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Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer with a poor prognosis that often shows resistance to chemotherapy. This study retrospectively analyzed 247 patients with OCCC who were admitted to the Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS) between August 2007 and August 2023. Univariate and multivariate Cox regression analyses were used to identify clinicopathological factors associated with OCCC, and a nomogram prediction model was developed to predict OCCC patient survival outcomes. KaplanâMeier survival analysis was used to compare survival outcomes among patients with recurrent disease. Compared with systemic therapy, secondary debulking surgery significantly improved the postrecurrence survival (PRS) rate (P = 0.006). Subgroup analysis revealed that the survival benefit was more pronounced in patients with recurrence and satisfactory tumor shrinkage (PPRS = 0.01, PPFS2 = 0.047). The multivariate analysis revealed that positive preoperative ascites, incomplete remission following initial treatment, and undergoing more than six cycles of postoperative chemotherapy were independent prognostic factors affecting overall survival (OS). Additionally, patients with a positive PD-L1 test who received immunotherapy did not experience relapse during the follow-up period. In conclusion, the secondary clearance procedure offers significant benefits for patients with recurrent OCCC, and patients may experience a survival benefit from supplemental immune or targeted therapy at the end of chemotherapy. The development of a personalized treatment plan can help achieve precise treatment, improve prognosis, and enhance patients' quality of life.
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BACKGROUND: Light chain cardiac amyloidosis (AL-CA) is associated with a high incidence of mortality. Big endothelin-1 (ET-1), the precursor of endothelial-vasoconstrictive ET-1, is closely related to the concentration of bioactive ET-1. Association between big ET-1 and prognosis of AL-CA has not yet been documented. The purpose of this study was to evaluate the prognostic value of big ET-1 for poor outcomes in moderate to severe AL-CA. METHODS: Big ET-1 levels were determined on admission in patients with newly diagnosed AL-CA with modified Mayo 2004 stage II or III. Primary outcome was all-cause mortality. The secondary outcomes included death from cardiac cause and the composite of the primary outcome or hospitalisations due to worsening heart failure. RESULTS: Overall, 141 patients were retrospectively included (57 stage II, 34 stage IIIa, 50 stage IIIb). During a median follow-up time of 25.7 months, 84 (59.6%) patients died. Patients with big ET-1 levels of ≤0.88 pmol/L had longer survival than those with >0.88 pmol/L (median survival time: 34.1 months vs 15.3 months, log-rank p<0.001), which was also observed in the validation cohort (log-rank p=0.026). Higher big ET-1 levels were predictive for all-cause mortality after multivariable adjustment (HR 1.91, 95% CI 1.05 to 3.49, p=0.035). Big ET-1 levels added an incremental prognostic value over modified Mayo 2004 stage (C-index: from 0.671 to 0.696, p=0.025; integrated discrimination improvement 0.168, p=0.047). CONCLUSIONS: Big ET-1 is a strong and independent predictor of mortality in patients with moderate to severe AL-CA, which may indicate a possible role for risk stratification in patients with this disease.
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Biomarcadores , Cardiomiopatías , Endotelina-1 , Humanos , Endotelina-1/sangre , Masculino , Femenino , Anciano , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Cardiomiopatías/sangre , Cardiomiopatías/mortalidad , Cardiomiopatías/diagnóstico , Biomarcadores/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Índice de Severidad de la Enfermedad , Valor Predictivo de las Pruebas , Factores de Riesgo , Medición de Riesgo/métodosRESUMEN
The rapid mutation of SARS-CoV-2 has led to multiple rounds of large-scale breakthrough infection and reinfection worldwide. However, the dynamic changes of humoral and cellular immunity responses to several subvariants after infection remain unclear. In our study, a 6-month longitudinal immune response evaluation was conducted on 118 sera and 50 PBMC samples from 49 healthy individuals who experienced BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection. By studying antibody response, memory B cell, and IFN-γ secreting CD4+/CD8+ T cell response to several SARS-CoV-2 variants, we observed that each component of immune response exhibited distinct kinetics. Either BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection induces relatively high level of binding and neutralizing antibody titers against Omicron subvariants at an early time point, which rapidly decreases over time. Most of the individuals at 6 months post-breakthrough infection completely lost their neutralizing activities against BQ.1.1, CH.1.1, BA.2.86, JN.1 and XBB subvariants. Individuals with BA.5/BF.7-XBB reinfection exhibit immune imprinting shifting and recall pre-existing BA.5/BF.7 neutralization antibodies. In the BA.5 breakthrough infection group, the frequency of BA.5 and XBB.1.16-RBD specific memory B cells, resting memory B cells, and intermediate memory B cells gradually increased over time. On the other hand, the frequency of IFN-γ secreting CD4+/CD8+ T cells induced by WT/BA.5/XBB.1.16 spike trimer remains stable over time. Overall, our research indicates that individuals with breakthrough infection have rapidly declining antibody levels but have a relatively stable cellular immunity that can provide some degree of protection from future exposure to new antigens.
