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It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Fragilidad , Lenalidomida , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Anciano , Estudios Prospectivos , Masculino , Femenino , Anciano de 80 o más Años , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Medicina de Precisión/métodos , Anciano Frágil , Evaluación Geriátrica/métodos , Anticuerpos MonoclonalesRESUMEN
Mitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines that are depleted of mitochondrial DNA. One week of ethidium bromide (EtBr) treatment led to â¼95 % reduction of mtDNA copy number (mtDNA-CN) in cells, which was further reduced by addition of 25 µM 2',3'-dideoxycytidin (ddC). Treatment for up to three weeks with EtBr and ddC led to near complete loss of mtDNA. The basal oxygen consumption rate (OCR) of mtDNA-depleted BET-1A and BEAS-2B cells dropped to near zero. Glycolysis measured by extracellular acidification rate (ECAR) increased â¼two-fold in cells when mtDNA was eliminated. BET-1A ρ0 and BEAS-2B ρ0 cells were cultured for two months, frozen and thawed, cultured for two more months, and maintained near zero mtDNA-CN. Mitochondrial DNA-depleted BET-1A ρ0 and BEAS-2B ρ0 cell lines are viable, lack the capacity for aerobic respiration, and increase glycolysis.â¢BET-1A and BEAS-2B cells were treated with ethidium bromide (EtBr) with or without 2',3'-dideoxycytidine (ddC) to create cells lacking mitochondrial DNA (mtDNA).â¢Cells' mtDNA copy number relative to nuclear DNA (nDNA) were verified by quantitative polymerase chain reaction (qPCR).â¢Cells were also assessed for oxidative phosphorylation by measures of oxygen consumption using the Seahorse analyzer.
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Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
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Introduction: Mitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines derived from primary airway epithelium that are depleted of mitochondrial DNA. Methods: We treated BET-1A and BEAS-2B cells with ethidium bromide (EtBr) with or without 2',3'-dideoxycytidine (ddC) to create cells lacking mitochondrial DNA (mtDNA). Cells' mtDNA copy number were verified by quantitative polymerase chain reaction (qPCR) in comparison to nuclear DNA (nDNA). Cells were also assessed for oxidative phosphorylation by measures of oxygen consumption using the Seahorse analyzer. Results: One week of EtBr treatment led to ~95% reduction of mtDNA copy number (mtDNA-CN) in cells (mtDNA-CN, mean±SE, baseline vs. treatment: BEAS-2B, 820 ± 62 vs. 56 ± 9; BET-1A, 957 ± 52 vs. 73 ± 2), which was further reduced by addition of 25 µM ddC (mtDNA-CN: BEAS-2B, 2.8; BET-1A, 47.9). Treatment for up to three weeks with EtBr and ddC led to near complete loss of mtDNA (mtDNA-CN: BEAS-2B, 0.1; BET-1A, 0.3). The basal oxygen consumption rate (OCR) of mtDNA-depleted BET-1A and BEAS-2B cells dropped to near zero. Glycolysis measured by extracellular acidification rate (ECAR) increased ~two-fold in cells when mtDNA was eliminated [ECAR (mpH/min/103 cells), baseline vs. treatment: BEAS-2B, 0.50 ± 0.03 vs. 0.94 ± 0.10 P=0.005; BET-1A, 0.80 ± 0.04 vs. 1.14 ± 0.06 P=0.001]. Conclusion: Mitochondrial DNA-depleted BET-1A ρ0 and BEAS-2B ρ0 cell lines are viable, lack the capacity for aerobic respiration, and increase glycolysis. This cell model system can be used to further test mitochondrial mechanisms of inflammation in bronchial epithelial cells.
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1q gain (+1q) is the most common high-risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097-1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk-scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re-stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression-free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high-risk patients, therefore underlining the necessity for their re-stratification. The proposed simple risk-scoring model can estimate the outcomes of patients with +1q, which may help guide risk-adapted treatment for such patients.
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Mieloma Múltiple , Humanos , Pronóstico , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Estudios Retrospectivos , Aberraciones Cromosómicas , Modelos de Riesgos ProporcionalesAsunto(s)
Mieloma Múltiple , Estudios de Cohortes , Humanos , Mieloma Múltiple/diagnóstico , PronósticoRESUMEN
Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.
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Asma , Eosinófilos , Humanos , Peroxidasa del Eosinófilo/metabolismo , Eosinófilos/metabolismo , Asma/diagnóstico , Asma/metabolismo , Esputo/metabolismo , Recuento de Leucocitos , Glucuronidasa/metabolismoRESUMEN
A colorimetric and fluorescent chemosensor (CS1) for Cu2+ based on the mechanism of internal charge transfer (ICT) has been successfully designed and prepared by simple condensation of 4_(diethylamino)salicylaldehyde and oxalyl dihydrazide. Cu2+ in solution (DMSO/H2O = 7:3, v/v) by 5 mM NaAc-HAc at pH 7.0 was determined through dual channels: (1) "naked-eye" observation, a visually dramatic color change from light green to orange, which can be used for qualitative determination of Cu2+; (2) spectrofluorometry, which can quantificationally assay Cu2+. It provides a simple-to-use platform for reliable detection of Cu2+ at concentrations ranging from 5.0 × 10-7 to 1.1 × 10-5 M with detection limit of 1.2 × 10-7 M, which is nearly 2 × 102 times lower than the maximum allowable level of inorganic Cu2+ in drinking water (1.3 ppm, â¼20 µM) permitted by the EPA (Environmental Protection Agency), and the sensing detection of Cu2+ ions was reversible.
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Colorimetría , Colorantes Fluorescentes , Cobre , Iones , Espectrometría de FluorescenciaRESUMEN
ABSTRACT: Our study investigated the correlation between sarcopenia and clinical outcomes in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. We retrospectively evaluated 40 consecutive patients with unresectable HCC receiving lenvatinib between November 2018 and May 2020 at the First Hospital of Jilin University. Skeletal muscle mass was measured before treatment initiation. Prognostic significance was assessed with univariate and multivariate Cox proportional hazards models. Overall survival (OS) and progression-free survival (PFS) were evaluated for patients with and without sarcopenia. Sarcopenia was present in 23/40 patients (57.5%). After a median follow-up of 9.2âmonths, patients with sarcopenia had significantly worse OS and PFS compared with those without sarcopenia (OS: 8.4âmonths [m] vs 14.7 m, Pâ=â.02; PFS: 4.2 m vs 9.0 m, Pâ=â.04). Multivariate Cox proportional hazards models identified presence of sarcopenia as an independent risk factor for shorter OS (hazard ratio [HR], 0.257; 95% confidence interval [CI], 0.083-0.794; Pâ=â.02). In subgroup analysis, sarcopenia was associated with worse survival than non-sarcopenic patients, irrespective of age, Barcelona clinic liver cancer stage, or albumin-bilirubin grade. Our results show sarcopenia may be a predictor of poor prognosis in patients with HCC receiving lenvatinib. Management of sarcopenia is a vital factor for improving survival outcomes in patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Sarcopenia , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Sarcopenia/complicacionesRESUMEN
Pulmonary arterial hypertension (PAH) is an insidious disease characterized by severe remodeling of the pulmonary vasculature caused in part by pathologic changes of endothelial cell functions. Although heterogeneity of endothelial cells across various vascular beds is well known, the diversity among endothelial cells in the healthy pulmonary vascular bed and the pathologic diversity among pulmonary arterial endothelial cells (PAEC) in PAH is unknown and previously unexplored. Here single-cell RNA sequencing technology was used to decipher the cellular heterogeneity among PAEC in the human pulmonary arteries isolated from explanted lungs from three patients with PAH undergoing lung transplantation and three healthy donor lungs not utilized for transplantation. Datasets of 36,368 PAH individual endothelial cells and 36,086 healthy cells were analyzed using the SeqGeq bioinformatics program. Total population differential gene expression analyses identified 629 differentially expressed genes between PAH and controls. Gene Ontology and Canonical Ingenuity analysis revealed pathways that are known to be involved in pathogenesis, as well as unique new pathways. At the individual cell level, dimensionality reduction followed by density based clustering revealed the presence of eight unique PAEC clusters that were typified by proliferative, angiogenic or quiescent phenotypes. While control and PAH harbored many similar subgroups of endothelial cells, PAH had greater proportions of angiogenic and proliferative subsets. These findings identify that only specific subgroups of PAH PAEC have gene expression different than healthy PAEC, and suggest these subpopulations lead to the pathologic functions leading to remodeling.
