Discovery of novel natural cardiomyocyte protectants from a toxigenic fungus Stachybotrys chartarum.

Stachybatranones A-F (1a/1b and 2-6) and three known analogues, namely methylatranones A and B (7 and 8) and atranone B (9), were isolated and identified from a toxigenic fungus Stachybotrys chartarum. Their structures and absolute configurations were elucidated via the extensive spectroscopic data, comparison of the experimental electronic circular dichroism (ECD) data, and single-crystal X-ray diffraction analyses. Structurally, compounds 2-6 belonged to a rare class of C-alkylated dolabellanes, featuring a unique five-membered hemiketal ring and a γ-butyrolactone moiety both fused to an 11-membered carbocyclic system, while compound 1 (1a/1b) represented the first example of a 5-11-6-fused atranone possessing a 2,3-butanediol moiety. The cardiomyocyte protective activity assay revealed that compounds 1-9 ameliorated cold ischemic injury at 24 h post cold ischemia (CI), with compounds 1 and 4 acting in a dose-dependent manner. Moreover, compound 1 prevented cold ischemia induced dephosphorylation of PI3K and AKT acting in a dose-dependent manner. In this study, a new class of natural products were found to protect cardiomyocytes against cold ischemic injury, providing a potential option for the development of novel cardioprotectants in heart transplant medicine.

Prevalence of and risk factors for surgical site infections after pancreaticoduodenectomy: a systematic review and meta-analysis.

Background: Surgical site infections (SSIs) are one of the most common complications after pancreaticoduodenectomy (PD); however, the global prevalence and risk factors for SSIs after PD remain unknown. Objectives: To investigate the prevalence of and risk factors for SSIs after PD. Methods: The PubMed, Embase, Cochrane Library, Web of Science, and Science Direct databases were systematically searched from inception to 1 December 2022. Observational studies reporting adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of risk factors for SSIs in patients undergoing PD were included. Two independent reviewers in teams performed data extraction, risk of bias assessment, and level of evidence analysis. The pooled results were estimated using a random-effects model. The I 2 statistic and Q χ 2 statistic were used to assess heterogeneity. Funnel plots, Egger's regression test, and the trim-and-fill method were used to determine publication bias. The primary outcomes were identifying risk factors for SSIs after PD. The secondary outcomes were the pooled prevalence rates of SSIs. Results: A total of 98 704 patients from 45 studies were included, and 80% of the studies were considered high quality. The estimated pooled prevalence of SSIs was 23% (0.19-0.27, I 2=97%). The prevalence of SSIs was found to be higher in Japan and lower in USA. Preoperative biliary stenting, higher body mass index (BMI), longer operation time, postoperative pancreatic fistula, soft pancreatic texture, perioperative blood transfusion, and cardiac disease were identified as significant risk factors for the development of SSIs after PD. Additionally, broad-spectrum antibiotics were a significant protective factor against SSIs. Subgroup analysis and sensitivity analysis showed that the results were robust. Conclusion and relevance: The prevalence of SSIs remains high and varies widely among regions. It is necessary to take effective preventive measures and carry out more prospective studies to further verify these results.

Pregnancy outcomes following natural conception and assisted reproduction treatment in women who received COVID-19 vaccination prior to conception: a population-based cohort study in China.

Introduction: The coronavirus disease-2019 (COVID-19) pandemic has swept across the world and continues to exert serious adverse effects on vulnerable populations, including pregnant women and neonates. The vaccines available at present were designed to prevent infection from COVID-19 strains and control viral spread. Although the incidence of pregnancy cycle outcomes are not likely to increase patients vaccinated prior to pregnancy compared with unvaccinated patients based on our knowledge of vaccination safety, there is no specific evidence to support this hypothesis. Therefore, the current study aimed to investigate the association between maternal vaccination prior to conception and pregnancy outcomes. Methods: We retrospectively analyzed 2,614 women who received prenatal care and delivered in the Obstetrical Department of The First Affiliated Hospital of Anhui Medical University between February 2022 and November 2022. Of the 1,380 eligible pregnant women, 899 women who had received preconception vaccination were assigned to a vaccine group and 481 women who were not vaccinated were control group. Of the enrolled patients, 291 women received fertility treatment (141 vaccinated women, 150 unvaccinated women). The primary outcomes were pregnancy complications (hypothyroidism, gestational diabetes mellitus, pregnancy-induced hypertension, polyhydramnios, oligohydramnios, premature rupture of membranes and postpartum hemorrhage), obstetric outcomes (preterm birth rate, cesarean section rate) and neonatal outcomes (birth-weight, body length, low-birth-weight rate, rate of congenital defects, neonatal mortality and admission to the neonatal intensive care unit). Results: There was no significant difference in the incidence of complications during pregnancy and delivery when compared between the vaccine group and control group in either univariate- or multivariate-models. The type of vaccine was not associated with the odds of adverse pregnancy outcome. Among the women with infertility treatment, the vaccinated group and the unvaccinated group had similar pregnancy outcomes. Conclusion: Women who received COVID-19 vaccination prior to conception had similar maternal and neonatal outcomes as women who were unvaccinated. Our findings indicate that COVID-19 vaccinations can be safely administered prior to pregnancy in women who are planning pregnancy or assisted reproductive treatment. During new waves of COVID-19 infection, women who are planning pregnancy should be vaccinated as soon as possible to avoid subsequent infections.

Effects of Magnesium Imbalance on Root Growth and Nutrient Absorption in Different Genotypes of Vegetable Crops.

Magnesium (Mg) plays a crucial role in crop growth, but how Mg supply level affects root growth and nutrient absorption in vegetable crops with different genotypes has not been sufficiently investigated. In this study, the responses of tomato (Solanum lycopersicum L.) and cucumber (Cucumis sativus L.) crops to different levels of Mg supply were explored. Four levels of Mg treatment (i.e., 0.2, 1.0, 2.0, 3.0 mmol/L) were applied under hydroponic conditions, denoted as Mg0.2, Mg1, Mg2, and Mg3, respectively. The results showed that with increasing Mg levels, the plant biomass, root growth, and nutrient accumulation in both vegetable crops all increased until reaching their maximum values under the Mg2 treatment and then decreased. The total biomass per tomato plant of Mg2 treatment was 30.9%, 14.0%, and 14.0% higher than that of Mg0.2, Mg1, and Mg3 treatments, respectively, and greater increases were observed in cucumber plant biomass (by 54.3%, 17.4%, and 19.9%, respectively). Compared with the Mg0.2 treatment, the potassium (K) and calcium (Ca) contents in various plant parts of both crops remarkably decreased under the Mg3 treatment. This change was accompanied by prominently increased Mg contents in various plant parts and para-hydroxybenzoic acid and oxalic acid contents in root exudates. Irrespective of Mg level, plant biomass, root growth, nutrient accumulation, and root exudation of organic acids were all higher in tomato plants than in cucumber plants. Our findings indicate that excessive Mg supply promotes the roots to exude phenolic acids and hinders the plants from absorbing K and Ca in different genotypes of vegetable crops despite no effect on Mg absorption. A nutritional deficiency of Mg stimulates root exudation of organic acids and increases the types of exuded organic acids, which could facilitate plant adaption to Mg stress. In terms of root growth and nutrient absorption, tomato plants outperform cucumber plants under low and medium Mg levels, but the latter crop is more tolerant to Mg excess.

Carbendazim exposure inhibits mouse oocytes meiotic maturation in vitro by destroying spindle assembly.

