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BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).
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Ado-Trastuzumab Emtansina/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivados , Inmunoconjugados/uso terapéutico , Trastuzumab/uso terapéutico , Ado-Trastuzumab Emtansina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Femenino , Humanos , Inmunoconjugados/efectos adversos , Estimación de Kaplan-Meier , Enfermedades Pulmonares Intersticiales/inducido químicamente , Persona de Mediana Edad , Neumonía/inducido químicamente , Supervivencia sin Progresión , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efectos adversosRESUMEN
OBJECTIVE: Probiotic Lactococcus lactis is known to confer health benefits to humans. Here, we aimed to investigate the role of L. lactis in colorectal cancer (CRC). DESIGN: L. lactis abundance was evaluated in patients with CRC (n=489) and healthy individuals (n=536). L. lactis was isolated from healthy human stools with verification by whole genome sequencing. The effect of L. lactis on CRC tumourigenesis was assessed in transgenic Apc Min/+ mice and carcinogen-induced CRC mice. Faecal microbiota was profiled by metagenomic sequencing. Candidate proteins were characterised by nano liquid chromatography-mass spectrometry. Biological function of L. lactis conditioned medium (HkyuLL 10-CM) and functional protein was studied in human CRC cells, patient-derived organoids and xenograft mice. RESULTS: Faecal L. lactis was depleted in patients with CRC. A new L. lactis strain was isolated from human stools and nomenclated as HkyuLL 10. HkyuLL 10 supplementation suppressed CRC tumourigenesis in Apc Min/+ mice, and this tumour-suppressing effect was confirmed in mice with carcinogen-induced CRC. Microbiota profiling revealed probiotic enrichment including Lactobacillus johnsonii in HkyuLL 10-treated mice. HkyuLL 10-CM significantly abrogated the growth of human CRC cells and patient-derived organoids. Such protective effect was attributed to HkyuLL 10-secreted proteins, and we identified that α-mannosidase was the functional protein. The antitumourigenic effect of α-mannosidase was demonstrated in human CRC cells and organoids, and its supplementation significantly reduced tumour growth in xenograft mice. CONCLUSION: HkyuLL 10 suppresses CRC tumourigenesis in mice through restoring gut microbiota and secreting functional protein α-mannosidase. HkyuLL 10 administration may serve as a prophylactic measure against CRC.
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Carcinogénesis , Neoplasias Colorrectales , Heces , Microbioma Gastrointestinal , Lactococcus lactis , Probióticos , alfa-Manosidasa , Animales , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/prevención & control , Microbioma Gastrointestinal/fisiología , Humanos , Ratones , Probióticos/uso terapéutico , Heces/microbiología , alfa-Manosidasa/metabolismo , Ratones Transgénicos , Femenino , MasculinoRESUMEN
OBJECTIVE: Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear. DESIGN: We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry. RESULTS: Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ+ and Granzyme B+ CD8+ T cells while enriching Arg-1+ myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8+ T cells and reduced Arg-1+ MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8+ T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8+ T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8+ T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8+ T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models. CONCLUSION: SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8+ T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.
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OBJECTIVE: Hepatitis B surface antigen (HBsAg) loss is the optimal outcome for patients with chronic hepatitis B (CHB) but this rarely occurs with currently approved therapies. We aimed to develop and validate a prognostic model for HBsAg loss on treatment using longitudinal data from a large, prospectively followed, nationwide cohort. DESIGN: CHB patients receiving nucleos(t)ide analogues as antiviral treatment were enrolled from 50 centres in China. Quantitative HBsAg (qHBsAg) testing was prospectively performed biannually per protocol. Longitudinal discriminant analysis algorithm was used to estimate the incidence of HBsAg loss, by integrating clinical data of each patient collected during follow-up. RESULTS: In total, 6792 CHB patients who had initiated antiviral treatment 41.3 (IQR 7.6-107.6) months before enrolment and had median qHBsAg 2.9 (IQR 2.3-3.3) log10IU/mL at entry were analysed. With a median follow-up of 65.6 (IQR 51.5-84.7) months, the 5-year cumulative incidence of HBsAg loss was 2.4%. A prediction model integrating all qHBsAg values of each patient during follow-up, designated GOLDEN model, was developed and validated. The AUCs of GOLDEN model were 0.981 (95% CI 0.974 to 0.987) and 0.979 (95% CI 0.974 to 0.983) in the training and external validation sets, respectively, and were significantly better than those of a single qHBsAg measurement. GOLDEN model identified 8.5%-10.4% of patients with a high probability of HBsAg loss (5-year cumulative incidence: 17.0%-29.1%) and was able to exclude 89.6%-91.5% of patients whose incidence of HBsAg loss is 0. Moreover, the GOLDEN model consistently showed excellent performance among various subgroups. CONCLUSION: The novel GOLDEN model, based on longitudinal qHBsAg data, accurately predicts HBsAg clearance, provides reliable estimates of functional hepatitis B virus (HBV) cure and may have the potential to stratify different subsets of patients for novel anti-HBV therapies.
