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Objective: Hungary has repeatedly been shown to have the highest cancer-related mortality and incidence in Europe. Despite lung cancer being the most abundant malignant diagnosis in Hungary, numerous concerns have been raised recently regarding the bias inherent to reported incidence estimates. Re-analysis of reimbursement claims has been suggested previously by our group as an alternative approach, offering revised figures of lung cancer incidence between 2011 and 2016. Leveraging on this methodology, we aimed at updating Hungarian lung cancer incidence estimates with an additional 5 years (2017-2021), including years affected by the COVID-19 pandemic. Additionally, we also attempted to improve the robustness of estimates by taking additional characteristics of the patient pathway into account. Methods: Lung cancer patients between 2011 and 2021 were identified based on reimbursement-associated ICD-10 codes, histology codes and time patterns. Multiple query architectures were tested for sensitivity and compared to official estimates of the Hungarian National Cancer Registry (HNCR). Epidemiological trends were estimated by Poisson-regression, corrected for age and sex. Results: A total of 89,948 lung cancer patients diagnosed in Hungary between 2011 and 2021 have been identified by our study. In 2019 alone, 7,887 patients were diagnosed according to our optimized query. ESP2013 standardized rate was estimated between 92.5/100,000 (2011) and 78.4/100,000 (2019). In 2019, standardized incidence was 106.8/100,000 for men and 59.7/100,000 for women. Up until the COVID-19 pandemic, lung cancer incidence was decreasing by 3.18% (2.1%-4.3%) yearly in men, while there was no significant decrease in women. Young age groups (40-49 and 50-59) featured the largest improvement, but women aged 60-79 are at an increasing risk for developing lung cancer. The COVID-19 pandemic resulted in a statistically significant decrease in lung cancer incidence, especially in the 50-59 age group (both sexes). Conclusion: Our results show that using an optimized approach, re-analysis of reimbursement claims yields robust estimates of lung cancer incidence. According to this approach, the incidence rate of male lung cancer is declining in Hungary, in concordance with the trend observed for lung cancer mortality. Among women aged 60-79, the incidence of lung cancer has risen, requiring more attention in the near future.
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COVID-19 , Neoplasias Pulmonares , Humanos , Hungría/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/mortalidad , Incidencia , Masculino , Femenino , COVID-19/epidemiología , Anciano , Persona de Mediana Edad , Adulto , SARS-CoV-2 , Anciano de 80 o más Años , Sistema de Registros , Pandemias , Adulto Joven , Fuentes de InformaciónRESUMEN
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.
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Cardiomiopatías , Hipertensión , Insuficiencia Renal Crónica , Humanos , Ratas , Animales , Masculino , Anciano , Kisspeptinas , Receptores de Kisspeptina-1 , Ratas Wistar , Insuficiencia Renal Crónica/complicaciones , Cardiomiopatías/complicaciones , Hipertensión/complicaciones , FibrosisRESUMEN
Chronic kidney disease (CKD) is associated with anxiety; however, its exact mechanism is not well understood. Therefore, the aim of the present study was to assess the effect of moderate CKD on anxiety in rats. 5/6 nephrectomy was performed in male Wistar rats. 7 weeks after, anxiety-like behavior was assessed by elevated plus maze (EPM), open field (OF), and marble burying (MB) tests. At weeks 8 and 9, urinalysis was performed, and blood and amygdala samples were collected, respectively. In the amygdala, the gene expression of Avp and the gene and protein expression of Crh, Crhr1, and Crhr2 were analyzed. Furthermore, the plasma concentration of corticosterone, uremic toxins, and tryptophan metabolites was measured by UHPLC-MS/MS. Laboratory tests confirmed the development of CKD. In the CKD group, the closed arm time increased; the central time and the total number of entries decreased in the EPM. There was a reduction in rearing, central distance and time in the OF, and fewer interactions with marbles were detected during MB. CKD evoked an upregulation of gene expression of Crh, Crhr1, and Crhr2, but not Avp, in the amygdala. However, there was no alteration in protein expression. In the CKD group, plasma concentrations of p-cresyl-sulfate, indoxyl-sulfate, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, 5-hydroxyindoleacetic acid, picolinic acid, and quinolinic acid increased. However, the levels of tryptophan, tryptamine, 5-hydroxytryptophan, serotonin, and tyrosine decreased. In conclusion, moderate CKD evoked anxiety-like behavior that might be mediated by the accumulation of uremic toxins and metabolites of the kynurenine pathway, but the contribution of the amygdalar CRH system to the development of anxiety seems to be negligible at this stage.
