The Fusion of CLEC12A and MIR223HG Arises from a trans-Splicing Event in Normal and Transformed Human Cells

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A-MIR223HG, a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA-223 host gene (MIR223HG), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A-MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A-MIR223HG expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that CLEC12A-MIR223HG is a product of trans-splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A-MIR223HG expression. CLEC12A-MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein–protein interactions. Taken together, our observations support a possible involvement of CLEC12A-MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs

Icodextrin does not impact infectious and culture-negative peritonitis rates in peritoneal dialysis patients: a 2-year multicentre, comparative, prospective cohort study

Background. Icodextrin is a glucose polymer derived by hydrolysis of cornstarch. The different biocompatibility profile of icodextrin-containing peritoneal dialysis (PD) solutions may have a positive influence on peritoneal host defence. Furthermore, cases of sterile peritonitis potentially associated with icodextrin have been reported

The Fusion of CLEC12A and MIR223HG Arises from a trans-Splicing Event in Normal and Transformed Human Cells

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A-MIR223HG, a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA-223 host gene (MIR223HG), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A-MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A-MIR223HG expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that CLEC12A-MIR223HG is a product of trans-splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A-MIR223HG expression. CLEC12A-MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein–protein interactions. Taken together, our observations support a possible involvement of CLEC12A-MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs

Free Time For Wellness: a co-designed intervention utilizing social networks to encourage physical activity for cancer prevention among low resourced mothers

Background Physical activity is central to chronic disease prevention. Low resource mothers face structural barriers preventing them from increasing their physical activity to reduce their chronic disease risk. We co-designed an intervention, with the ultimate goal of building social cohesion through social media to increase physical activity for low resourced mothers in urban settings. Methods In 2019, we interviewed 10 mothers of children (< 12 years) living in Washington Heights, Manhattan. The interviews were transcribed and coded for themes that guided the creation of a co-design workshop. Washington Heights-based mothers (n = 16) attended a co-design workshop to generate the blueprint for the Free Time for Wellness intervention. Results Mothers in our sample had limited time, external support and resources, which hindered them from increasing their physical activity; we learned that in addition to physical health, mental health was a concern for participants. Participants had varying degrees of self-efficacy and trust in social media. Bringing mothers and researchers together in a co-design workshop, we identified types of physical activities they would enjoy participating in, the ideal time to do so, the kind of childcare they needed, and their preferences for communication with the community champion. The interviews and workshop highlighted the need for a community space that mothers and children could co-occupy. The intervention was designed to be 3 months’ worth of sample programming with one activity per week, rotating between dance, yoga, food pantry visits and group playdates. Participants were invited to bring their children to a space with one room for the ‘participants only’ activity and a second room in which professional childcare providers supervised the children. Conclusions Through this two-phased co-design process, we created an intervention with mothers in an urban community with the goal of using social media to bring them together for wellness, primarily through increased physical activity. Despite the co-design of this intervention with a specific community, there are some universal applications of our findings, and of the use of co-design workshops, to other settings

Randomised Controlled Trial to determine the appropriate time to initiate peritoneal dialysis after insertion of catheter to minimise complications (Timely PD study)

Background. The most appropriate time to initiate dialysis after surgical insertion of Tenckhoff catheters is not clear in the literature. There is the possibility of peritoneal dialysis (PD) complications such as leakage and infection if dialysis is started too soon after insertion. However, much morbidity and expense could be saved by reducing dependency on haemodialysis (HD) by earlier initiation of PD post catheter insertion. Previous studies are observational and mostly compare immediate with delayed use. The primary objective is to determine the safest and shortest time interval between surgical placement of a Tenckhoff catheter and starting PD. Methods/Design. This is a randomised controlled trial of patients who will start PD after insertion of Tenckhoff catheter at Royal Brisbane and Women's Hospital (RBWH) or Rockhampton Base Hospital (RBH) who meet the inclusion criteria. Patients will be stratified by site and diabetic status. The patients will be randomised to one of three treatment groups. Group 1 will start PD one week after Tenckhoff catheter insertion, group 2 at two weeks and group 3 at four weeks. Nurses and physicians will be blinded to the randomised allocation. The primary end point is the complication rate (leaks and infection) after initiation of PD. Discussion. The study will determine the most appropriate time to initiate PD after placement of a Tenckhoff catheter

