Is osteoprotegerin (OPG) an early biomarker of arterial calcification in chronic renal failure?

info:eu-repo/semantics/publishe

Osteoprotegerin (OPG): A link between bone disease and arterial calcifications in chronic renal failure (CRF)?

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Plasma osteoprotegerin is an independent risk factor for mortality and an early biomarker of coronary vascular calcification in chronic kidney disease.

Cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease (CKD) and early biomarkers are required which can predict disease and death in such patients. The aim of our study was to investigate if osteoprotegerin (OPG) could be a predictor of coronary artery calcification (CAC) and mortality in CKD.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

OPG, RANK-L, and markers of bone metabolism in patients on peritoneal dialysis

OBJECTIVES: Bone turnover is regulated locally by osteoprotegerin (OPG) and receptor activator of NFkappaB ligand (RANK-L); it is not known how the circulating concentrations of these cytokines reflect renal osteodystrophy. METHODS: We measured serum OPG, RANK-L, parathyroid hormone (iPTH), collagen C-terminal cross-linked telopeptide (betaCrossLaps), and bone densitometry (BMD) in 79 patients with end-stage renal disease (ESRF) undergoing dialysis. A hand X-ray of these patients was also analyzed. Controls were 65 healthy subjects. RESULTS: ESRF patients had high OPG and RANK-L levels; RANK-L was higher in hemodialysis than in peritoneal dialysis. OPG and RANK-L did not depend on iPTH. The bone markers were significantly increased and correlated with serum iPTH, but not with OPG or RANK-L; neither OPG nor RANK-L correlated significantly with BMD. OPG was significantly higher in patients with acro-osteolysis. CONCLUSIONS: OPG and RANK-L serum concentrations do not strongly reflect bone status in ESRF. However, OPG was significantly higher in patients with acro-osteolysis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Surgical resection of symptomatic brain metastases improves the clinical status and facilitates further treatment

Background Brain metastases (BM) frequently cause focal neurological deficits leading to a reduced Karnofsky performance score (KPS). Since KPS is routinely used to guide the choice of adjuvant therapy, we hypothesized that improving KPS by surgical resection may improve the chance for adjuvant treatment and ultimately result in better survival. We therefore analyzed the course of a large cohort undergoing resection of symptomatic brain metastases in the context of further treatment and clinical outcome. Patients and methods In a bi-centric retrospective analysis we retrieved baseline, clinical, and treatment-related parameters of patients operated on BM between 2010 and 2019. Survival was calculated using Kaplan-Meier estimates; prognostic factors for survival were analyzed by Log-rank test and Cox proportional hazards. Results We included 750 patients with a median age of 61 (19-87) years. The functional status was significantly improved by surgical resection, with a median preoperative (KPS) of 80 (10-100) increasing to 90 (0-100) after surgery (P = 70;P < .0001). The postoperative clinical status, postoperative radiotherapy, systemic treatment, controlled systemic disease and < 4 BM were independent predictors for survival. Conclusion The resection of symptomatic BM may restore clinical status, so enhancing the likelihood of receiving adjuvant treatment, and therefore leading to improved overall survival

Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma. In line with uncontrolled cell cycle progression in SCLC, we find that CDC25A, B and C mRNAs are expressed at significantly higher levels in SCLC, compared to lung adenocarcinoma. We next profiled the efficacy of compounds targeting CHK1 and ATR. Both, ATR- and CHK1 inhibitors induce genotoxic damage and apoptosis in human and murine SCLC cell lines, but not in lung adenocarcinoma cells. We further demonstrate that murine SCLC tumors were highly sensitive to ATR- and CHK1 inhibitors, while Kras G12D -driven murine lung adenocarcinomas were resistant against these compounds and displayed continued growth under therapy. Altogether, our data indicate that SCLC displays an actionable dependence on ATR/CHK1-mediated cell cycle checkpoints

AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer

A fundamental principle in malignant tranformation is the ability of cancer cells to escape the naturally occurring cellintrinsic responses to DNA damage. Tumors progress despite the accumulation of DNA lesions. However, the underlying mechanisms of this tolerance to genotoxic stress are still poorly characterized. Here, we show that replication stress occurs in Kras-driven murine lung adenocarcinomas, as well as in proliferating murine embryonic and adult tissues. We identify the transcriptional regulator AATF/CHE-1 as a key molecule to sustain proliferative tissues and tumor progression in parts by inhibiting p53-driven apoptosis in vivo. In an autochthonous Kras-driven lung adenocarcinoma model, deletion of Aatf delayed lung cancer formation predominantly in a p53-dependent manner. Moreover, targeting Aatf in existing tumors through a dual recombinase strategy caused a halt in tumor progression. Taken together, these data suggest that AATF may serve as a drug target to treat KRAS-driven malignancies

Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner

KRAS-mutant lung adenocarcinoma is among the most common cancer entities and, in advanced stages, typically displays poor prognosis due to acquired resistance against chemotherapy, which is still largely based on cisplatin-containing combination regimens. Mechanisms of cisplatin resistance have been extensively investigated, and ERCC1 has emerged as a key player due to its central role in the repair of cisplatin-induced DNA lesions. However, clinical data have not unequivocally confirmed ERCC1 status as a predictor of the response to cisplatin treatment. Therefore, we employed an autochthonous mouse model of Kras-driven lung adenocarcinoma resembling human lung adenocarcinoma to investigate the role of Ercc1 in the response to cisplatin treatment. Our data show that Ercc1 deficiency in Tp53-deficient murine lung adenocarcinoma induces a more aggressive tumor phenotype that displays enhanced sensitivity to cisplatin treatment. Furthermore, tumors that relapsed after cisplatin treatment in our model develop a robust etoposide sensitivity that is independent of the Ercc1 status and depends solely on previous cisplatin exposure. Our results provide a solid rationale for further investigation of the possibility of preselection of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients might benefit from sequential cisplatin and etoposide chemotherapy. (C)2016 AACR

The Cdkn1a(SuPER) Mouse as a Tool to Study p53-Mediated Tumor Suppression

Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1a(SUPER) mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Krasdriven lung adenocarcinoma model, we show that Cdkn1a(SUPER) mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53 suPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1a(SUPER )allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression