Phyllanthus emblica Linn: A comprehensive review of botany, traditional uses, phytonutrients, health benefits, quality markers, and applications.

Phyllanthus emblica Linn is not only an edible fruit with high nutritional value, but also a medicinal plant with multiple bioactivities. It is widely used in clinical practice with functions of clearing heat, cooling blood, digesting food, strengthening stomach, promoting fluid production, and relieving cough. This review summarized a wide variety of phytonutrients, including nutritional components (mineral elements, amino acids, vitamins, polysaccharides, unsaturated free fatty acids) and functional components (phenolic acids (1-34), tannins (35-98), flavonoids (99-141), sterols (142-159), triterpenoids (160-175), lignans (176-183), alkaloids (184-197), alkanes (198-212), aromatic micromolecules (213-222), other compounds (223-239)). The isolated compounds and the various extracts of P. emblica Linn presented a diverse spectrum of biological activities such as anti-oxidant, anti-cancer, anti-inflammatory, anti-bacterial, hepatoprotective, hypoglycemic, anti-atherosclerosis, neuroprotective, enhancing immunity, anti-fatigue, anti-myocardial fibrosis. The quality markers of P. emblica Linn were predicted and analyzed based on traditional medicinal properties, traditional efficacy, plant genealogy and chemical component characteristics, biogenic pathway of chemical components, measurability of chemical components, transformation characteristics of polyphenolic components, homologous characteristics of medicine and food, compound compatibility environment, and clinical applications. This review also summarized and prospected applications of P. emblica Linn in beverages, preserved fruits, fermented foods, etc. However, the contents of mechanism, structure-activity relationship, quality control, toxicity, extraction, processing of P. emblica Linn are not clear, and are worth further studies in the future.

Prognostic value of aspartate aminotransferase/alanine aminotransferase ratio in hepatocellular carcinoma after hepatectomy.

BACKGROUND: The prognostic significance of the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio in hepatocellular carcinoma remains uncertain. The aim of the current study was to evaluate the association between the AST/ALT ratio and prognosis in patients with hepatocellular carcinoma after hepatectomy, and to explore the role of underlying liver diseases as mediators. METHODS: This retrospective study included patients with hepatocellular carcinoma who underwent hepatectomy between January 2014 and January 2018 at two Chinese hospitals. The maximally selected rank statistic and g-computation approach were used to quantify and visualize the association between the AST/ALT ratio and overall survival or recurrence-free survival. The role of mediators (chronic hepatitis B, hepatic steatosis and liver cirrhosis) was analysed. RESULTS: Among the 1519 patients (mean(s.d.) age at baseline, 50.5(11.3) years), 1309 (86.2%) were male. During a median follow-up of 46.0 months, 514 (33.8%) patients died and 358 (23.6%) patients experienced recurrence. The optimal cut-off value for the AST/ALT ratio was 1.4, and the AST/ALT ratio greater than or equal to 1.4 was independently associated with a 39.0% increased risk of death and a 30.0% increased risk of recurrence (overall survival: hazard ratio (HR), 1.39; 95% c.i. 1.15 to 1.68; recurrence-free survival: HR, 1.30; 95% c.i. 1.12 to 1.52) after adjusting for confounders. Chronic hepatitis B significantly mediated the association of the ratio of AST/ALT with both overall survival and recurrence-free survival (20.3% for overall survival; 20.1% for recurrence-free survival). CONCLUSION: The AST/ALT ratio greater than or equal to 1.4 was associated with shorter overall survival and recurrence-free survival in patients with hepatocellular carcinoma after hepatectomy, and chronic hepatitis B may play a role in their association.

The sources, properties, extraction, biosynthesis, pharmacology, and application of lycopene.