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The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum-neutralizing activity against diverse coronaviruses. Through single B-cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, PW5-570 potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1, and SARS-CoV viral challenge in golden Syrian hamsters, respectively. Importantly, post-exposure treatment with PW5-5 and PW5-535 also markedly protects against XBB.1 challenge in these models. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.
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BACKGROUND: Breast cancer (BC) is the most common cancer among women worldwide and a leading cause of cancer-associated deaths among women. However, there is a lack of accurate prognostic biomarkers for BC. In the present study, we aimed to identify a genomic instability (GI)-associated microRNA signature as a novel potential prognostic biomarker in BC. METHODS: We performed an integrative analysis to investigate the relationship between GI and BC and identify GI-associated microRNAs (miRNAs). Subsequently, we conducted a discovery and validation study using multicenter cohorts. The GI-associated miRNA signature was developed in the discovery cohort and independently validated in internal and external cohorts. RESULTS: GI-associated miRNAs expression in BC showed heterogeneity and was significantly correlated with BC prognosis. We identified a GI-associated two-miRNA signature (miR-105-5p and miR-767-5p), termed GI2miR, that stratified BC patients into high-risk and low-risk groups with significantly different clinical outcomes (log-rank p = 0.027) in The Cancer Genome Atlas (TCGA) discovery cohort (n = 763). The prognostic value of GI2miR was further validated in internal TCGA validation cohort (n = 253) (log-rank p = 0.035) and independent GSE22216 cohort (n = 210) (log-rank p = 0.036). The GI2miR demonstrated independent prognostic value in multivariate Cox proportional hazard regression analyses and stratification analysis. CONCLUSIONS: We have developed a novel prognostic signature based on GI-associated two miRNAs for BC, which may lay the foundation for BC to improve prognosis prediction.
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Neoplasias de la Mama , MicroARNs , Humanos , Femenino , Neoplasias de la Mama/genética , Pronóstico , MicroARNs/genética , MicroARNs/metabolismo , BiomarcadoresRESUMEN
Emerging SARS-CoV-2 sub-lineages like XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3 and the variant BA.2.86 have recently been identified. Understanding the efficacy of current vaccines on these emerging variants is critical. We evaluate the serum neutralization activities of participants who received COVID-19 inactivated vaccine (CoronaVac), those who received the recently approved tetravalent protein vaccine (SCTV01E), or those who had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Neutralization profiles against a broad panel of 30 sub-lineages reveal that BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibit heightened resistance to neutralization compared to previous variants. However, despite their extra mutations, BA.2.86 and the emerging XBB sub-lineages do not demonstrate significantly increased resistance to neutralization over XBB.1.5. Encouragingly, the SCTV01E booster consistently induces higher neutralizing titers against all these variants than breakthrough infection does. Cellular immunity assays also show that the SCTV01E booster elicits a higher frequency of virus-specific memory B cells. Our findings support the development of multivalent vaccines to combat future variants.
