On Smarandache's form of the individual Fermat-Euler theorem

In the paper it is shown how a form of the classical FERMAT-EULER Theorem discovered by F. SMARANDACHE fits into the generalizations found by S.SCHWARZ, M.LASSAK and the author. Then we show how SMARANDACHE'S algorithm can be used to effective computations of the so called group membership

Renal disease associated with myeloproliferative neoplasms and myelodysplastic syndrome/myeloproliferative neoplasms

AIMS Renal changes in patients with myeloproliferative neoplasms (MPNs) or myelodysplastic syndrome (MDS)/MPNs have been addressed by few, respectively no, reports. The aim of this study was to focus on a systematic evaluation of renal biopsies in patients with MPNs or MDS/MPNs. METHODS AND RESULTS The cohort comprised 29 patients (23 men) aged 67 ± 11 years (mean ± standard deviation), diagnosed with chronic myeloid leukaemia (n = 5), polycythaemia vera (n = 9), primary myelofibrosis (n = 5), essential thrombocythaemia (n = 2), or chronic myelomonocytic leukaemia (n = 4), as well as MPNs or MDS/MPNs not otherwise specified (n = 4). Patients manifested with proteinuria (93%), partially in the nephrotic range (46%), haematuria (72%), and impaired kidney function (93%). The most prominent histological findings included double-contoured glomerular basement membranes (71%), acute endothelial damage (68%), intracapillary platelet aggregation (62%), mesangiolysis (21%), thrombotic microangiopathy (24%), segmental glomerulosclerosis (66%), mesangial hypercellularity and sclerosis, extramedullary haematopoiesis (17%), and also IgA nephropathy (21%) and glomerulonephritis (GN) with features of infection-related GN (21%). MPN and MDS/MPN patients showed significantly more chronic changes than age-matched and sex-matched controls, including global and segmental glomerulosclerosis, mesangial sclerosis, and hypercellularity, whereas the extent of arteriosclerosis was comparable. CONCLUSIONS MPN and MDS/MPN patients show glomerular scarring that exceeds age-related phenomena. Ongoing endothelial damage, growth factors released by platelets and deposition of immune complexes are probably the causative mechanisms. Early recognition of renal failure heralded by proteinuria and haematuria, and consequent control of risk factors for kidney failure, should be recommended for MPN and MDS/MPN patients

ANLN and TLE2 in Muscle Invasive Bladder Cancer: A Functional and Clinical Evaluation Based on In Silico and In Vitro Data

Anilin actin binding protein (ANLN) and transducing-like enhancer protein 2 (TLE2) are associated with cancer patient survival and progression. The impact of their gene expression on progression-free survival (PFS) of patients with muscle invasive bladder cancer (MIBC) treated with radical cystectomy (RC) and subtype association has not yet been investigated. qRT-PCR was used to measure the transcript levels of ANLN and TLE2 in the Mannheim cohort, and validated in silico by The Cancer Genome Atlas (TCGA) cohort. Uni- and multivariate Cox regression analyses identified predictors for disease-specific survival (DSS) and overall survival (OS). In the Mannheim cohort, tumors with high ANLN expression were associated with lower OS and DSS, while high TLE2 expression was associated with a favorable OS. The TCGA cohort confirmed that high ANLN and low TLE2 expression was associated with shorter OS and disease-free survival (DFS). In both cohorts, multivariate analyses showed ANLN and TLE2 expression as independent outcome predictors. Furthermore, ANLN was more highly expressed in cell lines and patients with the basal subtype, while TLE2 expression was higher in cell lines and patients with the luminal subtype. ANLN and TLE2 are promising biomarkers for individualized bladder cancer therapy including cancer subclassification and informed MIBC prognosis

Renal disease associated with myeloproliferative neoplasms and myelodysplastic syndrome/myeloproliferative neoplasms

