Prevalence and risk evaluation of cardiovascular disease in the newly diagnosed prostate cancer population in China: A nationwide, multi-center, population-based cross-sectional study.

BACKGROUND: Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study was aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China. METHODS: Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher's exact test was used for comparison of categorical variables. RESULTS: A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received GnRH antagonists, in stark contrast to the grim situation of CVD prevalence and risk. CONCLUSIONS: Prostate cancer patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

Bacillus coagulans regulates gut microbiota and ameliorates the alcoholic-associated liver disease in mice.

Introduction: Alcoholic-associated liver diseases (ALD) are now widespread issues worldwide. Alcoholic-induced chronic dysbiosis of the gut microbiota is one of the factors in the pathophysiology of ALD. Methods: In this work, we employed a chronic-binge ethanol feeding mice model, as described in a previous report. Results: Our findings demonstrate that hepatic inflammatory injury damage and accumulation of fat can be effectively reduced in mice with ALD by altering the gut microbiota utilizing Bacillus coagulans. Treatment with B. coagulans significantly modulates the levels of TNF-α, IL-1ß, and IL-22 cytokines while maintaining tight junction proteins and mucin protein expressions to support intestinal barrier function restoration. Treatment with B. coagulans also alters the composition of the gut microbiota and increases the production of short-chain fatty acids (SCFAs). Discussion: This is mostly due to B. coagulans promotes the growth of bacteria that produce SCFAs, such as Ruminococcus species and Akkermansia, while inhibiting the growth of pathogenic bacteria like Escherichia Shigella. Moreover, treatment with B. coagulans causes levels of 2-Ketobutyric acid, ketoleucine, and indoleacetic acid increase while homovanillic acid and 3'-O-Methylguanosine metabolites decrease significantly. This study facilitates the development of therapeutic and preventive strategies for ALD using lactic acid bacteria.

Assessment tool based on fatty acid metabolic signatures for predicting the prognosis and treatment response in bladder cancer.

Background: Fatty acid metabolism (FAM) is closely connected with tumorigenesis as well as disease progression and affects the efficacy of platinum-based drugs. Exploring biomarkers related to FAM in bladder cancer (BLCA) is essential to improve cancer prognosis. Methods: High-throughput sequencing data from The Cancer Genome Atlas (TCGA) were bioinformatically resolved to identify molecular subtypes of fatty acid metabolic profiles in BLCA using coherent clustering analysis. Based on fatty acid metabolic profile, a prognostic model was created using COX and LASSO COX models. CIBERSORT, Estimation of STromal and Immune cells in MAlignant Tumours using Expression (ESTIMATE), MCP-Count, and single sample gene set enrichment analysis (ssGSEA) were used to assess the differences in tumor microenvironment (TME) among different molecular subtypes, prognostic groups. Kaplan-Meier (K-M) survival curve was plotted to assess patients' prognosis. Receiver operating characteristic curve (ROC) and the clinical prognostic value of prognostic models was evaluated by the Nomogram. Results: Three molecular subtypes (FAMC1, FAMC2, FAMC3) of fatty acid metabolic patterns were determined. FAMC1 showed significant prognostic advantage with immunoreactivity. Five key prognostic FAMGs were identified and RiskScore was developed. We found that patients with low RiskScore showed significantly better immune microenvironment status, survival and response to immunotherapy. Similarly, both Nomogram and RiskScore demonstrated excellent prognostic value. Conclusions: In conclusion, our study showed that the RiskScore was closely related to the clinical traits of BLCA patients. The RiskScore may provide essential clinical guidance for predicting prognosis and treatment response in bladder cancer.

Developing the Limosilactobacillus reuteri Chassis through an Endogenous Programmable Endonuclease-Based Genome Editing Tool.

