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N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.
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Enfermedades Cardiovasculares , Hepatocitos , Humanos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/química , Análisis Costo-Beneficio , ARN Bicatenario , Acetilgalactosamina/química , Proteína 3 Similar a la AngiopoyetinaRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to cancer progression. PFKP is a rate-limiting enzyme involved in aerobic glycolysis, which is overexpressed in various types of cancers. However, the underlying mechanisms and roles of the posttranslational modification of PFKP in TNBC remain unknown. METHODS: To explore whether PFKP protein has a potential role in the progression of TNBC, protein levels of PFKP in TNBC and normal breast tissues were examined by CPTAC database analysis, immunohistochemistry staining (IHC), and western blotting assay. Further CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments were used to detect the effect of PFKP on TNBC progression. To clarify the role of the USP5-PFKP pathway in TNBC progression, ubiquitin assay, co-immunoprecipitation (Co-IP), mass spectrometry-based protein identification, western blotting assay, immunofluorescence microscopy, in vitro binding assay, and glycolysis assay were conducted. RESULTS: Herein, we showed that PFKP protein was highly expressed in TNBC, which was associated with TNBC progression and poor prognosis of patients. In addition, we demonstrated that PFKP depletion significantly inhibited the TNBC progression in vitro and in vivo. Importantly, we identified that PFKP was a bona fide target of deubiquitinase USP5, and the USP5-mediated deubiquitination and stabilization of PFKP were essential for cancer cell aerobic glycolysis and TNBC progression. Moreover, we found a strong positive correlation between the expression of USP5 and PFKP in TNBC samples. Notably, the high expression of USP5 and PFKP was significantly correlated with poor clinical outcomes. CONCLUSIONS: Our study established the USP5-PFKP axis as an important regulatory mechanism of TNBC progression and provided a rationale for future therapeutic interventions in the treatment of TNBC.
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Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Proliferación Celular , Glucólisis , Xenoinjertos , Trasplante Heterólogo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: Emerging data suggested that lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Previous studies indicated fibrinogen (Fib) had synergetic effect on Lp(a)-induced events. However, combined impact of Fib and Lp(a) on ischemic stroke has not been elucidated. METHODS: In this prospective study, we consecutively enrolled 8263 patients with stable coronary artery diseases (CAD) from 2011 to 2017. Patients were categorized into three groups according to tertiles of Lp(a) levels [Lp(a)-low, Lp(a)-medium, and Lp(a)-high] and further divided into nine groups by Lp(a) and Fib levels. All subjects were followed up for the occurrence of ischemic stroke. RESULTS: During a median follow-up of 37.7 months, 157 (1.9%) ischemic strokes occurred. Stroke incidence increased by Lp(a) (1.1 vs. 2.1 vs. 2.5%, Cochran-Armitage p < .001) and Fib (1.1 vs. 2.0 vs. 2.6%, Cochran-Armitage p < .001) categories. When further classified into nine groups by Lp(a) and Fib levels, the incidence of ischemic stroke in group 9 [Lp(a)-high and Fib-high] was significantly higher than that in group 1 [Lp(a)-low and Fib-low] (3.1 vs. 6%, p < .001). The group 9 was associated with a highest risk for ischemic stroke (adjusted HR 4.907, 95% CI: 2.154-11.18, p < .001), compared with individuals in the Lp(a)-high (adjusted HR 2.290, 95% CI: 1.483-3.537, p < .001) or Fib-high (adjusted HR 1.184, 95% CI: 1.399-3.410, p = .001). Furthermore, combining Lp(a) with Fib increased C-statistics by .045 (p = .004). CONCLUSIONS: Current study first demonstrated that elevated Lp(a) combining with Fib evaluation enhanced the risk of ischemic stroke in patients with CAD beyond Lp(a) or Fib alone.