Lycopene is an important pigment with an alkene skeleton from Lycopersicon esculentum, which is also obtained from some red fruits and vegetables. Lycopene is used in the food field with rich functions and serves in the medical field with multiple clinical values because it has dual functions of both medicine and food. It was found that lycopene was mainly isolated by solvent extraction, ultrasonic-assisted extraction, supercritical fluid extraction, high-intensity pulsed electric field-assisted extraction, enzymatic-assisted extraction, and microwave-assisted extraction. Meanwhile, it was also obtained via 2 synthetic pathways: chemical synthesis and biosynthesis. Pharmacological studies revealed that lycopene has anti-oxidant, hypolipidemic, anti-cancer, immunity-enhancing, hepatoprotective, hypoglycemic, cardiovascular-protective, anti-inflammatory, neuroprotective, and osteoporosis-inhibiting effects. The application of lycopene mainly includes food processing, animal breeding, and medical cosmetology fields. It is hoped that this review will provide some useful information and guidance for future study and exploitation of lycopene.

Adjuvant immune checkpoint inhibitors associated with higher recurrence-free survival in postoperative hepatocellular carcinoma (PREVENT): a prospective, multicentric cohort study.

BACKGROUND: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. METHODS: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy between 13 March 2019 and 19 March 2022. This study was registered on ClinicalTrials.gov (NCT05221398). RESULTS: Of the 517 patients in final analysis, 432 (83.6%) received no adjuvant therapy, 53 (10.2%) received ICIs alone, and 32 (6.2%) received adjuvant ICIs and TKIs. During median follow-up of 34.0 months (IQR 27.8 to 41.6 months), RFS was significantly longer among patients who received either type of adjuvant therapy (25.2 months, 95%CI 16.4-34.0) than among those who received none (16.1 months, 95%CI 12.9-19.4), and this difference remained significant after propensity score matching (HR 0.52, 95%CI 0.35-0.76, P = 0.004). Overall survival was unaffected by either type of adjuvant therapy, while significant difference was observed between patients who received adjuvant therapy or not after propensity score matching (HR 0.31, 95%CI 0.17-0.59, P = 0.005). The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. CONCLUSIONS: ICIs alone or with TKIs may improve RFS of patients at high risk of HCC recurrence after curative resection.

Validation studies on migraine diagnostic tools for use in nonclinical settings: a systematic review / Estudos de validação de ferramentas de diagnóstico de enxaqueca (migrânea) para uso em ambientes não clínicos: uma revisão sistemática

Abstract Background Migraine underdiagnosis and undertreatment are so widespread, that hence is essential to diagnose migraine sufferers in nonclinical settings. A systematic review of validation studies on migraine diagnostic tools applicable to nonclinical settings can help researchers and practitioners in tool selection decisions. Objective To systematically review and critically assess published validation studies on migraine diagnostic tools for use in nonclinical settings, as well as to describe their diagnostic performance. Methods A multidisciplinary workgroup followed transparent and systematic procedures to collaborate on this work. PubMed, Medline, and Web of Science were searched for studies up to January 17, 2022. The QUADAS-2 was employed to assess methodological quality, and the quality thresholds adopted by the Global Burden Disease study were used to tail signaling questions. Results From 7,214 articles identified, a total of 27 studies examining 19 tools were eligible for inclusion. There has been no high-quality evidence to support any tool for use of migraine diagnosis in nonclinical settings. The diagnostic accuracy of the ID-migraine, structured headache and HARDSHIP questionnaires have been supported by moderate-quality evidence, with sensitivity and specificity above 70%. Of them, the HARDSHIP questionnaire has been the most extensively validated. The remaining 16 tools have provided poor-quality evidence for migraine diagnosis in nonclinical populations. Conclusions Up till now, the HARDSHIP questionnaire is the optimal choice for diagnosing migraine in nonclinical settings, with satisfactory diagnostic accuracy supported by moderate methodological quality. This work reveals the crucial next step, which is further high-quality validation studies in diverse nonclinical population groups.

