Poor Oral Health and Risk of Incident Dementia: A Prospective Cohort Study of 425,183 Participants.

BACKGROUND: The association between poor oral health and the risk of incident dementia remains unclear. OBJECTIVE: To investigate the associations of poor oral health with incident dementia, cognitive decline, and brain structure in a large population-based cohort study. METHODS: A total of 425,183 participants free of dementia at baseline were included from the UK Biobank study. The associations between oral health problems (mouth ulcers, painful gums, bleeding gums, loose teeth, toothaches, and dentures) and incident dementia were examined using Cox proportional hazards models. Mixed linear models were used to investigate whether oral health problems were associated with prospective cognitive decline. We examined the associations between oral health problems and regional cortical surface area using linear regression models. We further explored the potential mediating effects underlying the relationships between oral health problems and dementia. RESULTS: Painful gums (HR = 1.47, 95% CI [1.317-1.647], p < 0.001), toothaches (HR = 1.38, 95% CI [1.244-1.538], p < 0.001), and dentures (HR = 1.28, 95% CI [1.223-1.349], p < 0.001) were associated with increased risk of incident dementia. Dentures were associated with a faster decline in cognitive functions, including longer reaction time, worse numeric memory, and worse prospective memory. Participants with dentures had smaller surface areas of the inferior temporal cortex, inferior parietal cortex, and middle temporal cortex. Brain structural changes, smoking, alcohol drinking, and diabetes may mediate the associations between oral health problems and incident dementia. CONCLUSION: Poor oral health is associated with a higher risk of incident dementia. Dentures may predict accelerated cognitive decline and are associated with regional cortical surface area changes. Improvement of oral health care could be beneficial for the prevention of dementia.

Genomic and Metabolomic Analyses of the Medicinal Fungus Inonotus hispidus for Its Metabolite's Biosynthesis and Medicinal Application.

Inonotus hispidus mushroom is a traditional medicinal fungus with anti-cancer, antioxidation, and immunomodulatory activities, and it is used in folk medicine as a treatment for indigestion, cancer, diabetes, and gastric illnesses. Although I. hispidus is recognized as a rare edible medicinal macrofungi, its genomic sequence and biosynthesis potential of secondary metabolites have not been investigated. In this study, using Illumina NovaSeq combined with the PacBio platform, we sequenced and de novo assembled the whole genome of NPCB_001, a wild I. hispidus isolate from the Aksu area of Xinjiang Province, China. Comparative genomic and phylogenomic analyses reveal interspecific differences and evolutionary traits in the genus Inonotus. Bioinformatics analysis identified candidate genes associated with mating type, polysaccharide synthesis, carbohydrate-active enzymes, and secondary metabolite biosynthesis. Additionally, molecular networks of metabolites exhibit differences in chemical composition and content between fruiting bodies and mycelium, as well as association clusters of related compounds. The deciphering of the genome of I. hispidus will deepen the understanding of the biosynthesis of bioactive components, open the path for future biosynthesis research, and promote the application of Inonotus in the fields of drug research and functional food manufacturing.

Chromosome-Level Genome Sequences, Comparative Genomic Analyses, and Secondary-Metabolite Biosynthesis Evaluation of the Medicinal Edible Mushroom Laetiporus sulphureus.