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Enfermedad de la Arteria Coronaria , Fibrinógeno , Accidente Cerebrovascular Isquémico , Lipoproteína(a) , Humanos , Lipoproteína(a)/sangre , Lipoproteína(a)/metabolismo , Fibrinógeno/metabolismo , Masculino , Femenino , Enfermedad de la Arteria Coronaria/epidemiología , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular/epidemiología , Incidencia , Factores de RiesgoRESUMEN
PURPOSE OF REVIEW: The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression. RECENT FINDINGS: Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target.
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Aterosclerosis , Inflamación , Lipoproteína(a) , Humanos , Lipoproteína(a)/metabolismo , Lipoproteína(a)/sangre , Aterosclerosis/metabolismo , Aterosclerosis/inmunología , Inflamación/metabolismo , Animales , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Despite the benefits of artificial intelligence in small-bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning-based SmartScan (SS), which has been described previously. A total of 1069 magnetically controlled GI CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new artificial intelligence algorithm named SS Plus. A total of 342 fully automated, magnetically controlled CE examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-assisted reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (median, 1000; interquartile range [IQR], 814.50-1000) versus 44,322.73 (median, 42,393; IQR, 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 minutes (median, 8.51; IQR, 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded deep learning-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.
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In this paper, Au@Ag nanopencil is designed as a multimodality plasmonic nanoprobe based on asymmetric etching for the detection of SCN- and ClO- . Au@Ag nanopencil with Au tip and Au@Ag rod is prepared by asymmetric tailoring of uniformly grown silver-covered gold nanopyramids under the combined effect of partial galvanic replacement and redox reaction. By asymmetric etching in different systems, Au@Ag nanopencil exhibits diversified changes in the plasmonic absorption band: O2 â¢- facilitated by SCN- etches Au@Ag rod from the end to the tip, causing a blue shift of the localized surface plasmon resonance (LSPR) peak as the aspect ratio decreases; while the ClO- can retain Au@Ag shell and etch Ag within rod from the tip to the end, causing a redshift of the LSPR peak as the coupling resonance weakens. Based on peak shifts in different directions, a multimodality detection of SCN- and ClO- has been established. The results demonstrate the detection limits of SCN- and ClO- are 160 and 6.7 nm, and the linear ranges are 1-600 µm and 0.05-13 µm, respectively. The finely designed Au@Ag nanopencil not only broadens the horizon of designing heterogeneous structures, but also enriches the strategy of constructing multimodality sensing platform.
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Atherosclerosis, the key pathogenesis of cardiovascular disease, is a leading cause of death and disability worldwide. Statins are first-line lipid-lowering drugs, which have been demonstrated to be powerful agents for anti-atherosclerosis. Numerous studies have confirmed the cardiovascular benefits and long-term safety of statins in a wide range of patients. Statins play an indispensable and irreplaceable part in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). In this article, we summarize the evolution of statins and their role in the treatment of cholesterol. The anti-atherosclerotic mechanism of statins, its efficacy, safety and clinical outcomes in secondary and primary prevention of ACSVD in different patient populations, the combination treatment effects, and guideline recommendations are also detailed. This paper highlights the profound significance of statins as the most successful anti-atherogenic drug in the cardiovascular field.
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Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, but its pathogenesis is still poorly understood. Catheter ablation is one of the most effective treatments for AF, but recurrence after ablation remains a challenge. There has been much research into the association of AF recurrence with several factors, including genetics. Over the past decade or so, significant advances have been made in the genetic architecture of atrial fibrillation. Genome-wide association studies (GWAS) have identified over 100 loci for genetic variants associated with atrial fibrillation. However, there is relatively little information on the systematic assessment of the genes related to AF recurrence after ablation. In this review article, we highlight the value of genetic polymorphisms in atrial fibrillation recurrence after catheter ablation and their potential mechanisms in the recurrence process to enhance our understanding of atrial fibrillation recurrence and contribute to individualized treatment strategies for patients with AF.