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Infección Irruptiva , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Humanos , COVID-19/prevención & control , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
PURPOSE: To develop a partially interpretable neural network for joint suppression of banding and flow artifacts in non-phase-cycled bSSFP cine imaging. METHODS: A dual-stage neural network consisting of a voxel-identification (VI) sub-network and artifact-suppression (AS) sub-network is proposed. The VI sub-network provides identification of artifacts, which guides artifact suppression and improves interpretability. The AS sub-network reduces banding and flow artifacts. Short-axis cine images of 12 frequency offsets from 28 healthy subjects were used to train and test the dual-stage network. An additional 77 patients were retrospectively enrolled to evaluate its clinical generalizability. For healthy subjects, artifact suppression performance was analyzed by comparison with traditional phase cycling. The partial interpretability provided by the VI sub-network was analyzed via correlation analysis. Generalizability was evaluated for cine obtained with different sequence parameters and scanners. For patients, artifact suppression performance and partial interpretability of the network were qualitatively evaluated by 3 clinicians. Cardiac function before and after artifact suppression was assessed via left ventricular ejection fraction (LVEF). RESULTS: For the healthy subjects, visual inspection and quantitative analysis found a considerable reduction of banding and flow artifacts by the proposed network. Compared with traditional phase cycling, the proposed network improved flow artifact scores (4.57 ± 0.23 vs 3.40 ± 0.38, P = 0.002) and overall image quality (4.33 ± 0.22 vs 3.60 ± 0.38, P = 0.002). The VI sub-network well identified the location of banding and flow artifacts in the original movie and significantly correlated with the change of signal intensities in these regions. Changes of imaging parameters or the scanner did not cause a significant change of overall image quality relative to the baseline dataset, suggesting a good generalizability. For the patients, qualitative analysis showed a significant improvement of banding artifacts (4.01 ± 0.50 vs 2.77 ± 0.40, P < 0.001), flow artifacts (4.22 ± 0.38 vs 2.97 ± 0.57, P < 0.001), and image quality (3.91 ± 0.45 vs 2.60 ± 0.43, P < 0.001) relative to the original cine. The artifact suppression slightly reduced the LVEF (mean bias = -1.25%, P = 0.01). CONCLUSIONS: The dual-stage network simultaneously reduces banding and flow artifacts in bSSFP cine imaging with a partial interpretability, sparing the need for sequence modification. The method can be easily deployed in a clinical setting to identify artifacts and improve cine image quality.
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Artefactos , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Aumento de la Imagen/métodos , Estudios Retrospectivos , Volumen Sistólico , Interpretación de Imagen Asistida por Computador/métodos , Algoritmos , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Función Ventricular Izquierda , Redes Neurales de la Computación , Imagen por Resonancia CinemagnéticaRESUMEN
Evidence of antibody-dependent enhancement (ADE) of other viruses has raised concerns about the safety of SARS-CoV-2 vaccines and antibody therapeutics. In vitro studies have shown ADE of SARS-CoV-2 infection. In this study, we also found that vaccination/convalescent sera and some approved monoclonal antibodies can enhance SARS-CoV-2 infection of FcR-expressing B cells in vitro. However, the enhancement of SARS-CoV-2 infection can be prevented by blocking Fc-FcR interaction through the addition of human serum/IgG or the introduction of mutations in the Fc portion of the antibody. It should be noted that ADE activity observed on FcR-expressing cells in vitro may not necessarily reflect the situation in vivo; therefore, animal and clinical data should be included for ADE evaluation.
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The lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to the lesion core for precise treatment in the intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with a hierarchical structure is constructed using the double emulsion-extrusion method by integrating a neutrophil membrane, functional antibody, and gelled drug-loaded core as a three-stage booster to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating the neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, a myosin light chain 3 (MLC3) antibody is embedded to fulfill the second stage of CMEV accumulation in the lesion core. The gelled core containing CST-sodium alginate (NaAlg) with a pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization, and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy.
