Platinated Nucleotides are Substrates for the Human Mitochondrial Deoxynucleotide Carrier (DNC) and DNA Polymerase g: Relevance for the Development of New Platinum-Based Drugs.

cis-[PtCl2(NH3)2] (cisplatin) is among the highest effective antitumor drugs used for the chemotherapeutic treatment of a broad range of malignancies. Recently, alongside with the classical direct bond to DNA, an alternative mechanism of action mediated by N7 platinated nucleotides has been suggested for cisplatin. Considering that mitochondria play an important role in cell death activation and in a significant portion of the clinical activity and pharmacological properties associated with cisplatin, aim of this research was to evaluate the possibility that platinated deoxynucleotides, as the model complex [Pt(dien)(N7-5’-dGTP)] (1), dien=diethylenetriamine, could be transported into mitochondria and then incorporated into mtDNA. The kinetic characterization has revealed that the mitochondrial deoxynucleotide carrier (DNC) transports complex 1 with high affinity. Finally, a highly efficient in organello DNA synthesis system, followed by ICP-AES, has demonstrated that [Pt(dien)(N7-5’-dGTP)] is incorporated in the mitochondrial DNA by DNA polymerase g. These results may have critical implications in the development of new generations of anticancer and/or antiviral nucleotide analogues with more specific cellular targets and fewer side effects

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

BackgroundPre-existing chronic hypotension affects a percentage of kidney transplanted patients (KTs). Although a relationship with delayed graft function (DGF) has been hypothesized, available data are still scarce and inconclusive.MethodsA monocentric retrospective observational study was performed on 1127 consecutive KTs from brain death donors over 11 years (2003-2013), classified according to their pre-transplant Mean Blood Pressure (MBP) as hypotensive (MBP ResultsUnivariate analysis showed that a pre-existing hypotension is associated to DGF occurrence (p50 years old donor.ConclusionsOur findings suggest that pre-existing recipient hypotension, and the subsequent hypotension-related DGF, could be considered a significant detrimental factor, especially when elderly donors are involved in the transplant procedure

A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

Background Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Results We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification. Conclusions Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.Foundation KiKaChildren's Neuroblastoma Cancer FoundationSKK FoundationDutch Cancer Societ

Small renal masses in kidney transplantation : Overview of clinical impact and management in donors and recipients

Kidney transplantation is the best replacement treatment for the end-stage renal disease. Currently, the imbalance between the number of patients on a transplant list and the number of organs available constitutes the crucial limitation of this approach. To expand the pool of organs amenable for transplantation, kidneys coming from older patients have been employed; however, the combination of these organs in conjunction with the chronic use of immunosuppressive therapy increases the risk of incidence of graft small renal tumors. This narrative review aims to provide the state of the art on the clinical impact and management of incidentally diagnosed small renal tumors in either donors or recipients. According to the most updated evidence, the use of grafts with a small renal mass, after bench table tumor excision, may be considered a safe option for high-risk patients in hemodialysis. On the other hand, an early small renal mass finding on periodic ultrasound-evaluation in the graft should allow to perform a conservative treatment in order to preserve renal function. Finally, in case of a renal tumor in native kidney, a radical nephrectomy is usually recommended

Machine-Learning-Based Tool to Predict Target Prostate Biopsy Outcomes: An Internal Validation Study

Abstract: The aim of this study is to present a personalized predictive model (PPM) with a machine learning (ML) system that is able to identify and classify patients with suspected prostate cancer (PCa) following mpMRI. We extracted all the patients who underwent fusion biopsy (FB) from March 2014 to December 2019, while patients from August 2020 to April 2021 were included as a validation set. The proposed system was based on the following four ML methods: a fuzzy inference system (FIS), the support vector machine (SVM), k-nearest neighbors (KNN), and self-organizing maps (SOMs). Then, a system based on fuzzy logic (FL) + SVM was compared with logistic regression (LR) and standard diagnostic tools. A total of 1448 patients were included in the training set, while 181 patients were included in the validation set. The area under the curve (AUC) of the proposed FIS + SVM model was comparable with the LR model but outperformed the other diagnostic tools. The FIS + SVM model demonstrated the best performance, in terms of negative predictive value (NPV), on the training set (78.5%); moreover, it outperformed the LR in terms of specificity (92.1% vs. 83%). Considering the validation set, our model outperformed the other methods in terms of NPV (60.7%), sensitivity (90.8%), and accuracy (69.1%). In conclusion, we successfully developed and validated a PPM tool using the FIS + SVM model to calculate the probability of PCa prior to a prostate FB, avoiding useless ones in 15% of the cases

I.S.Mu.L.T. Achilles Tendon Ruptures Guidelines

This work provides easily accessible guidelines for the diagnosis, treatment and rehabilitation of Achilles tendon ruptures. These guidelines could be considered as recommendations for good clinical practice developed through a process of systematic review of the literature and expert opinion, to improve the quality of care for the individual patient and rationalize the use of resources. This work is divided into two sessions: 1) questions about hot topics; 2) answers to the questions following Evidence Based Medicine principles. Despite the frequency of the pathology andthe high level of satisfaction achieved in treatment of Achilles tendon ruptures, a global consensus is lacking. In fact, there is not a uniform treatment and rehabilitation protocol used for Achilles tendon ruptures