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Insuficiencia Renal Crónica , Triptófano , Ratas , Masculino , Animales , Triptófano/metabolismo , Quinurenina/metabolismo , Ratas Wistar , Tóxinas Urémicas , Espectrometría de Masas en Tándem , Amígdala del Cerebelo/metabolismo , Insuficiencia Renal Crónica/metabolismo , AnsiedadRESUMEN
Chronic kidney disease is a global health problem affecting 10% to 12% of the population. Uremic cardiomyopathy is often characterized by left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Dysregulation of neuregulin-1ß signaling in the heart is a known contributor to heart failure. The systemically administered recombinant human neuregulin-1ß for 10 days in our 5/6 nephrectomy-induced model of chronic kidney disease alleviated the progression of uremic cardiomyopathy and kidney dysfunction in type 4 cardiorenal syndrome. The currently presented positive preclinical data warrant clinical studies to confirm the beneficial effects of recombinant human neuregulin-1ß in patients with chronic kidney disease.
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Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 (ip. 13 µg/day), (iv) CKD treated with a higher dose of P234 (ip. 26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling (Ctgf, Tgfb, Col3a1, Mmp9), stretch (Nppa), and apoptosis (Bax, Bcl2, Casp7) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-ß-mediated pathways.
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Cardiomiopatías , Péptidos , Masculino , Ratas , Animales , Receptores de Kisspeptina-1 , Ratas Wistar , Apoptosis , Cardiomiopatías/etiologíaRESUMEN
Endometriosis is a chronic inflammatory gynaecological disease characterized by the growth of endometrial tissue outside the uterine cavity. There are currently no definitive non-invasive diagnostic tools. Glycosylation is the most common posttranslational modification of proteins and altered glycosylation has been found in many diseases, including chronic inflammatory conditions and cancer. Sialylation and galactosylation on serum IgG have previously been found to be altered in endometriosis and serum sialylation changed after Zoladex (Goserelin Acetate) therapy. Using IgG and whole serum glycoproteins, we investigated N-glycosylation in two clinical cohorts of women with and without endometriosis. PNGase F-digested serum samples were fluorescently labelled and N-glycans were profiled by ultra-performance liquid chromatography. Clinical data was collected to link glycomic findings with metabolic and hormonal profiles. Total serum glycoprotein and IgG glycosylation differed in patients with endometriosis compared to control cases. The most significantly altered was glycan peak 3 from IgG, containing bisected biantennary glycans, which was decreased in the endometriosis cohorts (p = 0.0000005-0.018). In conclusion, this is the first pilot study to identify changes in N-glycans from whole serum glycoproteins associated with endometriosis. A larger validation study is now warranted and such studies should include the follow-up of surgically and pharmacologically treated patients.
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Endometriosis , Humanos , Femenino , Proyectos Piloto , Glicoproteínas , Goserelina , Polisacáridos , Inmunoglobulina GRESUMEN
A recently discovered electrophysiological response, the social N400, suggests that we use our language system to track how social partners comprehend language. Listeners show an increased N400 response, when themselves not, only a communicative partner experiences a semantic incongruity. Does the N400 reflect purely semantic or mentalistic computations as well? Do we attribute language comprehension to communicative partners using our semantic systems? In five electrophysiological experiments we identified two subcomponents of the social N400. First, we manipulated the presence-absence of an Observer during object naming: the semantic memory system was activated by the presence of a social partner in addition to semantic predictions for the self. Next, we induced a false belief-and a consequent miscomprehension-in the Observer. Participants showed the social N400, over and above the social presence effect, to labels that were incongruent for the Observer, even though they were congruent for them. This effect appeared only if participants received explicit instructions to track the comprehension of the Observer. These findings suggest that the semantic systems of the brain are not merely sensitive to social information and contribute to the attribution of comprehension, but they appear to be mentalistic in nature.
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Electroencefalografía , Semántica , Comprensión/fisiología , Potenciales Evocados/fisiología , Femenino , Humanos , Lenguaje , MasculinoRESUMEN
Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.
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Cardiomiopatías , Cardiotoxicidad , Acetanilidas , Animales , Cardiomiopatías/inducido químicamente , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Doxorrubicina/efectos adversos , Losartán/efectos adversos , Masculino , Ratas , Ratas Wistar , TiazolesRESUMEN
Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Insuficiencia Cardíaca/prevención & control , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Losartán/uso terapéutico , Síndrome de Fibrosis por Radiación/tratamiento farmacológico , Animales , Quimasas/metabolismo , Modelos Animales de Enfermedad , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/prevención & control , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Síndrome de Fibrosis por Radiación/patología , Síndrome de Fibrosis por Radiación/prevención & control , Ratas , Ratas Sprague-Dawley , Proteína Smad2/análisis , Proteína smad3/análisis , Factor de Crecimiento Transformador beta1/análisisRESUMEN
Background: Endometriosis is a chronic gynaecological disease whose aetiology is still unknown. Despite its prevalence among women of reproductive age, the pathology of the disease has not yet been elucidated and only symptomatic treatment is available. Endometriosis has high latency and diagnostic methods are both limited and invasive. Aim of review: The aim of this review is to summarise minimally invasive or non-invasive diagnostic methods for endometriosis and their diagnostic efficiencies. Furthermore, we discuss the identification and diagnostic potential of novel disease biomarkers of microbial or glycan origin. Key scientific concepts of review: Great efforts have been made to develop minimally invasive or non-invasive diagnostic methods in endometriosis. The problem with most potential biomarker candidates is that they have high accuracy only in cases of severe disease. Therefore, it is necessary to examine other potential biomarkers more closely. Associations between gastrointestinal and genital tract microbial health and endometriosis have been identified. For instance, irritable bowel syndrome is more common in women with endometriosis, and hormonal imbalance has a negative impact on the microbiome of both the genital tract and the gastrointestinal system. Further interrogation of these associations may have potential diagnostic significance and may identify novel therapeutic avenues. Glycomics may also be a potent source of biomarkers of endometriosis, with a number of glyco-biomarkers already approved by the FDA. Endometriosis-associated microbial and glycomic profiles may represent viable targets for development of innovative diagnostics in this debilitating disease.
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Endometriosis , Síndrome del Colon Irritable , Microbiota , Biomarcadores , Endometriosis/diagnóstico , Femenino , HumanosRESUMEN
BACKGROUND: Uremic cardiomyopathy is a common cardiovascular complication of chronic kidney disease (CKD) characterized by left ventricular hypertrophy (LVH) and fibrosis enhancing the susceptibility of the heart to acute myocardial infarction. In the early stages of CKD, approximately 60% of patients are women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD. METHODS: CKD was induced by 5/6 nephrectomy in 9-week-old male and female Wistar rats. Two months later, serum and urine laboratory parameters were measured to verify the development of CKD. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular expression of A- and B-type natriuretic peptides (ANP and BNP) were measured by qRT-PCR and circulating BNP level was measured by ELISA. In a subgroup of animals, hearts were perfused according to Langendorff and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE (3 × 5 min I/R cycles applied before index ischemia). Then infarct size or phosphorylated and total forms of proteins related to the cardioprotective RISK (AKT, ERK1,2) and SAFE (STAT3) pathways were measured by Western blot. RESULTS: The severity of CKD was similar in males and females. However, CKD males developed more severe LVH compared to females as assessed by echocardiography. Histology revealed cardiac fibrosis only in males in CKD. LV ANP expression was significantly increased due to CKD in both sexes, however, LV BNP and circulating BNP levels failed to significantly increase in CKD. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the phospho-STAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. There were no significant differences in phospho-AKT/AKT and phospho-ERK1,2/ERK1,2 ratios between the groups. CONCLUSION: The infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats. Further research is needed to identify crucial molecular mechanisms in the cardioprotective effect of IPRE in CKD.
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Precondicionamiento Isquémico , Daño por Reperfusión Miocárdica , Insuficiencia Renal Crónica , Animales , Femenino , Corazón , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (ß3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the ß3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, ß3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the ß3-AR.
