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1.
Chem Sci ; 15(29): 11272-11278, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39055004

RESUMEN

Bispecific antibodies are artificial molecules that fuse two different antigen-binding sites of monoclonal antibodies into one single entity. They have emerged as a promising next-generation anticancer treatment. Despite the fascinating applications of bispecific antibodies, the design and production of bispecific antibodies remain tedious and challenging, leading to a long R&D process and high production costs. We herein report an unprecedented strategy to cyclise and conjugate tumour-targeting peptides on the surface of a monoclonal antibody to form a novel type of bispecific antibody, namely the peptidic bispecific antibody (pBsAb). Such design combines the merits of highly specific monoclonal antibodies and serum-stable cyclic peptides that endows an additional tumour-targeting ability to the monoclonal antibody for binding with two different antigens. Our results show that the novel pBsAb, which comprises EGFR-binding cyclic peptides and an anti-SIRP-α monoclonal antibody, could serve as a macrophage-engaging bispecific antibody to initiate enhanced macrophage-cancer cell interaction and block the "don't eat me" signal between CD47-SIRP-α, as well as promoting antibody-dependent cellular phagocytosis and 3D cell spheroid infiltration. These findings give rise to a new type of bispecific antibody and a new platform for the rapid generation of new bispecific antibodies for research and potential therapeutic uses.

2.
Cancer Med ; 12(11): 12299-12315, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37148547

RESUMEN

BACKGROUND: Cancer is currently the second leading cause of death globally. There is much uncertainty regarding the comparative risks of new-onset overall cancer and pre-specified cancer for Type 2 diabetes mellitus (T2DM) patients on sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus DPP4I. METHODS: This population-based cohort study patients included patients who were diagnosed with T2DM and administered either SGLT2 or DPP4 inhibitors between 1 January 2015 and 31 December 2020 in public hospitals of Hong Kong. RESULTS: This study included 60,112 T2DM patients (mean baseline age: 62.1 ± 12.4 years, male: 56.36%), of which 18,167 patients were SGLT2I users and 41,945 patients were dipeptidyl peptidase 4 inhibitor (DPP4I) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of all-cause mortality (HR: 0.92; 95% CI: 0.84-0.99; p= 0.04), cancer-related mortality (HR: 0.58; 95% CI: 0.42-0.80; p ≤ 0.001) and new diagnoses of any cancer (HR: 0.70; 95% CI: 0.59-0.84; p ≤ 0.001). SGLT2I use was associated with a lower risk of new-onset breast cancer (HR: 0.51; 95% CI: 0.32-0.80; p ≤ 0.001), but not of other malignancies. Subgroup analysis on the type of SGLT2I, dapagliflozin (HR: 0.78; 95% CI: 0.64-0.95; p = 0.01) and ertugliflozin (HR: 0.65; 95% CI: 0.43-0.98; p = 0.04) use was associated with lower risks of new cancer diagnosis. Dapagliflozin use was also linked to lower risks of breast cancer (HR: 0.48; 95% CI: 0.27-0.83; p = 0.001). CONCLUSION: Sodium-glucose cotransporter 2 inhibitor use was associated with lower risks of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I use after propensity score matching and multivariable adjustment.


Asunto(s)
Neoplasias de la Mama , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Masculino , Persona de Mediana Edad , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Estudios de Cohortes , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Resultado del Tratamiento , Hipoglucemiantes/uso terapéutico , Neoplasias de la Mama/complicaciones , Glucosa , Sodio , Estudios Retrospectivos
3.
Cancer Med ; 12(8): 9541-9546, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36808819

RESUMEN

BACKGROUND: While immune checkpoint inhibitors (ICIs) are associated with elevated cardiovascular risks, evidence of any association between ICIs and myocardial infarction (MI) was scarce, especially in Asians. METHODS: Using prospectively collected population-based data, this self-controlled case series included patients prescribed an ICI between 1/1/2014 and 31/12/2020 in Hong Kong who had MI within January 1, 2013 to December 31, 2021. Incidence rate ratios (IRRs) for MI during and after ICI exposure were estimated, compared to the year before ICI initiation. RESULTS: Of 3684 identified ICI users, 24 had MI during the study period. MI incidence increased significantly in the first 90 days of exposure (IRR 3.59 [95% confidence interval: 1.31-9.83], p = 0.013), but not days 91-180 (p = 0.148) or ≥181 (p = 0.591) of exposure, nor postexposure (p = 0.923). Sensitivity analyses excluding patients with MI-related death and incorporating extended exposure periods produced consistent results separately. CONCLUSIONS: ICIs were associated with increased MI incidence in Asian Chinese patients during the first 90 days of use, but not later.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Infarto del Miocardio , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Factores de Riesgo , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/epidemiología , Incidencia , Hong Kong/epidemiología
4.
Cancer Med ; 12(7): 8144-8153, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36647331

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly established cancer therapeutics, but they are associated with new-onset diabetes mellitus (DM). Such risks have not been adequately quantified, and between-class and -sex differences remain unexplored. METHODS: This was a prospective cohort study of cancer patients receiving any ICI in Hong Kong between 2013 and 2021. Patients with known DM were excluded. Due to few patients using other ICIs, only programmed cell death 1 inhibitors (PD-1i) and programmed death ligand 1 inhibitors (PD-L1i) were compared, alongside between-sex comparison. When comparing PD-1i against PD-L1i, patients with the use of other ICIs or both PD-1i and PD-L1 were further excluded. Inverse probability treatment weighting (IPTW) was used to minimize between-group covariate imbalances. RESULTS: Altogether, 3375 patients were analyzed (65.2% males, median age 62.2 [interquartile range 53.8-69.5] years old). Over a median follow-up of 1.0 [0.4-2.4] years, new-onset DM occurred in 457 patients (13.5%), with a 3-year risk of 14.5% [95% confidence interval 13.3%, 15.8%]. IPTW achieve acceptable covariate balance between sexes, and between PD-1i (N = 622) and PD-L1i (N = 2426) users. Males had significantly higher risk of new-onset DM (hazard ratio 1.35 [1.09, 1.67], p = 0.006), while PD-1i and PD-L1i users did not have significantly different risks (hazard ratio vs PD-L1i 0.81 [0.59, 1.11], p = 0.182). These were consistent in those with at least 1 year of follow-up, and on competing risk regression. CONCLUSION: Users of ICI may have a substantial risk of new-onset DM, which may be higher in males but did not differ between PD-1i and PD-L1i.


Asunto(s)
Antineoplásicos Inmunológicos , Diabetes Mellitus , Neoplasias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Estudios Prospectivos , Estudios de Cohortes , Neoplasias/inducido químicamente , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Antígeno B7-H1
5.
Rheumatology (Oxford) ; 62(4): 1501-1510, 2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-36066415

RESUMEN

OBJECTIVES: The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) vs dipeptidyl peptidase-4 inhibitors (DPP4I) on the risk of new-onset gout remains unknown. This study aims to compare the effects of SGLT2I against DPP4I on gout risks. METHODS: This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus treated with SGLT2I or DPP4I between 1 January 2015 and 31 December 2020 in Hong Kong. The study outcomes are new-onset gout and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I was performed. Univariable and multivariable Cox regression models were conducted. Competing risks models and multiple approaches based on the propensity score were applied. RESULTS: This study included 43 201 patients [median age: 63.23 years old (Interquartile range, IQR): 55.21-71.95, 53.74% males; SGLT2I group: n = 16 144; DPP4I group: n = 27 057] with a median follow-up of 5.59 years (IQR: 5.27-5.81 years) since initial drug exposure. The incidence rate of developing gout [Incidence rate (IR): 2.5; 95% CI: 2.2, 2.9] among SGLT2I users was significantly lower than DPP4I users (IR: 5.2; 95% CI: 4.8, 5.8). SGLT2I was associated with 51% lower risks of gout (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) and 51% lower risks of all-cause mortality (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory results. The results remained consistent on competing risk and other propensity score approaches. CONCLUSIONS: SGLT2I use was associated with lower risks of new gout diagnosis compared with DPP4I use.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Gota , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Masculino , Humanos , Persona de Mediana Edad , Femenino , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Dipeptidil Peptidasa 4/uso terapéutico , Estudios de Cohortes , Estudios Retrospectivos , Transportador 2 de Sodio-Glucosa/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Gota/tratamiento farmacológico , Gota/complicaciones
6.
Curr Probl Cardiol ; 48(1): 101421, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36167221

