BK polyomavirus-associated nephropathy occurs in kidney transplant recipients under immunosuppressive treatment. BK polyomavirus is implicated in cancer development and invasion, and case reports of ...renal cell carcinoma and urothelial carcinoma possibly associated with BK polyomavirus has been reported. Further, it has been suggested that the immune responses of KT-related diseases could play a role in the pathogenesis and progression of renal cell carcinoma. Thus, we thought to examine the relationship between BK polyomavirus-associated nephropathy and renal cell carcinoma in terms of gene expression. To identify the common and specific immune responses involved in kidney transplantation-related diseases with a specific focus on BK polyomavirus-associated nephropathy, we performed consensus weighted gene co-expression network analysis on gene profile datasets of renal biopsy samples from different institutions. After the identification of gene modules and validation of the obtained network by immunohistochemistry of the marker across kidney transplantation-related diseases, the relationship between prognosis of renal cell carcinoma and modules was assessed. We included the data from 248 patients and identified the 14 gene clusters across the datasets. We revealed that one cluster related to the translation regulating process and DNA damage response was specifically upregulated in BK polyomavirus-associated nephropathy. There was a significant association between the expression value of hub genes of the identified cluster including those related to cGAS-STING pathway and DNA damage response, and the prognosis of renal cell carcinoma. The study suggested the potential link between kidney transplantation-related diseases, especially specific transcriptomic signature of BK polyomavirus associated nephropathy and renal cell carcinoma.
Dynamic control of DNA assembly by external stimuli has received increasing attention in recent years. Dynamic ligand exchange in metal complexes can be a central element in the structural and ...functional transformation of DNA assemblies. In this study,
N
,
N
-dicarboxymethyl-5-aminouracil (
dcaU
) nucleoside with an iminodiacetic acid (IDA) ligand at the 5-position of the uracil base has been developed as a bifacial nucleoside that can form both hydrogen-bonded and metal-mediated base pairs. Metal complexation study of
dcaU
nucleosides revealed their ability to form a 2:1 complex with a Gd
III
ion at the monomeric level. The characteristics of base pairing of
dcaU
nucleosides were then examined inside DNA duplexes. The results revealed that the formation of the metal-mediated
dcaU
-Gd
III
-
dcaU
pair significantly stabilized the DNA duplex containing one
dcaU
-
dcaU
mismatch (Δ
T
m
= +16.1 °C). In contrast, a duplex containing a hydrogen-bonded
dcaU
-A pair was destabilized in the presence of Gd
III
(Δ
T
m
= −3.5 °C). The Gd
III
-dependent base pairing of
dcaU
bases was applied to control the hybridization preference of DNA in response to metal ions. The hybridization partner of a
dcaU
-containing strand was reversibly exchanged by the addition and removal of Gd
III
ions. Since the incorporation of a single
dcaU
base can switch the hybridization behavior of DNA, the bifacial
dcaU
base would be a versatile building block for imparting metal responsiveness to DNA assemblies, allowing the rational design of dynamic DNA systems.
A novel
N
,
N
-dicarboxymethyl-5-aminouracil (
dcaU
) nucleobase was found to form both a hydrogen-bonded
dcaU
-A and a metal-mediated
dcaU
-Gd
III
-
dcaU
base pair. The hybridization partner of the
dcaU
-containing DNA was altered in response to Gd
III
ions.
Residence times of microplastics were estimated based on the dependence of meso- and macrolitter residence times on their upward terminal velocities (UTVs) in the ocean obtained by one- and two-year ...mark-recapture experiments conducted on Wadahama Beach, Nii-jima Island, Japan. A significant linear relationship between the residence time and UTV was found in the velocity range of about 0.3–0.9ms−1, while there was no significant difference between the residence times obtained in the velocity range of about 0.9–1.4ms−1. This dependence on the UTV would reflect the uprush-backwash response of the target items to swash waves on the beach. By extrapolating the linear relationship down to the velocity range of microplastics, the residence times of microplastics and the 1D onshore-offshore diffusion coefficients were inferred, and are one to two orders of magnitude greater than the coefficients of the macroplastics.
•Significant relationship was found between residence time and upward velocity.•The relationship reflects uprush-backwash response of target items to swash waves.•Residence time of microplastics was one-fifth to one-fourth that of macroplastics.
We assessed the utility of two forms of osteopontin (OPN), OPN full and its cleaved form (OPN N-half), in plasma and urine as markers of disease activity in lupus nephritis (LN). Samples were ...collected from patients with systemic lupus erythematosus (SLE) (LN: N = 29, non-LN: N = 27), IgA nephropathy (IgAN) (N = 14), minimal change nephrotic syndrome (MCNS) (N = 5), diabetic nephropathy (DN) (N = 14) and healthy volunteers (HC) (N = 17). While there was no significant difference in urine OPN full concentration between groups, urine OPN N-half concentration was significantly higher in patients with LN than HC (p < 0.05). Moreover, urine OPN N-half was higher in LN patients with overt proteinuria (urine protein/creatinine ratio: P/C > 0.5) than LN patients with minimal proteinuria (P/C < 0.5, p < 0.0001), and also higher than in DN patients with overt proteinuria (P/C > 0.5, p < 0.01). Urine thrombin activity correlated with urine OPN N-half concentration (p < 0.0001), but not with urine OPN full concentration. These results suggest that urine OPN N-half concentration reflects renal inflammation. Thus, urine OPN N-half may be a novel disease activity marker for LN.
The amount of albumin filtered through the glomeruli and reabsorbed at the proximal tubules in normal and in diabetic kidneys is debated. The megalin/cubilin complex mediates protein reabsorption, ...but genetic knockout of megalin is perinatally lethal. To overcome current technical problems, we generated a drug-inducible megalin-knockout mouse line, megalin(lox/lox);Ndrg1-CreER
(iMegKO), in which megalin expression can be shut off at any time by administration of tamoxifen (Tam). Tam administration in adult iMegKO mice decreased the expression of renal megalin protein by 92% compared with that in wild-type C57BL/6J mice and almost completely abrogated renal reabsorption of intravenously injected retinol-binding protein. Furthermore, urinary albumin excretion increased to 175 μg/d (0.46 mg albumin/mg creatinine) in Tam-treated iMegKO mice, suggesting that this was the amount of total nephron albumin filtration. By comparing Tam-treated, streptozotocin-induced diabetic iMegKO mice with Tam-treated nondiabetic iMegKO mice, we estimated that the development of diabetes led to a 1.9-fold increase in total nephron albumin filtration, a 1.8-fold increase in reabsorption, and a significant reduction in reabsorption efficiency (86% efficiency versus 96% efficiency in nondiabetic mice). Insulin treatment normalized these abnormalities. Akita;iMegKO mice, another model of type 1 diabetes, showed equivalent results. Finally, nondiabetic iMegKO mice had a glomerular sieving coefficient of albumin of 1.7×10
, which approximately doubled in diabetic iMegKO mice. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy in mice, bringing new insights to our understanding of renal albumin dynamics associated with the hyperfiltration status of diabetic nephropathy.
Background and Aims The technical difficulties inherent in endoscopic submucosal dissection (ESD) for colorectal neoplasms may result in the failure of en bloc resection or perforation. The aim of ...this retrospective study was to assess the predictors of en bloc resection failure or perforation by using preoperatively available factors. Methods Between September 2002 and March 2013, 716 colorectal ESDs in 673 consecutive patients were performed at a tertiary cancer center. Patient characteristics, tumor location, tumor type, colonoscopy-related factors, and endoscopist experience were assessed based on a prospectively recorded institutional ESD database. Logistic regression analysis was performed to identify predictors of failure of en bloc resection or perforations, with subgroup analyses of ESDs performed by endoscopists less experienced in colorectal ESD (<40 cases) and for colonic lesions only. Results On multivariate analysis, independent predictors of failure of en bloc resection or perforations were the presence of fold convergence (odds ratio OR 4.4; 95% confidence interval 95% CI, 1.9-9.9), protruding type (OR 3.6; 95% CI, 1.8-7.1), poor endoscope operability (OR 3.5; 95% CI, 1.8-6.9), right-sided colonic lesions (OR 3.0; 95% CI, 1.5-6.3 vs rectal lesions), left-sided colonic lesions (OR 3.2; 95% CI, 1.7-6.3, vs rectal lesions), the presence of an underlying semilunar fold (OR 2.1; 95% CI, 1.3-3.6), and a less-experienced endoscopist (OR 2.1; 95% CI, 1.3-3.6). Among less-experienced endoscopists, colonic lesions were independent predictors (right-sided colonic lesions 8.1; 95% CI, 2.9-25.1; left-sided colonic lesions 8.1; 95% CI, 2.5-28.3 vs rectal lesions). For colonic lesions, the presence of fold convergence (OR 3.7; 95% CI, 1.6-8.6), poor endoscope operability (OR 3.6; 95% CI, 1.8-7.2), a less-experienced endoscopist (OR 3.0; 95% CI, 1.7-1.8), and the presence of an underlying semilunar fold (OR 2.7; 95% CI, 1.5-4.7) were identified predictors. Conclusion This study successfully identified predictors of en bloc resection failure or perforation. Understanding these indicators could help to accurately stratify lesions according to technical difficulty and to appropriately select endoscopists.
Background and aim
Several papers have shown that preoperative inflammation-based prognostic scores and/or immunonutritional status are associated with survival in patients with hepatocellular ...carcinoma (HCC). However, the validity of prognostic factors of these scores remains controversial. This study aimed to validate the power of prognostic scores based on the preoperative inflammatory and immunonutritional indices of patients who underwent hepatectomy for HCC with curative intent.
Methods
Clinicopathological parameters and inflammation-based prognostic scores and immunonutritional status, including the Glasgow Prognostic Score, neutrophil to lymphocyte ratio (NLR), and prognostic nutritional index (PNI), were retrospectively analyzed to identify the predictors of overall and recurrence-free survival in 256 patients.