Laetiporus sulphureus mushroom is a complementary and alternative medicine that has anticancer, antioxidation, and analgesic effects and immunomodulatory activity; it is used as a treatment for cough and rheumatism and is a functional food that can improve physical fitness. Even though L. sulphureus has garnered considerable biotechnological and pharmacological interest due to its excellent cellulose-degrading ability and diverse biological activities, its biosynthetic potential regarding polysaccharides and secondary metabolites has not been thoroughly examined. In this study, we sequenced and assembled the whole genome of a wild L. sulphureus isolate, NWAFU-1, from the Qinling Mountains in China. Comparative genomes analysis revealed genomic differences between subspecies, and phylogenomic analysis revealed evolutionary divergence as well as genome expansion and contraction of individual Polyporaceae family species. Bioinformatics investigation identified candidate genes associated with mating type, polysaccharide synthesis, carbohydrate-active enzymes, and secondary-metabolite biosynthesis, which included multiple terpenoids, nonribosomal peptides, and polyketides. The locations of biosynthetic core genes were mapped and displayed on chromosomes and contigs. Totals of 143 proteins from 126 coding genes were identified and divided into 14 cytochrome P450 families. Furthermore, the biosynthetic network of tetracyclic triterpenoid active components was postulated by genome mining of related genes combined with the molecular network of metabolites. The genome analysis of L. sulphureus in this study improves the understanding of the biosynthesis of active compounds, which will lay a theoretical foundation for subsequent research on active-compound biosynthesis and promote the application of Laetiporus in the field of drug research and functional-food creation. IMPORTANCE L. sulphureus is a parasitic basidiomycete fungus that causes brown rot. The fruiting bodies of L. sulphureus are used as ancient medicines in China and Europe to cure cancer, analgesia, cough, and rheumatism and are considered a functional food that regulates the body and improves health. L. sulphureus was inferred to be a tetrapolar system based on a high-quality genome, which will aid molecular breeding and artificial farming. Screening polysaccharide synthesis candidate genes and comparing carbohydrate-associated genes in brown-rot basidiomycetes help understand their growth. Identifying core genes for secondary-metabolite biosynthesis, gene cluster family analysis, and comparative cluster analysis will guide heterologous-biosynthesis investigations of these genes and help elucidate the biosynthetic pathways for L. sulphureus bioactive natural components. The biosynthesis network of tetracyclic triterpenes was mapped using metabolite profiling and genome scanning. This work explores the biosynthetic capacity of L. sulphureus-derived natural products and lays the foundation for biosynthetic studies of them.

A Novel Tumor Staging System Incorporating Tumor Regression Grade (TRG) With Lymph Node Status (ypN-Category) Results in Better Prognostication Than ypTNM Stage Groups After Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups. BACKGROUND: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups. METHODS: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system. RESULTS: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors. CONCLUSION: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups.

Improving Outcome of Superior Mediastinal Lymph Node Dissection During Esophagectomy: A Novel Approach Combining Continuous and Intermittent Recurrent Laryngeal Nerve Monitoring.

OBJECTIVE: This study aimed at demonstrating the effects and learning curve of utilizing combined intermittent and continuous recurrent laryngeal nerve (RLN) monitoring for lymphadenectomy during esophagectomy. BACKGROUND: RLN lymphadenectomy is oncologically important but is technically demanding. Vocal cord (VC) palsy as a result from RLN injury, carries significant morbidities. METHODS: This is a retrospective study of consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent transthoracic esophagectomy from 2010 to 2020. Combined nerve monitoring (CNM) included: CNM which involved a periodic stimulating left vagal electrode and intermittent nerve monitoring which utilized a stimulating probe to identify the RLNs. The integrity of the RLNs was assessed both intermittently and continuously. This technique was introduced in 2014. Patients were divided into "before CNM" and "CNM" groups. The primary outcome was the difference in number of RLN lymph nodes harvested and VC palsy rate. Learning curves were demonstrated by cumulative sum (CUSUM) analysis. RESULTS: Two hundred and fifty-five patients were included with 157 patients in "CNM" group. The mean number of RLN lymph nodes harvested was significantly higher (4.31 vs 0.45, P < 0.0001) for the "CNM" group. VC palsy rates were significantly lower (17.8% vs 32.7%, P = 0.007). There was an initial increase in VC palsy rate, peaked at around 46 cases. The increase in lymph nodes harvested above the mean plateaued at around 96 cases. CONCLUSIONS: CNM helped improve bilateral RLN lymphadenectomy. Lymph node harvesting was increased with reduction of VC palsy after a learning curve.