Successful fertilization and early embryonic development heavily depend on the quality of the oocytes. Carbendazim (CBZ), a broad-spectrum fungicide, is widely available in the environment and has adverse effects on organisms. The present study focused on exploring the potential reproductive toxicity of CBZ exposure by investigating its effects on the maturation of mouse oocytes. The results demonstrated that although no disruptions were observed in the G2/M stage transition for meiosis resumption, CBZ did hinder the polar body extrusion (PBE) occurring during oocyte maturation. Cell cycle distribution analysis revealed that CBZ exposure interfered with the meiotic process, causing oocytes to be arrested at the metaphase I (MI) stage. The subsequent investigation highlighted that CBZ exposure impeded the spindle assembly and chromosomal alignment, which was linked to a decline in the level of p-MAPK. Additionally, CBZ exposure adversely affected the kinetochore-microtubule (K-MT) attachment, leading to the persistent activation of the spindle-assembly checkpoint (SAC). The study further noticed a substantial rise in the acetylation of α-tubulin and a reduction in spindle microtubule stability in CBZ-treated oocytes. In addition, the distribution pattern of estrogen receptor alpha (ERα) was altered in oocytes treated with CBZ, with abnormal aggregation on the spindles. CBZ exposure also resulted in altered histone modifications. A notable finding from this research was that the meiotic maturation of some oocytes remained unaffected even after CBZ treatment. However, during the ensuing metaphase II (MII) stage, these oocytes displayed anomalies in their spindle morphology and chromosome arrangement and diminished ability to bind to the sperm. The observations made in this study underscore the potential for CBZ to disrupt the meiotic maturation of oocytes, leading to a decline in the overall quality of oocytes.

New alkaloids from Polygonatum zanlanscianense Pamp.

Sixteen alkaloid compounds were isolated from the dried rhizomes of P. zanlanscianense, including a pair of new enantiomers (R/S)-7'-ethoxy-trans-p-couma-royltyramine (1a/1b) and 14 known compounds (2-14) isolated from this plant for the first time. The structures of new compounds were identified by IR, NMR and MS spectroscopic analysis, and their absolute configurations were determined by comparison of the experimental and calculated ECD data.

High-resolution 3D demonstration of regional heterogeneity in the glymphatic system.

Accumulating evidence indicates that the glymphatic system has a critical role in maintaining brain homeostasis. However, the detailed anatomy of the glymphatic pathway is not well understood, mostly due to a lack of high spatial resolution 3D visualization. In this study, a fluorescence micro-optical sectioning tomography (fMOST) was used to characterize the glymphatic architecture in the mouse brain. At 30 and 120 min after intracisternal infusion with fluorescent dextran (Dex-3), lectin was injected to stain the cerebral vasculature. Using fMOST, a high-resolution 3D dataset of the brain-wide distribution of Dex-3 was acquired. Combined with fluorescence microscopy and microplate array, the heterogeneous glymphatic flow and the preferential irrigated regions were identified. These cerebral regions containing large-caliber penetrating arteries and/or adjacent to the subarachnoid space had more robust CSF flow compared to other regions. Moreover, the major glymphatic vessels for CSF influx and fluid efflux in the entire brain were shown in 3D. This study demonstrates the regional heterogeneity in the glymphatic system and provides an anatomical resource for further investigation of the glymphatic function.

Cost-effectiveness analysis of donafenib versus lenvatinib for first-line treatment of unresectable or metastatic hepatocellular carcinoma.

BACKGROUND: Donafenib and lenvatinib are approved by China National Medical Products Administration and recommended as first-line treatment of Metastatic Hepatocellular Carcinoma (HCC). The aim of this study was to assess the cost-effectiveness of donafenib compared with lenvatinib for first-line treatment of advanced HCC in China. METHODS: A partitioned survival model consisting with three health states was developed to simulate lifetime development of advanced HCC from China healthcare payer's perspective. The lifetime costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER) were calculated. The efficacy data were obtained from ZGDH3 and REFLECT trials. The cost and health outcomes were discounted at a rate of 5%. Sensitivity and scenario analyses were carried out to explore the variation of model results. RESULTS: Compared with lenvatinib, donafenib incurred more costs of $1500.86 and had 0.139 QALYs gained, resulting in an ICER of $10,790.18/QALY. The probability of being cost-effective was 84.9% at a willingness-to-pay threshold of gross domestic product per capita in 2020 in China ($31,499.2/QALY). Sensitive and scenario analysis results were in line with base-case analysis. CONCLUSIONS: Donafenib appears to be a cost-effective strategy compared with lenvatinib for the first-line treatment of patients with unresectable or metastatic HCC in China.

Cost-effectiveness analysis of sintilimab + chemotherapy versus camrelizumab + chemotherapy for the treatment of first-line locally advanced or metastatic nonsquamous NSCLC in China.

BACKGROUND AND OBJECTIVE: Sintilimab is a selective PD-1 inhibitor with efficacy in advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) patients. This study evaluated the cost-effectiveness of sintilimab + chemotherapy versus camrelizumab + chemotherapy as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in Chinese patients. In addition, this study aimed to reveal the impact of the reference treatment choice on the incremental cost-effectiveness ratio (ICER) results. METHODS: A partitioned survival model (PSM) with three health states was constructed in a 3-week cycle with a lifetime horizon from the Chinese healthcare system perspective. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from Orient-11. Sintilimab + chemotherapy was chosen as the reference treatments in scenarios 1 and 2, while the camrelizumab + chemotherapy was chosen as the reference treatments in scenario 3. The utility values of different health states were derived from the patient-level European Organization for Research and Treatment Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) scores by mapping to the EQ-5D-5L, and QALYs were calculated as the health outcomes. One-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were performed to explore model uncertainty. RESULTS: Compared to camrelizumab + chemotherapy, sintilimab + chemotherapy was associated with higher effectiveness (incremental QALYs ranged from 0.13-0.62) and lower total costs (incremental costs ranged from $1,099-$5,201), resulting in an ICER ranging from $6,440-$8,454/QALY. CONCLUSIONS: Sintilimab + chemotherapy is a cost-effective option compared with camrelizumab + chemotherapy as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in China.

A new abietane-type diterpenoid and a new long-chain alkenone from fungus Daldinia sp. TJ403-LS1.

A new abietane-type diterpenoid, dalterpenoid A (1), a new long-chain alkenone derivative, (3E,5E,10E)-8-hydroxytrideca-3,5,10,12-tetraen-2-one (2), together with six known compounds (3-8), namely epi-guaidiol A (3), xylaranol A (4), daldinone C (5), trans-3,4-dihydroxy-3,4-dihydro-anofinic acid (6), (R)-6-hydroxymellein (7), helicascolide A (8), were obtained from fungus Daldinia sp. TJ403-LS1, which was originally isolated from roots of the medicinally valuable plant Anoectochilus roxburghii. The structures of compounds 1 and 2 were established based on widespread spectroscopic methods, mainly including 1D & 2D NMR and HRESIMS analyses, and the absolute configuration of 1 was further confirmed by electronic circular dichroism (ECD) calculation. All new compounds were tested for the in vitro cytotoxicity against five human cancer cell lines.

Bipolaquinones A-J, Immunosuppressive Meroterpenoids from a Soil-Derived Bipolaris zeicola.

Ten new meroterpenoids, bipolaquinones A-J (1-10), and one known congener, isocochlioquinone F (11), were isolated and identified from the fermented rice cultures of a soil-derived fungus, Bipolaris zeicola. The planar structures of 1-10 were elucidated based on extensive spectroscopic analyses (including HRESIMS and 1D and 2D NMR data), and their absolute configurations were determined by single-crystal X-ray diffraction analyses, comparison of experimental electronic circular dichroism (ECD) data, ECD calculations, and hydrolysis reaction. The immunosuppressive activity assay revealed that compounds 2, 3, and 7-10 showed significant inhibitory activity against concanavalin A (ConA)-induced T lymphocyte proliferation with IC50 values ranging from 4.1 to 9.4 µM, which furnished potential lead molecules for the design and development of new immunosuppressants for treating autoimmune-associated diseases.

New secondary metabolites with immunosuppressive and BChE inhibitory activities from an endophytic fungus Daldinia sp. TJ403-LS1.

Five new acetylenic phenol derivatives (1-4 and 7), one new benzofuran derivative (8), one new naphthol derivative (9), and two known analogues (5 and 6), were isolated and identified from an endophytic fungus Daldinia sp. TJ403-LS1 that was isolated from the medicinally valuable plant Anoectochilus roxburghii. Their structures were elucidated by means of extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. In addition, compound 1 exhibited remarkable immunosuppressive activity against LPS and anti-CD3/anti-CD28 mAbs activated murine splenocytes proliferation with the same IC50 values of 0.06 µM and BChE inhibitory activity with an IC50 value of 6.93 ± 0.71 µM, and compounds 6, 8 and 9 showed excellent BChE inhibitory activity with IC50 values of 16.00 ± 0.30, 23.33 ± 0.55, and 15.53 ± 0.39 µM, respectively (positive drug neostigmine, IC50 = 49.60 ± 6.10 µM), highlighting the promising potentials to be designed and developed as immunosuppressive and BChE inhibitory agents.

Identification of anti-Parkinson's Disease Lead Compounds from Aspergillus ochraceus Targeting Adenosin Receptors A2A.

Two novel alkaloids compounds together with fifteen know metabolites were identified from Aspergillus ochraceus. The stereochemistry features of the new molecules were determined via HRESIMS, NMR, ECD, and XRD analyses. Amongst these, compounds two compounds exhibited potential efficacy as anti-Parkinson's disease with the EC50 values of 2.30 and 2.45 µM, respectively. ADMET prediction showed that these compounds owned favorable drug-like characteristics and safe toxicity scores towards CNS drugs. Virtual screening analyses manifested that the compounds exhibited not only robust and reliable interactions to adenosine receptors A2A , but also higher binding selectivity to A2A receptors than to A1 and A3 receptors. Molecular dynamics simulation demonstrated the reliability of molecular docking results and the stability of the complexes obtained with the novel compounds and A2A receptors in natural environments. It is the first time that anti-PD lead compounds have been identified from Aspergillus ochraceus and targeting adenosine A2A receptors.

Will the Markov model and partitioned survival model lead to different results? A review of recent economic evidence of cancer treatments.

Introduction: Balancing the high cost of treatment brought about by new therapies has become a problem that needs to be considered. Cost-effectiveness analysis (CEA) is a commonly used method that provides information on the potential value of new cancer treatments. The Markov and partitioned survival (PS) models are commonly used. Whether the results differ between the models in empirical research and the methodological differences remain unclear.Areas covered: A review was conducted to identify Canadian Agency for Drugs and Technologies in Health (CADTH) reports and papers published during the past 5 years that reported full economic evaluations of cancer treatments and used both models. In the included studies, most results except one obtained using the two models did not significantly differ.Expert opinion: Not enough evidence could support that there existed relevant bias in empirical studies about the PS model, and more methodological research and application of empirical research should be performed. We recommended that when individual data are available and the model structure is not complicated, the PS model is more appropriate. Both the PS and Markov models are recommended to assess model structure uncertainty.

Bioactive Polyketide-Terpenoid Hybrids from a Soil-Derived Fungus Bipolaris zeicola.

Nine novel polyketide-terpenoid hybrids (1-9), characterized by a 1-alkylated-3,5-dihydroxyphenyl derivative coupled with a modified farnesyl pyrophosphate (FPP) unit, were isolated from a soil-derived fungus Bipolaris zeicola. Their structures were determined by comprehensive spectroscopic data, single-crystal X-ray diffraction analyses, and electronic circular dichroism calculations. Structurally, compounds 1, 2, 5, and 6 possess a rare thiazole moiety; compounds 3 and 4 are the first examples of meroterpenoids featuring an undescribed 6/6/6/6/5 pentacyclic system and bearing a tetrahydrofuran ring fused to a polyketide and a sesquiterpenoid subunit; compounds 7 and 8 possess a rare 2H-1,4-thiazin-3(4H)-one moiety; and compound 9 represents the first example of meroterpenoid having an unusual thiazol-2(3H)-one moiety. The bioactivity assays revealed that compounds 1, 2, 5, 6, and 9 exhibited a significant immunosuppressive effect against concanavalin A (ConA)-induced T lymphocyte proliferation with IC50 values ranging from 5.6 to 8.8 µM, and compounds 1, 2, and 4 exhibited moderate cytotoxic activities with IC50 values ranging from 18.4 to 29.4 µM.

One-step electrosynthesis of visible light responsive double-walled alloy titanium dioxide nanotube arrays for use in photocatalytic degradation of dibutyl phthalate.

Using Ti-6Al-4V (TC4) alloy as a substrate, double-walled alloy titanium dioxide nanotube arrays (DW-ATNTAs) with a special porous inner wall and visible light response are synthesized in situ by an improved anodization method. During the anodization, the V element in the TC4 alloy converts into V2O5 which dominates the visible light response of DW-ATNTAs. After 3 h of irradiation with visible light, there is a nearly 97% reduction of dibutyl phthalate (DBP) by DW-ATNTAs in which the degradation kinetic constant is 50 and 7 times higher than that of titanium dioxide nanotube arrays (TNTAs) and alloy titanium dioxide layers (A-TiO2(plate)), respectively. The richly porous inner wall structure of DW-ATNTAs can provide sufficient vacancies for adsorption and active sites for photocatalytic reaction. Furthermore, the differences in the morphology of the inner and outer walls are attributed to the thicker carbon and fluorine-rich oxide layer (C, F-rich oxide layer) resulting from a longer time that the inner wall spends in contact with the electrolyte during the anodization process. This special porous inner wall structure was formed due to the anti-corrosion properties of the alloy caused by appropriate amounts of V and Al as well as the removal of C and F elements during the calcination process.

Analgesic and antipruritic effects of oxymatrine sustained-release microgel cream in a mouse model of inflammatory itch and pain.

BACKGROUND: Allergic contact dermatitis (ACD) is a highly prevalent inflammatory and immune skin disease accompanied with persistent pruritus and pain. Oxymatrine (OMT) exhibits antipruritic and anti-inflammatory effects in squaric acid dibutyl ester (SADBE) induced ACD mice model, but the need for frequent administration stipulated by short half-life and low bioavailability limits clinical application. OBJECTIVE: To evaluate the analgesic and antipruritic effects of OMT gel (OG), OMT sustained release microgel powder (OMP) and OMT sustained release microgel cream (OMC) in SADBE induced ACD mice, with subsequent study of the mechanism and side effects (irritation) of optimal dosage form. METHOD: On day 11, the thickness of the right cheek skin of mice was measured and mice spontaneous behaviors were recorded for 1.5 h. In the OMC experiment, hematoxylin-eosin and toluidine blue staining were performed on the cheek skin, and the irritation of OMC was tested on the back skin of rabbits. Blood analyzer was used to measure the counts of inflammatory cells in peripheral blood. The mRNA expressions of IL-1ß, TNF-α, CXCR3, CXCL10, IL-6, IL-10, IL-17A and IL-31 in cheek skin, TRPA1 and TRPV1 channels in trigeminal ganglion (TG), IFN-γ in spleen and IL-17A in thymus were measured by RT-qPCR. RESULTS: OMC, OMP and OG significantly decreased wipes and scratching bouts, alleviated skin inflammation. OMC required less frequent administration and is easier to apply, while its antipruritic effect was stronger than the analgesic effect. OMC rescued the deficits in epidermal keratinization and inflammatory cell infiltration, decreased the leukocyte count in peripheral blood, had no irritation to the broken rabbit's skin. Furthermore, OMC significantly down-regulated the mRNA expression of IL-1ß, TNF-α, CXCR3, CXCL10, IL-6, IL-10, IL-17A and IL-31 in cheek skin, TRPA1 and TRPV1 channels in TG, IFN-γ in thymus and IL-17A in spleen. CONCLUSION: We have demonstrated that OMC exhibits advanced analgesic, antipruritic and anti-inflammatory effects when compared with OG and OMP in ACD mice by regulating inflammation, chemokines, immune mediators and inhibiting the mRNA expression of TRPA1 and TRPV1. OMC has no irritation to the intact and damaged skin of rabbits.

Clinical characteristics associated with primary cardiac angiosarcoma outcomes: a surveillance, epidemiology and end result analysis.

