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1.
N Engl J Med ; 386(12): 1143-1154, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35320644

RESUMO

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.).


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Doenças Pulmonares Intersticiais/induzido quimicamente , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos
2.
Gut ; 73(9): 1478-1488, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38599786

RESUMO

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.


Assuntos
Carcinogênese , Neoplasias Colorretais , Fezes , Microbioma Gastrointestinal , Lactococcus lactis , Probióticos , alfa-Manosidase , Animais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Humanos , Camundongos , Probióticos/uso terapêutico , Fezes/microbiologia , alfa-Manosidase/metabolismo , Camundongos Transgênicos , Feminino , Masculino
3.
Gut ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38744443

RESUMO

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.

4.
Gut ; 73(10): 1725-1736, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-38902029

RESUMO

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.


Assuntos
Antivirais , Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Humanos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/sangue , Antivirais/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Prospectivos , China/epidemiologia , Estudos Longitudinais , Vírus da Hepatite B/imunologia , Prognóstico
5.
Lancet ; 401(10371): 105-117, 2023 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-36495879

RESUMO

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.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias da Mama/patologia , Receptor ErbB-2 , Trastuzumab/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-39181427

RESUMO

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk prediction models established in patients with chronic hepatitis B receiving a nucleos(t)ide analogue (NA) rarely include viral factors because of mediocre predictability of traditional viral markers. Here, we investigate the role of serum hepatitis B virus (HBV) RNA, a novel biomarker, in predicting HCC risk in NA-treated patients. METHODS: A total of 1374 NA-treated patients were enrolled from 2 prospective chronic hepatitis B cohorts. Serum HBV RNA was detected at baseline, year 1, 2 and 3 of treatment. Cox proportional-hazard model was used to investigate the association of HBV RNA kinetics with HCC risk. RESULTS: After a median follow-up of 5.4 years, 76 patients developed HCC. HBV RNA declines at year 1 (adjusted hazard ratio, 0.70, P = .009) and 2 (adjusted hazard ratio, 0.71; P = .016) were independently associated with HCC risk. Patients with less HBV RNA decline at year 1 (≤0.4 log10 copies/mL) or 2 (≤0.6 log10 copies/mL) had 2.22- and 2.09-folds higher HCC risk, respectively, than those with more declines. When incorporating these early on-treatment HBV RNA declines into existing HCC risk scores, including PAGE-B (age, sex, and platelets), modified PAGE-B (mPAGE-B) (age, sex, platelets, and albumin), and aMAP (age, sex, platelets, and albumin-bilirubin score) score, they could enhance their predictive performance (ie, C-index 0.814 vs 0.78 [model (PAGE-B + year-1 HBV RNA decline) vs PAGE-B score based on baseline parameters]). CONCLUSIONS: Serum HBV RNA declines at year 1 and 2 were significantly associated with on-treatment HCC risk. Incorporating early on-treatment HBV RNA declines into HCC risk prediction models can be useful tools to guide appropriate surveillance strategies in NA-treated patients.

7.
Biochem Biophys Res Commun ; 706: 149766, 2024 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-38484568

RESUMO

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.


Assuntos
Fator Estimulador de Colônias de Granulócitos , Receptores de Lisoesfingolipídeo , Esfingosina/análogos & derivados , Animais , Humanos , Receptores de Esfingosina-1-Fosfato , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Ligantes , Células HEK293 , Lisofosfolipídeos/farmacologia
8.
Small ; 20(2): e2305670, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37658521

RESUMO

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 Mg─B 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.

