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BACKGROUND: Angina pectoris, a debilitating manifestation of coronary artery disease, has been associated with various modifiable risk factors. However, the causal underpinnings of these associations remain unclear. This study leveraged Mendelian randomization (MR) to investigate the causal roles of dietary patterns, smoking behaviors, body mass index (BMI), and physical activity in the development of angina. METHODS: Two-sample MR analyses were performed using summary-level data from large-scale genome-wide association studies (GWASs) and biobank resources, including the UK Biobank (UKB) and FinnGen cohorts. Genetic variants associated with various types of exposure such as fruit and salad intake, smoking initiation and intensity, BMI, and physical activity were used as instrumental variables, and their causal effects on angina risk were assessed. RESULTS: In the UKB cohort (336,683 individuals, 10,618 cases), genetically proxied fruit (OR = 0.95, 95% CI: 0.93-0.97) and cheese intake (OR = 0.98, 95% CI: 0.97-0.99) were associated with decreased angina risk, while smoking initiation (OR = 1.01, 95% CI: 1.002-1.012), maternal smoking (OR = 1.06, 95% CI: 1.03-1.09), and BMI (OR = 1.01, 95% CI: 1.01-1.02) were associated with increased risk. In the FinnGen cohort (206,008 individuals, 18,168 cases), fruit (OR = 0.30, 95% CI: 0.17-0.53) and salad intake (OR = 0.31, 95% CI: 0.12-0.55) were found to be protective, while smoking initiation (OR = 1.20, 95% CI: 1.04-1.37) and intensity (OR = 1.15, 95% CI: 1.04-1.26) and BMI (OR = 1.31, 95% CI: 1.18-1.47) increased angina risk. CONCLUSIONS: This study provides robust evidence for the causal roles of various modifiable risk factors associated with angina development, highlighting the potential benefits of dietary interventions that promote increased fruit and vegetable consumption, smoking cessation, and weight management to mitigate angina risk. Further investigation is needed to generalize these findings to populations with diverse genetic backgrounds, lifestyles, and environmental exposures.

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Matrix metalloproteinase 9 (MMP9) and microRNA-145 (miR-145) have emerged as essential biomarkers in thyroid cancer progression and metastasis. However, their combined evaluation and clinical utility as a unified prognostic marker across diverse thyroid cancer subgroups remain unexplored. We investigated the diagnostic and prognostic value of the MMP9/miR-145 ratio in thyroid cancer, hypothesizing it may overcome inter-patient heterogeneity and serve as a versatile biomarker regardless of genetic mutations or autoimmune status. MMP9 and miR-145 expressions were analyzed in 175 paired papillary thyroid cancer (PTC) and normal tissues. Plasma levels were assessed perioperatively and longitudinally over 12-18 months in 86 matched PTC patients. The associations with clinicopathological parameters and patient outcomes were evaluated. MMP9 was upregulated, and miR-145 downregulated in cancer tissues, with a median MMP9/miR-145 ratio 17.6-fold higher versus controls. The tissue ratio accurately diagnosed thyroid malignancy regardless of BRAF mutation or Hashimoto's thyroiditis status, overcoming genetic and autoimmune heterogeneity. A high preoperative circulating ratio predicted aggressive disease features, including lymph node metastasis, extrathyroidal extension, progression/relapse, and recurrence. Although the preoperative plasma ratio was elevated in patients with unfavorable outcomes, it had limited utility for post-surgical monitoring. In conclusion, the MMP9/miR-145 ratio is a promising biomarker in PTC that bridges genetic and immunological variabilities, enhancing preoperative diagnosis and prognostication across diverse patient subgroups. It accurately stratifies heterogenous cases by aggressiveness. The longitudinal trends indicate decreasing applicability for post-thyroidectomy surveillance. Further large-scale validation and protocol standardization can facilitate clinical translation of the MMP9/miR-145 ratio to guide personalized thyroid cancer management.

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Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19-30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 µM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.