Using genetically tractable probiotics to engineer live biotherapeutic products (LBPs) for disease treatment is urgently needed. Limosilactobacillus reuteri is an important vertebrate gut symbiont, which has great potential for developing LBPs. However, in L. reuteri, synthetic biology work is largely limited by the long editing cycle. In this study, we identified a subtype II-A CRISPR-Cas9 system in L. reuteri 03 and found the endogenous Cas9 (LrCas9) recognizing a broad protospacer-adjacent motif (PAM) sequence (3'-NDR; N = A, G, T, C; D = A, G, T; R = A, G). We reprogrammed the LrCas9 for efficient gene deletion (95.46%), point mutation (86.36%), large fragment deletion (40 kb), and gene integration (1743 bp, 73.9%), which uncovered the function of the repeated conserved domains in mucus-binding protein. Moreover, we analyzed the distribution of endogenous endonucleases in 304 strains of L. reuteri and found the existence of programmable endonucleases in 98.36% of L. reuteri strains suggesting the potential to reprogram endogenous endonucleases for genetic manipulation in the majority of L. reuteri strains. In conclusion, this study highlights the development of a new probiotic chassis based on endogenous endonucleases in L. reuteri 03, which paves the way for the development of genome editing tools for functional genetic studies in other L. reuteri. We believe that the development of an endogenous endonuclease-based genetic tool will greatly facilitate the construction of LBPs.

Optimized titanium dioxide nanotubes for dental implants: Estimation of mechanical properties and effects on the biological behaviors of human gingival fibroblasts and oral bacteria.

The long-term successes of implant restorations rely on both appropriate osseointegration and robust soft tissue integration (STI). Numerous studies have reported that titanium dioxide nanotube (TNT) arrays formed by electrochemical anodization (EA) can promote early osteogenesis, but the mechanical stability of such modifications is often ignored and remains underexplored. In addition, relatively little research has been done on their effects on soft tissues integration. In this study, we developed mechanically robust TNT arrays using an optimized EA system. Subsequently, we immobilized a peptide, specifically D-amino K122-4, onto the anodized TNTs via polydopamine (PDA) films to enhance their mechanical properties. Surface morphology and composition were characterized by scanning electron microscopy (SEM), atomic force microscopy, and X-ray photoelectron spectroscopy. Mechanical properties, including the elastic modulus and hardness of TNTs modified Ti surfaces, were assessed using the nano-indention test. The adhesive strength of TNTs films to the substrate was measured using the nano scratch test. Furthermore, we evaluated the adhesion, spreading, and proliferation of human gingival fibroblasts (HGFs) and periodontal pathogenic bacteria such as Streptococcus mutans (S.m) and F. nucleatum (F.n) on the surface. Results showed that the elastic modulus, hardness, and adhesive strength of anodized TNTs were significantly enhanced by the incorporation of the D-amino K122-4 peptide. Live-dead staining and SEM observation suggested a decreased surface colonization by both bacterial species. The antibacterial rate of S.m and F. n was 81.5% and 71.7%, respectively, evaluated by colony counting method. Additionally, results of CCK8 assay showed that modified TNTs slightly stimulated HGFs attachment and proliferation while producing enhanced fluorescence of integrin ß1 and F-actin, confirmed by laser confocal microscopy observation. Thus, D-amino K122-4 biofunctionalized TNTs present significantly improved mechanical properties, and the mechanically robust structures modulate HGFs proliferation and alignment, resulting in decreased bacteria growth. This novel strategy has the potential to create a surface coating for implants that exhibits superior mechanical robustness and enhanced surface-to-implant interactions.

Comparison of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma with rhabdoid and sarcomatoid differentiations.