BACKGROUND: Primary cardiac angiosarcoma (PCAS) is a rare type of tumour. Furthermore, descriptions of the demographic features and prognostic factors of PCAS patients have been poorly reported. METHODS: A population cohort study was conducted using retrospectively extracted data from the SEER (Surveillance, Epidemiology and End Results) database for patients with histological diagnoses of PCAS; the extracted information included demographic, treatment and outcome data. RESULTS: A total of 168 cases of PCAS from 1973 to 2013 were included. The mean age at diagnosis was 44.4 ± 15.5 years. PCAS was more prevalent in men than in women. The majority of PCAS patients were white (67.3%), while the incidence of PCAS in black individuals was relatively infrequent (19.0%). In addition, 87 cases were classified as distant stage, 44 as regional stage, and 33 as localized stage. The median disease-specific survival (DSS) was 7.22 months, and the 1-, 2- and 5-year DSS rate for PCAS patients was 34.7%, 14.3% and 10.2%, respectively. Further multivariate analyses showed that an age at (greater than or equal to) 45 years (HR 2.165), no radiotherapy (HR 1.629), tumour size > 5 cm (HR 3.182), and the summary stage was associated with worse PCAS-related survival. Cancer-directed surgery and radiotherapy significantly improved the DSS for patients with PCAS (P < 0.05). The C-index of the nomograms was 0.706 (95% CI 0.654-0.758), and the calibration curves showed good agreement between the nomogram prediction and actual observation. CONCLUSION: PCAS is a rare cancer that is prone to have poor prognoses. To understand PCAS more thoroughly, more cases with adequate information are needed.

Inhibition of suilysin activity and inflammation by myricetin attenuates Streptococcus suis virulence.

Streptococcus suis (S. suis) is a gram-positive, zoonotic pathogenic bacterium that poses a serious threat to the pig industry and human health. This globally distributed pathogen can cause multiple diseases and fatal infections in both humans and animals. Suilysin (SLY) is an important extracellular secreted toxin regarded as an essential S. suis capsular type 2 (SS2) virulence factor and plays a key role in the infection and cytotoxicity of SS2. In addition, an excessive inflammatory response is also a serious hazard caused by SS2 infection. In this study, we demonstrated that the natural compound myricetin can inhibit the hemolytic activity of SLY and is effective at reducing the production of the inflammatory cytokines TNF-α and IL-1ß and reducing inflammation by downregulating the activation of P38. In addition, myricetin could effectively treat SS2 infections in vitro and in vivo. These findings may aid in the development of promising therapeutic candidates for treating SS2 infections.

Quercetin impairs Streptococcus pneumoniae biofilm formation by inhibiting sortase A activity.

Biofilm formation mediated by sortase A (srtA) is important for bacterial colonisation and resistance to antibiotics. Thus, the inhibitor of SrtA may represent a promising agent for bacterial infection. The structure of Streptococcus pneumoniae D39 srtA has been characterised by crystallisation. Site-directed mutagenesis was used for the determination of the key residues for the activity of S. pneumoniae D39 srtA. An effective srtA inhibitor, quercetin, and its mechanism was further identified using srtA activity inhibition assay and molecular modelling. In this study, the crystal structure of S. pneumoniae D39 srtA has been solved and shown to contain a unique domain B. Additionally, its transpeptidase activity was evaluated in vitro. Based on the structure, we identified Cys207 as the catalytic residue, with His141 and Arg215 serving as binding sites for the peptide substrate. We found that quercetin can specifically compete with the natural substrate, leading to a significant decrease in the catalytic activity of this enzyme. In cells co-cultured with this small molecule inhibitor, NanA cannot anchor to the cell wall effectively, and biofilm formation and biomass decrease significantly. Interestingly, when we supplemented cultures with sialic acid, a crucial signal for pneumococcal coloniation and the invasion of the host in the co-culture system, biofilm loss did not occur. This result indicates that quercetin inhibits biofilm formation by affecting sialic acid production. In conclusion, the inhibition of pneumococcal srtA by the small molecule quercetin offers a novel strategy for pneumococcal preventative therapy.