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1.
Phys Rev Lett ; 132(20): 200801, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38829067

RESUMEN

A fully homomorphic encryption system enables computation on encrypted data without the necessity for prior decryption. This facilitates the seamless establishment of a secure quantum channel, bridging the server and client components, and thereby providing the client with secure access to the server's substantial computational capacity for executing quantum operations. However, traditional homomorphic encryption systems lack scalability, programmability, and stability. In this Letter, we experimentally demonstrate a proof-of-concept implementation of a homomorphic encryption scheme on a compact quantum chip, verifying the feasibility of using photonic chips for quantum homomorphic encryption. Our work not only provides a solution for circuit expansion, addressing the longstanding challenge of scalability while significantly reducing the size of quantum network infrastructure, but also lays the groundwork for the development of highly sophisticated quantum fully homomorphic encryption systems.

2.
Clin Chim Acta ; 561: 119814, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38879063

RESUMEN

BACKGROUND: Hepatocellular cancer (HCC) is one of the most harmful tumors to human health. Currently, there is still a lack of highly sensitive and specific HCC biomarkers in clinical practice. In this study, we aimed to explore the diagnostic performance of prostaglandin A2 (PGA2) for the early detection of HCC. METHODS: Untargeted metabolomic analyses on normal control (NC) and HCC participants in the discovery cohort were performed, and PGA2 was identified to be dysregulated in HCC. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting serum PGA2 was established and applied to validate the dysregulation of PGA2 in another independent validation cohort. Receiver operating characteristic (ROC), decision curve analysis (DCA) and some other statistical analyses were performed to evaluate the diagnostic performance of PGA2 for HCC. RESULTS: At first, PGA2 was found to be dysregulated in HCC in untargeted metabolomic analyses. Then a precise quantitative LC-MS/MS method for PGA2 has been established and has passed rigorous method validation. Targeted PGA2 analyses confirmed that serum PGA2 was decreased in HCC compared to normal-risk NC and high-risk cirrhosis group. Subsequently, PGA2 was identified as a novel biomarker for the diagnosis of HCC, with an area under the ROC curve (AUC) of 0.911 for differentiating HCC from the combined NC + cirrhosis groups. In addition, PGA2 exhibited high performance for differentiating small-size (AUC = 0.924), early-stage (AUC = 0.917) and AFP (-) HCC (AUC = 0.909) from the control groups. The combination of PGA2 and AFP might be useful in the surveillance of risk population for HCC and early diagnosis of HCC. CONCLUSION: This study establishes that PGA2 might be a novel diagnostic biomarker for HCC.

3.
Front Aging Neurosci ; 16: 1404756, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38887608

RESUMEN

Purpose: The purpose of the present study was to identify predictors of severe white matter hyperintensity (WMH) with obesity (SWO), and to build a prediction model for screening obese people with severe WMH without Nuclear Magnetic Resonance Imaging (MRI) examination. Patients subjects and methods: From September 2020 to October 2021, 650 patients with WMH were recruited consecutively. The subjects were divided into two groups, SWO group and non-SWO group. Univariate and Logistic regression analysis were was applied to explore the potential predictors of SWO. The Youden index method was adopted to determine the best cut-off value in the establishment of the prediction model of SWO. Each parameter had two options, low and high. The score table of the prediction model and nomogram based on the logistic regression were constructed. Of the 650 subjects, 487 subjects (75%) were randomly assigned to the training group and 163 subjects (25%) to the validation group. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. Results: Logistic regression demonstrated that hypertension, uric acid (UA), complement 3 (C3) and Interleukin 8 (IL-8) were independent risk factors for SWO. Hypertension, UA, C3, IL-8, folic acid (FA), fasting C-peptide (FCP) and eosinophil could be used to predict the occurrence of SWO in the prediction models, with a good diagnostic performance, Areas Under Curves (AUC) of Total score was 0.823 (95% CI: 0.760-0.885, p < 0.001), sensitivity of 60.0%, specificity of 91.4%. In the development group, the nomogram's AUC (C statistic) was 0.829 (95% CI: 0.760-0.899), while in the validation group, it was 0.835 (95% CI: 0.696, 0.975). In both the development and validation groups, the calibration curves following 1,000 bootstraps showed a satisfactory fit between the observed and predicted probabilities. DCA showed that the nomogram had great clinical utility. Conclusion: Hypertension, UA, C3, IL-8, FA, FCP and eosinophil models had the potential to predict the incidence of SWO. When the total score of the model exceeded 9 points, the risk of SWO would increase significantly, and the nomogram enabled visualization of the patient's WMH risk. The application prospect of our models mainly lied in the convenient screening of SWO without MRI examination in order to detect SWO and control the WMH hazards early.

4.
Cancer Med ; 13(11): e7304, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38826094

RESUMEN

BACKGROUND: The surge in omicron variants has caused nationwide breakthrough infections in mainland China since the December 2022. In this study, we report the neutralization profiles of serum samples from the patients with breast cancer and the patients with liver cancer who had contracted subvariant breakthrough infections. METHODS: In this real-world study, we enrolled 143 COVID-19-vaccinated (81 and 62 patients with breast and liver cancers) and 105 unvaccinated patients with cancer (58 and 47 patients with breast and liver cancers) after omicron infection. Anti-spike receptor binding domain (RBD) IgGs and 50% pseudovirus neutralization titer (pVNT50) for the preceding (wild type), circulating omicron (BA.4-BA.5, and BF.7), and new subvariants (XBB.1.5) were comprehensively analyzed. RESULTS: Patients with liver cancer receiving booster doses had higher levels of anti-spike RBD IgG against circulating omicron (BA.4-BA.5, and BF.7) and a novel subvariant (XBB.1.5) compared to patients with breast cancer after breakthrough infection. Additionally, all vaccinated patients produced higher neutralizing antibody titers against circulating omicron (BA.4-BA.5, and BF.7) compared to unvaccinated patients. However, the unvaccinated patients produced higher neutralizing antibody against XBB.1.5 than vaccinated patients after Omicron infection, with this trend being more pronounced in breast cancer than in liver cancer patients. Moreover, we found that there was no correlation between anti-spike RBD IgG against wildtype virus and the neutralizing antibody titer, but a positive correlation between anti-spike RBD IgG and the neutralizing antibody against XBB.1.5 was found in unvaccinated patients. CONCLUSION: Our study found that there may be differences in vaccine response and protective effect against COVID-19 infection in patients with liver and breast cancer. Therefore, we recommend that COVID-19 vaccine strategies should be optimized based on vaccine components and immunology profiles of different patients with cancer.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Neoplasias de la Mama , Vacunas contra la COVID-19 , COVID-19 , Neoplasias Hepáticas , SARS-CoV-2 , Humanos , Femenino , COVID-19/inmunología , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/virología , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/epidemiología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/virología , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Persona de Mediana Edad , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , China/epidemiología , Vacunas contra la COVID-19/inmunología , Adulto , Anciano , Glicoproteína de la Espiga del Coronavirus/inmunología , Masculino , Brotes de Enfermedades , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología
5.
Front Public Health ; 12: 1320216, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38803807

RESUMEN

There is no clear explanation for the extraordinary rebound in China's population mortality over the past decade. This paper utilizes panel data from 31 Chinese provinces from 2010 to 2020 to determine the distinct impacts of public sports services (PSS), public health services (PMS), and their interaction on population mortality. Empirical results show that public sports services significantly reduce mortality. Every unit increase in public sports services reduces mortality by about 2.3%. It is characterized by delayed realization. Public health services were surprisingly associated with a rebound in mortality. Further studies found strong health effect from interaction of public sports and health services. The effect was significantly strengthened in areas with fewer extreme temperatures or developed economy. The findings have important policy implications for the high-quality development of public sports and health services. It also emphasizes integration of sports and medicine and mitigates health risks associated with extreme temperatures.


Asunto(s)
Salud Pública , Deportes , Humanos , China , Deportes/estadística & datos numéricos , Mortalidad/tendencias
6.
Elife ; 122024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38814697

RESUMEN

Almost all herbivorous insects feed on plants and use sucrose as a feeding stimulant, but the molecular basis of their sucrose reception remains unclear. Helicoverpa armigera as a notorious crop pest worldwide mainly feeds on reproductive organs of many plant species in the larval stage, and its adult draws nectar. In this study, we determined that the sucrose sensory neurons located in the contact chemosensilla on larval maxillary galea were 100-1000 times more sensitive to sucrose than those on adult antennae, tarsi, and proboscis. Using the Xenopus expression system, we discovered that Gr10 highly expressed in the larval sensilla was specifically tuned to sucrose, while Gr6 highly expressed in the adult sensilla responded to fucose, sucrose and fructose. Moreover, using CRISPR/Cas9, we revealed that Gr10 was mainly used by larvae to detect lower sucrose, while Gr6 was primarily used by adults to detect higher sucrose and other saccharides, which results in differences in selectivity and sensitivity between larval and adult sugar sensory neurons. Our results demonstrate the sugar receptors in this moth are evolved to adapt toward the larval and adult foods with different types and amounts of sugar, and fill in a gap in sweet taste of animals.