Resumo Antecedentes O sub-diagnóstico e o subtratamento da enxaqueca são tão difundidos que, portanto, é essencial para diagnosticar os portadores de enxaqueca em ambientes não-clínicos. Uma revisão sistemática dos estudos de validação das ferramentas de diagnóstico da enxaqueca aplicáveis a ambientes não-clínicos pode ajudar os pesquisadores e profissionais nas decisões de seleção de ferramentas. Objetivo Revisar sistematicamente e avaliar criticamente estudos de validação publicados sobre ferramentas de diagnóstico da enxaqueca para uso em ambientes não-clínicos, bem como descrever seu desempenho diagnóstico. Métodos Um grupo de trabalho multidisciplinar seguiu procedimentos transparentes e sistemáticos para colaborar neste trabalho. PubMed, Medline e Web of Science foram pesquisados por estudos até 17 de janeiro de 2022. O QUADAS-2 foi empregado para avaliar a qualidade metodológica, e os limites de qualidade adotados pelo estudo da Global Burden Disease foram usados para responder a questões de sinalização. Resultados De 7.214 artigos identificados, um total de 27 estudos examinando 19 ferramentas foram elegíveis para inclusão. Não houve evidência de alta qualidade para apoiar qualquer ferramenta para o uso de diagnóstico de enxaqueca em ambientes não clínicos. A precisão diagnóstica do ID-Migraine, questionário de dor de cabeça estruturada e questionário HARDSHIP foram apoiados por evidências de qualidade moderada, com sensibilidade e especificidade acima de 70%. Deles, o questionário HARDSHIP foi o mais amplamente validado. As 16 ferramentas restantes forneceram provas de má qualidade para o diagnóstico de enxaqueca em populações não-clínicas. Conclusões Até agora, o questionário HARDSHIP é a escolha ideal para o diagnóstico da enxaqueca em ambientes não-clínicos, com precisão diagnóstica satisfatória apoiada por uma qualidade metodológica moderada. Este trabalho revela o próximo passo crucial, que é a realização de mais estudos de validação de alta qualidade em diversos grupos populacionais não-clínicos.

Hippophae rhamnoides L.: A Comprehensive Review on the Botany, Traditional Uses, Phytonutrients, Health Benefits, Quality Markers, and Applications.

Hippophae rhamnoides L. (sea buckthorn), consumed as a food and health supplement worldwide, has rich nutritional and medicinal properties. Different parts of H. rhamnoides L. were used in traditional Chinese medicines for relieving cough, aiding digestion, invigorating blood circulation, and alleviating pain since ancient times. Phytochemical studies revealed a wide variety of phytonutrients, including nutritional components (proteins, minerals, vitamins, etc.) and functional components like flavonoids (1-99), lignans (100-143), volatile oils (144-207), tannins (208-230), terpenoids (231-260), steroids (261-270), organic acids (271-297), and alkaloids (298-305). The pharmacological studies revealed that some crude extracts or compounds of H. rhamnoides L. demonstrated various health benefits, such as anti-inflammatory, antioxidant, hepatoprotective, anticardiovascular disease, anticancer, hypoglycemic, hypolipidemic, neuroprotective, antibacterial activities, and their effective doses and experimental models were summarized and analyzed in this paper. The quality markers (Q-markers) of H. rhamnoides L. were predicted and analyzed based on protobotanical phylogeny, traditional medicinal properties, expanded efficacy, pharmacokinetics and metabolism, and component testability. The applications of H. rhamnoides L. in juice, wine, oil, ferment, and yogurt were also summarized and future prospects were examined in this review. However, the mechanism and structure-activity relationship of some active compounds are not clear, and quality control and potential toxicity are worth further study in the future.

Triple targeting host-guest drug delivery system based on lactose-modified azocalix[4]arene for tumor ablation.

Host-guest drug delivery systems (HGDDSs) have been studied in an effort to modify the characteristics of therapeutic agents through noncovalent interactions, reduce toxic side effects and improve therapeutic effects. However, it is still an important task to continuously improve the targeting ability of HGDDSs, which is conducive to the development of precision medicine. Herein, we utilize the lactose-modified azocalix[4]arene (LacAC4A) as a triple targeting drug carrier customized for antitumor purposes. LacAC4A integrates three targeting features, passive targeting through the enhancing permeability and retention effect, active targeting by the interactions of lactose and the asialoglycoprotein receptors on the surface of tumor cells, and stimuli-responsive targeting via the reduction of the azo group under a hypoxia microenvironment. After loading doxorubicin (DOX) in LacAC4A, the supramolecular nanoformulation DOX@LacAC4A clearly showed the effective suppression of tumor growth through in vivo experiments. LacAC4A can achieve effective targeting, rapid release, and improve drug bioavailability. This design principle will provide a new material for drug delivery systems.

Prognosis after hepatic resection of patients with hepatocellular carcinoma related to non-alcoholic fatty liver disease: meta-analysis.

BACKGROUND: Whether the safety and efficacy of hepatic resection differ between patients whose hepatocellular carcinoma (HCC) is related to non-alcoholic fatty liver disease (NAFLD) or has other aetiologies is unknown. A systematic review was performed to explore potential differences between such conditions. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies that reported hazard ratios (HRs) for overall and recurrence-free survival between patients with NAFLD-related HCC or HCC of other aetiologies. RESULTS: The meta-analysis involved 17 retrospective studies involving 2470 patients (21.5 per cent) with NAFLD-related HCC and 9007 (78.5 per cent) with HCC of other aetiologies. Patients with NAFLD-related HCC were older and had higher body mass index (BMI), but were less likely to have cirrhosis (50.4 per cent versus 64.0 per cent, P < 0.001). The two groups suffered similar rates of perioperative complications and mortality. Patients with NAFLD-related HCC had slightly higher overall survival (HR 0.87, 95 per cent c.i. 0.75 to 1.02) and recurrence-free survival (HR 0.93, 95 per cent c.i. 0.84 to 1.02) than those with HCC of other aetiologies. In the various subgroup analyses, the only significant finding was that Asian patients with NAFLD-related HCC had significantly better overall survival (HR 0.82, 95 per cent c.i. 0.71 to 0.95) and recurrence-free survival (HR 0.88, 95 per cent c.i. 0.79 to 0.98) than Asian patients with HCC of other aetiologies. CONCLUSION: The available evidence suggests that patients with NAFLD-related HCC have similar perioperative complications and mortality, but potentially longer overall and recurrence-free survival, compared with those with HCC of other aetiologies. Tailored surveillance strategies should be developed for patients with NAFLD without cirrhosis.

Inhibition of Pro-Survival Autophagy Induced by Rare-Earth Nanocomposites for Promoting Photothermal Therapy of Visualized Tumors.

Manipulation of autophagic processes has emerged as a promising strategy for synergizing nanoagent-mediated photothermal therapy (PTT). Most of the current studies focus on improving PTT efficacy by inhibiting pro-survival autophagy induced by the heat generated from the photothermal process. However, autophagy induced by the nanoagents is usually ignored, which may weaken the effect of autophagy-mediated efficacy improvement in PTT if induced autophagy is pro-death. Therefore, this work aims at developing a nanoagent that is able to induce heat-synergetic pro-survival autophagy to optimize the efficacy of PTT. An approach is developed to coat carbon layer, polyethylenimine (PEI), and folic acid (FA) on NaYF4 :Er,Yb,Nd@NaNdF4 (DCNPs@C@PEI@FA, DCPF) nanoparticles successively, giving access to the nanoagent to induce pro-survival autophagy. The synthetic imaging-guided photothermal nanoagent displays outstanding targeting ability and biocompatibility based on the surface modification of PEI and FA. By using an autophagy inhibitor chloroquine, a conspicuously synergistic effect on DCPF-mediated PTT in vitro and in vivo tumor models (HeLa) is achieved. A promising strategy is presented here to enhance the efficacy of imaging-guided PTT by modulating the autophagy induced by the nanoagent.