Results
In multivariate analysis, NLR was an independent prognostic factor for overall, and recurrence-free survival (hazard ratio HR 2.59, 95 % confidence interval CI 1.56–4.31,
P
< 0.001, and HR 2.11, 95 % CI 1.44–3.11,
P
< 0.001, respectively). Additionally, PNI was an independent predictor of overall survival (HR 2.01, CI 1.21–3.36,
P
= 0.007).
Conclusions
The present study shows that the NLR and PNI based on preoperative inflammatory and immunonutritional indices are predictors of overall survival in patients who undergo hepatectomy for HCC with curative intent.
This study investigated recent clinical outcomes and prognostic factors of metastasectomy for pulmonary metastasis (PM) from colorectal cancer.
Data for 785 patients with PM from colorectal cancer ...who underwent curative resection, including 376 patients treated with postmetastasectomy adjuvant chemotherapy, between 2004 and 2008, were collected from 46 Japanese hospitals. Disease-free and overall survival was analyzed. Potential prognostic factors were assessed.
The 5-year disease-free and overall survival rates (95% confidence interval) of all patients were 37.1% (33.7% to 40.9%) and 68.1% (64.6% to 71.8%), respectively, over a median follow-up of 65 months. On multivariable analysis, no survival benefit for postmetastasectomy adjuvant chemotherapy was observed (hazard ratio, 0.85; 95% confidence interval, 0.65 to 1.12; p = 0.25), and the independent poor prognostic factors for overall survival (hazard ratio, 95% confidence interval) were age 70 years and older (1.50, 1.15 to 1.97), disease-free interval of less than 2 years (1.76, 1.31 to 2.35), extrathoracic metastatic lesion treated curatively before PM resection (1.35, 1.01 to 1.79), abnormal carcinoembryonic antigen level (1.99, 1.53 to 2.58), and three or more PMs (1.72, 1.20 to 2.45). The 5-year overall survival rates (95% confidence interval) of the low-risk (no prognostic factor, n = 87), moderate-risk (1 to 2 factors, n = 539), and high-risk (≥3 factors, n = 159) groups were 89.4% (82.2% to 98.2%), 72.5% (68.3% to 76.8%), and 48.9% (41.7% to 57.3%), respectively.
Metastasectomy of PM from colorectal cancer was associated with a favorable prognosis. Patients could be classified into three risk groups using five prognostic factors. This grouping may be useful for identifying an optimal treatment strategy according to risk in future studies.
Aims/hypothesis
The accumulation of extracellular matrix (ECM) is a characteristic of diabetic nephropathy, and is partially caused by profibrotic proteins TGF-β and connective tissue growth factor ...(CTGF). We aimed to identify microRNAs (miRNAs) targeting
CTGF
on podocytes in diabetic nephropathy.
Methods
We investigated miRNAs targeting
CTGF
on podocytes with miRNA array analysis and identified a candidate miRNA, miR-26a. Using overexpression and silencing of miR-26a in cultured podocytes, we examined changes of ECM and its host genes. We further investigated glomerular miR-26a expression in humans and in mouse models of diabetic nephropathy.
Results
miR-26a, which was downregulated by TGF-β1, was expressed in glomerular cells including podocytes and in tubules by in situ hybridisation. Glomerular miR-26a expression was downregulated by 70% in streptozotocin-induced diabetic mice. Transfection of miR-26a mimics in cultured human podocytes decreased the CTGF protein level by 50%, and directly inhibited
CTGF
expression in podocytes, as demonstrated by a reporter assay with the 3′-untranslated region of the
CTGF
gene. This effect was abolished by a mutant plasmid. miR-26a mimics also inhibited TGF-β1-induced collagen expression, SMAD-binding activity and expression of its host genes
CTDSP2
and
CTDSPL
. Knockdown of
CTDSP2
and
CTDSPL
increased collagen expression in TGF-β-stimulated podocytes, suggesting that host genes also regulate TGF-β/SMAD signalling. Finally, we observed a positive correlation between microdissected glomerular miR-26a expression levels and estimated GFR in patients with diabetic nephropathy.
Conclusions/interpretation
The downregulation of miR-26a is involved in the progression of diabetic nephropathy both in humans and in mice through enhanced TGF-β/CTGF signalling.
BK polyomavirus (BKPyV) infection causes various diseases in immunocompromised patients. Cells from human lung and kidney were infected with BKPyV and treated with commercially available intravenous ...immunoglobulin G (IVIG). Its effects on BKPyV replication and spread of infection were investigated, focusing on administration timing. IVIG treatment 3 hours after infection suppressed BKPyV replication assessed by real-time PCR and expression of the viral capsid protein 1 and large T-antigen. IVIG effectively reduced the number of BKPyV-infected cells 2 weeks after infection in an antibody titer-dependent manner. Virus release in the culture supernatants was not influenced by IVIG treatment 6-80 hours and 3-9 days after infection. Collectively, IVIG did not affect viral release from infected cells but inhibited the spread of infection by neutralizing the released virus and blocking the new infected cell formation, indicating greater efficacy in early localized infection. BKPyV replication resumed in IVIG-treated cultures at 7 days after IVIG removal. Early prophylactic administration of IVIG is expected to reduce the growth and spread of BKPyV infection, resulting in the reduction of infected cell lesions and prevention of BKPyV-associated diseases.
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