RESUMEN

Dyslipidemia is associated with increased cancer risk. However, the prognostic value of visit-to-visit lipid variability (VVLV) is unexplored in this regard. To investigate the associations between the VVLV and the risk of incident cancer, we conducted a retrospective cohort study on adult patients attending a family medicine clinic in Hong Kong during 2000-2003, excluding those with <3 tests for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and total cholesterol (TC) each, those with prior cancer diagnosis, and those with <1 year of follow-up. Visit-to-visit LDL-C, HDL-C, TC, and triglycerides variabilities were measured by the coefficient of variation (CV). Patients were followed up until 31st December 2019 for the primary outcome of incident cancer. Altogether, 69,186 patients were included (26,679 males (38.6%); mean age 60 ± 13 years; mean follow-up 16 ± 3 years); 7958 patients (11.5%) had incident cancer. Higher variability of LDL-C, HDL-C, TC, and TG was associated with higher risk of incident cancer. Patients in the third tercile of the CV of LDL-C (adjusted hazard ratio (aHR) against first tercile 1.06 [1.00, 1.12], P = 0.049), HDL-C (aHR 1.37 [1.29, 1.44], P< 0.001), TC (aHR 1.10 [1.04, 1.17], P = 0.001), and TG (aHR 1.11 [1.06, 1.18], P < 0.001) had the highest risks of incident cancer. Among these, only HDL-C variability remained associated with the risk of incident cancer in users of statins/fibrates. To conclude, higher VVLV was associated with significantly higher long-term risks of incident cancer. VVLV may be a clinically useful tool for cancer risk stratification.


Asunto(s)
Neoplasias , Adulto , Masculino , Humanos , Persona de Mediana Edad , Anciano , LDL-Colesterol , Estudios de Cohortes , Estudios Retrospectivos , Factores de Riesgo , HDL-Colesterol , Triglicéridos , Neoplasias/diagnóstico , Neoplasias/epidemiología
7.
J Endocr Soc ; 6(11): bvac138, 2022 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-36267596

RESUMEN

Context: Diabetes mellitus (DM) is associated with the development of pancreatic cancer (PaC), but few large-scale studies have examined its predictive risk factors. Objective: The present study aims to examine the predictors for PaC in patients with type 2 diabetes mellitus (T2DM) in a territory-wide, retrospective cohort study. Methods: This was a territory-wide, retrospective cohort study of patients with T2DM mellitus older than 40 years with no prior history of PaC. Baseline demographics, use of antidiabetic medications, comorbidities, and biochemical parameters were extracted. Cox regression was used to calculate hazard ratios (HR) with 95% CI. Subgroup analyses based on chronic kidney disease (CKD) stages were performed. Results: This study consisted of 273 738 patients (age = 65.4 ± 12.7 years, male = 48.2%, follow-up duration = 3547 ± 1207 days, disease duration = 4.8 ± 2.3 years), of whom 1148 developed PaC. The number of antidiabetic medications prescribed (HR: 1.20; 95% CI, 1.01-1.42; P = .040), diabetic microvascular complications (HR: 1.91; 95% CI, 1.30-2.81; P < .001), chronic kidney disease (HR: 1.81; 95% CI, 1.25-2.64; P = .002), use of acarbose (HR: 2.24; 95% CI, 1.35-3.74; P = .002), and use of glucagon-like peptide-1 receptor agonist (HR: 4.00; 95% CI: 1.28-12.53, P = .017) were associated with PaC development on multivariable Cox regression adjusting for the duration of DM, mean glycated hemoglobin A1c, and history of pancreatic diseases. Stage 3A CKD or below was associated with PaC but not stage 3B or beyond. Conclusion: Diabetic microvascular complications, especially stage 1, 2, and 3A CKD, were associated with PaCs.

8.
Artículo en Inglés | MEDLINE | ID: mdl-35822699

RESUMEN

The development of nanotheranostics for precision imaging-guided regulated cell death-mediated synergistic tumor therapy is still challenging. Herein, a novel multifunctional nanotheranostic agent, iRGD-coated maleimide-poly(ethylene glycol)-poly(lactic acid/glycolic acid)-encapsulated hydrophobic gold nanocages (AuNCs) and hydrophilic epigallocatechin gallate (EGCG) (PAuE) is developed for multispectral optoacoustic tomography (MSOT)-guided photothermal therapy (PTT) and chemotherapy. The portions of necroptotic and apoptotic tumor cells were 52.9 and 5.4%, respectively, at 6 h post-incubation after the AuNC-induced mild PTT treatment, whereas they became 14.0 and 46.1% after 24 h, suggesting that the switch of the cell death pathway is a time-dependent process. Mild PTT facilitated the release of EGCG which induces the downregulation of hypoxia-inducible factor-1 (HIF-1α) expression to enhance apoptosis at a later stage, realizing a remarkable tumor growth inhibition in vivo. Moreover, RNA sequence analyses provided insights into the significant changes in genes related to the cross-talk between necroptosis and apoptosis pathways via PAuE upon laser irradiation. In addition, the biodistribution and metabolic pathways of PAuE have been successfully revealed by 3D MSOT. Taken together, this strategy of first combination of EGCG and AuNC-based photothermal agent via triggering necroptosis/apoptosis to downregulate HIF-1α expression in a tumor environment provides a new insight into anti-cancer therapy.

9.
J Natl Compr Canc Netw ; 20(6): 674-682.e15, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35714677

RESUMEN

BACKGROUND: The aim of this study was to compare the risks of new-onset prostate cancer between metformin and sulfonylurea users with type 2 diabetes mellitus (T2DM). METHODS: This population-based retrospective cohort study included male patients with T2DM presenting to public hospitals/clinics in Hong Kong between January 1, 2000, and December 31, 2009. We only included patients prescribed either, but not both, metformin or sulfonylurea. All patients were followed up until December 31, 2019. The primary outcome was new-onset prostate cancer and the secondary outcome was all-cause mortality. One-to-one propensity score matching was performed between metformin and sulfonylurea users based on demographics, comorbidities, antidiabetic and cardiovascular medications, fasting blood glucose level, and hemoglobin A1c level. Subgroup analyses based on age and use of androgen deprivation therapy were performed. RESULTS: The final study cohort consisted of 25,695 metformin users (mean [SD] age, 65.2 [11.8] years) and 25,695 matched sulfonylurea users (mean [SD] age, 65.3 [11.8] years) with a median follow-up duration of 119.6 months (interquartile range, 91.7-139.6 months) after 1:1 propensity score matching of 66,411 patients. Metformin users had lower risks of new-onset prostate cancer (hazard ratio, 0.80; 95% CI, 0.69-0.93; P=.0031) and all-cause mortality (hazard ratio, 0.89; 95% CI, 0.86-0.92; P<.0001) than sulfonylurea users. Metformin use was more protective against prostate cancer but less protective against all-cause mortality in patients aged <65 years (P for trend <.0001 for both) compared with patients aged ≥65 years. Metformin users had lower risk of all-cause mortality than sulfonylurea users, regardless of the use of androgen deprivation therapy (P for trend <.0001) among patients who developed prostate cancer. CONCLUSIONS: Metformin use was associated with significantly lower risks of new-onset prostate cancer and all-cause mortality than sulfonylurea use in male patients with T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Neoplasias de la Próstata , Anciano , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Masculino , Metformina/efectos adversos , Puntaje de Propensión , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/etiología , Estudios Retrospectivos , Compuestos de Sulfonilurea/efectos adversos
10.
Cardiooncology ; 8(1): 5, 2022 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-35300724