Aims Renal changes in patients with myeloproliferative neoplasms (MPNs) or myelodysplastic syndrome (MDS)/MPNs have been addressed by few, respectively no, reports. The aim of this study was to focus on a systematic evaluation of renal biopsies in patients with MPNs or MDS/MPNs. Methods and results The cohort comprised 29 patients (23 men) aged 67 ± 11 years (mean ± standard deviation), diagnosed with chronic myeloid leukaemia (n = 5), polycythaemia vera (n = 9), primary myelofibrosis (n = 5), essential thrombocythaemia (n = 2), or chronic myelomonocytic leukaemia (n = 4), as well as MPNs or MDS/MPNs not otherwise specified (n = 4). Patients manifested with proteinuria (93%), partially in the nephrotic range (46%), haematuria (72%), and impaired kidney function (93%). The most prominent histological findings included double‐contoured glomerular basement membranes (71%), acute endothelial damage (68%), intracapillary platelet aggregation (62%), mesangiolysis (21%), thrombotic microangiopathy (24%), segmental glomerulosclerosis (66%), mesangial hypercellularity and sclerosis, extramedullary haematopoiesis (17%), and also IgA nephropathy (21%) and glomerulonephritis (GN) with features of infection‐related GN (21%). MPN and MDS/MPN patients showed significantly more chronic changes than age‐matched and sex‐matched controls, including global and segmental glomerulosclerosis, mesangial sclerosis, and hypercellularity, whereas the extent of arteriosclerosis was comparable. Conclusions MPN and MDS/MPN patients show glomerular scarring that exceeds age‐related phenomena. Ongoing endothelial damage, growth factors released by platelets and deposition of immune complexes are probably the causative mechanisms. Early recognition of renal failure heralded by proteinuria and haematuria, and consequent control of risk factors for kidney failure, should be recommended for MPN and MDS/MPN patients

Subtype specific expression and survival prediction of pivotal lncRNAs in muscle invasive bladder cancer

Abstract Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype (p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype (p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs

Deep learning-based classification of blue light cystoscopy imaging during transurethral resection of bladder tumors

Bladder cancer is one of the top 10 frequently occurring cancers and leads to most cancer deaths worldwide. Recently, blue light (BL) cystoscopy-based photodynamic diagnosis was introduced as a unique technology to enhance the detection of bladder cancer, particularly for the detection of flat and small lesions. Here, we aim to demonstrate a BL image-based artificial intelligence (AI) diagnostic platform using 216 BL images, that were acquired in four different urological departments and pathologically identified with respect to cancer malignancy, invasiveness, and grading. Thereafter, four pre-trained convolution neural networks were utilized to predict image malignancy, invasiveness, and grading. The results indicated that the classification sensitivity and specificity of malignant lesions are 95.77% and 87.84%, while the mean sensitivity and mean specificity of tumor invasiveness are 88% and 96.56%, respectively. This small multicenter clinical study clearly shows the potential of AI based classification of BL images allowing for better treatment decisions and potentially higher detection rates

Hepatitis C Virus Induced Endothelial Inflammatory Response Depends on the Functional Expression of TNF alpha Receptor Subtype 2

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I: C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I: C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFa). HCV-RNA induces the endothelial expression of TNFa and TNFa receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections

Glucosylceramide Synthase Is Involved in Development of Invariant Natural Killer T Cells

Invariant natural killer T (iNKT) cells represent a unique population of CD1d-restricted T lymphocytes expressing an invariant T cell receptor encoded by Vα14-Jα18 and Vα24-Jα18 gene segments in mice and humans, respectively. Recognition of CD1d-loaded endogenous lipid antigen(s) on CD4/CD8-double positive (DP) thymocytes is essential for the development of iNKT cells. The lipid repertoire of DP thymocytes and the identity of the decisive endogenous lipid ligands have not yet been fully elucidated. Glycosphingolipids (GSL) were implicated to serve as endogenous ligands. However, further in vivo investigations were hampered by early embryonal lethality of mice deficient for the key GSL-synthesizing enzyme glucosylceramide (GlcCer) synthase [GlcCer synthase (GCS), EC 2.4.1.80]. We have now analyzed the GSL composition of DP thymocytes and shown that GlcCer represented the sole neutral GSL and the acidic fraction was composed of gangliosides. Furthermore, we report on a mouse model that by combination of Vav-promoter-driven iCre and floxed GCS alleles (VavCreGCSf/f) enabled an efficient depletion of GCS-derived GSL very early in the T cell development, reaching a reduction by 99.6% in DP thymocytes. Although the general T cell population remained unaffected by this depletion, iNKT cells were reduced by approximately 50% in thymus, spleen, and liver and showed a reduced proliferation and an increased apoptosis rate. The Vβ-chains repertoire and development of iNKT cells remained unaltered. The GSL-depletion neither interfered with expression of CD1d, SLAM, and Ly108 molecules nor impeded the antigen presentation on DP thymocytes. These results indicate that GlcCer-derived GSL, in particular GlcCer, contribute to the homeostatic development of iNKT cells

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBR(Ob/Ob)mice

Objective: To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). Methods: hCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice. Results: hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator–activated receptor-alpha have been reported to play essential roles in DKD. Conclusions: Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. Key messages: Increased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD).BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype.Microarray revealed alterations by CN1 which are not altered by hyperglycemia.These genes have been described to play essential roles in DKD.Inhibiting CN1 could be beneficial in DKD