9.
Artigo em Inglês | MEDLINE | ID: mdl-39315881

RESUMO

BACKGROUND: To investigate susceptibility to contezolid, a novel oxazolidinone, multicentre surveillance was conducted involving 2449 strains of Staphylococcus and Enterococcus collected from 65 hospitals across China. METHODS: The MICs of contezolid, linezolid and other clinically significant antibiotics were determined by the broth microdilution method. Consistency with the broth microdilution method for contezolid was assessed using agar dilution method, as well as disc diffusion and ETEST for linezolid, respectively. WGS was conducted on all 20 linezolid-resistant and 30 randomly non-resistant strains to analyse linezolid resistance genes (optrA, poxtA, cfr) and 23S rRNA mutation sites. RESULTS: All strains exhibited WT susceptibility to contezolid, while resistance proportions to daptomycin, vancomycin, teicoplanin, tigecycline and eravacycline ranged from 0% to 5.2% in Staphylococcus, and from 0% to 7.8% in Enterococcus. Linezolid resistance was higher in Enterococcus faecalis (4.4%) compared with Enterococcus faecium (0.2%). Contezolid showed a lower MIC50 (0.5 mg/L) than linezolid (2 mg/L) for methicillin-resistant Staphylococcus. Against Enterococcus, contezolid demonstrated a cumulative MIC percentage of 70% for VRE and 39.1% for E. faecalis (at MIC = 1 mg/L), whereas linezolid showed 0% and 1.1%, respectively. Among the 20 linezolid-resistant Enterococcus strains, all carried the optrA gene without 23S rRNA mutations. For contezolid, MICs were 4 mg/L for 19 strains and 2 mg/L for 1 strain. The ETEST, agar dilution and disc diffusion methods showed essential and categorical agreements of >90% for linezolid, with no major errors or very major errors. CONCLUSIONS: Contezolid demonstrated significant in vitro antibacterial activity against methicillin-resistant Staphylococcus, VRE and linezolid-resistant E. faecalis.

10.
Langmuir ; 40(18): 9543-9555, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38651309

RESUMO

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.

11.
Anal Bioanal Chem ; 416(22): 4861-4872, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38942955

RESUMO

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.


Assuntos
Enzima de Conversão de Angiotensina 2 , Padrões de Referência , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Biotinilação , COVID-19/virologia , Teste Sorológico para COVID-19/métodos
12.
J Phys Chem A ; 128(18): 3571-3578, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38656182

RESUMO

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 -N═ 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.

13.
Appl Microbiol Biotechnol ; 108(1): 418, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39012538

RESUMO

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.


Assuntos
4-Butirolactona , Biofilmes , Caenorhabditis elegans , Pseudomonas aeruginosa , Percepção de Quorum , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/genética , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Percepção de Quorum/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Animais , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/metabolismo , Antibacterianos/farmacologia , Perfilação da Expressão Gênica , Homosserina/análogos & derivados , Homosserina/metabolismo , Homosserina/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos
14.
Cochrane Database Syst Rev ; 8: CD015924, 2024 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-39136257

RESUMO

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.


Assuntos
Estimulação Encefálica Profunda , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Tourette , Síndrome de Tourette/terapia , Estimulação Encefálica Profunda/métodos , Humanos , Adulto , Adolescente
15.
Clin Lab ; 70(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38345992

RESUMO

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. 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.


Assuntos
Antígenos de Neoplasias , Carcinoma Pulmonar de Células não Pequenas , Queratina-19 , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno Carcinoembrionário , Neoplasias Pulmonares/patologia , Metástase Linfática , Canal de Potássio KCNQ1/genética , Prognóstico , Biomarcadores Tumorais/genética , Polimorfismo Genético
16.
Curr Osteoporos Rep ; 22(3): 353-365, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38652430

RESUMO

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.


Assuntos
Antioxidantes , Osteoporose , Quercetina , Quercetina/uso terapêutico , Quercetina/farmacologia , Humanos , Osteoporose/tratamento farmacológico , Antioxidantes/uso terapêutico , Antioxidantes/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Células-Tronco Mesenquimais , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia
17.
Cell Mol Biol Lett ; 29(1): 22, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308199

RESUMO

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.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Melatonina , Animais , Ratos , Cálcio/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Melatonina/farmacologia , Melatonina/uso terapêutico , Ratos Sprague-Dawley
18.
BMC Ophthalmol ; 24(1): 175, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627709

RESUMO

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.


Assuntos
Lentes Intraoculares , Miopia , Lentes Intraoculares Fácicas , Feminino , Humanos , Masculino , Olho , Implante de Lente Intraocular , Miopia/cirurgia , Dor/cirurgia , Estudos Prospectivos , Adulto Jovem , Adulto
19.
Altern Ther Health Med ; 30(10): 152-156, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38518126

RESUMO

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.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Intolerância Alimentar , Estilo de Vida , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Masculino , Feminino , Intolerância Alimentar/epidemiologia , Relações Familiares/psicologia , Adolescente
20.
Mycopathologia ; 189(3): 35, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637433

RESUMO

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.


Assuntos
Antifúngicos , Candidíase , Humanos , Antifúngicos/farmacologia , Candidíase/microbiologia , Candida auris , Candida , Anfotericina B/farmacologia , Farmacorresistência Fúngica/genética , Testes de Sensibilidade Microbiana
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