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Células Endoteliales/metabolismo , Hipertensión Arterial Pulmonar/genética , Arteria Pulmonar/metabolismo , Adulto , Estudios de Casos y Controles , Células Cultivadas , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Análisis de la Célula Individual/métodos , TranscriptomaRESUMEN
BACKGROUND AND AIMS: To compare the efficacy and safety of physical thermal ablation (PTA), including radiofrequency ablation (RFA) and microwave ablation (MWA), combined with sorafenib and physical thermal ablation alone for the control and treatment of hepatocellular carcinoma (HCC) according to the available literature. METHODS: Comprehensive searches were performed on PubMed, Embase, CNKI, the Cochrane Library, China Biomedical Literature Database (known as CBM), Weipu Journal, and Wanfang Database. Meta-analysis was performed using Revman 5.3 software. RESULTS: A total of 15 studies, consisting of 2,227 HCC patients, were selected and included in this meta-analysis. Compared with the RFA-alone group, the patients in the RFA+sorafenib group had longer 1-, 2-, and 3-year overall survival (all p<0.05), better overall efficacy (p<0.0001), longer radiofrequency interval (p<0.001), and lower 2-year recurrence rate (p=0.02). The 1-year overall survival (p=0.003) and overall efficacy (p=0.002) of the MWA+sorafenib group were also higher than those of the MWA-alone group. The incidences of adverse reactions in the RFA+sorafenib group, such as hand-foot skin reactions (p<0.001), diarrhea and constipation (p=0.0001), hypertension (p=0.009), and alopecia (p<0.001), were significantly higher than those in the RFA-alone group. CONCLUSIONS: RFA or MWA combined with sorafenib has produced a better therapeutic effect on HCC than physical thermal ablation alone; however, adverse reactions have been obvious. It is necessary to evaluate the safety of combination therapy, and pay close attention to the adverse reactions that develop in patients.
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The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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Inhibidores de la Angiogénesis/farmacología , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , Pulmón/efectos de los fármacos , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos , Enzima Convertidora de Angiotensina 2/genética , Animales , Benzamidas/farmacología , COVID-19/genética , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Pulmón/metabolismo , Pulmón/virología , Masculino , Ratones , Nitrilos/farmacología , Feniltiohidantoína/farmacología , Serina Endopeptidasas/genética , FumadoresRESUMEN
BACKGROUND: Antiphospholipid syndrome (APS) is an acquired pre-thrombotic autoimmune condition, which produces autoantibodies called antiphospholipid antibodies (APL) against phospholipid-binding plasma proteins. The diagnosis of APS requires at least one of Sapporo standard clinical manifestations and one laboratory criteria (persistently medium/high titer anticardiolipin antibodies, and/or medium/high titer anti-ß2-glycoprotein I antibodies, and/or a positive lupus anticoagulant test). Gastrointestinal lesions are rarely reported in APS patients. APS cases with recurrent abdominal pain as the first clinical manifestation are even rarer. CASE PRESENTATION: This report describes an APS case with recurrent abdominal pain as the first clinical manifestation of antiphospholipid syndrome. The patient has a history of two miscarriages. Computed tomography of the abdomen confirmed mesenteric thrombosis and intestinal obstruction while laboratory tests for serum antiphospholipid and anti-ß2-glycoprotein I antibodies were positive. This led to the diagnosis of APS. CONCLUSIONS: This paper provides useful information on gastrointestinal manifestations and APS, also including a brief literature review about possible gastrointestinal symptoms of APS.
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Síndrome Antifosfolípido , Trombosis , Anticuerpos Anticardiolipina , Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/diagnóstico , Autoanticuerpos , Humanos , Trombosis/etiologíaRESUMEN
Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signaling. Here, we review the alterations in metabolic pathways that are linked to the pathologic vascular phenotype of PAH, including abnormalities in glycolysis and glucose oxidation, fatty acid oxidation, glutaminolysis, arginine metabolism, one-carbon metabolism, the reducing and oxidizing cell environment, and the tricarboxylic acid cycle, as well as the effects of PAH-associated nuclear and mitochondrial mutations on metabolism. Understanding of the metabolic mechanisms underlying PAH provides important knowledge for the design of new therapeutics for treatment of patients.