OBJECTIVE: To investigate the efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell carcinoma (mRCC) with rhabdoid (mRCC-R) and sarcomatoid (mRCC-S) differentiations. MATERIALS AND METHODS: In this single-institutional cohort study, we included patients with RCC with rhabdoid (RCC-R) and sarcomatoid (RCC-S) differentiation, who were treated with TKIs after metastasis at our institute from 2013 to 2021. Patient characteristics, treatments, and clinical outcomes were recorded and analyzed. RESULTS: We identified 111 patients with RCC-R or RCC-S differentiations, of which 23 patients were included in the final analysis. Of the 23 patients, 10 (43.5%) were grouped as mRCC-R and 13 (56.5%) as mRCC-S. At a median follow-up of 40 months, mRCC-R and mRCC-S progressed in 7 of 10 and 12 of 13 patients, respectively. In addition, four and eight patients died in the mRCC-R and mRCC-S groups, respectively. The median progression-free survival (PFS) of the two groups was 19 months (mRCC-R: 95% confidence interval [CI] 4.08-33.92) and 7 months (mRCC-S: 95% CI 2.03-11.96), while the median overall survival (OS) was 32 months and 21 months, respectively. mRCC-S had a worse prognosis than mRCC-R. Based on the univariate Cox regression model, single metastasis or multiple metastasis of tumor, rhabdoid differentiation, and sarcomatoid differentiation were predictors of PFS but not OS. CONCLUSION: The efficacy of TKIs in the treatment of mRCC-R and mRCC-S may be different.

Use of PARP inhibitors in prostate cancer: from specific to broader application.

Prostate cancer (PC) is one of the major health issues of elderly men in the word. It is showed that there were approximately 1.414 million patients with PC in 2020 worldwide, with a high mortality rate in metastatic cases. In the present choices of treatment in PC, androgen deprivation therapy has long been as a backbone of them. But the clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) were not ideal because of their poor prognosis, more effective therapeutic approaches are still necessary to further improve this problem. Poly (ADP-ribose) polymerase (PARP) inhibitors lead to the single-strand DNA breaks and/or double-strand DNA breaks, and result in synthetic lethality in cancer cells with impaired homologous recombination genes. It is estimated that approximately 20~25% of patients with mCRPC have a somatic or germinal DNA damage repair gene mutation. Furthermore, in "BRCAness" cases, which has been used to describe as tumors that have not arisen from a germline BRCA1 or BRCA2 mutation, there were also a number of studies sought to extend these promising results of PARP inhibitors. It is worth noting that an interaction between androgen receptor signaling and synthetic lethality with PARP inhibitors has been proposed. In this review, we discussed the mechanism of action and clinical research of PARP inhibitors, which may benefit population from "specific" to the "all-comer" in patients with PC when combined with novel hormonal therapies.

Postbiotics from Pichia kudriavzevii promote intestinal health performance through regulation of Limosilactobacillus reuteri in weaned piglets.

Postbiotics are attractive as alternatives to antibiotics for use against post-weaning diarrhea. However, their beneficial mechanisms are largely unknown. In the current study, we first demonstrated that supplementation with 0.5% Pichia kudriavzevii FZ12 postbiotics in the diet significantly reduced diarrhea incidence, promoted growth performance, improved gut health performance, and significantly enriched beneficial bacteria, particularly Lactobacillus spp., in the intestines of weaned piglets. Importantly, we identified a heat- and proteinase K-sensitive component, cytochrome c, of the postbiotics that significantly promoted the growth and biofilm formation of Limosilactobacillus reuteri FP13. We demonstrated the importance of P. kudriavzevii FZ12 postbiotics in improving the intestinal health of a model animal and revealed that cytochrome c is one of the important components of yeast postbiotics. These findings may provide new insights into microbe-postbiotics interplay that can be applied to guidelines for dietary modulation to alleviate weaning-induced diarrhea.

The significance of EphA2-regulated Wnt/ß-catenin signal pathway in promoting the metastasis of HBV-related hepatocellular carcinoma.