Sintilimab in Patients with Previously Treated Metastatic Neuroendocrine Neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) are a group of diseases that show high heterogeneity but have limited treatment options. This phase I study evaluated the safety and efficacy of sintilimab, anti-PD-1 monoclonal antibody, in treating advanced NENs. METHODS: We prospectively enrolled patients pathologically diagnosed with NENs after standard treatment failure. Neuroendocrine neoplasms were classified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine cancers (NECs). Every patient received sintilimab, and response was assessed every 9 weeks. RESULTS: Twenty-four patients with a median age of 57.0 years were enrolled from November 2016 to 2017. The median Ki-67 index was 60%. Five patients had NET, 1 had NET G3, 17 had NEC, and 1 had mixed adenocarcinoma-neuroendocrine carcinoma. The most common primary tumor sites were the pancreas and gastrointestinal tract in 7 and 10 patients, respectively. In phase Ia trial, 2 patients received sintilimab 1 mg/kg every 2 weeks, one received 3 mg/kg every 2 weeks, and 21 patients enrolled in the phase Ib trial received 200 mg every 3 weeks. The objective response rate was 20.8% in all enrolled patients and 27.8% in NEC patients. The median progression-free survival was 2.2 and 2.1 months in patients with NET and NEC, respectively. The median OS was not applicable (NA) and 10.8 months (95% CI, 4.3, NA) with NET and NEC, respectively. The duration of response (DOR) was not reached, with a median follow-up time of 20.7 months. Treatment-related adverse events (TRAE) occurred in 17 (70.8%) patients. The most frequent TRAE was thyroid dysfunction (41.7%), and a grade 3 pulmonary infection occurred in 1 patient. The programmed cell death 1-ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) rate was 18.8% (3 out of 16) and the expression of PD-L1 did not correlate with response. CONCLUSION: Sintilimab was well-tolerated and showed encouraging response in NECs. CLINICALTRIALS.GOV IDENTIFIER: NCT02937116.

Synthesis, Renal Clearance, and Photothermal Therapy Based on the Self-Assembly of a Nanomedicine Consisting of Quaterrylene Bisimide and Glycocluster Conjugates.

Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation → self-regulating the aggregate size through the renal filtration thresholds → reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.

Laboratory investigation of pollutant emissions and PM2.5 toxicity of underground coal fires.

Widespread underground coal fires (UCFs) release large amounts of pollutants, thus leading to air pollution and health impacts. However, this topic has not been widely investigated, especially regarding the potential health hazards. We quantified the pollutant emissions and analyzed the physicochemical properties of UCF PM2.5 in a laboratory study of coal smoldering under a simulated UCF background. The emission factors of CO2, CO, and PM2.5 were 2489 ± 35, 122 ± 9, 12.90 ± 1.79 g/kg, respectively. UCF PM2.5 are carbonaceous particles with varied morphology and complex composition, including heavy metals, silica and polycyclic aromatic hydrocarbons (PAHs). The main PAHs components were those with 2-4 rings. Benzoapyrene (BaP) and indeno[1,2, 3-cd]pyrene (IcdP) were important contributors to the carcinogenesis of these PAHs. We quantitatively evaluate the toxicity of inhaled UCF PM2.5 using a nasal inhalation exposure system. The target organs of UCF PM2.5 are lungs, liver, and kidneys. UCF PM2.5 presented an enriched chemical composition and induced inflammation and oxidative stress, which together mediated multiple organ injury. Long-term PM2.5 metabolism is the main cause of persistent toxicity, which might lead to long-term chronic diseases. Therefore, local authorities should recognize the importance and effects of UCF emissions, especially PM2.5, to establish control and mitigation measures.

