Trial watch - inhibiting PARP enzymes for anticancer therapy.

Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability.

Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy.

The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR-CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background.

Effects of tapering on physical match activities in professional soccer players.

This study aimed to examine: (i) the effect of decreasing training load (TL) during taper weeks on physical match activities in professional soccer players, and (ii) to disclose the relationship between weekly TL and physical match activities. Rating of perceived exertion was collected after each training session and match to quantify the TL in 19 professional players over 17 standard and 7 taper weeks during the season. Physical match activities were quantified by a computerised match analysis system and compared between standard training and taper weeks.

Predictors and clinical consequences of starting androgen therapy in men with low testosterone: results from the SIAMO-NOI registry.

Purpose: Management of late onset hypogonadism (LOH) is not homogenous. The aim of the study is to observe the management of patients with low testosterone (T) in highly specialized Italian centres.

Methods: The SIAMO-NOI is an observational longitudinal disease registry for the evaluation of the clinical management of patients with low T levels (total T < 12 nmol/L, calculated free T < 225 pmol/l or already in treatment) in 15 Italian centers members of the Italian Society for Andrology and Sexual Medicine (SIAMS).

P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development.

It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized.

Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1.

The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF1) blocks the reversal of the F1Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration. By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo-ATPsynthase expression ratio occurs in neurons.

Karyotypic Aberrations in Oncogenesis and Cancer Therapy.

The propagation of whole-chromosome (aneuploid) or whole-genome (polyploid) defects is normally prevented by robust cell-intrinsic mechanisms. Moreover, non-diploid cells are under strict immunological surveillance. Nonetheless, tumors contain a high percentage of non-diploid genomes, indicating that malignant cells acquire the ability to bypass these control mechanisms and obtain a survival/proliferation benefit from bulky karyotypic defects.

Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer.

Background: Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC.

Patients And Methods: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC.

Group-based task-oriented exercises aimed at managing kinesiophobia improved disability in chronic low back pain.

Background: There are still doubts concerning the clinical impact of multidisciplinary cognitive behavioural rehabilitation programmes conducted in group-based settings and about their long-term effects on subjects with chronic low back pain (CLBP). This randomized, parallel-group superiority-controlled trial aimed at evaluating the effect of such a programme on disability, kinesiophobia, catastrophizing, pain and quality of life in CLBP.

Methods: One hundred and fifty patients were randomly assigned to a 5-week group-based multidisciplinary programme of task-oriented exercises integrated with cognitive behavioural therapy mainly aimed at managing kinesiophobia (experimental group, 75 subjects) or group-based traditional exercises (control group, 75 subjects).

Controlled and Impaired Mitochondrial Quality in Neurons: Molecular Physiology and Prospective Pharmacology.

Tuned mitochondrial physiology is fundamental for qualitative cellular function. This is particularly relevant for neurons, whose pathology is frequently associated with mitochondrial deficiencies. Defects in mitochondria are indeed key features in most neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS).

Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms.

Objectives: To investigate whether there are sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis and to examine their association with symptoms of dysmenorrhea and abnormal uterine bleeding.

Methods: This was a prospective observational study including women referred from a gynecology outpatient center to our university hospital for ultrasound examination. Inclusion criteria were age between 18 and 30 years, regular menstrual cycle and nulligravid status.

Conversion of cytochrome c into a peroxidase: inhibitory mechanisms and implication for neurodegenerative diseases.

A further function of cytochrome c (cyt c), beyond respiration, is realized outside mitochondria in the apoptotic program. In the early events of apoptosis, the interaction of cyt c with a mitochondrion-specific phospholipid, cardiolipin (CL), brings about a conformational transition of the protein and acquirement of peroxidase activity. The hallmark of cyt c with peroxidase activity is its partial unfolding accompanied by loosening of the Fe sixth axial bond and an enhanced access of the heme catalytic site to small molecules like H2O2.

Nonlinear control techniques for the heart rate regulation in treadmill exercises.

It has been recently shown in the literature that a robust output feedback controller for the heart rate regulation can be designed for an experimentally validated second order nonlinear model of the human heart rate response during long-duration treadmill exercises: It is based on piecewise linear approximations of the original nonlinear model and involves (local) robust linear control techniques. In this letter, we resort to recent nonlinear advanced control techniques in order to illustrate the existence of a nonlocal and nonswitching control which guarantees heart rate regulation with no exact knowledge of model parameters and nonlinearities: It simply generalizes to the nonlinear framework the classical proportional-integral control design for linear models of heart rate response during treadmill exercises. Simulation and experimental results demonstrate the effectiveness of the proposed approach in typical training exercises involving warm up/holding/cool down phases.

Microsurgery flap in endodontic surgery: case report.

In periodontal plastic surgery it is increasingly more evident the relavance of the protection of the gingival marginal anatomy through the realization of a conservative flap. Minimizing the recession of the treated tissue. A correct healing always needs to take into account the diameter and type of the suture and the time of removal from the wound.

PACAP and type I PACAP receptors in human prostate cancer tissue.

We characterized the expression and localization of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific type I receptor variants in prostatic, hyperplastic, and carcinomatous tissue collected from patients undergoing prostate biopsy and surgery for benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The immunohistochemical studies using an indirect immunoperoxidase technique evidenced positive immunostaining for PACAP in the cytoplasm of epithelial cells of hyperplastic and carcinomatous prostate specimens and in some scattered cells of the stroma. Type I PACAP receptors (PAC1 R) in healthy and BPH tissues were localized in all epithelial cells lining the lumen of the acini and in some stromal cells, while in specimens from PCa the anti-PAC1 R antibody stained the apical portion of a large percentage of cells.

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities.

Objective: A novel study has been carried out to characterize the amount and activity levels of metalloproteinases (i.e., MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13) and of their inhibitors (i.

Aneuploidy in metaphases II of spermatocytes of wild house mice from a hybrid zone between a Robertsonian population (CD: 2n = 22) and a population with the standard karyotype (2n = 40).

Meiotic metaphases II from archival slides were studied of male house mice caught in a hybrid zone between a population monomorphic for nine centric fusions (2n = 22) and a population with the standard karyotype (2n = 40), near Rome. The frequency of aneuploidy increases, up to 50%, with increasing number of heterozygous centric fusions (1-4).

Phosphotyrosine protein phosphatases and diabetic pregnancy: an association between low molecular weight acid phosphatase and degree of glycemic control.

Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146-1158 sequence of the human insulin receptor, and shows a high affinity for it. This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes.

Phosphotyrosine-protein-phosphatases and human reproduction: an association between low molecular weight acid phosphatase (ACP1) and spontaneous abortion.

ACP1 (low molecular weight acid phosphatase) genetic polymorphism has been studied in 173 women with a history of two or more consecutive spontaneous abortions and in 1508 control subjects, including 482 normal pregnant women. The proportion of carriers of ACP1*C allele (*A/ *C, *B/*C) in women with a history of repeated spontaneous abortion is lower than in normal pregnant women and other control groups. Women with repeated spontaneous abortion show a specific decrease of ACP1 S isoform concentration as compared to normal pregnant women.

Haptoglobin development in newborn infants from diabetic mothers.

Haptoglobin (Hp) development during the neonatal period has been studied in 325 newborn infants from normal pregnancies and in 242 infants from diabetic mothers. In infants from diabetic mothers Hp development is delayed as compared to infants from normal pregnancies. This delay is associated with a change in the pattern of relationship between Hp development and the polymorphism of acid phosphatase (ACP1) (an enzyme which shows phosphotyrosine phosphatase (PTPase) activity).