RESUMEN

BACKGROUND: Programmed death-1 (PD-1) and programmed death- ligand 1 (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors. METHODS: Patients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2019 at publicly funded hospitals of Hong Kong, China, without pre-existing cardiac complications were included. The primary outcome was a composite of incident heart failure, acute myocardial infarction, atrial fibrillation, or atrial flutter with the last follow-up date of 31st December 2020. Propensity score matching between PD-L1 inhibitor use and PD-1 inhibitor use with a 1:2 ratio for patient demographics, past comorbidities and non-PD-1/PD-L1 medications was performed with nearest neighbour search strategy (0.1 caliper). Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple propensity matching approaches were considered for sensitivity analysis. RESULTS: A total of 1959 patients were included. Over a median follow-up of 247 days (interquartile range [IQR]: 72-506), 320 (incidence rate [IR]: 16.31%) patients met the primary outcome after PD-1/PD-L1 treatment: 244 (IR: 12.57%) with heart failure, 38 (IR: 1.93%) with acute myocardial infarction, 54 (IR: 2.75%) with atrial fibrillation, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with lower risks of the composite outcome both before (hazard ratio [HR]: 0.32, 95% CI: [0.18-0.59], P value=0.0002) and after matching (HR: 0.34, 95% CI: [0.18-0.65], P value=0.001), and lower all-cause mortality risks before matching (HR: 0.77, 95% CI: [0.64-0.93], P value=0.0078) and after matching (HR: 0.80, 95% CI: [0.65-1.00], P value=0.0463). Patients who developed cardiac complications had shorter average readmission intervals and a higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors in both the unmatched and matched cohorts (P value<0.0001). Multivariable Cox regression models, competing risk analysis with cause-specific and subdistribution hazard models, and multiple propensity approaches confirmed these observations. CONCLUSIONS: Compared with PD-1 treatment, PD-L1 treatment was significantly associated with lower risk of new onset cardiac complications and all-cause mortality both before and after propensity score matching.

11.
Theranostics ; 12(3): 1161-1172, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35154480

RESUMEN

Aims: Neonatal immunity is functionally immature and skewed towards a TH2-driven, anti-inflammatory profile. This neonatal immunotolerance is partly driven by the type 2 cytokines: interleukin-4 (IL-4) and interleukin-13 (IL-13). Studies on neonatal cardiac regeneration reveal the beneficial role of an anti-inflammatory response in restoring cardiac function after injury. However, the role of an imbalanced immune repertoire observed in neonates on tissue regeneration is poorly understood; specifically, whether IL-4 and IL-13 actively modulate neonatal immunity during cardiac injury. Methods and results: Neonatal mice lacking IL-4 and IL-13 (DKOs) examined at 2 days after birth exhibited reduced anti-inflammatory immune populations with basal cardiac immune populations like adult mice. Examination of neonates lacking IL-4 and IL-13 at 2 days post cardiac ischemic injury, induced on the second day after birth, showed impaired cardiac function compared to their control counterparts. Treatment with either IL-4 or IL-13 cytokine during injury restored both cardiac function and immune population profiles in knockout mice. Examination of IL-4/IL-13 downstream pathways revealed the role of STAT6 in mediating the regenerative response in neonatal hearts. As IL-4/IL-13 drives polarization of alternatively activated macrophages, we also examined the role of IL-4/IL-13 signaling within the myeloid compartment during neonatal cardiac regeneration. Injury of IL-4Rα myeloid specific knockout neonates 2 days after birth revealed that loss of IL-4/IL-13 signaling in macrophages alone was sufficient to impair cardiac regeneration. Conclusions: Our results confirm that the TH2 cytokines: IL-4 and IL-13, which skews neonatal immunity to a TH2 profile, are necessary for maintaining and mediating an anti-inflammatory response in the neonatal heart, in part through the activation of alternatively activated macrophages, thereby permitting a niche conducive for regeneration.


Asunto(s)
Lesiones Cardíacas , Interleucina-13 , Animales , Inmunidad Innata , Interleucina-13/metabolismo , Interleucina-13/farmacología , Interleucina-4/metabolismo , Macrófagos/metabolismo , Ratones , Miocitos Cardíacos/metabolismo
12.
Rev Cardiovasc Med ; 23(7): 231, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39076921

RESUMEN

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a hereditary disease characterized by fibrofatty infiltration of the right ventricular myocardium that predisposes affected patients to malignant ventricular arrhythmias, dual-chamber cardiac failure and sudden cardiac death (SCD). The present study aims to investigate the risk of detrimental cardiovascular events in an Asian population of ARVC/D patients, including the incidence of malignant ventricular arrhythmias, new-onset heart failure with reduced ejection fraction (HFrEF), as well as long-term mortality. Methods and Results: This was a territory-wide retrospective cohort study of patients diagnosed with ARVC/D between 1997 and 2019 in Hong Kong. This study consisted of 109 ARVC/D patients (median age: 61 [46-71] years; 58% male). Of these, 51 and 24 patients developed incident VT/VF and new-onset HFrEF, respectively. Five patients underwent cardiac transplantation, and 14 died during follow-up. Multivariate Cox regression identified prolonged QRS duration as a predictor of VT/VF (p < 0.05). Female gender, prolonged QTc duration, the presence of epsilon waves and T-wave inversion (TWI) in any lead except aVR/V1 predicted new-onset HFrEF (p < 0.05). The presence of epsilon waves, in addition to the parameters of prolonged QRS duration and worsening ejection fraction predicted all-cause mortality (p < 0.05). Clinical scores were developed to predict incident VT/VF, new-onset HFrEF and all-cause mortality, and all were significantly improved by machine learning techniques. Conclusions: Clinical and electrocardiographic parameters are important for assessing prognosis in ARVC/D patients and should in turn be used in tandem to aid risk stratification in the hospital setting.

13.
J Biomed Nanotechnol ; 17(11): 2186-2197, 2021 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-34906279

RESUMEN

Hypoxia is an important phenomenon due to insufficient oxygen supply in tumor tissue, and nitroreductase (NTR) is a characteristic enzyme used for evaluating hypoxia level in tumors. In this work, we designed a smart gold nanoparticle (AuNPs), modified by 16-mercaptoundecanoic acid (MHDA) and hypoxia-responsive 11-(2-nitro-1H-imidazol-1-yl)undecane-1-thiol (NI) ligand, that responds to the hypoxic environment in tumor sites. With proper surface ligand composition, the responsive nanoprobe exhibited aggregation through the bioreduction of the nitro group on NI ligands under hypoxic conditions and the UV-vis absorption peak maximum would shift to 630 nm from 530 nm, which acts as an "off-on" contrast agent for tumor hypoxic photoacoustic (PA) imaging. In vitro and in vivo experiments revealed that AuNPs@MHDA/NO2 exhibited an enhanced PA signal in hypoxic conditions. This study demonstrates the potential of hypoxia-responsive AuNPs as novel and sensitive diagnostic agents, which lays a firm foundation for precise cancer treatment in the future.


Asunto(s)
Nanopartículas del Metal , Técnicas Fotoacústicas , Oro , Nitrorreductasas , Hipoxia Tumoral
14.
Nanomaterials (Basel) ; 11(10)2021 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-34685131

RESUMEN

A novel mesoporous Zn/MgO hexagonal-nano-plate catalyst was synthesized by a simple template-free hydrothermal method and applied in the base-catalyzed transesterification of Camelina oil for biodiesel synthesis. The Zn/MgO catalyst calcinated at 873 K exhibited the highest catalytic activity with a yield of 88.7%. This catalytic reaction was performed using 3% w/w of the catalyst with a methanol-to-oil molar ratio of 24:1 at 393 K in 8 h. The excellent catalytic performance is possibly attributed to its favorable textural features with relatively high surface area (69.1 m2 g-1) and appropriate size of the mesopores (10.4 nm). In addition, the as-synthesized catalyst demonstrated a greater basic sites density than single mesoporous MgO, which might have been promoted by the addition of Zn, leading to a synergetic interaction that enhanced its catalytic activity. This catalytic system demonstrated high stability for five catalytic runs and catalytic activity with over 84% yield.

15.
Clin Exp Pharmacol Physiol ; 48(8): 1043-1058, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33987869

RESUMEN

Crocodile blood has long been used as a traditional medicine in many Asian countries to treat diseases such as asthma, allergies, and many others. Yet, only recently has the safety and effectiveness of using crocodile blood as a medicine been examined using modern scientific methods; with both conserved and novel active components identified from crocodile blood. Further in vitro and in vivo investigations found that crocodile blood can have a wide range of beneficial effects, including antimicrobial, antiviral, anti-oxidative, anti-inflammatory, antitumour effects, anti-anaemia, and enhancement of wound healing. A systematic research of literature published in English-language journals up to April 2020 was conducted in PubMed, Google Scholar, and Web of Science. Based on the biological and chemical knowledge of crocodile immunity and crocodile blood, this article aims to: provide a critical review on the proposed properties of crocodile blood, identify the knowledge gap and offer some insights for future investigations regarding the use of crocodile blood as a medication or dietary supplement.


Asunto(s)
Caimanes y Cocodrilos , Cicatrización de Heridas , Animales , Antibacterianos
16.
Adv Sci (Weinh) ; 8(2): 2003041, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33511018

RESUMEN

Metal phosphorous trichalcogenides (MPX3) are novel 2D nanomaterials that have recently been exploited as efficient photothermal-chemodynamic agents for cancer therapy. As a representative MPX3, FePSe3 has the potential to be developed as magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) agents due to the composition of Fe and the previously revealed PA signal. Here, a FePSe3-based theranostic agent, FePSe3@APP@CCM, loaded with anti-PD-1 peptide (APP) as the inner component and CT26 cancer cell membrane (CCM) as the outer shell is reported, which acts as a multifunctional agent for MR and PA imaging and photothermal and immunotherapy against cancer. FePSe3@APP@CCM induces highly efficient tumor ablation and suppresses tumor growth by photothermal therapy under near-infrared laser excitation, which further activates immune responses. Moreover, APP blocks the PD-1/PD-L1 pathway to activate cytotoxic T cells, causing strong anticancer immunity. The combined therapy significantly prolongs the lifespan of experimental mice. The multimodal imaging and synergistic therapeutic effects of PTT and its triggered immune responses and APP-related immunotherapy are clearly demonstrated by in vitro and in vivo experiments. This work demonstrates the potential of MPX3-based biomaterials as novel theranostic agents.

17.
ACS Appl Bio Mater ; 4(5): 4152-4164, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35006828

RESUMEN

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo. Meanwhile, the utilization of iRGD-targeted PPC815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Nanopartículas/química , Técnicas Fotoacústicas , Terapia Fototérmica , Polietilenglicoles/farmacología , Poliglactina 910/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Ensayo de Materiales , Ratones , Imagen Óptica , Tamaño de la Partícula , Polietilenglicoles/química , Poliglactina 910/química
18.
Int J Nanomedicine ; 15: 10271-10284, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33364758

RESUMEN

INTRODUCTION: Cancer theragnosis involving cancer diagnosis and targeted therapy simultaneously in one integrated system would be a promising solution of cancer treatment. Herein, a convenient and practical cancer theragnosis agent was constructed by combining gold nanocages (AuNCs) covered with selenium and a chitosan (CS) shell (AuNCs/Se) to incorporate the anti-cancer drug doxorubicin (DOX) as a multifunctional targeting nanocomposite (AuNCs/DOX@Se-iRGD) for photoacoustic imaging (PAI)-guided chemo-photothermal synergistic therapy that contributes to enhanced anti-cancer efficacy. The novel design of AuNCs/DOX@Se-iRGD gives the nanocomposite two outstanding properties: (1) AuNCs, with excellent LSPR property in the NIR region, act as a contrast agent for enhanced PAI and photothermal therapy (PTT); (2) Se acts as an anti-cancer nanoagent and drug delivery cargo. METHODS: The photothermal performance of these nanocomposites was evaluated in different concentrations with laser powder densities. These nanocomposites were also incubated in pH 5.3, 6.5, 7.4 PBS and NIR laser to study their drug release ability. The cellular uptake was studied by measuring the Se and Au concentrations inside the cells using inductively coupled plasma-mass spectrometry (ICP-MS). Besides, in vitro and in vivo anti-tumor activity were carried out by cytotoxicity assay MTT and tumor model nude mice, respectively. As for imaging, the PA value and images of these nanocomposites accumulated in the tumor site were sequentially collected at specific time points for 48 h. RESULTS AND DISCUSSION: The prepared AuNCs/DOX@Se-iRGD showed excellent biocompatibility and physiological stability in different media. In vivo results indicated that the targeting nanocomposite presented the strongest contrast-enhanced PAI signals, which could provide contour and location information of tumor, 24 h after intravenous injection. Likewise, the combined treatment of chemo- and photothermal synergistic therapy significantly inhibited tumor growth when compared with the two treatments carried out separately and showed negligible acute toxicity to the major organs. CONCLUSION: This study demonstrates that AuNCs/DOX@Se-iRGD has great prospect to become a multifunctional anti-tumor nanosystem for PAI-guided chemo- and photothermal synergistic therapy.


Asunto(s)
Portadores de Fármacos/química , Oro/química , Técnicas Fotoacústicas , Terapia Fototérmica/métodos , Selenio/química , Nanomedicina Teranóstica/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Humanos , Ratones , Ratones Desnudos
19.
Microb Pathog ; 142: 104036, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32017958

RESUMEN

BACKGROUND: In the immunocompromised conditions following renal transplantation, BK virus can reactivate and cause BK virus associated nephropathy (BKVN). Increased BK viral loads and extended duration of infection have been linked to development of BKVN. The aim of this study was to observe the incidence of BKV infection and BKVN, and kinetics of infection and disease in renal transplantation recipients. METHODS: From 2014 to 2018, we conducted a longitudinal cohort observational study of 139 renal transplantation patients treated at a single clinic. Quantitative PCR assay was conducted to assess longitudinal BK viral loads. Analysis of patient clinical characteristics was performed to determine risk factors for BKV infection and associated disease. RESULTS: Of our cohort, 29 (20.9%) patients developed high BK viremia, and 7 (5.0%) developed biopsy-confirmed BKVN. Clinical parameters associated with diabetes (FBS, HbA1c) and hyperlipidemia (TG, TC, LDL-C) were found to be correlated with development of high BK viremia or BKVN. In 3 of 4 patients receiving intravenous immunoglobulin (IVIG) treatment, BK viral loads were reduced by at least 1 log within 2-3 months of administration. Significant differences were measured in BK viral loads and kidney function between BK viremic patients and BKVN patients by 3-9 months post-transplantation. CONCLUSIONS: We identified diabetes and hyperlipidemia as potential risk factors for development of high BK viremia and/or BKVN. IVIG was seen to be effective in reducing viral titers. The period 3-9 months post-transplantation was identified as important for development of BKVN from high BK viremia.

20.
Ageing Res Rev ; 58: 101021, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31968269

RESUMEN

The integrity of the cytoskeleton is essential to diverse cellular processes such as phagocytosis and intracellular trafficking. Disruption of the organization and dynamics of the actin cytoskeleton leads to age-associated symptoms and diseases, ranging from cancer to neurodegeneration. In addition, changes in the integrity of the actin cytoskeleton disrupt the functioning of not only somatic and stem cells but also gametes, resulting in aberrant embryonic development. Strategies to preserve the integrity and dynamics of the cytoskeleton are, therefore, potentially therapeutic to age-related disorders. The objective of this article is to revisit the current understanding of the roles played by the actin cytoskeleton in aging, and to review the opportunities and challenges for the transition of basic research into intervention development. It is hoped that, with the snapshot of evidence regarding changes in actin dynamics with advanced age, insights into future research directions can be attained.


Asunto(s)
Citoesqueleto de Actina , Envejecimiento , Citoesqueleto , Actinas , Envejecimiento/fisiología , Movimiento Celular , Humanos
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