Neoadjuvant Chemoradiotherapy Using Cisplatin and 5-Fluorouracil (PF) Versus Carboplatin and Paclitaxel (CROSS Regimen) for Esophageal Squamous Cell Carcinoma (ESCC): A Propensity Score-matched Study.

OBJECTIVE: This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC. BACKGROUND: PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed. METHODS: This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis ("CROSS Eligibility") was performed based on tumor length, cT-stage, cM-stage, age, and performance status. RESULTS: One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For "CROSS Eligible subgroup," the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093). CONCLUSIONS: There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.

Isolation and synthesis of a new benzylated alkamide from the roots of Lepidium meyenii.

A new benzylated alkamide, N-(3,4-dimethoxybenzyl)-9Z-oleamide (1), along with two known ones (2 and 3) were isolated from the roots of Lepidium meyenii collected from Lijiang, Yunnan Province of China. Their structures were elucidated by extensive spectroscopic analyses and the new compound further confirmed by a one-step synthesis. All the isolated alkamides were evaluated for their cytotoxicity against five human cancer cell lines. However, no significant activities were detected at concentrations up to 40 µM.

Pediatric low-grade gliomas can be molecularly stratified for risk.

Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.

Biomarker-based prognostic stratification of young adult glioblastoma.

While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.

Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats.

In hypertensive animals and patients, oxidative stress represents the primary risk factor for progression of renal disease. Recently, it has been demonstrated that hydrogen, as a novel antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite anion to exert therapeutic antioxidant activity. Herein, we investigated the protective effect of hydrogen-rich water (HW) against renal injury in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into HW-treated (1.3 ± 0.2 mg/l for 3 months, drinking) and vehicle-treated group. Although treatment with HW had no significant effect on blood pressure, it significantly ameliorated renal injury in SHR. Treatment with HW lowered reactive oxygen species formation, upregulated the activities of superoxide dismutase, glutathione peroxidase, glutathione-S-epoxide transferase, and catalase, and suppressed NADPH oxidase activity. Treatment with HW in SHR depressed pro-inflammatory cytokines expression including TNF-α, IL-6, IL-1ß, and macrophage chemoattractant protein 1, which might be mediated by suppressing nuclear factor-κB activation. In addition, treatment with HW had protective effect on mitochondrial function including adenosine triphosphate formation and membrane integrity in SHR. In conclusion, consumption of HW is a promising strategy to alleviate renal injury as a supplement for anti-hypertensive therapy.

Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin.

In recent years, enterovirus 71 (EV71) infections have caused an increasing epidemic in young children, accompanying with more severe nervous system disease and more deaths. Unfortunately, there is no specific medication for it so far. Here we investigated the anti-EV71 activity of chrysosplenetin and penduletin, two o-methylated flavonols isolated from the leaves of Laggera pterodonta. These two compounds were found to have strong activity in vitro against EV71 with low cytotoxicity. In the cytopathic effect (CPE) inhibition assays, both plaque reduction assay and virus yield inhibition assay, the compounds showed a similar 50% inhibitory concentration (IC(50)) value of about 0.20 µM. The selectivity indices (SI) of chrysosplenetin and penduletin were 107.5 and 655.6 in African green monkey kidney (Vero) cells, and 69.5 and 200.5 in human rhabdomyosarcoma (RD) cells, accordingly. The preliminary mechanism analysis indicates that they function not through blocking virus entry or inactivating virus directly but inhibiting viral RNA replication. In the time-of-addition assay, both compounds inhibited progeny virus production and RNA replication by nearly 100% when introduced within 4h post infection. In addition to EV71, both compounds inhibited several other human enteroviruses with similar efficacy. These findings provide a significant lead for the discovery of anti-EV71 drug.

Nonleukemic myeloid sarcoma of the liver: a case report and review of literature.