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BACKGROUND: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. FINDINGS: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. INTERPRETATION: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. FUNDING: Daiichi Sankyo and AstraZeneca.
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Neoplasias de la Mama , Humanos , Femenino , Ado-Trastuzumab Emtansina/uso terapéutico , Neoplasias de la Mama/patología , Receptor ErbB-2 , Trastuzumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Secretory myeloid-derived growth factor (MYDGF) exerts beneficial effects on organ repair, probably via a plasma membrane receptor; however, the identity of the expected receptor has remained elusive. In a recent study, MYDGF was reported as an agonist of the sphingosine-1-phosphate receptor 2 (S1PR2), an A-class G protein-coupled receptor that mediates the functions of the signaling lipid, sphingosine-1-phosphate (S1P). In the present study, we conducted living cell-based functional assays to test whether S1PR2 is a receptor for MYDGF. In the NanoLuc Binary Technology (NanoBiT)-based ß-arrestin recruitment assay and the cAMP-response element (CRE)-controlled NanoLuc reporter assay, S1P could efficiently activate human S1PR2 overexpressed in human embryonic kidney (HEK) 293T cells; however, recombinant human MYDGF, overexpressed either from Escherichia coli or HEK293 cells, had no detectable effect. Thus, the results demonstrated that human MYDGF is not a ligand of human S1PR2. Considering the high conservation of MYDGF and S1PR2 in evolution, MYDGF is also probably not a ligand of S1PR2 in other vertebrates.
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Factor Estimulante de Colonias de Granulocitos , Receptores de Lisoesfingolípidos , Esfingosina/análogos & derivados , Animales , Humanos , Receptores de Esfingosina-1-Fosfato , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Ligandos , Células HEK293 , Lisofosfolípidos/farmacologíaRESUMEN
N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of MgâB compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.
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Corrosion protection of metal has become an important and urgent topic, which requires the development of an inexpensive, environmentally friendly, and highly efficient corrosion inhibitor. Herein, a sweet potato leaf extract (SPL) was obtained by a simple water-based extraction method and then as a green corrosion inhibitor for 6N01 Al alloy in the seawater was well investigated by the weight loss method and various electrochemical tests. Fourier transform infrared (FT-IR) and ultraviolet-visible (UV-vis) spectroscopies were carried out to investigate the compositions of SPL. The findings from the potentiodynamic polarization (PDP) curves suggest that SPL functions as a typical mixed-type corrosion inhibitor. Notably, the maximum corrosion inhibition efficiency reaches 94.6% following a 36 h immersion period at 25 °C. The adsorption behavior of SPL on the Al alloy surface belongs to the Langmuir adsorption isotherm. The Gibbs free energy value illustrates that the adsorption of SPL contains both physisorption and chemisorption. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) indicate that SPL is firmly attached to the Al alloy surface by making a protective layer, which can effectively inhibit the corrosion of the Al alloy in the seawater. Furthermore, quantum chemical calculations were applied to validate the chemical adsorption and elucidate the relationship between the electronic structure of the active components in SPL and their effectiveness in corrosion inhibition.