Asunto(s)
Larva , Mariposas Nocturnas , Sensilos , Sacarosa , Animales , Sacarosa/metabolismo , Sacarosa/farmacología , Larva/fisiología , Mariposas Nocturnas/fisiología , Mariposas Nocturnas/efectos de los fármacos , Sensilos/fisiología , Sensilos/metabolismo , Gusto/fisiología , Percepción del Gusto/fisiología , Helicoverpa armigera
7.
Food Chem ; 451: 139205, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38653102

RESUMEN

Sodium alginate hydrogel beads and sodium alginate/gellan gum composite hydrogel beads crosslinked by calcium chloride were prepared with different alginate concentrations (3-20 mg·mL-1). Additionally, a simple method for growing CaCO3in situ on the hydrogel to create novel inorganic-organic hybrid hydrogel beads was presented. FT-IR analysis revealed the involvement of hydrogen bonding and electrostatic interactions in bead formation. Swelling behavior in acidic conditions showed a maximum of 13 g/g for composite hydrogels and CaCO3-incorporated hybrid hydrogels. Lactoferrin encapsulation efficiency within these hydrogels ranged from 44.9 to 56.6%. In vitro release experiments demonstrated that these hydrogel beads withstand harsh gastric environments with <16% cumulative release of lactoferrin, achieving controlled release in intestinal surroundings. While composite sodium alginate/gellan gum beads exhibited slower gastrointestinal lactoferrin digestion, facile synthesis and pH responsiveness of CaCO3-incorporated hybrid hydrogel also provide new possibilities for future studies to construct a novel inorganic-organic synergetic system for intestinal-specific oral delivery.


Asunto(s)
Alginatos , Carbonato de Calcio , Hidrogeles , Lactoferrina , Alginatos/química , Carbonato de Calcio/química , Hidrogeles/química , Lactoferrina/química , Lactoferrina/administración & dosificación , Humanos , Administración Oral , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Concentración de Iones de Hidrógeno
8.
Sci Total Environ ; 931: 172782, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38679099

RESUMEN

Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression.


Asunto(s)
Neoplasias de la Mama , Carbanilidas , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Transducción de Señal , Triclosán , Carbanilidas/toxicidad , Transducción de Señal/efectos de los fármacos , Triclosán/toxicidad , Humanos , Femenino , Neoplasias de la Mama/patología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Estrógenos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Animales , Movimiento Celular/efectos de los fármacos
9.
J Ethnopharmacol ; 330: 118179, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38636575

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is a typical chronic microvascular complication of diabetes, characterized by proteinuria and a gradual decline in renal function. At present, there are limited clinical interventions aimed at preventing the progression of DN to end-stage renal disease (ESRD). However, Chinese herbal medicine presents a distinct therapeutic approach that can be effectively combined with conventional Western medicine treatments to safeguard renal function. This combination holds considerable practical implications for the treatment of DN. AIM OF THE STUDY: This review covers commonly used Chinese herbal remedies and decoctions applicable to various types of DN, and we summarize the role played by their active ingredients in the treatment of DN and their mechanisms, which includes how they might improve inflammation and metabolic abnormalities to provide new ideas to cope with the development of DN. MATERIALS AND METHODS: With the keywords "diabetic nephropathy," "Chinese herbal medicine," "clinical effectiveness," and "bioactive components," we conducted an extensive literature search of several databases, including PubMed, Web of Science, CNKI, and Wanfang database, to discover studies on herbal formulas that were effective in slowing the progression of DN. The names of the plants covered in the review have been checked at MPNS (http://mpns.kew.org). RESULTS: This review demonstrates the superior total clinical effective rate of combining Chinese herbal medicines with Western medicines over the use of Western medicines alone, as evidenced by summarizing the results of several clinical trials. Furthermore, the review highlights the nephroprotective effects of seven frequently used herbs exerting beneficial effects such as podocyte repair, anti-fibrosis of renal tissues, and regulation of glucose and lipid metabolism through multiple signaling pathways in the treatment of DN. CONCLUSIONS: The potential of herbs in treating DN is evident from their excellent effectiveness and the ability of different herbs to target various symptoms of the condition. However, limitations arise from the deficiencies in interfacing with objective bioindicators, which hinder the integration of herbal therapies into modern medical practice. Further research is warranted to address these limitations and enhance the compatibility of herbal therapies with contemporary medical standards.


