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Papachristou, E.

Publications and source records attributed to Papachristou, E..

2 recordsLinked to original sources

Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy

Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up.\n\nAimof the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN.\n\nPatients-MethodsClinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens.\n\nResultsTwenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87)yrs, M/F 467/285), followed for 10.1{+/-}5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n=381) compared to those initially treated with Cyclo (n=110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p=0.04, respectively.\n\nConclusionsLong term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.

immunology

Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer

Somatic DNA copy number variations (CNVs) are prevalent in cancer and can drive cancer progression albeit with often uncharacterized roles in altering cell signaling states. Here, we integrated genomic and proteomic data for 5598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulated known kinase-substrate relationships and further network analysis prioritized likely driver genes. A total of 44 robust pan-cancer gene-phosphosite associations were replicated in cell line samples. Of these, ARHGEF17, a predicted regulator of hippo-signaling, was further studied through (phospho)proteomics analysis where ARHGEF17 knockdown cells showed dys-regulation of hippo- and p38 signaling as well as immune related pathways. Using, RNAi, CRISPR and drug screening data we find evidence of kinase addiction in cancer cell lines identifying inhibitors for targeting of kinase-dependent cell lines. We propose copy number status of genes as useful predictors of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.

genomics