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Accurate diagnostic and serology assays are required for the continued management of the COVID-19 pandemic yet spike protein mutations and intellectual property concerns with antigens and antibodies used in various test kits render comparability assessments difficult. As the use of common, well-characterized reagents can help address this lack of standardization, the National Research Council Canada has produced two protein reference materials (RMs) for use in SARS-CoV-2 serology assays: biotinylated human angiotensin-converting enzyme 2 RM, ACE2-1, and SARS-CoV-2 Omicron BA.4/5 spike protein RM, OMIC-1. Reference values were assigned through a combination of amino acid analysis via isotope dilution liquid chromatography tandem mass spectrometry following acid hydrolysis, and ultraviolet-visible (UV-Vis) spectrophotometry at 280 nm. Vial-to-vial homogeneity was established using UV-Vis measurements, and protein oligomeric status, monitored by size exclusion liquid chromatography (LC-SEC), was used to evaluate transportation, storage, and freeze-thaw stabilities. The molar protein concentration in ACE2-1 was 25.3 ± 1.7 µmol L-1 (k = 2, 95% CI) and consisted almost exclusively (98%) of monomeric ACE2, while OMIC-1 contained 5.4 ± 0.5 µmol L-1 (k = 2) spike protein in a mostly (82%) trimeric form. Glycoprotein molar mass determination by LC-SEC with multi-angle light scattering detection facilitated calculation of corresponding mass concentrations. To confirm protein functionality, the binding of OMIC-1 to immobilized ACE2-1 was investigated with surface plasmon resonance and the resulting dissociation constant, KD ~ 4.4 nM, was consistent with literature values.
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Enzima Convertidora de Angiotensina 2 , Estándares de Referencia , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Biotinilación , COVID-19/virología , Prueba Serológica para COVID-19/métodosRESUMEN
It is of great importance to understand the intrinsic relationship between phototautomerization and photoelectric properties for the exploration of novel organic materials. Here, in order to chemically control the protonation process, the aminated isoxazole derivative (2,2'-(isoxazolo[5,4-d]isoxazole-3,6-diyl)dibenzenaminium, DP-DA-DPIxz) with -Nâ as the proton acceptor was designed to achieve the twisted intramolecular charge transfer (TICT) state which was triggered by an excited-state intramolecular proton transfer (ESIPT) process. This kind of protonation enhanced the intramolecular hydrogen bonding, conjugative effect, and steric hindrance effects, ensuring a barrierless spontaneous TICT process. Through the intramolecular proton transfer, the configuration torsion and conjugation dissociation of the DP-DA-DPIxz molecule was favored, which led to efficient charge separation and remarkable variations in light-emitting properties. We hope the present investigation will provide a new approach to design novel optoelectronic organic materials and shine light on the understanding of the charge transfer and separation process in molecular science.
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Pseudomonas aeruginosa (P. aeruginosa) biofilm formation is a crucial cause of enhanced antibiotic resistance. Quorum sensing (QS) is involved in regulating biofilm formation; QS inhibitors block the QS signaling pathway as a new strategy to address bacterial resistance. This study investigated the potential and mechanism of L-HSL (N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide) as a QS inhibitor for P. aeruginosa. The results showed that L-HSL effectively inhibited the biofilm formation and dispersed the pre-formed biofilm of P. aeruginosa. The production of extracellular polysaccharides and the motility ability of P. aeruginosa were suppressed by L-HSL. C. elegans infection experiment showed that L-HSL was non-toxic and provided protection to C. elegans against P. aeruginosa infection. Transcriptomic analysis revealed that L-HSL downregulated genes related to QS pathways and biofilm formation. L-HSL exhibits a promising potential as a therapeutic drug for P. aeruginosa infection. KEY POINTS: ⢠Chemical synthesis of N-(3-cyclic butyrolactone)-4-trifluorophenylacetamide, named L-HSL. ⢠L-HSL does not generate survival pressure on the growth of P. aeruginosa and can inhibit the QS system. ⢠KEGG enrichment analysis found that after L-HSL treatment, QS-related genes were downregulated.
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4-Butirolactona , Biopelículas , Caenorhabditis elegans , Pseudomonas aeruginosa , Percepción de Quorum , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Pseudomonas aeruginosa/genética , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Percepción de Quorum/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Animales , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacología , 4-Butirolactona/metabolismo , Antibacterianos/farmacología , Perfilación de la Expresión Génica , Homoserina/análogos & derivados , Homoserina/metabolismo , Homoserina/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacosRESUMEN
OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and harm of deep brain stimulation for motor symptoms, with psychiatric and behavioural comorbidities, either individually or in combination, in adults and adolescents with Tourette's syndrome compared to placebo, sham intervention, or the best available behavioural and pharmacological treatment.
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Estimulación Encefálica Profunda , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome de Tourette , Síndrome de Tourette/terapia , Estimulación Encefálica Profunda/métodos , Humanos , Adulto , AdolescenteRESUMEN
BACKGROUND: This study was conducted to investigate the correlation between KCNQ1 rs2237895 A/C gene polymorphism and blood indexes and prognosis in non-small cell lung cancer (NSCLC). METHODS: A total of 260 NSCLC patients were selected and classified into stage I - II (n = 109) and stage III - IV (n = 151) according to by American Joint Committee on Cancer Staging Manual. A control group was established with another 92 healthy subjects. The genotype distribution of rs2237895 was analyzed in all subjects. ï£2 analysis or Fisher's test was employed to analyze the association between genotype and allele distribution frequencies with carcinoembryonic antigen (CEA), squamous cell carcinoma antigen, and cytokeratin fragment 19 (CyfrA 21-1). Overall survival was compared by genotype stratification using Kaplan-Meier analysis. Univariate and multivariate Cox risk regression analyses were used to determine the prognostic value of allele C in NSCLC. RESULTS: AC/CC genotypes in NSCLC patients were associated with gender, hypertension, smoking, clinical TNM stage, lymph node metastasis, and distant metastasis. C allele was associated with higher risk levels of serum tumor markers. Patients with allele C (AC + CC) had lower overall survival than patients with genotype AA. Finally, clinical stage, lymph node metastasis, higher CEA and CyfrA 21-1 serum levels, and rs2237895 A/C gene poly-morphism were independent prognostic factors of NSCLC. CONCLUSIONS: rs2237895 A/C polymorphism of the KCNQ1 gene can be a prognostic predictor in patients with surgically treated NSCLC.
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Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas , Queratina-19 , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Antígeno Carcinoembrionario , Neoplasias Pulmonares/patología , Metástasis Linfática , Canal de Potasio KCNQ1/genética , Pronóstico , Biomarcadores de Tumor/genética , Polimorfismo GenéticoRESUMEN
PURPOSE OF REVIEW: This review aims to provide a theoretical basis and insights for quercetin's clinical application in the prevention and treatment of osteoporosis (OP), analyzing its roles in bone formation promotion, bone resorption inhibition, anti-inflammation, antioxidant effects, and potential mechanisms. RECENT FINDINGS: OP, a prevalent bone disorder, is marked by reduced bone mineral density and impaired bone architecture, elevating the risk of fractures in patients. The primary approach to OP management is pharmacotherapy, with quercetin, a phytochemical compound, emerging as a focus of recent interest. This natural flavonoid exerts regulatory effects on bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts and promotes bone health and metabolic equilibrium via anti-inflammatory and antioxidative pathways. Although quercetin has demonstrated significant potential in regulating bone metabolism, there is a need for further high-quality clinical studies focused on medicinal quercetin.
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Antioxidantes , Osteoporosis , Quercetina , Quercetina/uso terapéutico , Quercetina/farmacología , Humanos , Osteoporosis/tratamiento farmacológico , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Antiinflamatorios/uso terapéutico , Resorción Ósea/tratamiento farmacológico , Osteoblastos/efectos de los fármacos , Células Madre Mesenquimatosas , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/farmacologíaRESUMEN
INTRODUCTION: There is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs. METHODS: Hepatic mechanical injury was established in Sprague-Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, apoptosis, MAMs formation, mitochondrial function and signaling pathways. RESULTS: Significant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 µmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin's inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation. CONCLUSION: Melatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Melatonina , Animales , Ratas , Calcio/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Melatonina/farmacología , Melatonina/uso terapéutico , Ratas Sprague-DawleyRESUMEN
PURPOSE: The purpose of this study was to compare the preoperative anxiety, aqueous humor monocyte chemoattractant protein-1 (MCP-1) concentration, intraoperative pain, and degree of cooperation of the first eye implantable collamer lens (ICL) surgery with the second eye surgery, of the 1-day interval group with the 1-week interval group, and to investigate the possible causes of these differences, as well as to determine the appropriate interval between bilateral eye ICL surgeries. METHOD: The study was a prospective observational study. A total of 120 patients who underwent bilateral ICL surgery at the Department of Ophthalmology, West China Fourth Hospital, Sichuan University, from July to September 2023, were enrolled. The patients were divided into a 1-day interval group and a 1-week interval group. The ICL surgery was performed on both eyes according to the schedule. Anxiety levels, aqueous humor MCP1, cooperativeness, surgical time, pain and satisfaction, and patients' estimations of the time spent in the operation were recorded for each eye. The patients were instructed to recall the intraoperative pain of the first eye surgery after the operation of the second eye. Statistical analyses (two independent samples t-test,two paired samples t-test, the rank-sum test, the chi-square test, non-parametric test with multiple independent samples) were performed to compare the differences between each score in both eyes and two groups. Furthermore, we examined the relationship between pain levels and the reproductive history of the patients. RESULTS: In the 1-day interval group, male/female is 22/52, average age is 25.24±5.00. In the 1-week interval group, male/female is 17/29, average age is 25.39±5.57. There was no statistically significant difference between the two groups. In both groups, patients were less nervous, had significantly more pain, had less surgical satisfaction, had a longer estimated operative time, and had elevated preoperative MCP1 during the second eye operation. In the second eye surgery, the patient's cooperation worsened, but it did not lead to an increase in surgical time. A significant proportion of patients, particularly in the 1-week interval group, recalled experiencing reduced pain during the first eye surgery. The 1-week interval group had a higher difference in all indicators between the bilateral surgeries. In the second eye surgery, patients in the 1-week interval group experienced more severe pain, less cooperation, longer estimated operation duration, and a greater MCP1 than those in the 1-day interval group. CONCLUSION: Patients undergoing second eye ICL surgery had decreased nervousness, increased pain, decreased cooperation, and satisfaction, and increased MCP1 compared to the first eye surgery. It is recommended that an interval of about one week should be avoided between bilateral surgeries when developing a surgical schedule to improve patients' cooperation, satisfaction, and comfort.