BACKGROUND: Hepatitis B virus (HBV) infection is closely associated with the malignant progression of hepatocellular carcinoma (HCC). However, the mechanism involved in the HBV-related HCC development remains poorly understood. Hence, the aim of this study is to investigate the regulatory mechanism of EphA2-induced epithelial-mesenchymal transition (EMT) in the metastasis of HBV-related HCC cells. METHODS AND RESULTS: The expression level of EphA2 was determined in HBV-related human HCC cells. Then, the effects of EphA2 silencing on the EMT-associated proteins, the Wnt/ß-catenin signal pathway and the metastatic potential of HBV-related HCC cells were evaluated. Finally, the inhibitory role of Entecavir (a potent antiviral drug for HBV) on EphA2-induced EMT was explored. The present study revealed that the EphA2 expression level was increased in HBV-related HCC cells compared with non-related HCC cells. Following EphA2 knockdown, the downregulation of Vimentin, ß-catenin and p-GSK-3ßSer9 expressions, the upregulation of E-cadherin expression, and the suppressed migration and invasion ability of HBV-related HCC cells were found. Additionally, Entecavir was proved to have a significant inhibitory effect on EphA2-induced EMT via attenuating the Wnt/ß-catenin signal pathway. CONCLUSIONS: In this study, we found that EphA2-induced EMT was involved in the enhanced metastatic potential of HBV-related HCC cells through the activation of the Wnt/ß-catenin signal pathway.

Enrofloxacin-induced transfer of multiple-antibiotic resistance genes and emergence of novel resistant bacteria in red swamp crayfish guts and pond sediments.

Antibiotic resistance genes (ARGs) can be transferred from environmental microbes to human pathogens, thus leading to bacterial infection treatment failures. The aquaculture polluted by over-used antibiotics is considered as a notorious reservoir of ARGs. However, the origin, diachronic changes, and mobility of ARGs under antibiotic exposure in aquaculture systems remain elusive. Our findings showed that enrofloxacin application also increased the relative abundance of various ARGs in addition to quinolone-resistance genes and induced ARG dissemination in crayfish gut and sediment bacteria. Further investigation indicated that the transposase-mediated recombination was the major driver of horizontal gene transfer (HGT) of ARGs under antibiotic stress. Notably, enrofloxacin application also induced the generation of some metagenome-assembled genomes (MAGs) carrying multiple ARGs, which were identified as novel species. Additionally, Enterobacteriaceae constituted a mobile ARG pool in aquaculture. Therefore, aquaculture provides potential wide environmental pathways for generation and spread of antibiotic resistance. Our findings of ARG temporal variations and dissemination pattern in aquaculture with artificial use of antibiotics are critical to the management of antibiotic resistance, which is of great ecosystem and health implications.

Effective gossypol removal from cottonseed meal through optimized solid-state fermentation by Bacillus coagulans.

BACKGROUND: Cottonseed meal (CSM) is the main by-product of the cottonseed oil extraction process with high protein content, which is an important protein source for feed industry. However, CSM contains free gossypol (FG), a toxic substance that is detrimental to animal health and greatly limits its application. Microbial fermentation is currently considered to be one of the most effective methods to reduce FG and other anti-nutritional factors in CSM. Previously, yeast and bacteria species are used for degradation of FG in CSM, but showing less detoxification efficiency. Bacillus coagulans combines the properties of both lactic acid bacteria and Bacillus, producing both lactic acid and spores, and is considered a potential probiotic. In this study, we aimed to evaluate and optimize the effect of the solid-state fermentation process using a Bacillus coagulans to gossypol removal contained cottonseed meal. RESULTS: 36 B. coagulans strains were isolated and found to have the ability to remove free gossypol. Through the evaluation of strains and optimization of fermentation conditions including fermentation temperature, ratio of material to water, inoculation amount, fermentation time and pH, we have established a solid-state fermentation process using a Bacillus coagulans strain S17 on CSM substrate with 1:1 of the material-to-water ratio, 15% (v/w) seed inoculation, 2% expanded corn flour, 1% bran, and 0.3%-0.8% metal irons at 40 °C for 52 h. After fermentation, the FG content in CSM was reduced from 923.80 to 167.90 mg/kg with 81.83% detoxification efficiency. Meanwhile, the crude protein content in CSM increased from 47.98 to 52.82%, and importantly, the spore concentration of strain S17 reached 1.68 × 1010 CFU/g dry material. CONCLUSION: The study showed that B. coagulans have the potential strong ability to degrade free gossypol through cottonseed meal fermentation. This study presents a feasible process for improving the resource utilization rate and nutritional value of CSM via solid-state fermentation through B. coagulans S17.