Asunto(s)
Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Nefropatías Diabéticas/tratamiento farmacológico , Humanos , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Animales , Medicina Tradicional China/métodos , Fitoterapia
10.
Nano Lett ; 24(18): 5474-5480, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38652833

RESUMEN

Grain boundaries (GBs) and twin boundaries (TBs) in copper (Cu) are two major planar defects that influence electrical conductivity due to their complex electron transport characteristics, involving electron scattering and electron concentration. Understanding their local electronic states is crucial for the design of future conductor materials. In this study, we characterized electron behaviors at TBs and GBs within one Cu grain using atomic force microscopy. Our findings revealed that, compared with GBs, TBs exhibit better current transport capability (direct-current mode) and larger electromagnetic loss (high-frequency microwave mode). Both kelvin probe force microscopy and theoretical analysis suggested that TBs with smaller lattice disorder possess lower density of states at the Fermi level. The reduced density of states may result in decreased electron scattering and a lower electron concentration at TBs. The latter can be highlighted by the high-frequency skinning effect, manifested as larger electromagnetic loss and weaker high-frequency conductivity.

11.
Biochem Pharmacol ; 224: 116207, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38621425

RESUMEN

Osimertinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), acting as the first-line medicine for advanced EGFR-mutated NSCLC. Recently, the acquired resistance to osimertinib brings great challenges to the advanced treatment. Therefore, it is in urgent need to find effective strategy to overcome osimertinib acquired resistance. Here, we demonstrated that SREBP pathway-driven lipogenesis was a key mediator to promote osimertinib acquired resistance, and firstly found Tanshinone IIA (Tan IIA), a natural pharmacologically active constituent isolated from Salvia miltiorrhiza, could overcome osimertinib-acquired resistance in vitro and in vivo via inhibiting SREBP pathway-mediated lipid lipogenesis by using LC-MS based cellular lipidomics analysis, quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, flow cytometry, small interfering RNAs transfection, and membrane fluidity assay et al. The results showed that SREBP1/2-driven lipogenesis was highly activated in osimertinib acquired resistant NSCLC cells, while knockdown or inhibition of SREBP1/2 could restore the sensitivity of NSCLC to osimertinib via altered the proportion of saturated phospholipids and unsaturated phospholipids in osimertinib acquired-resistant cells. Furthermore, Tanshinone IIA (Tan IIA) could reverse the acquired resistance to osimertinib in lung cancer. Mechanically, Tan IIA inhibited SREBP signaling mediated lipogenesis, changed the profiles of saturated phospholipids and unsaturated phospholipids, and thus promoted osimertinib acquired resistant cancer cells to be attacked by oxidative stress-induced damage and reduce the cell membrane fluidity. The reversal effect of Tan IIA on osimertinib acquired resistant NSCLC cells was also confirmed in vivo, which is helpful for the development of strategies to reverse osimertinib acquired resistance.


Asunto(s)
Abietanos , Acrilamidas , Resistencia a Antineoplásicos , Lipogénesis , Neoplasias Pulmonares , Ratones Desnudos , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Abietanos/farmacología , Animales , Acrilamidas/farmacología , Lipogénesis/efectos de los fármacos , Ratones , Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Ratones Endogámicos BALB C , Línea Celular Tumoral , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Masculino , Femenino , Indoles , Pirimidinas
12.
Heliyon ; 10(7): e28629, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38590883

RESUMEN

Objectives: The present study was conducted to explore the performance of micronutrients in the prediction and prevention of coronavirus disease 2019 (COVID-19). Methods: This is an observational case-control study. 149 normal controls (NCs) and 214 COVID-19 patients were included in this study. Fat-soluble and water-soluble vitamins were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and inorganic elements were detected by inductively coupled plasma-mass spectrometry (ICP-MS) analysis. A logistic regression model based on six micronutrients were constructed using DxAI platform. Results: Many micronutrients were dysregulated in COVID-19 compared to normal control (NC). 25-Hydroxyvitamin D3 [25(OH)D3], magnesium (Mg), copper (Cu), calcium (Ca) and vitamin B6 (pyridoxic acid, PA) were significantly independent risk factors for COVID-19. The logistic regression model consisted of 25(OH)D3, Mg, Cu, Ca, vitamin B5 (VB5) and PA was developed, and displayed a strong discriminative capability to differentiate COVID-19 patients from NC individuals [area under the receiver operating characteristic curve (AUROC) = 0.901]. In addition, the model had great predictive ability in discriminating mild/normal COVID-19 patients from NC individuals (AUROC = 0.883). Conclusions: Our study showed that micronutrients were associated with COVID-19, and our logistic regression model based on six micronutrients has potential in clinical management of COVID-19, and will be useful for prediction of COVID-19 and screening of high-risk population.

13.
Adv Healthc Mater ; : e2400580, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38574340

RESUMEN

High glucose blood and bacterial infection remain major issues for the slow healing of diabetic wounds, so developing functional biosensing composite with excellent antibacterial and remarkable glucose response sensitivity is necessary and prospective. Herein, by in situ synthesis AgNPs on the surface of self-prepared PTIGA elastomers, PTIGA-AgNPs conductive composites are obtained with efficient synergistic antibacterial effect, excellent mechanical and self-healing properties. The strain of the composites can reach 1800%, and its self-healing efficiency exceeds 90% at 60 °C within 8 h. Both elastomers and composites represent excellent biocompatibility and the antibacterial rate against E. coli and S. aureus exceeded 90%. Moreover, the biosensor assembled from the conductive composites exhibits excellent glucose response sensitivity and stability, with a sensitivity coefficient of 0.518 mA mm-1 in the range of 0.2-3.6 × 10-3 m glucose concentration, as well as a low detection limit of 0.08 × 10-3 m. Furthermore, based on the remarkable antibacterial performance and bioactivity derived from GA, the composites reduce the expression of pro-inflammatory factors and promote the production of anti-inflammatory factors, and effectively promote the regeneration of skin and granulation tissue of wounds in a diabetic full-thickness skin defect model, demonstrating the enormous therapeutic potential in diabetic wound healing.

14.
Cells ; 13(6)2024 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-38534371

RESUMEN

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.


Asunto(s)
Compuestos de Anilina , Antineoplásicos , Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Sulfonamidas , Trombocitopenia , Humanos , Ratones , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Proteína bcl-X/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Antineoplásicos/farmacología , Modelos Animales de Enfermedad
15.
bioRxiv ; 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38464204

RESUMEN

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216+venetoclax to reduce the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b leads to significant tumor growth delay similar to the DT2216+venetoclax combination in H146 xenografts by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. 753b at this dosage was well tolerated in mice without induction of severe thrombocytopenia as seen with navitoclax nor induced significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients warranting clinical trials in future.

16.
Phys Med Biol ; 69(9)2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38527368

RESUMEN

Transbronchial microwave ablation (MWA) with flexible antennas has gradually become an attractive alternative to percutaneous MWA for lung cancer due to its characteristic of non-invasiveness. However, flexible antennas for the precision ablation of lung tumors that are adjacent to critical bronchial structures are still not available. In this study, a non-invasive flexible directional (FD) antenna for early stage central lung tumors surrounding the bronchia was proposed. A comprehensive numerical MWA model with the FD antenna was developed in a real human-sized left lung model. The structure of the antenna and the treatment protocol were optimized by a generic algorithm for the precision ablation of two cases of early stage central lung cancer (i.e. spherical-like and ellipsoidal tumors). The electromagnetic efficiency of the optimized antenna was also improved by implementing an optimizedπ-matching network for impedance matching. The results indicate that the electromagnetic energy of MWA can be restricted to a particular area for precision ablation of specific lung tumors using the FD antenna. This study contributes to the field of lung cancer management with MWA.


Asunto(s)
Técnicas de Ablación , Neoplasias Pulmonares , Microondas , Microondas/uso terapéutico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/radioterapia , Humanos , Técnicas de Ablación/métodos , Técnicas de Ablación/instrumentación
17.
Appl Environ Microbiol ; 90(4): e0000724, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38501861

RESUMEN

With its estrogenic activity, (S)-equol plays an important role in maintaining host health and preventing estrogen-related diseases. Exclusive production occurs through the transformation of soy isoflavones by intestinal bacteria, but the reasons for variations in (S)-equol production among different individuals and species remain unclear. Here, fecal samples from humans, pigs, chickens, mice, and rats were used as research objects. The concentrations of (S)-equol, along with the genetic homology and evolutionary relationships of (S)-equol production-related genes [daidzein reductase (DZNR), daidzein racemase (DDRC), dihydrodaidzein reductase (DHDR), tetrahydrodaidzein reductase (THDR)], were analyzed. Additionally, in vitro functional verification of the newly identified DDRC gene was conducted. It was found that approximately 40% of human samples contained (S)-equol, whereas 100% of samples from other species contained (S)-equol. However, there were significant variations in (S)-equol content among the different species: rats > pigs > chickens > mice > humans. The distributions of the four genes displayed species-specific patterns. High detection rates across various species were exhibited by DHDR, THDR, and DDRC. In contrast, substantial variations in detection rates among different species and individuals were observed with respect to DZNR. It appears that various types of DZNR may be associated with different concentrations of (S)-equol, which potentially correspond to the regulatory role during (S)-equol synthesis. This enhances our understanding of individual variations in (S)-equol production and their connection with functional genes in vitro. Moreover, the newly identified DDRC exhibits higher potential for (S)-equol synthesis compared to the known DDRC, providing valuable resources for advancing in vitro (S)-equol production. IMPORTANCE: (S)-equol ((S)-EQ) plays a crucial role in maintaining human health, along with its known capacity to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. However, factors affecting individual variations in (S)-EQ production and the underlying regulatory mechanisms remain elusive. This study examines the association between functional genes and (S)-EQ production, highlighting a potential correlation between the DZNR gene and (S)-EQ content. Various types of DZNR may be linked to the regulation of (S)-EQ synthesis. Furthermore, the identification of a new DDRC gene offers promising prospects for enhancing in vitro (S)-EQ production.


Asunto(s)
Equol , Isoflavonas , Animales , Humanos , Ratones , Ratas , Porcinos , Equol/genética , Equol/metabolismo , Racemasas y Epimerasas , Pollos/metabolismo , Isoflavonas/metabolismo , Oxidorreductasas/metabolismo
19.
J Colloid Interface Sci ; 665: 109-124, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38520928

RESUMEN

In this research, a self-healing nano-coating with excellent photo-thermal response to near-infrared (NIR) laser is prepared. This coating incorporates silver sulfide anchored bismuth molybdate (Ag2S@Bi2MoO6) into a shape memory epoxy resin to achieve for a good photo-thermal conversion capability. The Ag2S@Bi2MoO6 p-n heterojunction could photo-generate more electron-holes pairs under the NIR laser irradiation. Also, it shows a wider absorption range of visible light, leading to effectively absorb the light energy, generate enough heat to induce the shape memory recovery in the coating, and seal the scratch. The results indicate that the temperature of EP-1 % Ag2S@Bi2MoO6 coating has reached about 88 °C, while good self-healing and anti-corrosion properties with a self-healing rate of 88.41 % have been achieved. Furthermore, calculations based on Density Functional Theory and Finite Element Method pointed out that the formation of p-n heterojunction effectively has enhanced the photo-thermal effect. This research opens a new way for developing self-healing coatings with an ultra-fast response time and high self-healing efficiency.

20.
Sensors (Basel) ; 24(6)2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38544163

RESUMEN

Crowd movement analysis (CMA) is a key technology in the field of public safety. This technology provides reference for identifying potential hazards in public places by analyzing crowd aggregation and dispersion behavior. Traditional video processing techniques are susceptible to factors such as environmental lighting and depth of field when analyzing crowd movements, so cannot accurately locate the source of events. Radar, on the other hand, offers all-weather distance and angle measurements, effectively compensating for the shortcomings of video surveillance. This paper proposes a crowd motion analysis method based on radar particle flow (RPF). Firstly, radar particle flow is extracted from adjacent frames of millimeter-wave radar point sets by utilizing the optical flow method. Then, a new concept of micro-source is defined to describe whether any two RPF vectors originated from or reach the same location. Finally, in each local area, the internal micro-sources are counted to form a local diffusion potential, which characterizes the movement state of the crowd. The proposed algorithm is validated in real scenarios. By analyzing and processing radar data on aggregation, dispersion, and normal movements, the algorithm is able to effectively identify these movements with an accuracy rate of no less than 88%.

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