Myeloid sarcoma (MS) is a neoplasm of immature granulocytes, monocytes, or both involving extramedullary sites. MS with no evidence of leukemia (nonleukemic MS) is very rare and the initial diagnosis can be difficult. This report describes an unusual case of nonleukemic MS of the liver in a 16-year-old patient presenting as debilitating hepatomegaly. A liver biopsy revealed diffuse infiltration by neoplastic cells of myeloid lineage (CD68, myeloperoxidase). A bone marrow biopsy showed no evidence of medullary involvement. The patient subsequently developed heart failure. Autopsy revealed infiltration of most organs by neoplastic cells but failed to identify abnormal myeloid cells in bone marrow.

Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials.

PURPOSE: High-grade bleeding is a serious adverse event associated with bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor and widely used in the current cancer treatments. The aim of this study was to gain a better understanding of the overall incidence and risk of high-grade bleeding in cancer patients who receive bevacizumab therapy. METHODS: We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, Embase, and American Society of Clinical Oncology conferences. Overall relative risks (RRs), incidence rates, and 95% confidence intervals (CIs) were calculated using a random-effects model. The primary clinical endpoint was high-grade bleeding (grade 3 or above). RESULTS: A total of 14,277 patients with a variety of solid tumors from 22 RCTs were included in the present analysis. The addition of bevacizumab to cancer chemotherapy significantly increased the risk of high-grade bleeding (RR 1.60, 95% CI 1.19-2.15), with RRs of high-grade bleeding among patients receiving bevacizumab at 2.5 and 5 mg/kg per week of 1.27 (95% CI 0.95-1.71) and 3.02 (95% CI 1.85-4.95), respectively. The overall incidence of high-grade bleeding among patients receiving bevacizumab was 2.8% (95% CI 2.1-3.8). Higher risks were observed in patients with non-small-cell lung cancer (RR 3.41, 95% CI 1.68-6.91), renal cell carcinoma (RR 6.37, 95% CI 1.43-28.33), and colorectal cancer (RR 9.11, 95% CI 1.70-48.79) who were receiving bevacizumab at 5 mg/kg per week. CONCLUSIONS: Among the patients included in the trials analyzed in this meta-analysis, the addition of bevacizumab to cancer chemotherapy significantly increased the risk of high-grade bleeding. The risk may be dose-dependent and may vary with tumor type.

Effect of oxymatrine on the replication cycle of hepatitis B virus in vitro.

AIM: To determine the antiviral mechanism or target of oxymatrine against hepatitis B virus (HBV). METHODS: HepG2.2.15 cells were incubated with culture medium containing 500 microg/mL of oxymatrine for 2 and 5 d. The surface antigen of HBV (HBsAg) and e antigen of HBV (HBeAg) in supernatant were determined by ELISA. HBV DNA in supernatant, and intracellular covalently closed circular DNA (cccDNA), relaxed circular DNA (rcDNA) and pregenomic RNA (pgRNA) were quantified by specific real-time polymerase chain reaction (PCR) or reverse transcription (RT)-PCR. RESULTS: Treatment with oxymatrine for 2 d and 5 d reduced the production of HBV by the cell line, as indicated by the decline of HBsAg (22.67%, t = 5.439, P = 0.0322 and 22.39%, t = 5.376, P = 0.0329, respectively), HBeAg (55.34%, t = 9.859, P = 0.0101 and 43.97%, t = 14.080, P = 0.0050) and HBV DNA (40.75%, t = 4.570, P = 0.0447 and 75.32%, t = 14.460, P = 0.0047) in the supernatant. Intracellular cccDNA was also markedly reduced by 63.98% (t = 6.152, P = 0.0254) and 80.83% (t = 10.270, P = 0.0093), and intracellular rcDNA by 34.35% (t = 4.776, P = 0.0413) and 39.24% (t = 10.050, P = 0.0097). In contrast, intracellular pgRNA increased by 6.90-fold (t = 8.941, P = 0.0123) and 3.18-fold (t = 7.432, P = 0.0176) after 500 microg/mL of oxymatrine treatment for 2 d and 5 d, respectively. CONCLUSION: Oxymatrine may inhibit the replication of HBV by interfering with the process of packaging pgRNA into the nucleocapsid, or inhibiting the activity of the viral DNA polymerase.