Asunto(s)

Antineoplásicos , Inhibidores de Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Topoisomerasa I/farmacología , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Bases de Schiff/farmacología , Relación Estructura-Actividad , Antineoplásicos/farmacología , Proliferación Celular , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo II/farmacología

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Purpose: We assessed the attitudes of Jazan University medical students toward professionalism and evaluated the associations of those attitudes with demographic factors. Materials and Methods: Seven hundred ninety-seven respondents (88.85% response rate) out of 898 students who were invited to this study (50.7% were men and 49.3% were women) were studied by their response to the Learner's Attitude of Medical Professionalism Scale (LAMPS) that assess their level of agreement with 28 items, each reflecting a single professionalism competency within the subscales of Altruism, Excellence, Duty/Accountability, Honor/Integrity, and Respect for Others. Results: Of 797 respondents (88.85% response rate), 50.7% were men and 49.3% were women. Subscales with high agreement scores were Excellence (median, 21.0; range, 6-30) and Duty/Accountability (median, 21.0; range, 7-35). Subscales with slightly lower agreement scores were Respect for Others (median, 15.0; range, 5-25), Altruism (median, 15.0; range, 5-25), and Honor/Integrity (median, 12.0; range, 5-25). No sex differences were observed for most subscales; however, men gave higher agreement scores on the Excellence subscale, and compared with year 3 respondents (preclinical phase), year 6 respondents (clinical phase) gave higher agreement scores on the Excellence, Altruism, and Respect for Others subscales. Conclusion: Overall, medical students at Jazan University indicated high agreement with all attitudes to professionalism subscales on the LAMPS.

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Long non-coding RNAs (lncRNAs) have key roles in tumor development and the progress of many cancers, including breast cancer (BC). This study aimed to explore for the first time the association of the migration/differentiation-associated lncRNA SENCR rs12420823C/T variant with BC risk and prognosis. Genotyping was carried out for 203 participants (110 patients and 93 controls) using the TaqMan allelic discrimination technique. The corresponding clinicopathological data, including the recurrence/survival times, were analyzed with the different genotypes. After adjustment by age and risk factors, the T/T genotype carrier patients were more likely to develop BC under homozygote comparison (T/T vs. C/C: OR = 8.33, 95% CI = 2.44-25.0, p = 0.001), dominant (T/T-C/T vs. C/C: OR = 3.70, 95% CI = 1.72-8.33, p = 0.027), and recessive (T/T vs. C/T-C/C: OR = 2.17, 95% CI = 1.08-4.55, p < 0.001) models. Multivariate logistic regression analysis showed that the T/T genotype carriers were more likely to be triple-negative sub-type (OR = 2.66, 95% CI = 1.02-6.95, p = 0.046), at a higher risk of recurrence (OR = 3.57, 95% CI = 1.33-9.59, p = 0.012), and had short survival times (OR = 3.9, 95% CI = 1.52-10.05, p = 0.005). Moreover, Cox regression analysis supported their twofold increased risk of recurrence (HR = 2.14, 95% CI = 1.27-3.59, p = 0.004). Furthermore, the predictive nomogram confirmed the high weight for SENCR rs12420823*T/T and C/T genotypes in predicting recurrence within the first year. The Kaplan-Meier survival curve demonstrated low disease-free survival (T/T: 12.5 ± 1.16 months and C/T: 15.9 ± 0.86 months versus C/C: 22.3 ± 0.61 months, p < 0.001). In conclusion, the LncRNA SENCR rs12420823*C/T may be associated with an increased risk of BC in women and could be a promising genetic variant for predicting recurrence and survival.

Asunto(s)

Neoplasias de la Mama , ARN Largo no Codificante , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Pronóstico , ARN Largo no Codificante/genética

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Background: Recently, long non-coding RNAs (lncRNAs) have emerged as potential molecular biomarkers for sepsis. We aimed to profile the expression signature of three inflammation-related lncRNAs, MALAT1, ANRIL, and HHOTAIR, in the plasma of neonates with sepsis and correlate these signatures with the phenotype. Patients and Methods: This case-control study included 124 neonates with sepsis (88 survivors/36 non-survivors) admitted to the neonatal ICU and 17 healthy neonates. The relative expressions were quantified by real-time PCR and correlated to the clinic-laboratory data. Results: The three circulating lncRNAs were upregulated in the cases; the median levels were MALAT1 (median = 1.71, IQR: -0.5 to 3.27), ANRIL (median = 1.09, IQR: 0.89 to 1.30), and HOTAIR (median = 1.83, IQR: 1.44 to 2.41). Co-expression analysis showed that the three studied lncRNAs were directly correlated (all p-values <0.001). Overall and stratification by sex analyses revealed significantly higher levels of the three lncRNAs in non-survivors compared to the survivor group (all p-values <0.001). Principal component analysis showed a clear demarcation between the two study cohorts in males and females. Cohorts with upregulated ANRIL (hazard ratio; HR = 4.21, 95% CI = 1.15-10.4, p=0.030) and HOTAIR (HR = 2.49, 95% CI = 1.02-6.05, p=0.044) were at a higher risk of mortality. Conclusion: Circulatory MALAT1, ANRIL, and HOTAIR were upregulated in neonatal sepsis, and the latter two may have the potential as prognostic biomarkers for survival in neonatal sepsis.

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Accumulating evidence supports the implication of long non-coding RNAs (lncRNAs) in autoimmune diseases, including systemic lupus erythematosus (SLE). LncRNA variants could impact the development and/or outcome of the disease with variable diagnostic/prognostic utility in the clinic. We aimed to explore the contribution of HOTAIR (rs10783618), LINC-ROR (rs1942347), and MALAT1 (rs3200401) variants to SLE susceptibility and/or severity in 163 SLE patients and age-/sex-matched controls using real-time TaqMan allelic discrimination PCR. HOTAIR rs10783618*C/C was associated with a 77% increased risk of SLE (OR = 1.77, 95%CI = 1.09−2.87, p = 0.020) under the recessive model. Similarly, MALAT1 rs3200401*T/T carriers were three times more likely to develop SLE (OR = 2.89, 95%CI = 1.42−5.90) under the recessive model. While the rs3200401*T/C genotype was associated with a 49−57% decreased risk of SLE under codominant (OR = 0.51, 95%CI = 0.31−0.82, p < 0.001) and over-dominant (OR = 0.43, 95%CI = 0.27−0.68, p < 0.001) models. LINC-ROR rs1942347*A/A patients were more likely to have a positive family history of SLE. At the same time, HOTAIR rs10783618*C/C was associated with a higher frequency of arthritis (p = 0.001) and the presence of oral ulcers (p = 0.002), while patients carrying rs10783618*T/T genotype were more likely to develop hair loss (p < 0.001), weight loss (p = 0.001), and neurological symptoms (p = 0.003). In conclusion, the studied lncRNAs, HOTAIR, and MALAT1 gene polymorphisms confer susceptibility for SLE, providing a potential theoretical basis for their clinical translation in SLE disease.

RESUMEN

Accumulating evidence indicates the implication of microRNAs (miRs) in cutaneous and hair follicle immunobiology. We evaluated, for the first time, the miR-17-92a-1 cluster host gene (MIR17HG) expression in peripheral blood of 248 unrelated alopecia areata (AA) patients compared to 244 matched controls using Real-Time qPCR. We also tested its association with different rs4284505A>G genotypes (based on TaqMan allelic discrimination PCR) and the available clinical data. The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated for each genetic association model. The upregulation of miR-17 was observed in the serum of patients with alopecia compared to controls (p-value = 0.004). The ROC curve showed high diagnostic performance of miR-17 in differentiating between patients and controls (AUC = 0.85, p-value < 0.001). rs4284505*A/G heterozygotes were more susceptible to the disease (OR = 1.57, 95% CI = 1.01−2.45) under the over-dominant model. Interestingly, patients with the rs4284505*G/G genotype had a higher level of miR-17 than those with the A/A and A/G genotypes. The G/G genotype was associated with the severe phenotype (p-value = 0.038). A/G carriers were the youngest (p-value < 0.001), had more frequent scalp infection (p-value = 0.006), exhibited the worst dermatology life quality index score (p-value = 0.037), and responded less to treatment (p-value = 0.033). In conclusion, MIR17HG expression and the rs4284505 variant were significantly associated with AA and could play a role in pathogenesis and phenotype in the Egyptian population. Further multi-center studies in other ethnicities are warranted to replicate the findings.

Asunto(s)

Alopecia Areata , MicroARNs , ARN Largo no Codificante , Alelos , Alopecia Areata/genética , Estudios de Casos y Controles , Humanos , MicroARNs/genética , ARN Largo no Codificante/genética

