Exosomes: The endogenous nanomaterials packed with potential for diagnosis and treatment of neurologic disorders.

Neurologic disorders (NDs) are serious diseases that threaten public health. However, due to the complex pathogenesis and significant individual differences in traditional treatments, specific treatment methods for NDs are still lacking. Exosomes, the smallest extracellular vesicles secreted by eukaryotic cells, are receiving increasing attention in the field of NDs. They contain misfolded proteins related to various NDs, including amyloid-beta, Tau proteins, and α-synuclein, indicating their promising roles in the diagnosis and treatment of NDs. In this review, an overview of the biogenesis, composition, and biological functions of exosomes is provided. Moreover, we summarize their potential roles in the pathogenesis of three prevalent NDs (including Alzheimer's disease, Ischemic stroke, and Parkinson's disease). On this basis, the diagnostic potential and therapeutic value of exosomes carrying various bioactive molecules are discussed in detail. Also, the concerns and perspectives of exosome-based diagnosis and therapy are discussed.

Involvement of functional metabolism promotes the enrichment of antibiotic resistome in drinking water: Based on the PICRUSt2 functional prediction.

Biofilters are the important source and sink of antibiotic resistance genes (ARGs) and antibiotic resistance bacteria (ARB) in the drinking water. Current studies generally ascribed the prevalence of BAR in biofilter from the perspective of gene behavior, i.e. horizontal gene transfer (HGT), little attentions have been paid on the ARGs carrier- ARB. In this study, we proposed the hypothesis that ARB participating in pollutant metabolism processes and becoming dominant is an important way for the enrichment of ARGs. To verify this, the antibiotic resistome and bacterial functional metabolic pathways of a sand filter was profiled using heterotrophic bacterial plate counting method (HPC), high-throughput qPCR, Illumina Hiseq sequencing and PICRUSt2 functional prediction. The results illustrated a significant leakage of ARB in the effluent of the sand filter with an average absolute abundance of approximately 102-103 CFU/mL. Further contribution analysis revealed that the dominant genera, such as Acinetobacter spp., Aeromonas spp., Elizabethkingia spp., and Bacillus spp., were primary ARGs hosts, conferring resistance to multiple antibiotics including sulfamethoxazole, tetracycline and ß-lactams. Notably, these ARGs hosts were involved in nitrogen metabolism, including extracellular nitrate/nitrite transport and nitrite reduction, which are crucial in nitrification and denitrification in biofilters. For example, Acinetobacter spp., the dominant bacteria in the filter (relative abundance 69.97 %), contributed the majority of ARGs and 53.79 % of nitrite reduction function. That is, ARB can predominate by participating in the nitrogen metabolism pathways, facilitating the enrichment of ARGs. These findings provide insights into the stable presence of ARGs in biofilters from a functional metabolism perspective, offering a significant supplementary to the mechanisms of the emergence, maintenance, and transmission of BARin drinking water.

Development and validation of an ultrasound­based radiomics nomogram to predict lymph node status in patients with high-grade serous ovarian cancer: a retrospective analysis.

BACKGROUND: Despite advances in medical imaging technology, the accurate preoperative prediction of lymph node status remains challenging in ovarian cancer. This retrospective study aimed to investigate the feasibility of using ultrasound-based radiomics combined with preoperative clinical characteristics to predict lymph node metastasis (LNM) in patients with high-grade serous ovarian cancer (HGSOC). RESULTS: Patients with 401 HGSOC lesions from two institutions were enrolled: institution 1 for the training cohort (n = 322) and institution 2 for the external test cohort (n = 79). Radiomics features were extracted from the three preoperative ultrasound images of each lesion. During feature selection, primary screening was first performed using the sample variance F-value, followed by recursive feature elimination (RFE) to filter out the 12 most significant features for predicting LNM. The radscore derived from these 12 radiomic features and three clinical characteristics were used to construct a combined model and nomogram to predict LNM, and subsequent 10-fold cross-validation was performed. In the test phase, the three models were tested with external test cohort. The radiomics model had an area under the curve (AUC) of 0.899 (95% confidence interval [CI]: 0.864-0.933) in the training cohort and 0.855 (95%CI: 0.774-0.935) in the test cohort. The combined model showed good calibration and discrimination in the training cohort (AUC = 0.930) and test cohort (AUC = 0.881), which were superior to those of the radiomic and clinical models alone. CONCLUSIONS: The nomogram consisting of the radscore and preoperative clinical characteristics showed good diagnostic performance in predicting LNM in patients with HGSOC. It may be used as a noninvasive method for assessing the lymph node status in these patients.

Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.

Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Streptococcus salivarius K12 Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors: A Randomized Controlled Trial.

PURPOSE: Oral mucositis (OM) is a common debilitating toxicity associated with radiotherapy (RT) for malignant head and neck tumors. This prospective, randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of Streptococcus salivarius K12 (SsK12) in reducing the incidence, duration, and severity of severe OM (SOM). METHODS: A total of 160 patients with malignant head and neck tumors undergoing definitive or postoperative adjuvant RT were randomly assigned (1:1) to receive SsK12 probiotic (n = 80) or placebo (n = 80) at West China Hospital, Sichuan University, Chengdu, China. Patients were instructed to suck SsK12 or placebo lozenges thrice daily from the initiation to the end of RT. OM was evaluated twice a week during RT and once a week thereafter for up to 8 weeks. The primary end point was the incidence of SOM. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Baseline patient characteristics were similar in the SsK12 and placebo groups. The incidence of SOM was significantly lower in the SsK12 group as compared with the placebo group (36.6% v 54.2%; P = .0351). The duration (median, 0.0 days v 7.0 days; mean, 8.9 days v 18.3 days; P = .0084) and time to develop SOM (median, not estimable v 42.0 days; hazard ratio, 0.55 [95% CI, 0.34 to 0.89]; log-rank test: P = .0123) were also improved in the case of the SsK12 group. Adverse events were similar between the groups, and mild or moderate gastrointestinal reactions (flatulence or dyspepsia) associated with the lozenges were observed in two patients in the SsK12 group. High-throughput sequencing results indicated that SsK12 inhibited opportunistic pathogens and enriched oral commensals during RT. CONCLUSION: In this prospective, randomized clinical trial, SsK12 probiotic significantly reduced the incidence, onset, and duration of SOM with a good safety profile.

The association between thyroid and breast cancers: a bidirectional mendelian randomization study.

Background: Thyroid and breast cancers are the two most frequent types of endocrine-related tumors among women worldwide, and their incidence is still on the rise. Observational studies have shown a relationship between thyroid and breast cancers. Nevertheless, many confounders predispose the results to interference. Accordingly, we performed a two-sample Mendelian randomization (MR) study to investigate the causal association between thyroid and breast cancers. Methods: We acquired breast cancer data from the UK Biobank (13,879 breast cancer cases and 198,523 controls) and the Breast Cancer Association Consortium (BCAC; 122,977 breast cancer cases and 105,974 controls), and thyroid cancer data from FinnGen Biobank (989 thyroid cancer and 217,803 controls). Then, the multiplicative random effects inverse variance weighting (IVW), weight median (WM), and MR Egger methods were executed for MR analysis. Results: Overall, IVW showed a causal effect of breast cancer on thyroid cancer using the BCAC dataset (odds ratio [OR] = 1.17; 95% confidence interval [CI] = 1.036-1.322; P = 0.011), and this relationship was also supported by the UK Biobank dataset (OR = 23.899; 95% CI = 2.331-245.003; P = 0.007), which showed that breast cancer patients were more likely to be diagnosed with thyroid cancer. On the whole, the reverse MR analysis did not show a causal effect of breast cancer on thyroid cancer. However, IVW showed a causal effect of thyroid cancer on estrogen receptor -negative breast cancer using the BCAC dataset (OR = 1.019; 95% CI = 1.001-1.038; P = 0.043), which suggested that people with thyroid cancer were more likely to develop breast cancer. Conclusions: Breast cancer represents a possible risk factor for thyroid cancer and thyroid cancer also represents a possible risk factor for ER-negative breast cancer. Future studies using powerful genetic tools to determine the causal relationship between breast and thyroid cancers are required.