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PURPOSE OF REVIEW: Acute coronary syndrome (ACS) and non-alcoholic fatty liver disease (NAFLD) are two clinically common disease entities that share numerous risk factors. This review aimed to discuss the impacts of NAFLD on ACS. RECENT FINDINGS: In an era of improved control of traditional risk factors, the substantial burden of cardiometabolic abnormalities has caused widespread concern. NAFLD is considered the hepatic component of metabolic syndrome, which can exert an impact on human health beyond the liver. Accumulating studies have demonstrated that NAFLD is closely related to cardiovascular disease, especially coronary artery disease. Interestingly, although recent data have suggested an association between NAFLD and the incidence and outcomes of ACS, the results are not consistent. In this review, we comprehensively summarized evidence and controversies regarding whether NAFLD is a contributor to either the development of ACS or worse outcomes in patients with ACS. The potential pathophysiological and molecular mechanisms involved in the impacts of NAFLD on ACS were also elucidated.
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Síndrome Coronario Agudo , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Síndrome Coronario Agudo/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Magnifying image-enhanced endoscopy (MIEE) is an advanced endoscopy with image enhancement and magnification used in preoperative examination. However, its impact on the detection rate is unknown. METHODS: We conducted an open-label, randomized, parallel (1:1:1), controlled trial in 6 hospitals in China. Patients were recruited between February 14, 2022 and July 30, 2022. Eligible patients were aged ≥18 years and undergoing gastroscopy in outpatient departments. Participants were randomly assigned to the MIEE-only mode (o-MIEE) group, white-light endoscopy-only mode (o-WLE) group, and MIEE when necessary mode (n-MIEE) group (initial WLE followed by switching to another endoscope with MIEE if necessary). Biopsy sampling of suspicious lesions of the lesser curvature of the gastric antrum was performed. Primary and secondary aims were to compare detection rates and positive predictive value (PPV) of early cancer and precancerous lesions in these 3 modes, respectively. RESULTS: A total of 5100 recruited patients were randomly assigned to the o-MIEE (n = 1700), o-WLE (n = 1700), and n-MIEE (n = 1700) groups. In the o-MIEE, o-WLE, and n-MIEE groups, 29 (1.51%; 95% confidence interval [CI], 1.05-2.16), 4 (.21%; 95% CI, .08-.54), and 8 (.43%; 95% CI, .22-.85) early cancers were found, respectively (P < .001). The PPV for early cancer was higher in the o-MIEE group compared with the o-WLE and n-MIEE groups (63.04%, 33.33%, and 38.1%, respectively; P = .062). The same trend was seen for precancerous lesions (36.67%, 10.00%, and 21.74%, respectively). CONCLUSIONS: The o-MIEE mode resulted in a significant improvement in diagnosing early upper GI cancer and precancerous lesions; thus, it could be used for opportunistic screening. (Clinical trial registration number: ChiCTR2200064174.).
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Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Adolescente , Adulto , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/patología , Gastroscopía/métodos , Valor Predictivo de las Pruebas , BiopsiaRESUMEN
PURPOSE: Given the beneficial effects of sacubitril/valsartan on blood pressure generally, this study investigates its antihypertension effects in diabetes mellitus (DM) patients with primary hypertension specifically, and the effect of sacubitril/valsartan on glycolipid metabolism. METHODS: We conducted a randomized, open-label, active-controlled study to compare the antihypertension effects of sacubitril/valsartan in DM individuals with primary hypertension. The primary end point was reduction in mean systolic blood pressure (SBP) from baseline with sacubitril/valsartan vs. olmesartan at week 8. The secondary endpoints included the changes in diastolic blood pressure (DBP), daytime SBP/DBP, nighttime SBP/DBP, BP achievement (office sitting BP < 130/80 mmHg), and lipid profile. The trial was registered with chictr.org.cn (ChiCTR2200066428) on Dec 22, 2022. RESULTS: A total of 124 patients were included in the final analysis. SBP decreased to a greater extent in the sacubitril/valsartan group from baseline to 8 weeks [between-treatment difference: 3.51 mm Hg, 95% confidence interval (95% CI) 0.41 to 6.62 mm Hg, P = 0.03]. Furthermore, more patients achieved the blood pressure goal with sacubitril/valasartan (74.60% vs. 54.70%, P = 0.03). Multiple logistical regression analysis showed that sacubitril/valsartan was associated with BP achievement [odds ratio (OR) 0.33, 95% CI 0.14-0.73, P = 0.007], but the difference in SBP, DBP, day time SBP/DBP, and night time SBP/DBP reduction did not approach statistical significance. HbA1C1, total cholesterol, and low-density lipoprotein-cholesterol were lower than baseline in both groups (P < 0.05); however, there was no difference in the effects on glucose and lipid metabolism from sacubitril/valsartan compared to olmesartan. CONCLUSIONS: Sacubitril/valsartan not only provided superior BP reduction compared to olmesartan, it did so without adverse effects on glycemic control and lipid parameters in DM patients with primary hypertension.