RESUMEN

Long non-coding RNAs (lncRNAs) have emerged as essential biomolecules with variable diagnostic and/or prognostic utility in several diseases, including coronary artery disease (CAD). We aimed for the first time to investigate the potential association of five angiogenesis-related lncRNAs (PUNISHER, SENCR, MIAT, MALAT1, and GATA6-AS) variants with CAD susceptibility and/or severity. TaqMan Real-Time genotyping for PUNISHER rs12318065A/C, SENCR rs12420823C/T, MIAT rs1061540C/T, MALAT1 rs3200401T/C, and GATA6-AS1 rs73390820A/G were run on the extracted genomic DNA from 100 unrelated patients with stable CAD undergoing diagnostic coronary angiography and from 100 controls. After adjusting covariates, the studied variants showed no association with disease susceptibility; however, MIAT*T/T genotype was associated with a more severe Gensini score. In contrast, MALAT1*T/C heterozygosity was associated with a lower score. The lipid profile, and to a lesser extent smoking status, male sex, weight, hypertension, and MALAT1 (T > C) (negative correlation), explained the variance between patients/control groups via a principal component analysis. Incorporating the principal components into a logistic regression model to predict CAD yielded a 0.92 AUC. In conclusion: MIAT rs1061540 and MALAT1 rs3200401 variants were associated with CAD severity and Gensini score in the present sample of the Egyptian population. Further large multi-center and functional analyses are needed to confirm the results and identify the underlying molecular mechanisms.

Asunto(s)

Enfermedad de la Arteria Coronaria , ARN Largo no Codificante , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/genética , Genotipo , Humanos , Masculino , Neovascularización Patológica , ARN Largo no Codificante/genética

RESUMEN

BACKGROUND: Emerging evidence indicates group-specific component (GC) variants are associated with ethnicity. We aimed to investigate the association of GC variants and protein expression level with T2DM and diabetic nephropathy (DN) in Saudi patients. SUBJECTS AND METHODS: A total of 200 participants (120 T2DM/80 controls) were genotyped for GC-rs7041/GC-rs4588 by real-time polymerase chain reaction. Serum GC was assessed by ELISA and in silico analysis was executed. RESULTS: GC-rs7041 frequency distribution showed no difference between the study groups, while GC-rs4588 showed association with T2DM under all genetic models. rs4588*AA variant was correlated with higher serum GC globulin, albuminuria, and poor glycaemic control. A higher frequency of rs7041*TT and rs4588*AA was evident in macroalbuminuria vs. normoalbuminuria group. Carrying GC-2 haplotype was 2.5 more likely to develop diabetes and correlated with the levels of albuminuria. CONCLUSIONS: GC variants could have independent effects on the risk of T2DM and DN in the study population.

Asunto(s)

Albuminuria , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Proteína de Unión a Vitamina D , Albuminuria/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Exones , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Proteína de Unión a Vitamina D/genética

RESUMEN

Diabetic nephropathy (DN) is a major risk factor for end-stage renal disease (ESRD). MicroRNAs (miRNAs/miRs) and their variants may be implicated in health and disease, including DN. The present study aimed to investigate the association of the miRNA-499a gene (MIR499A) A/G seed region variant (rs3746444) with DN-associated ESRD susceptibility in patients with diabetes mellitus, and to determine whether there was an association between the different genotypes and the patients' laboratory and clinical data. A case-control pilot study was conducted on 180 adult patients with type 2 diabetes mellitus. A total of 90 patients with ESRD on regular hemodialysis were considered as the cases, and 90 age-, sex- and ethnicity-matched diabetic patients with normo-albuminuria were considered as the controls. MIR499A genotyping was performed using a TaqMan Real-Time allele discrimination assay. Results demonstrated that the MIR499A rs3746444*G variant conferred susceptibility to the development of ESRD under co-dominant [(odds ratio (95% confidence interval): 2.49 (1.41-3.89) and 2.41 (1.61-6.68) for heterozygous and homozygous comparison, respectively], dominant [2.30 (1.18-3.90)] and allelic [1.82 (1.17-2.83)] models. Different genotypes of the specified variant did not exhibit significant associations with the clinic-laboratory data of the studied patients or the circulating miR-499a plasma levels. In conclusion, results of the present study suggested that MIR499A rs3746444 may be a susceptibility variant for DN-associated ESRD in the study population. However, larger sample size studies with different ethnicities are warranted to verify these findings.

