.48 ± 0.48 mm; P =.042) and CDI increase (358 ± 249; P =.011) than the ME group. The JSW narrowing of the healthy control group was 0.22 ± 0.27 mm. The cartilage T2 values of the extrusion subgroup were similar to those of the ME group, with more OA features, whereas the T2 values of the nonextrusion subgroup were closer to those of the healthy control group. The extrusion distance in the 90° direction (P =.002) and the follow-up time (P =.019) significantly affected the CDI increase in the multivariate regression model. The average extrusion distance in the 45°, 90°, and 135° directions better predicted chondroprotection compared with the other individual directions. Conclusion: MAT had moderate advantages in chondroprotection compared with meniscectomy in the long term. Graft extrusion distance strongly affected the chondroprotective effect of MAT. The chondroprotective effect of the nonextruded meniscal allograft was close to that of the native meniscus, whereas the allografts with an extrusion >3 mm completely lost their function after meniscectomy. [ABSTRACT FROM AUTHOR]

The chemically synthesised silver nanoparticles in colloidal solution were assembled on the methyl silicone oil membrane supported on the graphite-epoxy composite electrode, and monitored by cyclic voltammetry. The assembling kinetics follows a diffusion-controlled Brownian movements of the nanoparticles with a Weibull function and a rate constant of 0.02548/min. The assembled silver nanoparticles undergo a self reorganisation process in the methyl silicone oil membrane in contact with 0.1 M KCl electrolyte solution due to the interaction of silver atoms with chloride ions, and follows another Weibull function with a rate constant of 0.0467/min. The reorganised silver nanoparticles in methyl silicone oil membrane show a surface-controlled electrochemical behaviour. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) accounts for high mortality. RNA methylation has recently gained interest as markers in specific tumors. This study aimed to uncover the function of the roles of 25 RNA methylation regulators in GC. Methods: RNA sequence and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. "STRING" and R were performed to analyze the correlation among the methylase. COX and LASSO were performed to screen for prognostic associated RNA methylation regulators. A prognostic model was established based on the expression of methylase. RT-PCR and immunohistochemistry detected the expression of methylase in GC cells and tissue. Kaplan–Meier curve and Cox analysis were applied to evaluate the effectiveness of the model. Results: The prediction model was established based on the expression of m6A RNA methylation regulators FTO (fat mass and obesity-associated) and RBM15 (RNA binding motif protein 15). Based on the model, GC patients were divided into "high risk" and "low risk" groups to compare the differences in survival. The model was re-evaluated with the clinical data of our center. Conclusion: The two-methylase combination model was an independent prognostic factor of GC. [ABSTRACT FROM AUTHOR]

Objective: The benefit of adjuvant therapy (AT) remains controversial in stage IB gastric cancer (GC). This study aimed to offer a reference for the rational indications of AT. Methods: We retrospectively included 1216 stage IB GC who experienced curative surgery from the SEER database between 2004 and 2015. These patients were allocated into two groups: Group AT and Group surgery alone (Group SA). We established a nomogram to predict OS and then divided whole cohort into low-risk and high-risk groups based on the OS predicted by the nomogram. Results: Six variables, which were significantly related with OS of entire patients after matched, were incorporated in the nomogram. These variables were age, examined lymph nodes, tumor site, marital, family income and stage IB. The C-index of the model was 0.637 and the calibration curve showed that the anticipated values were in accordance with the actual values. The decision curve demonstrated that the optimal clinical impact was achieved when the threshold possibility was 0–56%. Then, the entire cohort was separated into low-risk (≤159 points) as well as high-risk (>159 points) groups based on the projected 5-year OS of recursive partitioning analysis. Group SA revealed a significantly poorer OS than Group AT for high-risk patients (p <.001); on the other hand, there was a comparable OS for low-risk patients (p =.361). Conclusions: We have developed an effective, intuitional and applied prognostic tool to clinical decision-making. For stage IB GC after surgical resection, AT was only recommended for high-risk patients. However, AT may be dispensable for low-risk patients. [ABSTRACT FROM AUTHOR]

Background. Previous studies have revealed that gene polymorphisms of inflammatory factors may influence the development or progression of periodontitis, a main cause of tooth loss in adults; however, due to limitations of individual studies, inconsistent findings were reported. Objective. To meta-analytically investigate the relationship between periodontitis and the Interleukin-4 (IL-4) and Interleukin-4 receptor (IL-4R) gene polymorphisms. Methods. Databases were searched for relevant case-control studies. After study selection based on the predefined selection criteria, methodological quality assessment and data extraction were conducted independently by two reviewers, before subsequent statistical analyses. Results. 37 studies involving 4,385 patients and 5,168 controls were included. All the studied IL-4 polymorphisms were not significantly associated with periodontitis, except the -33C/T (CT versus CC: OR = 0.50, 95% CI = 0.28–0.88) associated with reduced AgP susceptibility. Positive association was found between IL-4R Q551 polymorphism and periodontitis susceptibility in three genetic models (R versus Q: OR = 1.59, 95% CI = 1.14–2.22; QR versus QQ: OR = 1.84, 95% CI = 1.21–2.80; RR + QR versus QQ: OR = 1.82, 95% CI = 1.22–2.72). Conclusions. A positive association exists between the IL-4R Q551R polymorphism and occurrence of CP. The IL-4 -33 CT genotype is negatively associated with the occurrence of AgP. [ABSTRACT FROM AUTHOR]

The article presents a case study aimed to compare the efficacy between the combined induction of thalidomide, bortezomib and dexamethasone (VTD) with that of the combination adramycin, thalidomide and dexamethasone (ATD) induction in myeloma. The study is performed through a survival analysis done by univariate Cox regression wherein a Kaplan-Meier survival curve is derived. The results of the study show that VTD induction is superior than the ATD in terms of early and long-term efficacy.

Although the association between CAG and GGN repeats in the androgen receptor gene and prostate cancer risk has been widely studied, it remains controversial from previous meta-analyses and narrative reviews. Therefore, we performed this meta-analysis to provide more precise estimates with sufficient power. A total of 51 publications with 61 studies for CAG repeats and 14 publications with 16 studies for GGN repeats were identified in the meta-analysis. The results showed that short CAG repeats (<22 repeats) carriers presented an elevated risk of prostate cancer than long CAG repeats (≥22) carriers (OR = 1.31, 95% CI 1.16 to 1.47). Prostate cancer cases presented an average fewer CAG repeats (MD = −0.85, 95% CI −1.28 to −0.42) than controls. Short GGN repeats (≤16) carriers presented an increased risk of prostate cancer than long GGN repeats (>16) carriers (OR = 1.38, 95% CI 1.05 to 1.82). In subgroup analyses, the abovementioned significant association was predominantly observed in Caucasian populations. The meta-analysis showed that short CAG and GGN repeats in androgen receptor gene were associated with increased risk of prostate cancer, especially in Caucasians. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare plasmakinetic resection of the prostate (PKRP) with transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) in terms of efficacy and safety. Published RCTs were searched from PubMed, Embase, Science Citation Index, and Cochrane Library up to April 10, 2014. After methodological quality assessment and data extraction, meta-analysis was performed using the STATA 12.0 software. 18 reports of 16 RCTs were included in this analysis. Meta-analyses showed that PKRP significantly improved Qmax at 12 months, but no significant difference was found for other efficacy outcomes. In terms of safety, treatment of PKRP was associated with reduced drop in serum sodium, lower TUR syndrome, reduced need of blood transfusion, clot retention, and shorter catheterization time and hospital stay; in contrast, there were no significant differences in the analysis of operative time, postoperative fever, and long-term postoperative complications. In summary, current evidence suggests that, although PKRP and TURP are both effective for BPH, PKRP is associated with additional potential benefits in efficacy and more favorable safety profile. It may be possible that PKRP may replace the TURP in the future and become a new standard surgical procedure. [ABSTRACT FROM AUTHOR]