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BACKGROUND: Familial hypercholesterolemia (FH) leads to high plasma low-density lipoprotein cholesterol (LDL-C) levels and early cardiovascular morbidity and mortality. We treated a pair of siblings with FH. The cardiovascular manifestations in the proband were more severe than those in his elder sister, although they had almost similar LDL-C levels, ages, and lifestyles. Herein, we report the cases of this family to explore the possible causes of clinical phenotypic differences within the same genetic background. CASE PRESENTATION: We treated a 27-year-old male patient and his 30-year-old sister, both with FH. The coronary angiogram in the male patient revealed 80, 70, and 100% stenosis of the initial, distal right coronary artery branch, and left anterior descending branch, respectively, whereas his sister had almost no coronary stenosis. We treated them accordingly and performed family screening. We found that the LDL-C/particle discordance of the proband is much greater than that of his elder sister. In addition, the average size of LDL-C particle in the proband was smaller than that in his sister. CONCLUSIONS: Patients with FH have a much higher risk of premature atherosclerotic cardiovascular disease, but the clinical manifestations are heterogeneous. The smaller LDL particle size may be the underlying cause for different clinical outcomes in this pair of FH cases and be a potential novel indicator for predicting the prognosis of FH.
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Hiperlipoproteinemia Tipo II , Hermanos , Masculino , Humanos , LDL-Colesterol , Constricción Patológica , FenotipoRESUMEN
BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a malignant tumor responsible for a heavy disease burden. Previously, only one pan-cancer study of Transmembrane channel-like protein 5 (TMC5) showed that TMC5 was highly expressed in PAAD, but the results lacked comprehensive verification, and the mechanism of TMC5 in PAAD was still unclear. METHODS: For exploring the expression and clinical value of TMC5 in PAAD better, we adopted a comprehensive evaluation method, using internal immunohistochemistry (IHC) data combined with microarray and RNA-sequencing data collected from public databases. The single cell RNA-sequencing (scRNA-seq) data were exploited to explore the TMC5 expression in cell populations and intercellular communication. The potential mechanism of TMC5 in PAAD was analyzed from the aspects of immune infiltration, transcriptional regulation, function and pathway enrichment. RESULTS: Our IHC data includes 148 PAAD samples and 19 non-PAAD samples, along with the available microarray and RNA-sequencing data (1166 PAAD samples, 704 non-PAAD samples). The comprehensive evaluation results showed that TMC5 was evidently up-regulated in PAAD (SMD = 1.17). Further analysis showed that TMC5 was over-expressed in cancerous epithelial cells. Furthermore, TMC5 was up-regulated in more advanced tumor T and N stages. Interestingly, we found that STAT3 as an immune marker of Th17 cells was not only positively correlated with TMC5 and up-regulated in PAAD tissues, but also the major predicted TMC5 transcription regulator. Moreover, STAT3 was involved in cancer pathway of PAAD. CONCLUSION: Up-regulated TMC5 indicates advanced tumor stage in PAAD patients, and its role in promoting PAAD development may be regulated by STAT3.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Neoplasias Pancreáticas/genética , Comunicación Celular , Costo de Enfermedad , Pronóstico , Regulación Neoplásica de la Expresión Génica , Neoplasias PancreáticasRESUMEN