Lower risk of hepatocellular carcinoma with tenofovir than entecavir treatment in subsets of chronic hepatitis B patients: an updated meta-analysis.

BACKGROUND AND AIM: Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model. RESULTS: Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies). CONCLUSION: Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.

Structurally diverse biflavonoids from the fruits of Citrus medica L. var. sarcodactylis Swingle and their hypolipidemic and immunosuppressive activities.

The fruit of Citrus medica L. var. sarcodactylis Swingle is not only used as a traditional medicinal plant, but also served as a delicious food. Six new (3'→7″)-biflavonoids (1-6), and twelve known biflavonoid derivatives (7-18) were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. Their structures were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, and IR spectral data coupled with the data described in the literature. Compounds (1-18) were evaluated for their hypolipidemic activities with Orlistat as the positive control, and assayed for their immunosuppressive activities with Dexamethasone as the positive control, respectively. Among them, compounds (1-3) exhibited moderate inhibition of pancreatic lipase activity by inhibiting 68.56 ± 1.40%, 56.18 ± 1.57%, 53.51 ± 1.59% of pancreatic lipase activities at the concentration of 100 µM, respectively. Compounds (4-6) and 8 showed potent immunosuppressive activities with the IC50 values from 16.83 ± 1.32 to 50.90 ± 1.79 µM. The plausible biogenetic pathway and preliminary structure activity relationship of the selected compounds were scientifically summarized and discussed in this study.

Nucleus-targeting imaging and enhanced cytotoxicity based on naphthalimide derivatives.

Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.

The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis.

Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)-target genes, and meanwhile suppresses type I interferons (IFNs) and IFN-stimulated genes (ISGs) to promote ERα-positive breast cancer cell growth and tumorigenesis. KDM5C-interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.

Machine learning models to predict red blood cell transfusion in patients undergoing mitral valve surgery.

BACKGROUND: Red blood cell (RBC) transfusion therapy has been widely used in surgery, and has yielded excellent treatment outcomes. However, in some instances, the demand for RBC transfusion is assessed by doctors based on their experience. In this study, we use machine learning models to predict the need for RBC transfusion during mitral valve surgery to guide the surgeon's assessment of the patient's need for intraoperative blood transfusion. METHODS: We retrospectively reviewed 698 cases of isolated mitral valve surgery with and without combined tricuspid valve operation. Seventy percent of the database was used as the training set and the remainder as the testing set for 13 machine learning algorithms to build a model to predict the need for intraoperative RBC transfusion. According to the characteristic value of model mining, we analyzed the risk-related factors to determine the main effects of variables influencing the outcome. RESULTS: A total of 166 patients of the cases considered had undergone intraoperative RBC transfusion (24.52%). Of the 13 machine learning algorithms, CatBoost delivered the best performance, with an AUC of 0.888 (95% CI: 0.845-0.909) in testing set. Further analysis using the CatBoost model revealed that hematocrit (<37.81%), age (>64 y), body weight (<59.92 kg), body mass index (BMI) (<22.56 kg/m2), hemoglobin (<122.6 g/L), type of surgery (median thoracotomy surgery), height (<160.61 cm), platelet (>194.12×109/L), RBC (<4.08×1012/L), and gender (female) were the main risk-related factors for RBC transfusion. A total of 204 patients were tested, 177 of whom were predicted accurately (86.8%). CONCLUSIONS: Machine learning models can be used to accurately predict the outcomes of RBC transfusion, and should be used to guide surgeons in clinical practice.

Isolation and characterization of neolignan derivatives with hepatoprotective and neuroprotective activities from the fruits of Citrus medica L. var. Sarcodactylis Swingle.

