Bladder cancer is the 9th leading cause of cancer death worldwide. The major problem in bladder cancer is primarily the high recurrence rate after drug treatment and resection. Although conventional screening methods, such as cystoscopy, urinary cytology and ultrasound sonography, have become widely used in clinical settings, the diagnostic performance of these modalities is unsatisfactory due to low accuracy or high invasiveness. Because circulating micro RNA (miRNA) profiles have recently been reported as an attractive tool for liquid biopsy in cancer screening, here, we performed global miRNA profiling of 392 serum samples of bladder cancer patients with 100 non-cancer samples and 480 samples of other types of cancer as controls. We randomly classified the bladder cancer and control samples into 2 cohorts, a training set (N = 486) and a validation set (N = 486). By comparing both controls, we identified specific miRNA, such as miR-6087, for diagnosing bladder cancer in the training and validation sets. Furthermore, we found that a combination of 7 miRNA (7-miRNA panel: miR-6087, miR-6724-5p, miR-3960, miR-1343-5p, miR-1185-1-3p, miR-6831-5p and miR-4695-5p) could discriminate bladder cancer from non-cancer and other types of tumors with the highest accuracy (AUC: .97; sensitivity: 95%; specificity: 87%). The diagnostic accuracy was high, regardless of the stage and grade of bladder cancer. Our data demonstrated that the 7-miRNA panel could be a biomarker for the specific and early detection of bladder cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cas.13856

Circulating miRNA panels for specific and early detection in bladder cancer.

MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2/B1) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers, readers, and erasers of m6A and report that HNRNPA2/B1 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental, tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA2/B1 affects miRNA expression, HNRNPA2/B1 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated, respectively, 48 h after transfection and 177 and 172 up- and down-regulated, respectively, 72 h after transfection. MetaCore Enrichment analysis identified progesterone receptor action and transforming growth factor β (TGFβ) signaling via miRNA in breast cancer as pathways downstream of the upregulated miRNAs and TGFβ signaling via SMADs and Notch signaling as pathways of the downregulated miRNAs. GO biological processes for mRNA targets of HNRNPA2/B1-regulated miRNAs included response to estradiol and cell-substrate adhesion. qPCR confirmed HNRNPA2B1 downregulation of miR-29a-3p, miR-29b-3p, and miR-222 and upregulation of miR-1266-5p, miR-1268a, miR-671-3p. Transient overexpression of HNRNPA2/B1 reduced MCF-7 sensitivity to 4-hydroxytamoxifen and fulvestrant, suggesting a role for HNRNPA2/B1 in endocrine-resistance.

/pdf/hnrnpa2-b1-is-upregulated-in-endocrine-resistant-lcc9-breast-3a1ldhbd0h.pdf

HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells

Although long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been suggested to play important roles in the pathogenesis of diseases, atherosclerosis-related lncRNAs and circRNAs remain rarely reported. This study aimed to explore the underlying molecular mechanisms of atherosclerosis based on the competing endogenous RNA (ceRNA) regulatory hypothesis of lncRNAs and circRNAs. The expression profiles of circRNAs, lncRNAs, and mRNAs in human THP-1 macrophages treated with oxidized low-density lipoprotein (an in vitro atherosclerosis model), or not, were obtained from the Gene Expression Omnibus database under accession numbers GSE107522, GSE54666, and GSE54039, respectively. The present study identified 29 differentially expressed circRNAs in GSE107522, 544 differentially expressed genes (DEGs) in GSE54666, and 502 DEGs and 231 differentially expressed lncRNAs in GSE54039 datasets by using the Linear Models for Microarray Data method. Eight DEGs were found to be shared and expressed with the consistent trend in GSE54666 and GSE54039 datasets. Two of them (ASPH, aspartate beta-hydroxylase; and PDE3B, phosphodiesterase 3B) were suggested to be crucial based on functional enrichment, protein-protein interaction, and ceRNA network analyses. ASPH, through interaction with CACNA2D4 (calcium voltage-gated channel auxiliary subunit alpha2delta 4), may be associated with atherosclerosis by regulating the cellular response to calcium ion; and PDE3B may exert roles in negative regulation of angiogenesis through cross talk with ELMO1 (engulfment and cell motility 1). Furthermore, the expression of ASPH and PDE3B may be regulated by hsa_circ_0028198/hsa_circ_0092317/XIST-miR-543; PDE3B expression may be also modulated by hsa_circ_0092317/hsa_circ_0003546/H19/XIST-miR-326. In conclusion, our identified ceRNA interaction axes may possibly be important targets for treatment of atherosclerosis.

circRNA/lncRNA-miRNA-mRNA Network in Oxidized, Low-Density, Lipoprotein-Induced Foam Cells

Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.

https://www.mdpi.com/1422-0067/21/4/1372/pdf

The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis.

Our understanding of circulating microRNAs (miRNAs) related to systemic lupus erythematosus (SLE) remains very limited. In this study, we screened SLE-specific miRNAs in plasma from 42 B cell-related miRNAs by using miRNA PCR Array. The selected miRNAs were first confirmed in plasma samples from 50 SLE patients, 16 rheumatoid arthritis (RA) patients, and 20 healthy donors using qRT-PCR. We then investigated the relationship between expressions of the selected miRNAs and SLE clinical indicators. As a result, 14 miRNAs (miR-103, miR-150, miR-20a, miR-223, miR-27a, miR-15b, miR-16, miR-181a, miR-19b, miR-22, miR-23a, miR-25, miR-92a, and miR-93) were significantly decreased in the plasma of SLE patients compared with healthy controls (P < 0.05) and could act as the diagnostic signature to distinguish SLE patients from healthy donors. Six miRNAs (miR-92a, miR-27a, miR-19b, miR-23a, miR-223, and miR-16) expressed in plasma were significantly lower in SLE patients than in RA patients (P < 0.05), revealing the potentially diagnostic signature to distinguish SLE patients from RA patients. Furthermore, the downregulated expression of miR-19b, miR-25, miR-93, and miR-15b was associated with SLE disease activity (P < 0.05) while miR-15b and miR-22 expressions were significantly lower in SLE patients with low estimate glomerular filtration rate (eGFR < 60 ml/min/1.73 m2) (P < 0.05). The diagnostic potential of miR-15b for SLE disease activity and lupus nephritis (LN) with low eGFR was validated on an independent validation set with 69 SLE patients and a cross-validation set with 80 SLE patients. In summary, the signature of circulating miRNAs will provide novel biomarkers for the diagnosis of SLE and evaluation of disease activity and LN.

/pdf/b-cell-related-circulating-micrornas-with-the-potential-5cz9m4gaai.pdf

B Cell-Related Circulating MicroRNAs With the Potential Value of Biomarkers in the Differential Diagnosis, and Distinguishment Between the Disease Activity and Lupus Nephritis for Systemic Lupus Erythematosus.

Renal involvement in Systemic Lupus Erythematous (SLE) patients is one of the leading causes of morbidity and a significant contributor to mortality. It’s estimated that nearly 50% of SLE individuals develop kidney disease in the first year of the diagnosis. Class IV lupus nephritis (LN-IV) is the class of lupus nephritis most common in Colombian patients with SLE. Altered miRNAs expression levels have been reported in human autoimmune diseases including lupus. Variations in the expression pattern of peripheral blood circulating miRNAs specific for this class of lupus nephritis could be correlated with the pathophysiological status of this group of individuals. The aim of this study was to evaluate the relative abundance of circulating microRNAs in peripheral blood from Colombian patients with LN-IV. Circulating miRNAs in plasma of patients with diagnosis of LN-IV were compared with individuals without renal involvement (LNN group) and healthy individuals (CTL group). Total RNA was extracted from 10 ml of venous blood and subsequently sequenced using Illumina. The sequences were processed and these were analyzed using miRBase and Ensembl databases. Differential gene expression analysis was carried out with edgeR and functional analysis were done with DIANA-miRPath. Analysis was carried out using as variables of selection fold change (≥2 o ≤-2) and false discovery rate (0.05). We identified 24 circulating microRNAs with differential abundance between LN-IV and CTL groups, fourteen of these microRNAs are described for the first time to lupus nephritis (hsa-miR-589-3p, hsa-miR-1260b, hsa-miR-4511, hsa-miR-485-5p, hsa-miR-584-5p, hsa-miR-543, hsa-miR-153-3p, hsa-miR-6087, hsa-miR-3942-5p, hsa-miR-7977, hsa-miR-323b-3p, hsa-miR-4732-3p and hsa-miR-6741-3p). These changes in the abundance of miRNAs could be interpreted as alterations in the miRNAs-mRNA regulatory network in the pathogenesis of LN, preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of LN.