Nitric oxide synthase isoforms play distinct roles during acute peritonitis

Background. Acute peritonitis is the most frequent complication of peritoneal dialysis (PD). Increased nitric oxide (NO) release by NO synthase (NOS) isoforms has been implicated in acute peritonitis, but the role played by the NOS isoforms expressed in the peritoneum is unknown

Proteinuria Is Associated with Quality of Life and Depression in Adults with Primary Glomerulopathy and Preserved Renal Function

BACKGROUND: There is no information about HRQoL, depression and associated factors in adult with nephrotic syndrome-associated glomerulopathy. METHODOLOGY/PRINCIPAL FINDINGS: Patients with primary glomerulopathy where compared with age and sex-matched hemodialysis patients and healthy subjects. Laboratory data, medical history, comorbid conditions were collected to evaluate factors associated with HRQoL (SF-36) and Depression (Hamilton Depression Rating Scale-HAMD). Glomerulopathy patients had low HRQoL in all eight SF-36 domains and two composite scores (physical and mental) in comparison with healthy subjects. HAMD score also was elevated and there was high depression prevalence. Overall, these data were comparable between glomerulopathy and hemodialysis patients. Using multiple regression analysis, factors associated with low HRQoL physical composite score were: last 24 h-urine protein excretion (-0.183, 95%CI -0.223 to -0.710 for each gram of proteinuria, p = 0.01) and cyclosporine use (-15.315, 95%CI -25.913 to -2.717, p = 0.03). Low HRQoL mental composite score was associated with last 24 h-urine protein excretion (-0.157, 95%CI -0.278 to -0.310 for each gram of proteinuria, p = 0.03) and HMAD score was independently associated with age (0.155, 95%CI 0.318 to 0.988 for each year, p = 0.04), female sex (4.788, 95%CI 1.005 to 8.620, 0 = 0.03), disease duration (0.074, 95%CI 0.021 to 0.128 for each month, p = 0.01) and last 24 h-urine protein excretion (0.050, 95%CI 0.018 to 0.085 for each gram of proteinuria, p = 0.02). CONCLUSIONS/SIGNIFICANCE: Nephrotic-syndrome associated glomerulopathy patients have low HRQoL and high prevalence of depression symptoms, comparable with those of hemodialysis patients. Last 24 h-protein excretion rate is independently associated with physical and mental HRQoL domains in addition to depression

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>Macrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients.</p> <p>Methods</p> <p>We conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl.</p> <p>Results</p> <p>The mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035).</p> <p>Conclusions</p> <p>Macrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.</p

A Crosstalk between the Smad and JNK Signaling in the TGF-β-Induced Epithelial-Mesenchymal Transition in Rat Peritoneal Mesothelial Cells

Transforming growth factor β (TGF-β) induces the process of epithelial-mesenchymal transition (EMT) through the Smad and JNK signaling. However, it is unclear how these pathways interact in the TGF-β1-induced EMT in rat peritoneal mesothelial cells (RPMCs). Here, we show that inhibition of JNK activation by introducing the dominant-negative JNK1 gene attenuates the TGF-β1-down-regulated E-cadherin expression, and TGF-β1-up-regulated α-SMA, Collagen I, and PAI-1 expression, leading to the inhibition of EMT in primarily cultured RPMCs. Furthermore, TGF-β1 induces a bimodal JNK activation with peaks at 10 minutes and 12 hours post treatment in RPMCs. In addition, the inhibition of Smad3 activation by introducing a Smad3 mutant mitigates the TGF-β1-induced second wave, but not the first wave, of JNK1 activation in RPMCs. Moreover, the inhibition of JNK1 activation prevents the TGF-β1-induced Smad3 activation and nuclear translocation, and inhibition of the TGF-β1-induced second wave of JNK activation greatly reduced TGF-β1-induced EMT in RPMCs. These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-β1-induced EMT and fibrotic process in RPMCs. Therefore, our findings may provide new insights into understanding the regulation of the TGF-β1-related JNK and Smad signaling in the development of fibrosis