RESUMEN

BACKGROUND: Long non-coding RNAs (lncRNAs) play essential roles in molecular diagnosis and therapeutic response in several diseases. PURPOSE: For the first time, we aimed to evaluate the association of four lncRNAs TUG1 (rs7284767G/A), MIAT (rs1061540T/C), MALAT1 (rs3200401C/T), and SENCR (rs12420823C/T) variants with susceptibility to diabetic retinopathy (DR), disease severity, and early therapeutic response to intravitreous anti-vascular endothelial growth factor aflibercept therapy. PATIENTS AND METHODS: This case-control study enrolled 126 adult patients with type 2 diabetes. TaqMan assays using Real-Time PCR were run for genotyping. Multivariable regression analyses were applied to assess the role of each polymorphism after the adjustment of covariates. RESULTS: Carriers of TUG1 A/G and MIAT T/C and C/C genotypes were more likely to develop DR [OR=3.15 (95% CI=1.15-8.64), and OR=4.31 (95% CI=1.78-10.47)], while MALAT1 T/C conferred protection (OR=0.40, 95% CI=0.16-0.99). For TUG1, MALAT1, MIAT, and SENCR genotype combinations, GTCT and GCCC had a higher disease risk (P=0.012). For disease severity, MIAT T/T homozygosity was associated with higher DR grade [33.3% (T/T) vs 10% (C/C) and 4.2% (C/T) carriers, P=0.012]. Otherwise, patients with the SENCR T variant exhibited better pre-treatment best-corrected visual acuity level (p=0.021). Following aflibercept administration, carrying the TUG1 A or MIAT T/C was associated with a poor therapeutic response (OR=5.02, 95% CI=1.60-15.76, and OR=10.23, 95% CI=1.51-69.15, respectively). CONCLUSION: The lncRNAs TUG1 (rs7284767G/A) and MIAT (rs1061540T/C) were associated with increased DR susceptibility and poor response to aflibercept treatment, while MALAT1 (rs3200401C/T) conferred protection to DR. These genetic determinants could be useful in DR risk stratification and pharmacogenetics after validation in large-scale studies.

RESUMEN

Toll-like receptor (TLR) family signature has been implicated in sepsis etiopathology. We aimed to evaluate the genetic profile of TLR pathway-related key genes; the myeloid differentiation protein 88 (MYD88), IL1 receptor-associated kinase 1 (IRAK1), the nuclear factor kappa-B1 (NFKB1), and interleukin 6 (IL6) in the blood of neonates with sepsis at the time of admission and post-treatment for the available paired-samples. This case-control study included 124 infants with sepsis admitted to the neonatal intensive care unit and 17 controls. The relative gene expressions were quantified by TaqMan Real-Time qPCR and correlated to the clinic-laboratory data. MYD88, NFKB1, and IL6 relative expressions were significantly higher in sepsis cases than controls. Higher levels of MYD88 and IL6 were found in male neonates and contributed to the sex-based separation of the cases by the principal component analysis. ROC analysis revealed MYD88 and NFKB1 transcripts to be good biomarkers for sepsis. Furthermore, patients with high circulatory MYD88 levels were associated with poor survival, as revealed by Kaplan-Meier curves analysis. MYD88, NFKB1, and IL6 transcripts showed association with different poor-outcome manifestations. Clustering analysis split the patient cohort into three distinct groups according to their transcriptomic signature and CRP levels. In conclusion, the study TLR pathway-related transcripts have a gender-specific signature, diagnostic, and prognostic clinical utility in neonatal sepsis.

Asunto(s)

Interleucina-6/sangre , Factor 88 de Diferenciación Mieloide/sangre , Subunidad p50 de NF-kappa B/sangre , Sepsis Neonatal/sangre , Sepsis Neonatal/mortalidad , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Masculino , Sepsis Neonatal/patología , Pronóstico , Transducción de Señal/genética

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Dysregulation of mitochondrial function often precedes malignant transformation of hematopoietic stem cells (HSCs). Mitochondria have a direct role in the maintenance of HSC functions. For example, D-2-hydroxyglutarate, generated due to the activity of mutated mitochondrial isocitrate dehydrogenase (IDH), has been implicated in the pathogenesis of leukemia. Furthermore, disturbances in the fatty acid breakdown and pyruvate oxidation are often seen in leukemic cells. These and other abnormalities expedite leukemogenesis and chemoresistance of leukemic cells. However, it needs to be elucidated whether these aberrations are the result or cause of leukemogenesis. Accordingly, for this review, a search was carried out in PubMed and Google Scholar databases until June 2019 to assess the relationship between metabolic pathways in altered mitochondria and leukemia development. In the present review, an overview of mitochondria-related mechanisms and their abnormalities in leukemia is presented, with mitochondrial pathways and factors, such as mitophagy, intermediary metabolism enzymes, oncometabolites and reactive oxygen species' generation, discussed as potential diagnostic and therapeutic targets in leukemia.

RESUMEN

Background: Circulating non-coding RNAs (ncRNAs) have been implicated in health and disease. This study aimed to evaluate the serum expression profile of microRNA-499a (miR-499a) and its selected bioinformatically predicted partner long-ncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) in diabetes-related end-stage renal disease (ESRD) patients and to correlate the expressions with the patients' clinicolaboratory data.Subjects and methods: Real-time quantitative polymerase chain reaction was applied in diabetics with and without ESRD (n = 90 for each).Results: Serum MALAT1 expression levels were increased in the ESRD group relative to diabetics without ESRD with median (quartile) values of 10.5 (1.41-126.7) (p < .001). However, miR-499a levels were decreased in more than half of ESRD patients with a median of 0.96 (0.13-3.14). Both MALAT1 and miR-499a expression levels were inversely correlated in the ESRD patient-group.Conclusions: MALAT1 up-regulation and miR-499 down-regulation might be involved in diabetic nephropathy-related ESRD pathogenesis. Functional validation studies are warranted to confirm the MALAT1/miR-499a partnership.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Fallo Renal Crónico/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Diálisis Renal , Adulto , Anciano , Emparejamiento Base , Secuencia de Bases , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/terapia , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Masculino , MicroARNs/sangre , Persona de Mediana Edad , ARN Largo no Codificante/sangre

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PURPOSE: Putative roles of long non-coding RNAs (lncRNAs) as indicators for diabetic retinopathy (DR) and associated complications are beginning to emerge. We aimed to evaluate a panel of circulating hyperglycemia-related lncRNAs: RNCR2, NEAT2, CDKN2B-AS1, and PVT1 in type 2 diabetes patients with/without DR and to correlate their levels with the clinical characteristics and response to aflibercept intravitreal injection in terms of visual acuity (VA) improvement, central macular thickness (CMT) decline, and macular edema resolution after 4 weeks of the initial injection. METHODS: Pre-treatment plasma relative expression levels of the specified lncRNAs were quantified in 130 consecutive patients with diabetes (75 and 55 with/without DR, respectively) and 108 controls using quantitative real-time PCR. RESULTS: One month after aflibercept injection, significant reductions in CMT and VA were observed in DR cohorts. The four lncRNAs were over-expressed in DM compared with those in controls. However, downregulated baseline plasma levels of RNCR2 and NEAT2 were observed in glycemic-controlled DR patients. None of the lncRNAs showed a correlation with the severity of retinopathy or drug response. CONCLUSION: Though circulating levels of the analyzed lncRNAs did not show an association with DR progression or aflibercept therapy response, the expression pattern demonstrated good diagnostic performance in differentiating DM from controls and DR.

Asunto(s)

Retinopatía Diabética/sangre , ARN Largo no Codificante/sangre , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN/genética , ARN Largo no Codificante/genética , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Retina/patología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Agudeza Visual

RESUMEN

Glioblastoma multiforme (GBM) (grade IV astrocytoma) has been assumed to be the most fatal type of glioma with low survival and high recurrence rates, even after prompt surgical removal and aggressive courses of treatment. Transcriptional reprogramming to stem cell-like state could explain some of the deregulated molecular signatures in GBM disease. The present study aimed to quantify the expression profiling of longevity-related transcriptional factors SOX2, OCT3/4, and NANOG to evaluate their diagnostic and performance values in high-grade gliomas. Forty-four specimens were obtained from glioblastoma patients (10 females and 34 males). Quantitative real-time polymerase chain reaction was applied for relative gene expression quantification. In silico network analysis was executed. NANOG and OCT3/4 mRNA expression levels were significantly downregulated while that of SOX2 was upregulated in cancer compared to noncancer tissues. Receiver operating characteristic curve analysis showed high diagnostic performance of NANOG and OCT3/4 than SOX2. However, the aberrant expressions of the genes studied were not associated with the prognostic variables in the current population. In conclusion, the current study highlighted the aberrant expression of certain longevity-associated transcription factors in glioblastoma multiforme which may direct the attention towards new strategies in the treatment of such lethal disease.