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Apoptosis , Cardiomiopatías , Humanos , Membrana Celular , PéptidosRESUMEN
OBJECTIVES: The HFA-PEFF score has been validated to hold great diagnostic and prognostic utility for heart failure with preserved ejection fraction (HFpEF). Idiopathic inflammatory myopathy (IIM) is recognized as one of the potential etiologies underlying HFpEF. Here, we intended to investigate the real prevalence of HFpEF in IIM via the HFA-PEFF score and explore the prognostic value of this score. METHODS: Two hundred twenty IIM patients were enrolled for assessment. The cohort was divided into low, intermediate and high tertiles of the HFA-PEFF score. Spearman's correlation analysis was used to explore the association between the score and disease activity. Chi-square test was applied to investigate the distribution discrepancy of HFA-PEFF tertiles among patients with different myositis-specific antibodies (MSAs) or myositis-associated antibodies (MAAs). Univariate and multivariate ordinal regression analyses were performed to screen risk factors for high HFA-PEFF scores. Survival curves were obtained using the Kaplan-Meier method and log-rank tests. RESULTS: In total, 79 (35.9%), 107 (48.6%) and 34 (15.5%) patients were rated low, intermediate and high probability of HFpEF, respectively. The HFA-PEFF score correlated well with disease activity. Patients with positive AMA-M2 scored higher in the HFA-PEFF score (p = 0.011). During follow-up, patients with positive AMA-M2 or anti-SRP antibody developed an inclination towards concentric hypertrophy on echocardiography. Additionally, palpitation symptom, AMA-M2 positivity and elevated serum levels of LDH, cTnI were independent risk factors for high HFA-PEFF scores. Finally, a high-tertile HFA-PEFF score was related to lower overall survival rate (p < 0.001). Patients with positive AMA-M2 had poorer outcomes (p = 0.002). CONCLUSION: HFpEF was prevailing in IIM patients according to the HFA-PEFF score. The HFA-PEFF score correlated well with disease activity and held significant prognostic value. Patients with AMA-M2 antibody were prone to have poor outcomes.
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Insuficiencia Cardíaca , Miositis , Humanos , Insuficiencia Cardíaca/diagnóstico , Volumen Sistólico , Pronóstico , Anticuerpos , Miositis/diagnóstico , AlgoritmosRESUMEN
BACKGROUND: Insulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice. METHODS: HER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored. RESULTS: Of 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006). CONCLUSION: Insulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.
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Fibrilación Atrial , Neoplasias de la Mama , Cardiopatías , Resistencia a la Insulina , Adulto , Femenino , Humanos , Persona de Mediana Edad , Fibrilación Atrial/complicaciones , Neoplasias de la Mama/patología , Cardiotoxicidad/etiología , Cardiotoxicidad/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Remodelación VentricularRESUMEN
Human enterovirus A71 (EV-A71) is the major causative agent of hand, foot, and mouth disease (HFMD), which may lead to neurological sequelae and even death. Although EV-A71 seriously threatens public health, there remains no efficient drug for the treatment of EV-A71 infection. We previously demonstrated that ROCK1 is a novel host dependency factor for EV-A71 replication and can serve as a target for the development of anti-EV-A71 therapeutics. In this study, we identified a subset of inhibitors with potential anti-EV-A71 activity by virtual screening using ROCK1 as a target. Among the hits, Dasabuvir, an HCV polymerase inhibitor, was found to have the best antiviral activity which is consistent with the ranking scores in Autodock Vina and iGEMDOCK. We found that Dasabuvir efficiently suppressed EV-A71 replication in a dose-dependent manner. Moreover, Dasabuvir not only efficiently suppressed the replication of EV-A71 in RD cells, but also in multiple cell lines, including HEK-293T, Caco-2, HT-29, HepG2, and Huh7. Besides, Dasabuvir alleviated the release of proinflammatory cytokines caused by EV-A71 infection. Notably, Dasabuvir also exhibited antiviral activity of CVA10, indicating it may have broad-spectrum antiviral activity against species Enteroviruses A. Hence, our results further confirm that ROCK1 can be a potential drug target and suggest Dasabuvir could be a clinical candidate for the treatment of EV-A71 infection.
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Enterovirus Humano A , Infecciones por Enterovirus , Enterovirus , Enfermedad de Boca, Mano y Pie , Humanos , Células CACO-2 , Infecciones por Enterovirus/tratamiento farmacológico , Antivirales/farmacología , Quinasas Asociadas a rhoRESUMEN
This study aimed to identify microbial signatures that contribute to the shared etiologies between chronic heart failure (CHF), type 2 diabetes, and chronic kidney disease. The serum levels of 151 microbial metabolites were measured in 260 individuals from the Risk Evaluation and Management of heart failure cohort, and it was found that those metabolites varied by an order of 105 fold. Out of 96 metabolites associated with the three cardiometabolic diseases, most were validated in two geographically independent cohorts. In all three cohorts, 16 metabolites including imidazole propionate (ImP) consistently showed significant differences. Notably, baseline ImP levels were three times higher in the Chinese compared with the Swedish cohorts and increased by 1.1-1.6 fold with each additional CHF comorbidity in the Chinese population. Cellular experiments further supported a causal link between ImP and distinct CHF relevant phenotypes. Additionally, key microbial metabolite-based risk scores were superior in CHF prognosis than the traditional Framingham or Get with the Guidelines-Heart Failure risk scores. Interactive visualization of these specific metabolite-disease links is available on our omics data server (https://omicsdata.org/Apps/REM-HF/).
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Comorbilidad , Enfermedad Crónica , Factores de Riesgo , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiologíaRESUMEN
Background Catestatin has been reported as a pleiotropic cardioprotective peptide. Heart failure with preserved ejection fraction (HFpEF) was considered a heterogeneous syndrome with a complex cause. We sought to investigate the role of catestatin in HFpEF and diastolic dysfunction. METHODS AND RESULTS Administration of recombinant catestatin (1.5 mg/kg/d) improved diastolic dysfunction and left ventricular chamber stiffness in transverse aortic constriction mice with deoxycorticosterone acetate pellet implantation, as reflected by Doppler tissue imaging and pressure-volume loop catheter. Less cardiac hypertrophy and myocardial fibrosis was observed, and transcriptomic analysis revealed downregulation of mitochondrial electron transport chain components after catestatin treatment. Catestatin reversed mitochondrial structural and respiratory chain component abnormality, decreased mitochondrial proton leak, and reactive oxygen species generation in myocardium. Excessive oxidative stress induced by Ru360 abolished catestatin treatment effects on HFpEF-like cardiomyocytes in vitro, indicating the beneficial role of catestatin in HFpEF as a mitochondrial ETC modulator. The serum concentration of catestatin was tested among 81 patients with HFpEF and 76 non-heart failure controls. Compared with control subjects, serum catestatin concentration was higher in patients with HFpEF and positively correlated with E velocity to mitral annular e' velocity ratio, indicating a feedback compensation role of catestatin in HFpEF. Conclusions Catestatin protects against diastolic dysfunction in HFpEF through attenuating mitochondrial electron transport chain-derived reactive oxygen species generation. Serum catestatin concentration is elevated in patients with HFpEF, probably as a relatively insufficient but self-compensatory mechanism.