STUDY DESIGN: Retrospective epidemiological study. OBJECTIVES: To determine the characteristics of sports-related spinal cord injury (SCI) in China and assess changes in the trend of these injuries that may impact policy making. SETTING: China Rehabilitation Research Center (CRRC), Beijing. METHODS: Of the 2448 SCI cases reviewed, 6.7% (n = 164) were caused by sport- and recreation-related accidents. They were admitted to the CRRC between January 1, 2013 and December 31, 2019. We collected data on age, sex, etiology, the neurological level of injury, the American Spinal Injury Association (ASIA) Impairment Scale (AIS) scores on admission, and the neurological recovery results at discharge. RESULTS: Dancing (58.6%), followed by water sports (14.7%) and taekwondo (4.2%) were the leading etiologies. Of the SCIs caused by dancing, 27.1% of the individuals had incomplete injury, and of these, 57.7% showed improved neurological function. However, 72.9% had complete injury, and these individuals did not show any improvement in neurological function. Individuals with dance-related SCIs graded as A and D according to the AIS, showed no significant improvement in their motor function scores at the time of discharge. While the scores of those graded B and C increased significantly, there were no significant differences in the light touch and pin touch scores. CONCLUSIONS: The etiology of sports-related SCI in China has changed dramatically, with dancing replacing water sports as the primary cause of SCIs. Individuals with dance-related SCIs have a poor prognosis. In China, prevention of dance-related SCIs has become a priority.
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Traumatismos de la Médula Espinal , Deportes Acuáticos , Humanos , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/etiología , Estudios Retrospectivos , China/epidemiologíaRESUMEN
Objective To analyze the genetic subtypes of human immunodeficiency virus (HIV) and the prevalence of pretreatment drug resistance in the newly reported HIV-infected men in Guangxi. Methods The stratified random sampling method was employed to select the newly reported HIV-infected men aged≥50 years old in 14 cities of Guangxi from January to June in 2020.The pol gene of HIV-1 was amplified by nested reverse transcription polymerase chain reaction and then sequenced.The mutation sites associated with drug resistance and the degree of drug resistance were then analyzed. Results A total of 615 HIV-infected men were included in the study.The genetic subtypes of CRF01_AE,CRF07_BC,and CRF08_BC accounted for 57.4% (353/615),17.1% (105/615),and 22.4% (138/615),respectively.The mutations associated with the resistance to nucleoside reverse transcriptase inhibitors (NRTI),non-nucleoside reverse transcriptase inhibitors (NNRTI),and protease inhibitors occurred in 8 (1.3%),18 (2.9%),and 0 patients,respectively.M184V (0.7%) and K103N (1.8%) were the mutations with the highest occurrence rates for the resistance to NRTIs and NNRTIs,respectively.Twenty-two (3.6%) patients were resistant to at least one type of inhibitors.Specifically,4 (0.7%),14 (2.3%),4 (0.7%),and 0 patients were resistant to NRTIs,NNRTIs,both NRTIs and NNRTIs,and protease inhibitors,respectively.The pretreatment resistance to NNRTIs had much higher frequency than that to NRTIs (2.9% vs.1.3%;χ2=3.929,P=0.047).The prevalence of pretreatment resistance to lamivudine,zidovudine,tenofovir,abacavir,rilpivirine,efavirenz,nevirapine,and lopinavir/ritonavir was 0.8%, 0.3%, 0.7%, 1.0%, 1.3%, 2.8%, 2.9%, and 0, respectively. Conclusions CRF01_AE,CRF07_BC,and CRF08_BC are the three major strains of HIV-infected men≥50 years old newly reported in Guangxi,2020,and the pretreatment drug resistance demonstrates low prevalence.