Concurrency of additional canals in mandibular incisors and second mesiobuccal canal in maxillary first molars: A cone-beam computed tomography investigation.

This study investigated the concurrency of additional canals in mandibular incisors and the second mesiobuccal canal in maxillary first molars among the Chinese population. In total, 8644 cone-beam computed tomography images from 8644 patients with bilateral mandibular incisors and maxillary first molars were examined. The data were analysed using Chi-square test, binary logistic regression analysis and receiver operating characteristic curve. Among the patients with additional canals in mandibular central and lateral incisors, 96.2% and 95.5% of them had second mesiobuccal canal in maxillary first molars, respectively. Additional canals of mandibular incisors and second mesiobuccal canal in maxillary first molars exhibited a concurrent relationship. The prevalence of second mesiobuccal canal in maxillary first molars increased with the number of mandibular incisors with additional canals. Moreover, when there was at least one mandibular incisor with additional canals, the presence of the second mesiobuccal canal in maxillary first molars could be highly expected.

KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes.

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.

Efficacy and safety of endocrine therapy after mastectomy in patients with hormone receptor positive breast ductal carcinoma in situ: Retrospective cohort study.

Background: More than half of Chinese patients with hormone receptor positive (HR+) ductal carcinoma in situ (DCIS) are treated with mastectomy, and usually subjected to postoperative endocrine therapy (ET). Given that long-term ET can cause severe adverse effects it is important to determine the beneficial effect and safety of post-mastectomy ET on the disease-free survival (DFS) and adverse events in patients with HR+ DCIS. Methods: To explore beneficial effect and safety of post-mastectomy ET in patients with HR+ DCIS, we performed a multicenter, population-based study. This retrospective study analyzed the DFS and adverse events in 1037 HR+ DCIS Chinese patients with or without post-mastectomy ET from eight breast centers between 2006 and 2016. The median follow-up time period was 86 months. Results: There were 791 DCIS patients receiving ET (ET group). Those patients were followed up for a median of 86 months (range, 60-177 months). There were 23 cases with tumor recurrence or distant metastasis. There were similar 5-year DFS rates and DFS between the ET and non-ET groups, even for those with high-risk factors. Conversely, 37.04% of patients suffered from adverse events after ET, which were significantly higher than those in the non-ET group. Conclusions: ET after mastectomy did not benefit patients with HR+ DCIS for their DFS, rather increased adverse events in those patients. Therefore, ET after mastectomy may not be recommended for patients with HR+ DCIS, even for those with high-risk factors, such as multifocal, microinvasive, and higher T stage. Funding: This study was supported by grants from Outstanding Scientific Fund of Shengjing Hospital (201803) and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells.

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.

Stereodiverse Iterative Synthesis of 1,3-Polyol Arrays through Asymmetric Catalytic Hydrogenation. Formal Total Synthesis of (-)-Cyanolide A.

An iterative protocol was developed for highly diastereo- and enantioselective construction of high-order 1,3-polyols via iridium-catalyzed asymmetric hydrogenation of ß-alkyl-ß-keto esters. The protocol involves four operations-asymmetric hydrogenation, hydroxy protection, ester hydrolysis, and C-acylation-and the catalyst loading can be as low as 0.005 mol %. The configurations of all stereogenic centers of 1,3-polyols are controlled by the catalyst. By the use of this protocol, a formal total synthesis of the polyketide cyanolide A was achieved with high diastereoselectivity and enantioselectivity.