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Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Ratones , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/prevención & control , Volumen Sistólico/fisiología , Especies Reactivas de Oxígeno , Miocardio , Función Ventricular Izquierda/fisiología , Disfunción Ventricular Izquierda/prevención & controlRESUMEN
INTRODUCTION: Lung cancer is a major global health problem because of its high incidence and mortality. Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung cancer (NSCLC). Nevertheless, recent studies demonstrated that cardiovascular disease (CVD) was the second leading cause of mortality in cancer survivors now, management of patients' cardiovascular health during the course of anticancer therapy has become a great challenge faced by the oncologists. Anticancer related cardiovascular (CV) complications are not limited to traditional chemotherapy, but are also increasingly recognized in targeted therapy. CASE REPORT: We present a case of pulmonary embolism (PE) and bradycardia in a 91-year-old NSCLC patient treated with crizotinib for a rare MET Y1003S mutation. To our knowledge, this is the second report to show antitumor response of crizotinib in lung cancer patients with such a rare mutation. However, the patient complained chest tightness and shortness of breath after a month of standard dose crizotinib therapy. Non-invasive examination revealed new onset bradycardia and PE. MANAGEMENT & OUTCOME: Such clinical manifestations were associated with targeted therapy-related CV toxicity, on which the emerging discipline cardio-oncology focused, and a multidisciplinary investigation and treatment was conducted. DISCUSSION: This case highlights the CV adverse events of novel therapies and the current challenges to be tackled in cardio-oncology.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Embolia Pulmonar , Humanos , Anciano de 80 o más Años , Crizotinib/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Bradicardia/inducido químicamente , Embolia Pulmonar/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.
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COVID-19 , SARS-CoV-2 , Humanos , Anticuerpos ampliamente neutralizantes , Pandemias , Anticuerpos NeutralizantesRESUMEN
Advanced glycation endproducts (AGEs) have been confirmed to play a causative role in the development of diabetic nephropathy (DN). In this study, we revealed that AGE-induced kidney injury with characteristic patterns in different stages and moesin phosphorylation plays a role in these processes. In WT mice treated with AGE-modified bovine serum albumin (AGE-BSA), distinct abnormal angiogenesis in Bowman's capsule of the kidney emerged early after 1 m under AGE-BSA stimulation, while these neovessels became rare after 6 m. AGE-BSA also induced glomerular hypertrophy and mesangial expansion at 1 m but glomerular atrophy and fibrosis at 6 m. Electron microscopy imaging demonstrated the damage of foot process integrity in podocytes and the uneven thickening of the glomerular basement membrane in the AGE-BSA-treated group, which was more significant after 6 m of AGE-BSA treatment than 1 m. The kidney dysfunction appeared along with these AGE-induced morphological changes. However, these AGE-BSA-induced pathological changes were significantly attenuated in RAGE-knockout mice. Moreover, moesin phosphorylation was accompanied by AGE-BSA-induced alterations and moesin deficiency in mice attenuated by AGE-BSA-induced fibrosis. The investigation on glomerular endothelial cells (GECs) also confirmed that the phosphorylation of moesin T558 is critical in AGE-induced tube formation. Overall, this study suggests that AGEs mediate kidney injury with characteristic patterns by binding with RAGE and inducing moesin phosphorylation.
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BACKGROUND AND AIM: Vascular endothelial cadherin (VE-cadherin) is an important element of adherens junctions (AJs) between endothelial cells. Its expression and proper distribution are critical for AJ formation and vascular integrity. Our previous studies have demonstrated that moesin phosphorylation mediated the hyper-permeability in endothelial monolayer and microvessels. However, the role of moesin and its phosphorylation in VE-cadherin expression and distribution is not clear. METHODS AND RESULTS: In vivo, expression of VE-cadherin was significantly reduced in retina and other various tissues in moesin knock out mice (Msn-/Y). In vitro, by regulating moesin expression with siRNA and adenovirus transfection, we verified that moesin has an effect on VE-cadherin expression in HUVECs, while transcription factor KLF4 may participate in this process. In addition, treatment of advanced glycation end products (AGEs) induced abnormal distribution of VE-cadherin in retinal microvessels from C57BL/6 wild type mice, and in vitro studies indicated that moesin Thr558 phosphorylation had a critical role in AGE-induced VE-cadherin internalization from cytomembrane to cytoplasm. Further investigation demonstrated that the inhibition of F-actin polymerization with cytochalasin D could abolish AGE- and Thr558 phosphor-moesin-mediated VE-cadherin internalization. CONCLUSION: This study suggests that moesin regulates VE-cadherin expression through KLF4 and the state of moesin phosphorylation at Thr558 affects the integrity of VE-cadherin-based AJs. Thr558 phosphor-moesin mediates AGE-induced VE-cadherin internalization through cytoskeleton reassembling.