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Acetanilidas/farmacología , Cardiomiopatías/tratamiento farmacológico , Losartán/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Insuficiencia Renal Crónica/complicaciones , Tiazoles/farmacología , Uremia/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Antihipertensivos/farmacología , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Masculino , Nefrectomía/efectos adversos , Óxido Nítrico Sintasa de Tipo III/genética , Ratas , Ratas Wistar , Uremia/etiología , Uremia/metabolismo , Uremia/patologíaRESUMEN
Cancer management has undergone significant improvements, which led to increased long-term survival rates among cancer patients. Radiotherapy (RT) has an important role in the treatment of thoracic tumors, including breast, lung, and esophageal cancer, or Hodgkin's lymphoma. RT aims to kill tumor cells; however, it may have deleterious side effects on the surrounding normal tissues. The syndrome of unwanted cardiovascular adverse effects of thoracic RT is termed radiation-induced heart disease (RIHD), and the risk of developing RIHD is a critical concern in current oncology practice. Premature ischemic heart disease, cardiomyopathy, heart failure, valve abnormalities, and electrical conduct defects are common forms of RIHD. The underlying mechanisms of RIHD are still not entirely clear, and specific therapeutic interventions are missing. In this review, we focus on the molecular pathomechanisms of acute and chronic RIHD and propose preventive measures and possible pharmacological strategies to minimize the burden of RIHD.
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Benchmarking/métodos , Manejo de la Enfermedad , Cardiopatías/diagnóstico , Corazón/efectos de la radiación , Oncología Médica , Sistemas de Atención de Punto/organización & administración , Traumatismos por Radiación/diagnóstico , Cardiopatías/terapia , Humanos , Traumatismos por Radiación/terapiaRESUMEN
BACKGROUND: Oral and enteral mucositis due to high-dose cytostatic treatment administered during autologous and allogeneic stem-cell transplantation increases mortality. Salivary secretory immunoglobulin A (sIgA) is a basic pillar of local immunity in the first line of defense. Altered salivary sialoglycoprotein carbohydrates are important in the pathologies in the oral cavity including inflammation, infection and neoplasia. Therefore, we assessed whether changes in the salivary and serum IgA glycosylation correlated with development and severity of oral mucositis. METHODS: Using capillary electrophoresis, comparative analysis of serum and salivary IgA total N-glycans was conducted in 8 patients with autologous peripheral stem-cell transplantation (APSCT) at four different stages of transplantation (day -3/-7, 0, +7, +14) and in 10 healthy controls. RESULTS: Fourteen out of the 31 structures identified in serum and 6 out of 38 in saliva showed significant changes upon transplantation compared with the control group. Only serum core fucosylated, sialylated bisecting biantennary glycan (FA2BG2S2) showed significant differences between any two stages of transplantation (day -3/-7 and day +14; p = 0.0279). CONCLUSION: Our results suggest that changes in the serum IgA total N-glycan profile could serve as a disease-specific biomarker in patients undergoing APSCT, while analysis of salivary IgA N-glycan reflects the effect of APSCT on local immunity.
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AIMS: Application of capillary electrophoresis with laser induced fluorescence detection (CE-LIF) to identify the N-glycosylation structures of serum and saliva IgA from healthy controls and patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. BACKGROUND: Altered N-glycosylation of body fluid glycoproteins can be an effective indicator of most inflammatory processes. Immunoglobulin A (IgA) is the second highest abundant immunoglobulin and has a major role in the immune-defense against potential pathogen attacks. While IgA is abundant in serum, secretory immunoglobulin A (sIgA) is one of the most prevalent proteins in mucosal surfaces, such as in saliva. OBJECTIVE: Our aim was to investigate the changes of IgA glycosylation in serum and saliva as a response to an administered cytostatic treatment in patients with malignant hematological disorders. METHODS: Capillary electrophoresis with laser induced fluorescent detection (CE-LIF) was used to analyze the N-glycosylation profiles of Z(IgA1) partitioned immunoglobulin A in pooled serum and saliva of 10 control subjects and 8 patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. RESULTS: Eight of 31 and four of 38 N-glycans in serum and saliva, respectively, showed significant (p<0.05) differences upon comparison to the control group. Thirteen glycans were present in the saliva but not in the serum, on the other hand, six structures were found in the serum samples not present in the saliva. CONCLUSION: The developed Z(IgA1) partitioning and the high resolution CE-LIF based glyocoanalytical methods provided an efficient and sensitive workflow to detect and monitor IgA glycosylation alterations in serum and saliva with the scope for widespread molecular medicinal use.