A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) is an inherited neurodegenerative disease caused by mutations in GBA1 gene and is associated with premature death. Neuroinflammation plays a critical role in disease pathogenesis which is characterized by microgliosis, reactive astrocytosis, and neuron loss, although molecular mechanisms leading to neuroinflammation are not well-understood. In this report, we developed a convenient tool to quantify microglia proliferation and activation independently and uncovered abnormal proliferation of microglia (∼2-fold) in an adult genetic nGD model. The nGD-associated pattern of inflammatory mediators pertinent to microglia phenotypes was determined, showing a unique signature favoring pro-inflammatory chemokines and cytokines. Moreover, highly polarized (up or down) dysregulations of mTORC1 signaling with varying lysosome dysfunctions (numbers and volume) were observed among three major cell types of nGD brain. Specifically, hyperactive mTORC1 signaling was detected in all disease-associated microglia (Iba1high) with concurrent increase in lysosome function. Conversely, the reduction of neurons presenting high mTORC1 activity was implicated (including Purkinje-like cells) which was accompanied by inconsistent changes of lysosome function in nGD mice. Undetectable levels of mTORC1 activity and low Lamp1 puncta were noticed in astrocytes of both diseased and normal mice, suggesting a minor involvement of mTORC1 pathway and lysosome function in disease-associated astrocytes. These findings highlight the differences and complexity of molecular mechanisms that are involved within various cell types of the brain. The quantifiable parameters established and nGD-associated pattern of neuroinflammatory mediators identified would facilitate the efficacy evaluation on microgliosis and further discovery of novel therapeutic target(s) in treating neuronopathic Gaucher disease.

Bacillus coagulans in Combination with Chitooligosaccharides Regulates Gut Microbiota and Ameliorates the DSS-Induced Colitis in Mice.

Ulcerative colitis (UC) are chronic inflammatory disorders, which may be caused by intestinal barrier dysfunction, immune system disorders and intestinal microbiota dysbiosis. Synbiotic, the combination of probiotics and prebiotics, is thought to be a pragmatic approach in mitigating inflammation in UC. Bacillus coagulans has been recognized as a potential probiotic for treating intestinal diseases because of its favorable industrial and probiotic properties, including sporulation and lactic acid production. In this study, we evaluated the treatment effects of the B. coagulans FCYS01 spores with or without the chitooligosaccharides (COSs) on UC generated using dextran sulfate sodium (DSS) in mice. Supplementation of B. coagulans spores, prebiotic COSs or the synbiotic (the spores + COSs) had a significant positive effect on DSS-induced UC. The disease activity index and histological damage score were significantly reduced after these supplementations. Compared to DSS group, these supplementations also significantly modulated the cytokines IL-4, IL-6, IL-8, IL-10, and C-reactive protein (CRP) levels and significantly maintained expressions of tight junction proteins and mucin protein and promotes recovery of the intestinal barrier. In addition, these supplementations regulate the composition of gut microbiota and improve the production of short-chain fatty acids (SCFAs), through enrichment of SCFA-producing bacteria, such as Akkermansia and Ruminococcus species. In summary, the synbiotic ameliorated the overall inflammatory status of the experimental UC model and showed a better treatment effect than B. coagulans or COSs did alone as revealed by the markers such as, colon length, IL-4 and Occludin levels. IMPORTANCE Probiotic and prebiotic are believed to be useful in alleviating the inflammatory, thereby resolving or preventing the severity of UC. Spore-forming bacteria Bacillus coagulans show advantages of stability and probiotic effects, being suggested as the important probiotics for UC treatment. Here, we demonstrate that administration of B. coagulans spores, chitooligosaccharides (COSs), or the synbiotic attenuates DSS-induced colitis and significantly correlates with altered gut immune responses. The treatment effect of the synbiotic is inferred to be relied on the enrichment of probiotic bacteria, such as Akkermansia and Ruminococcaceae species, which are reported to be crucial important for gut health. Our findings facilitate the development of therapeutic and preventive strategies for UC using spore-forming lactic acid bacteria in combination with COSs.