/pdf/profiling-analysis-of-circulating-microrna-in-peripheral-1n1j4opbqe.pdf

Profiling analysis of circulating microRNA in peripheral blood of patients with class IV lupus nephritis.

Glomerular filtration rate (GFR) and proteinuria-albuminuria are the renal functional parameters currently used to evaluate chronic kidney disease (CKD) severity. However, tubular secretion is another important renal functional parameter to be taken into account since proximal tubule (PT) secretion, in particular, is a crucial renal mechanism for endogenous organic cations, anions and drug elimination. The residual diuresis is a relevant survival predictor in patients on dialysis, since their urine is produced by the glomerular and tubular functions. It has been hypothesized that drugs which up-regulate some renal tubular transporters could contribute to uremic toxin excretion, and nephroprevention. However, if tubular transporters' down-regulation observed in CKD patients and experimental models is a PT adaptation to avoid intracellular accumulation and damage from uremic toxins, consequently the increase of toxin removal by inducing tubular transporters' up-regulation could be deleterious to the kidney. Therefore, a deeper understanding of this phenomenon is currently needed. In conclusion, tubular function has an important role for endogenous organic cations, anions and drug excretion in CKD patients, and a deeper understanding of its multiple mechanisms could provide new therapeutic alternatives in this population.

/pdf/the-importance-of-tubular-function-in-chronic-kidney-disease-26781vidww.pdf

The Importance of Tubular Function in Chronic Kidney Disease.

Even though there are many definitions of acute kidney injury (AKI), it is classically defined as a heterogeneous group of conditions characterized by a sudden decrease in glomerular filtration rate (GFR), expressed as an increase in serum creatinine (serum creatinine ≥ 0.3 mg/dl within 48 hours or serum creatinine ≥ 1.5 times baseline within the prior 7 days) or urine volume reduction (< 0.5 ml/kg/h for 6 hours).1,2 However, this definition does not exactly reflect the whole pathophysiology of this syndrome, since an acute renal injury can be limited to the tubules without compromising the glomeruli, and consequently reducing neither the patient ́s GFR nor his/her diuresis. This phenomenon is clinically observed in some drug-induced kidney injuries (eg: aminoglycosides) or in partial kidney ischemia, since renal medulla is more sensitive to hypoxia than renal cortex.3,4 Therefore, the current AKI definition can avoid its diagnosis in some particular cases. In addition, there are two additional inconveniences derived from the current AKI definition: Firstly, non oliguric AKI diagnosis is based on detecting a GFR reduction but the diagnostic marker usually used is serum creatinine, which is a late marker due to the fact that it rises after a GFR reduction of at least 50 %. This fact inexorably leads to a late AKI diagnosis, delayed treatment and worse prognosis.1,3 Secondly, despite having described novel and earlier AKI biomarkers, they have reduced availability, low specificity, usefulness not in all causes of AKI, insufficient patient outcome and cost-effectiveness studies, and mainly they do not guarantee the immediate AKI detection since their request is subject to the clinical suspicion of this condition by the attending physician, which definitely depends on the AKI definition currently used.5,6 In order to overcome these difficulties we present here the following proposals, valid for both the adult and pediatric patient. Firstly, to change the current AKI diagnosis definition to a more complete one, such as: Acute kidney injury is a heterogeneous group of conditions characterized by a sudden alteration of tubular function, decrease in GFR or urine volume reduction. The idea of modifying AKI definition is not just for academic reasons but mainly Looking for a better definition and diagnostic strategy for acute kidney injury: a new proposal

/pdf/looking-for-a-better-definition-and-diagnostic-strategy-for-1m1ikll537.pdf

Looking for a better definition and diagnostic strategy for acute kidney injury: a new proposal.

Estudio de utilización de antibióticos en Hospitales de Mediana y Alta Complejidad del Departamento del Atlántico-Colombia entre el 2016 y 2017

/pdf/development-and-use-of-an-application-programming-interface-4c8s3fpdlw.pdf

Henry González-Torres

Papers

Profiling analysis of circulating microRNA in peripheral blood of patients with class IV lupus nephritis.

The Importance of Tubular Function in Chronic Kidney Disease.

Looking for a better definition and diagnostic strategy for acute kidney injury: a new proposal.

Estudio de utilización de antibióticos en Hospitales de Mediana y Alta Complejidad del Departamento del Atlántico-Colombia entre el 2016 y 2017

Development and use of an application programming interface modified from GoogleMaps© for the georeferencing of patients with glomerular disease.