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Proteínas Sanguíneas/metabolismo , Enfermedades Hematológicas/complicaciones , Inmunoglobulina A/metabolismo , Enfermedades de la Boca/diagnóstico , Polisacáridos/química , Saliva/química , Proteínas y Péptidos Salivales/metabolismo , Adulto , Estudios de Casos y Controles , Electroforesis Capilar , Femenino , Glicómica , Glicosilación , Humanos , Inmunoglobulina A/química , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/etiología , Enfermedades de la Boca/metabolismo , Mucosa Bucal/metabolismo , Mucosa Bucal/patologíaRESUMEN
BACKGROUND: The protective/inhibitory B subunits of coagulation factor XIII (FXIII-B) is a ~80 kDa glycoprotein containing two N-glycosylation sites. Neither the structure nor the functional role of the glycans on FXIII-B has been explored. OBJECTIVE: To reveal the glycan structures linked to FXIII-B, to design a method for deglycosylating the native protein, to find out if deglycosylation influences the dimeric structure of FXIII-B and its clearance from the circulation. METHODS: Asparagine-linked carbohydrates were released from human FXIIII-B by PNGase F digestion. The released N-linked oligosaccharides were fluorophore labeled and analyzed by capillary electrophoresis. Structural identification utilized glycan database search and exoglycosidase digestion based sequencing. The structure of deglycosylated FXIII-B was investigated by gel filtration. The clearance of deglycosylated and native FXIII-B from plasma was compared in FXIII-B knock out mice. RESULTS: PNGase F completely removed N-glycans from the denatured protein. Deglycosylation of the native protein was achieved by repeated digestion at elevated PNGase F concentration. The total N-glycan profile of FXIII-B featured nine individual structures; three were fucosylated and each structure contained at least one sialic acid. Deglycosylation did not change the native dimeric structure of FXIII-B, but accelerated its clearance from the circulation of FXIII-B knock out mice. CONCLUSION: Characterization of the glycan moieties attached to FXIII-B is reported for the first time. Complete deglycosylation of the native protein was achieved by a deglycosylation workflow. The associated glycan structure is not required for FXIII-B dimer formation, but it very likely prolongs the half-life of FXIII-B in the plasma.
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Coagulación Sanguínea , Factor XIII , Pruebas de Coagulación Sanguínea , Factor XIII/genética , Factor XIII/metabolismo , Glicósido Hidrolasas , GlicosilaciónRESUMEN
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are prevalent ailments with a great challenge to distinguish them based on symptoms only. Since they require different treatments, it is important to find non-invasive methods capable to readily diagnose them. Moreover, COPD increases the risk of lung cancer development, leading to their comorbidity. In this pilot study the N-glycosylation profile of pooled human serum samples (90 patients each) from lung cancer, COPD and comorbidity (LC with COPD) patients were investigated in comparison to healthy individuals (control) by capillary gel electrophoresis with high sensitivity laser-induced fluorescence detection. Sample preparation was optimized for human serum samples introducing a new temperature adjusted denaturation protocol to prevent precipitation and increased endoglycosidase digestion time to assure complete removal of the N-linked carbohydrates. The reproducibility of the optimized method was <3.5%. Sixty-one N-glycan structures were identified in the pooled control human serum sample and the profile was compared to pooled lung cancer, COPD and comorbidity of COPD with lung cancer patient samples. One important finding was that no other sugar structures were detected in any of the patient groups, only quantitative differences were observed. Based on this comparative exercise, a panel of 13 N-glycan structures were identified as potential glycobiomarkers to reveal significant changes (>33% in relative peak areas) between the pathological and control samples. In addition to N-glycan profile changes, alterations in the individual N-glycan subclasses, such as total fucosylation, degree of sialylation and branching may also hold important glycobiomarker values.
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Electroforesis Capilar/métodos , Neoplasias Pulmonares , Polisacáridos , Enfermedad Pulmonar Obstructiva Crónica , Comorbilidad , Glicómica , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/metabolismo , Proyectos Piloto , Polisacáridos/sangre , Polisacáridos/química , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: A number of human inflammatory diseases and tumors have been shown to cause alterations in the glycosylation pattern of plasma proteins in a specific manner. These highly variable and versatile post-translational modifications finetune protein functions by influencing sorting, folding, enzyme activity and subcellular localization. However, relatively little is known about regulatory factors of this procedure and about the accurate causative connection between glycosylation and disease. OBJECTIVE: The aim of the present study was to investigate whether certain single nucleotide polymorphisms (SNPs) in genes encoding glycosyltransferases and glycosidases could be associated with elevated risk for chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma. METHODS: A total of 32 SNPs localized in genes related to N-glycosylation were selected for the association analysis. Polymorphisms with putative biological functions (missense or regulatory variants) were recruited. SNPs were genotyped by a TaqMan OpenArray platform. A single base extension-based method in combination with capillary gel electrophoresis was used for verification. RESULTS: The TaqMan OpenArray approach provided accurate and reliable genotype data (global call rate: 94.9%, accuracy: 99.6%). No significant discrepancy was detected between the obtained and expected genotype frequency values (Hardy-Weinberg equilibrium) in the healthy control sample group in case of any SNP confirming reliable sampling and genotyping. Allele frequencies of the rs3944508 polymorphism localized in the 3' UTR of the MGAT5 gene significantly differed between the sample groups compared. CONCLUSION: Our results suggest that the rs34944508 SNP might modulate the risk for lung cancer by influencing the expression of MGAT5. This enzyme catalyzes the addition of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides, thus, increasing branching that is the characteristic of invasive malignancies.
Asunto(s)
Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Much of the psychiatric literature about prisoners concerns the associations between psychiatric conditions and criminality. More recently, there has been increased psychiatric interest in the moral emotions (i.e., emotions related to the rightness or wrongness of an individual's actions) and their association with psychological problems and psychopathology. The role of moral emotions has never previously been studied in relation to prison adaptation on initial incarceration. Their impact in adaptation to prison life was studied longitudinally. Immediately after prison incarceration, 316 adult male offenders were assessed in relation to moral emotions, coping strategies, and somatization symptoms. After four months, information relating to their prison adaptation were recorded using official data. Findings showed that (i) offence-related shame correlated positively with somatization symptoms, distraction, and self-blame, and that (ii) offence-related guilt correlated positively with self-blame, and negatively with venting on emotion. The relationship between self-blame and somatization was partly mediated by offence-related shame and guilt. Previous research has demonstrated that moral emotions are associated with increased severity of psychopathology such as depression, suicidal ideation, and psychological problems generally. Therefore, it is important that psychiatrists are aware of the effect that moral emotions can have on psychological functioning. Implications for prison psychiatrists are discussed.
Asunto(s)
Adaptación Psicológica , Prisioneros/psicología , Adulto , Depresión/psicología , Emociones , Femenino , Culpa , Humanos , Institucionalización , Estudios Longitudinales , Masculino , Principios Morales , Prisiones , Psicopatología , VergüenzaRESUMEN
Chronic kidney disease (CKD) is a public health problem and a recognized risk factor for cardiovascular diseases (CVD). CKD could amplify the progression of chronic heart failure leading to the development of type 4 cardio-renal syndrome (T4CRS). The severity and persistence of heart failure are strongly associated with mortality risk in T4CRS. CKD is also a catabolic state leading to renal sarcopenia which is characterized by the loss of skeletal muscle strength and physical function. Renal sarcopenia also promotes the development of CVD and increases the mortality in CKD patients. In turn, heart failure developed in T4CRS could result in chronic muscle hypoperfusion and metabolic disturbances leading to or aggravating the renal sarcopenia. The interplay of multiple factors (e.g., comorbidities, over-activated renin-angiotensin-aldosterone system [RAAS], sympathetic nervous system [SNS], oxidative/nitrative stress, inflammation, etc.) may result in the progression of T4CRS and renal sarcopenia. Among these factors, oxidative/nitrative stress plays a crucial role in the complex pathomechanism and interrelationship between T4CRS and renal sarcopenia. In the heart and skeletal muscle, mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, uncoupled nitric oxide synthase (NOS) and xanthine oxidase are major ROS sources producing superoxide anion (O2·-) and/or hydrogen peroxide (H2O2). O2·- reacts with nitric oxide (NO) forming peroxynitrite (ONOO-) which is a highly reactive nitrogen species (RNS). High levels of ROS/RNS cause lipid peroxidation, DNA damage, interacts with both DNA repair enzymes and transcription factors, leads to the oxidation/nitration of key proteins involved in contractility, calcium handling, metabolism, antioxidant defense mechanisms, etc. It also activates the inflammatory response, stress signals inducing cardiac hypertrophy, fibrosis, or cell death via different mechanisms (e.g., apoptosis, necrosis) and dysregulates autophagy. Therefore, the thorough understanding of the mechanisms which lead to perturbations in oxidative/nitrative metabolism and its relationship with pro-inflammatory, hypertrophic, fibrotic, cell death and other pathways would help to develop strategies to counteract systemic and tissue oxidative/nitrative stress in T4CRS and renal sarcopenia. In this review, we also focus on the effects of some well-known and novel pharmaceuticals, nutraceuticals, and physical exercise on cardiac and skeletal muscle oxidative/nitrative stress in T4CRS and renal sarcopenia.