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Lentes Intraoculares , Miopía , Lentes Intraoculares Fáquicas , Femenino , Humanos , Masculino , Ojo , Implantación de Lentes Intraoculares , Miopía/cirugía , Dolor/cirugía , Estudios Prospectivos , Adulto Joven , AdultoRESUMEN
Objective: This study analyzes the relationship between ADHD, family relationships, lifestyle, and food intolerance. Methods: This study consisted of 240 children who received treatment at the researchers' hospital from January 2022 to November 2022. Out of these, 120 children belonged to the ADHD group, while the remaining 120 children were part of the healthy control group. The researchers compared these two groups of children on factors such as family relationships, lifestyle, and food intolerance. Results: The general data of the two groups were not statistically significant but comparable (P > .05); family relationships, lifestyle, and food intolerance all affected children with ADHD (P < .01). Conclusion: In the investigation of children with ADHD compared to healthy children, the influence of family relationships, lifestyle, and food intolerance can all cause ADHD.
RESUMEN
Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.
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Antifúngicos , Candidiasis , Humanos , Antifúngicos/farmacología , Candidiasis/microbiología , Candida auris , Candida , Anfotericina B/farmacología , Farmacorresistencia Fúngica/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND & AIMS: Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures. METHODS: A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development. RESULTS: We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p = 0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001). CONCLUSIONS: aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance. IMPACT AND IMPLICATIONS: In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , alfa-Fetoproteínas , Estudios de Cohortes , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/genética , Cirrosis Hepática/complicaciones , Hepatitis B Crónica/complicacionesRESUMEN
BACKGROUND & AIMS: The enteric mycobiota is a major component of the human gut microbiota, but its role in colorectal cancer (CRC) remains largely elusive. We conducted a meta-analysis to uncover the contribution of the fungal mycobiota to CRC. METHODS: We retrieved fecal metagenomic data sets from 7 previous publications and established an additional in-house cohort, totaling 1329 metagenomes (454 with CRC, 350 with adenoma, and 525 healthy individuals). Mycobiota composition and microbial interactions were analyzed. Candidate CRC-enriched fungal species (Aspergillus rambellii) was functionally validated in vitro and in vivo. RESULTS: Multicohort analysis revealed that the enteric mycobiota was altered in CRC. We identified fungi that were associated with patients with CRC or adenoma from multiple cohorts. Signature CRC-associated fungi included 6 enriched (A rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsici) and 1 depleted species (A kawachii). Co-occurrent interactions among CRC-enriched fungi became stronger in CRC compared with adenoma and healthy individuals. Moreover, we reported the transkingdom interactions between enteric fungi and bacteria in CRC progression, of which A rambellii was closely associated with CRC-enriched bacteria Fusobacterium nucleatum. A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. We further identified that combined fungal and bacterial biomarkers were more accurate than panels with pure bacterial species to discriminate patients with CRC from healthy individuals (the area under the curve relative change increased by 1.44%-10.60%). CONCLUSIONS: This study reveals enteric mycobiota signatures and pathogenic fungi in stages of colorectal tumorigenesis. Fecal fungi can be used, in addition to bacteria, for noninvasive diagnosis of patients with CRC.