The fruit of Citrus medica L. var. sarcodactylis Swingle is a functional food with rich nutrients and medicinal values because of its content of bioactive compounds. A bioactivity-guided chemical investigation from the fruits of C. medica L. var. sarcodactylis Swingle afforded three new benzodioxane neolignans (1-3), three new phenanthrofuran neolignan glycosides (4-6), two new biphenyl-ketone neolignans (7-8), two new 1',7'-bilignan neolignans (9-10), as well as fourteen known neolignan derivatives (11-24), which were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. These neolignan derivatives were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, IR spectral data and compared with the data described in the literature. Among them, compounds 1-3 and 12-13 exhibited moderate hepatoprotective activities to improve the survival rates of HepG2 cells from 46.26 ± 1.90% (APAP, 10 mM) to 67.23 ± 4.25%, 62.87 ± 4.43%, 60.06 ± 6.34%, 56.75 ± 2.30%, 58.35 ± 6.14%, respectively. Additionally, compounds 7-8 and 21-22 displayed moderate neuroprotective activities to raise the survival rates of PC12 cells from 55.30 ± 2.25% to 66.94 ± 3.37%, 70.98 ± 5.05%, 64.64 ± 1.93%, and 62.81 ± 4.11% at 10 µM, respectively. The plausible biogenetic pathway and preliminary structure-activity relationship of the selected compounds were scientifically summarized and discussed in this paper.

Post-radiation circulating tumor DNA as a prognostic factor in locally advanced esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant and deadly tumor. Radiation therapy is one of the primary treatments for locally advanced ESCC. However, the biomarkers for prognosis of definitive radiation remain undefined. Peripheral blood circulating tumor (ct)DNA provides information of tumor genetic alterations and has been confirmed as a potential non-invasive biomarker for several types of cancer. The present study investigated the clinical implications of ctDNA detection in patients with ESCC and receiving definitive radiation therapy. Patients with locally advanced ESCC were retrospectively recruited. Plasma samples were collected before, during and following radiation therapy. Next-generation sequencing was performed to identify somatic mutations in 180 genes. A total of 69 baseline and post-radiation plasma samples were collected from 25 patients. A total of 59 non-silent single nucleotide variants were present in 33 genes. All pre-radiation and 58.3% (14/24) of post-radiation samples had at least one mutation. Patients with lymph node metastases (LNM) exhibited a higher number of pre-radiation mutations compared with those without LNM. The variables, progression-free survival (PFS) and overall survival (OS) of the patients with one baseline mutation were not significantly different compared with that in patients with more than one baseline mutation. Patients with initial ctDNA-positive post-radiation samples exhibited significantly reduced PFS (P=0.047) and OS (P=0.005) compared with that in patients with ctDNA-negative samples. The post-radiation plasma ctDNA status was an independent prognostic factor from univariate and multivariate analyses. Dynamic monitoring of ctDNA during follow-up was examined. The results indicated that ctDNA was a predictive and prognostic marker in patients with ESCC and receiving definitive radiation therapy, which may guide subsequent treatment.

Structurally diverse coumarin-homoisoflavonoid derivatives with hepatoprotective activities from the fruits of Cucumis bisexualis.

Cucumis bisexualis is a favorite wild fruit with high nutritional and medicinal values because of its bioactive constituents. Four previously undescribed coumarin-homoisoflavonoid derivatives (1-4), together with seven known coumarin and homoisoflavonoid derivatives (5-11) were isolated from the fruits of C. bisexualis for the first time. All the compounds were elucidated by their extensive and comprehensive spectroscopic data and references. Compounds (1-11) were evaluated for their hepatoprotective activities in HepG2 cells by the acetaminophen (APAP)-induced damage model at 10.0 µM with bicyclol as the positive control. Among them, compounds 1, 3, 5, and 6 showed moderately hepatoprotective activities to improve the HepG2 cell survival rates from 51.68 ± 2.49% (APAP, 10 mM) to 71.55 ± 4.08%, 65.95 ± 4.39%, 60.77 ± 3.44%, 62.94 ± 2.30%, respectively.