Semi-Supervised Cell Detection with Reliable Pseudo-Labels.

Pathological images play an important role in the diagnosis, treatment, and prognosis of cancer. Usually, pathological images contain complex environments and cells of different shapes. Pathologists consume a lot of time and labor costs when analyzing and discriminating the cells in the images. Therefore, fully annotated pathological image data sets are not easy to obtain. In view of the problem of insufficient labeled data, we input a large number of unlabeled images into the pretrained model to generate accurate pseudo-labels. In this article, we propose two methods to improve the quality of pseudo-labels, namely, the pseudo-labeling based on adaptive threshold and the pseudo-labeling based on cell count. These two pseudo-labeling methods take into account the distribution of cells in different pathological images when removing background noise, and ensure that accurate pseudo-labels are generated for each unlabeled image. Meanwhile, when pseudo-labels are used for model retraining, we perform data distillation on the feature maps of unlabeled images through an attention mechanism, which further improves the quality of training data. In addition, we also propose a multi-task learning model, which learns the cell detection task and the cell count task simultaneously, and improves the performance of cell detection through feature sharing. We verified the above methods on three different data sets, and the results show that the detection effect of the model with a large number of unlabeled images involved in retraining is improved by 9%-13% compared with the model that only uses a small number of labeled images for pretraining. Moreover, our methods have good applicability on the three data sets.

Context-aware learning for cancer cell nucleus recognition in pathology images.

MOTIVATION: Nucleus identification supports many quantitative analysis studies that rely on nuclei positions or categories. Contextual information in pathology images refers to information near the to-be-recognized cell, which can be very helpful for nucleus subtyping. Current CNN-based methods do not explicitly encode contextual information within the input images and point annotations. RESULTS: In this article, we propose a novel framework with context to locate and classify nuclei in microscopy image data. Specifically, first we use state-of-the-art network architectures to extract multi-scale feature representations from multi-field-of-view, multi-resolution input images and then conduct feature aggregation on-the-fly with stacked convolutional operations. Then, two auxiliary tasks are added to the model to effectively utilize the contextual information. One for predicting the frequencies of nuclei, and the other for extracting the regional distribution information of the same kind of nuclei. The entire framework is trained in an end-to-end, pixel-to-pixel fashion. We evaluate our method on two histopathological image datasets with different tissue and stain preparations, and experimental results demonstrate that our method outperforms other recent state-of-the-art models in nucleus identification. AVAILABILITY AND IMPLEMENTATION: The source code of our method is freely available at https://github.com/qjxjy123/DonRabbit. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Correction: Synthesis of TiO2 nanotubes with ZnO nanoparticles to achieve antibacterial properties and stem cell compatibility.

Correction for 'Synthesis of TiO2 nanotubes with ZnO nanoparticles to achieve antibacterial properties and stem cell compatibility' by Wenwen Liu et al., Nanoscale, 2014, 6, 9050-9062, DOI: 10.1039/C4NR01531B.

DNA-repair status should be assessed in treatment-emergent neuroendocrine prostate cancer before platinum-based therapy.

OBJECTIVES: This study sought to provide contemporary data from a multi-institution with respect to DNA-repair genes (DRGs) status and its impact on effects of platinum-based chemotherapy in treatment-emergent neuroendocrine prostate cancer (t-NEPC), for which little data exist. PATIENTS AND METHODS: All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression-free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair-deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19-0.93), and the HR for death was 0.65 (95% CI: 0.24-1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%). CONCLUSION: The DRGs status is therapeutically meaningful in t-NEPC. Given the potential responses to platinum-based chemotherapy, our findings support the clinical use of NGS in t-NEPC patients to identify DRGs aberrations.

Association of tumor mutational burden with genomic alterations in Chinese urothelial carcinoma.

The tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is a promising biomarker for the response to immune checkpoint inhibition (ICIs) in solid tumors. However, WES is not feasible in the routine clinical setting. In addition, the characteristics of the TMB in Chinese urothelial carcinoma (UC) are unclear. The aim of this study was to demonstrate the reliability of an Acornmed 808 panel and analyze the characteristics of the TMB in Chinese UC. An Acornmed 808 panel was designed and virtually validated using UC data from the cancer genome atlas (TCGA). Comprehensive analysis of sequencing and clinical data was performed to explore the characteristics of the TMB for 143 Chinese UC patients. Compared to the TMB calculated with random 808-, 500-, and 250-gene panels, the TMB calculated with the Acornmed 808 panel was closer to that calculated by WES. There were marked disparities in the mutational landscape and TMB between Chinese and TCGA UC data. The TMB was negatively associated with copy number variation (CNV). In contrast, the TMB was positive correlation with numbers of mutated DDR genes. Exposure to aristolochic acid signature was observed only in the TMB-high groups. The Acornmed 808 panel is a clinically practical method to assess the TMB. The TMB was associated with the DDR gene status and CNV counts and might be a biomarker for further stratification of UC patients. The study suggested that patients with high TMB may have a unique carcinogenic mechanism.

Preparation, characterization and antimicrobial activities of cyclic substituted chitosan derivatives.

Six cyclic substituted chitosan derivatives were synthesized, and their structures were characterized by FTIR, 13C NMR and elemental analyses. Additionally, their antimicrobial properties were studied. The synthesized derivatives showed significantly greater zones of inhibition compared with chitosan. The zone of inhibition values produced by C2-2-naphthylamine formamide-C6-2-naphthylamine formyl ester-polymer chitosan against Sarcina sp., Staphylococcus aureus and Escherichia coli were 24 mm, 21 mm and 21 mm, respectively, whereas those of C2-cyclohexylamine formamide-C6-cyclohexylamine formyl ester-low chitosan against Fusarium equiseti and Verticillium dahliae were 14 mm and 15 mm, respectively. The antibacterial abilities of chitosan and its derivatives against the Gram-positive bacteria Sarcina sp. and Staphylococcus aureus were stronger than those against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. In addition, all of the high and low molecular weight chitosan derivatives showed greater bacteriostatic activities than antifungal activities. The results provided a useful reference for the development of chitosan and its derivatives used as new pesticides.

The immunogenic reaction and bone defect repair function of ε-poly-L-lysine (EPL)-coated nanoscale PCL/HA scaffold in rabbit calvarial bone defect.

Tissue engineering is a promising strategy for bone tissue defect reconstruction. Immunogenic reaction, which was induced by scaffolds degradation or contaminating microorganism, influence cellular activity, compromise the efficiency of tissue engineering, or eventually lead to the failure of regeneration. Inhibiting excessive immune response through modulating scaffold is critical important to promote tissue regeneration. Our previous study showed that ε-poly-L-lysine (EPL)-coated nanoscale polycaprolactone/hydroxyapatite (EPL/PCL/HA) composite scaffold has enhanced antibacterial and osteogenic properties in vitro. However, the bone defect repair function and immunogenic reaction of EPL/PCL/HA scaffolds in vivo remains unclear. In the present study, three nanoscale scaffolds (EPL/PCL/HA, PCL and PCL/HA) were transplanted into rabbit paraspinal muscle pouches, and T helper type 1 (Th1), T helper type 2 (Th2), T helper type 17 (Th17), and macrophage infiltration were analyzed after 1 week and 2 weeks to detect their immunogenic reaction. Then, the different scaffolds were transplanted into rabbit calvarial bone defect to compare the bone defect repair capacities. The results showed that EPL/PCL/HA composite scaffolds decreased pro-inflammatory Th1, Th17, and type I macrophage infiltration from 1 to 2 weeks, and increased anti-inflammatory Th2 infiltration into the regenerated area at 2 weeks in vivo, when compared to PCL and PCL/HA. In addition, EPL/PCL/HA showed an enhanced bone repair capacity compared to PCL and PCL/HA when transplanted into rabbit calvarial bone defects at both 4 and 8 weeks. Hence, our results suggest that EPL could regulate the immunogenic reaction and promote bone defect repair function of PCL/HA, which is a promising agent for tissue engineering scaffold modulation.