Asunto(s)

Neoplasias Encefálicas/genética , Glioblastoma/genética , Longevidad/genética , Transcriptoma , Adulto , Área Bajo la Curva , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Modelos Lineales , Masculino , Persona de Mediana Edad , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Estadificación de Neoplasias , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Curva ROC , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Regulación hacia Arriba

RESUMEN

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The oncogenic function of the long non-coding RNA; metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HCC remains unclear. We aimed to evaluate MALAT1 serum expression profile in HCC and explore its relation to the clinicopathological features. Quantitative Real Time-Polymerase Chain Reaction was applied in 70 cohorts (30 HCC, 20 HCV, 20 controls). Further meta-analysis of clinical studies and in vitro validated experiments was employed. Serum MALAT1 showed area under the curve of 0.79 and 0.70 to distinguish patients with cancer from normal and cirrhotic individuals at fold change of 1.0 and 1.26, respectively. Expression level was significantly higher in males (P <0.001) and patients with massive ascites (P = 0.005). Correlation analysis showed positive correlation of MALAT1 with total bilirubin (r = 0.456, P <0.001) and AST (r = 0.280, P = 0.019), and negative correlation with the hemoglobin level (r = 0.312, P = 0.009). Meta-analysis showed that the over-expressed MALAT1 was linked to tumor number [Cohen's d = 0.450, 95% CI (0.21 to 0.68)], clinical stage [Cohen's d = 0.048, 95% CI (-0.83 to 0.74)], and AFP level [Cohen's d = 0.354, 95% CI (0.1 to 0.57)]. In silico data analysis and systematic review confirmed MALAT1 oncogenic function in cancer development and progression. In conclusion, circulatory MALAT1 might represent a putative non-invasive prognostic biomarker indicating worse liver failure score in HCV-related HCC patients with traditional markers. Large-scale verification is warranted in future studies.

Asunto(s)

Carcinogénesis/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Hepacivirus/fisiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , ARN Largo no Codificante/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Carcinoma Hepatocelular/sangre , Estudios de Casos y Controles , Simulación por Computador , Demografía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/genética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Sesgo de Publicación , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcriptoma/genética , alfa-Fetoproteínas/metabolismo

RESUMEN

BACKGROUND: Small non-coding RNAs (microRNAs) have been evolved to master numerous cellular processes. Genetic variants within microRNA seed region might influence microRNA biogenesis and function. The study aimed at determining the role of microRNA-499 (MIR-499) gene family polymorphism as a marker for susceptibility and progression of bronchial asthma and to analyze the structural and functional impact of rs3746444 within the seed region. METHODS: Genotyping for 192 participants (96 patients and 96 controls) in the discovery phase and 319 subjects (115 patients and 204 controls) in the replication phase was performed via Real Time-Polymerase Chain Reaction technology. Patients underwent the methacholine challenge test and biochemical analysis. Gene structural and functional analysis, target prediction, annotation clustering, and pathway enrichment analysis were executed. Predicted functional effect of rs37464443 SNP was analyzed. RESULTS: miR-499 gene family is highly implicated in inflammation-related signaling pathways. Rs374644 (A > G) in MIR499A and MIR499B within the seed region could disrupt target genes and create new genes. The G variant was associated with high risk of developing asthma under all genetic association models (G versus A: OR = 3.27, 95% CI = 2.53-4.22; GG versus AA: OR = 9.52, 95% CI = 5.61-16.5; AG versus AA: OR = 2.13, 95% CI = 1.24-3.46; GG + AG versus AA: OR = 4.43, 95% CI = 2.88-6.82). GG genotype was associated with poor pre-bronchodilator FEV1 (p = 0.047) and the worst bronchodilator response after Salbutamol inhalation, represented in low peaked expiratory flow rate (p = 0.035). CONCLUSIONS: miR-499 rs3746444 (A > G) polymorphism was associated with asthma susceptibility and bronchodilator response in Egyptian children and adolescents. Further functional analysis is warranted to develop more specific theranostic agents for selecting targeted therapy.

Asunto(s)

Asma/diagnóstico , Asma/genética , Variación Genética/genética , MicroARNs/genética , Adolescente , Asma/epidemiología , Secuencia de Bases , Niño , Preescolar , Egipto/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , MicroARNs/química , Filogenia , Polimorfismo de Nucleótido Simple/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos

RESUMEN

BACKGROUND: 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1-BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. METHODS: Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. RESULTS: Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader-Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1-BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.

Asunto(s)

Discapacidad Intelectual/genética , Adolescente , Niño , Preescolar , Aberraciones Cromosómicas , Duplicación Cromosómica , Cromosomas Humanos Par 15/genética , Hibridación Genómica Comparativa , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Estudios Retrospectivos , Adulto Joven