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Infecciones por VIH , VIH-1 , Masculino , Humanos , Persona de Mediana Edad , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Farmacorresistencia Viral/genética , China/epidemiología , Mutación , VIH-1/genética , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , GenotipoRESUMEN
BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited. METHODS: This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years. RESULTS: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months. CONCLUSIONS: These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC. LAY SUMMARY: The utility of serial circulating tumor DNA (ctDNA) monitoring for predicting disease recurrence and survival for early-stage non-small cell lung cancer (NSCLC) has not been well characterized. The detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence and long-term patient outcomes for resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than routine radiologic imaging. ctDNA analyses can detect minimal residual disease for resectable NSCLC and thus can facilitate early intervention.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/cirugía , ADN Tumoral Circulante/sangre , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms. METHODS: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence. RESULTS: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1ß and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway. CONCLUSIONS: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia.
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Aterosclerosis , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Aterosclerosis/complicaciones , Aterosclerosis/metabolismo , Humanos , Hipercolesterolemia/complicaciones , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Inflamasomas/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Lipoproteínas LDL/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión al ARN , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated. METHODS: A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed. RESULTS: Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15-3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C < 2.6 mmol/L. CONCLUSIONS: The combination of elevated levels of RC, Lp(a), and hsCRP potentiated the adverse effect on MACEs among statin-treated patients with CCS, suggesting that multiple RCVR factors assessment may be a better strategy to improve stratification in very-high risk population.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Lipoproteína(a) , Proteína C-Reactiva/metabolismo , LDL-Colesterol , Progresión de la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inflamación/complicaciones , Pronóstico , Factores de Riesgo , SíndromeRESUMEN
With rapid economic growth and changes at all levels (including environmental, social, individual), China is facing a cardiovascular disease (CVD) crisis. In China, more than 40% of deaths are attributable to CVDs, and the number of CVD deaths has almost doubled in the past decades, in contrast to a decline in high-income countries. The increasing prevalence of cardiometabolic risk factors underlies the rise of CVDs, and thus curbing the rising cardiometabolic pandemic is imperative. Few articles have addressed this topic and provided an updated review of the epidemiology of cardiometabolic risk factors in China.In this narrative review, we describe the temporal changes in the prevalence of cardiometabolic risk factors in the past decades and their management in China, including both the well-recognized risk factors (general obesity, central obesity, diabetes, prediabetes, dyslipidemia, hypertension) and the less recognized ones (hyperhomocysteinemia, hyperuricemia, and high C-reactive protein). We also summarize findings from landmark clinical trials regarding effective interventions and treatments for cardiometabolic risk factors. Finally, we propose strategies and approaches to tackle the rising pandemic of cardiometabolic risk factors in China. We hope that this review will raise awareness of cardiometabolic risk factors not only in Chinese population but also global visibility, which may help to prevent cardiovascular risk.
Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Factores de Riesgo Cardiometabólico , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , China/epidemiología , Humanos , Hipertensión/epidemiología , Obesidad/complicaciones , Prevalencia , Factores de RiesgoRESUMEN
The triglyceride-glucose (TyG) index has been identified as a reliable alternative biomarker of insulin resistance (IR). Recently, a considerable number of studies have provided robust statistical evidence suggesting that the TyG index is associated with the development and prognosis of cardiovascular disease (CVD). Nevertheless, the application of the TyG index as a marker of CVD has not systemically been evaluated, and even less information exists regarding the underlying mechanisms associated with CVD. To this end, in this review, we summarize the history of the use of the TyG index as a surrogate marker for IR. We aimed to highlight the application value of the TyG index for a variety of CVD types and to explore the potential limitations of using this index as a predictor for cardiovascular events to improve its application value for CVD and provide more extensive and precise supporting evidence.