Cardiac arrhythmias and rhabdomyolysis in Bartter-Gitelman patients

Recent data demonstrate that patients affected with hypokalemic salt-losing tubulopathies are prone to acute cardiac arrhythmias and rhabdomyolysis. The tendency to these potentially fatal complications is especially high if chronic hypokalemia is severe, in patients with diarrhea, vomiting or a prolonged QT interval on standard electrocardiography, in patients on drug management with compounds prolonging the electrocardiographic QT interval (including antiarrhythmic agents, some antihistamines, macrolides, antifungals, psychotropics, ß2-adrenergic agonists or cisapride), following acute alcohol abuse and during exercise. Cardiac arrhythmias and rhabdomyolysis occur with sufficient frequency in hypokalemic salt-losing tubulopathies to merit wider awareness of their presence and the preparation of specific prevention and management recommendation

Silent recovery of native kidney function after transplantation in a patient with membranous nephropathy

Recurrence of membranous nephropathy (MN) is frequently seen after transplantation. However, there are no published data about the course of MN in the native kidneys after transplantation. Disease progression in almost all cases is assumed to be the ‘natural' course after transplantation. We report on a patient suffering from end-stage renal disease due to MN. Eight years after transplantation, nephrectomy was performed due to chronic rejection and unexpectedly, partial recovery of native kidney function was noted. As far as we know, there is no other similar case reported in the literature. The potential impact of the immunosuppression, especially of calcineurin inhibitors, is discusse

Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(η6- p -MeC6H4Pr i )2Ru2(SC6H4- p -X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential

A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(η6-p-MeC6H4Pr i )2Ru2(SC6H4-p-X)3]+ (1 Xis H, 2 Xis Me, 3 Xis Ph, 4 Xis Br, 5 Xis OH, 6 Xis NO2, 7 Xis OMe, 8 Xis CF3, 9 Xis F, 10 Xis Pr i , 11 Xis Bu t ) have been synthesized from the reaction of [(η6-p-MeC6H4Pr i )RuCl2]2 with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(η6-C6H6)2Ru2(SC6H5)3]+ (12) and [(η6-C6Me6)2Ru2(SC6H5)3]+ (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50% inhibition of cancer cell growth (IC50 values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC50 value of 0.03µM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC50 values and the turnover frequencies at about 50% conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants σ p) and the lipophilicity of the thiols p-XC6H4SH (calculated logP parameters

Efficient near-infrared organic light-emitting diodes with emission from spin doublet excitons

The development of luminescent organic radicals has resulted in materials with excellent optical properties for near-infrared (NIR) emission. Applications of light generation in this range span from bioimaging to surveillance. Whilst the unpaired electron arrangements of radicals enable efficient radiative transitions within the doublet-spin manifold in organic light-emitting diodes (OLEDs), their performance is limited by non-radiative pathways introduced in electroluminescence. Here, we present a host:guest design for OLEDs that exploits energy transfer with demonstration of up to 9.6% external quantum efficiency (EQE) for 800 nm emission. The tris(2,4,6-trichlorophenyl)methyl-triphenylamine (TTM-TPA) radical guest is energy-matched to the triplet state in a charge-transporting anthracene-derivative host. We show from optical spectroscopy and quantum-chemical modelling that reversible host-guest triplet-doublet energy transfer allows efficient harvesting of host triplet excitons

SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma

The Sonic Hedgehog (SHH) pathway is crucial regulator of embryonic development and stemness. Its alteration leads to medulloblastoma (MB), the most common malignant pediatric brain tumor. The SHH-MB subgroup is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Here, we show that the pro-oncogenic stemness regulator Spalt-like transcriptional factor 4 (SALL4) is re-expressed in mouse SHH-MB models, and its high levels correlate with worse overall survival in SHH-MB patients. Proteomic analysis revealed that SALL4 interacts with REN/KCTD11 (here REN), a substrate receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and a tumor suppressor lost in ~30% of human SHH-MBs. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppresses SHH-MB growth both in murine and patient-derived xenograft models. Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers

ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP.

The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCFβTrCP ubiquitin ligase, and promotes βTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors

Oncologic Outcomes of Incidental Versus Biopsy-diagnosed Grade Group 1 Prostate Cancer:A Multi-institutional Study

Background and objective: Patients diagnosed with grade group (GG) 1 prostate cancer (PCa) following treatment for benign disease (“incidental” PCa) are typically managed with active surveillance (AS). It is not known how their outcomes compare with those observed in patients diagnosed with GG1 on biopsy. We aimed at determining whether long-term oncologic outcomes of AS for patients with GG1 PCa differ according to the type of diagnosis: incidental versus biopsy detected. Methods: A retrospective, multi-institutional analysis of PCa patients with GG1 on AS at eight institutions was conducted. Competing risk analyses estimated the incidence of metastases, PCa mortality, and conversion to treatment. As a secondary analysis, we estimated the risk of GG ≥2 on the first follow-up biopsy according to the type of initial diagnosis. Key findings and limitations: A total of 213 versus 1900 patients with incidental versus biopsy-diagnosed GG1 were identified. Patients with incidental cancers were followed with repeated biopsies and multiparametric magnetic resonance imaging less frequently than those diagnosed on biopsy. The 10-yr incidence of treatment was 22% for incidental cancers versus 53% for biopsy (subdistribution hazard ratio [sHR] 0.34, 95% confidence interval [CI] 0.26–0.46, p &lt; 0.001). Distant metastases developed in one patient with incidental cancer versus 17 diagnosed on biopsy and were diagnosed with molecular imaging in 13 (72%) patients. The 10-yr incidence of metastases was 0.8% for patients with incidental PCa and 2% for those diagnosed on biopsy (sHR 0.35, 95% CI 0.05–2.54, p = 0.3). The risk of GG ≥2 on the first follow-up biopsy was low if the initial diagnosis was incidental (7% vs 22%, p &lt; 0.001). Conclusions and clinical implications: Patients with GG1 incidental PCa should be evaluated further to exclude aggressive disease, preferably with a biopsy. If no cancer is found on biopsy, then they should receive the same follow-up of a patient with a negative biopsy. Further research should confirm whether imaging and biopsies can be avoided if postoperative prostate-specific antigen is low (&lt;1–2 ng/ml). Patient summary: We compared the outcomes of patients with low-grade prostate cancer on active surveillance according to the type of their initial diagnosis. Patients who have low-grade cancer diagnosed on a procedure to relieve urinary symptoms (incidental prostate cancer) are followed less intensively and undergo curative-intended treatment less frequently. We also found that patients with incidental prostate cancer are more likely to have no cancer on their first follow-up biopsy than patients who have low-grade cancer initially diagnosed on a biopsy. These patients have a more favorable prognosis than their biopsy-detected counterparts and should be managed the same way as patients with negative biopsies if they undergo a subsequent biopsy that shows no cancer.</p

Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed–validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs