Treatment of Bladder Stones in Adults and Children : A Systematic Review and Meta-analysis on Behalf of the European Association of Urology Urolithiasis Guideline Panel

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The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia

Recent studies on young men from the general population have demonstrated geographic and ethnic differences in semen quality. The aim of this study was to investigate whether reported ethnic differences in semen quality might be associated with the maternally derived CAG and GGN polymorphisms in the androgen receptor gene or paternal ethnicity. In total 114 military conscripts from Latvia were included in the study. Information on maternal and parental ethnicity was collected by questionnaires. CAG and GGN repeats were analysed by direct sequencing of leukocyte DNA. Men with Latvian mothers (n = 83) had marginally shorter CAG repeat length (21.6 ± 2.9) as compared with those with non-Latvian mothers (22.9 ± 3.2, n = 31), not reaching statistical significance (p = 0.053). Sperm concentration did not differ significantly between these two groups (76 ± 59 and 70 ± 52, p = 0.9 respectively). In contrast, significantly higher sperm concentration and total sperm count were found in men with Latvian fathers (n = 77) as compared with men with non-Latvian fathers (n = 37) (80 ± 61 vs. 62 ± 48, p = 0.035, for sperm concentration and 225.7 ± 209 vs. 158.4 ± 134.4, p = 0.002, for total sperm count respectively). CAG repeat length did not correlate with any semen parameters in the whole population. However, GGN repeat length correlated with semen volume: men with GGN > 23 presented with higher semen volume (3.2 ± 2.1) as compared with men with GGN = 23 (2.6 ± 1.3, p = 0.04) or GGN < 23 (2.0 ± 1.2, p = 0.006). We conclude that GGN repeat length has an impact on semen volume, whereas differences in sperm numbers are associated with the paternal ethnicity.Peer reviewe

Walking of antitumor bifunctional trinuclear PtII complex on double-helical DNA

The trinuclear BBR3464 ([{trans-PtCl(NH3)2}2µ-(trans-Pt(NH3)2(H2N(CH2)6NH2)2)]4+) belongs to the polynuclear class of platinum-based anticancer agents. DNA adducts of this complex differ significantly in structure and type from those of clinically used mononuclear platinum complexes, especially, long-range (Pt, Pt) intrastrand and interstrand cross-links are formed in both 5′–5′ and 3′–3′ orientations. We show employing short oligonucleotide duplexes containing single, site-specific cross-links of BBR3464 and gel electrophoresis that in contrast to major DNA adducts of clinically used platinum complexes, under physiological conditions the coordination bonds between platinum and N7 of G residues involved in the cross-links of BBR3464 can be cleaved. This cleavage may lead to the linkage isomerization reactions between this metallodrug and double-helical DNA. Differential scanning calorimetry of duplexes containing single, site-specific cross-links of BBR3464 reveals that one of the driving forces that leads to the lability of DNA cross-links of this metallodrug is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule

The status of platinum anticancer drugs in the clinic and in clinical trials

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, LipoplatinTM and ProLindacTM). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade

Male Subfertility and Prostate Cancer Risk: Epidemiological and Genetic Studies

Androgen action plays a pivotal role in male reproductive tract physiology and pathology. The androgen receptor (AR) gene harbors two codon repeat tracts: the CAG and GGN repeats, encoding corresponding amino acid sequences of variable length; the polyglutamine and polyglycine stretches, respectively. Variation in CAG repeat length had been associated with a number of andrological disorders, whereas very little was known about the GGN repeat when the work for this thesis was started. We hypothesized that variation in GGN length may modulate AR activity, and hence the individual susceptibility to male reproductive tract disorders. We also assessed the relationship between male subfertility-dependent childlessness and prostate cancer (PCa) risk in a nested case-control study to test the hypothesis that subfertile men are at lower risk of developing PCa than fertile men, since they are frequently hypogonadal secondary to testicular dysfunction. Our specific aims were to investigate: 1) whether the AR codon repeats are associated with clinical reproductive parameters, subfertility, hypospadias, or cryptorchidism; 2) whether childlessness secondary to male subfertility is associated with reduced PCa risk; and 3) the possible involvement of genetic variants in reducing PCa risk in subfertile men, including in the sex steroid signaling pathway and aryl hydrocarbon receptor (AHR) pathway, which mediates some of the effects of endocrine disrupting chemicals, and also in PCa risk genes implicated in previous genome-wide association studies. Our main findings were that: 1) GGN repeat lengths were significantly longer in men with penile hypospadias or cryptorchidism than in controls (median 24 vs. 23) and that the longer allele may be associated with superior AR function; 2) subfertile men were at reduced PCa risk compared with fertile men, OR: 0.45 (95% CI: 0.25-0.83); and 3) genes harboring variants that may play a role in reducing PCa risk in subfertile men include AHR, its partner molecule AHR nuclear translocator (ARNT), and estrogen receptor beta (ESR2), as well as a number of other genes, of which poly (ADP-ribose) polymerase 2 (PARP2) showed the most robust association. We conclude that: 1) longer GGN repeat lengths may be associated with cryptorchidism and hypospadias; 2) subfertile involuntarily childless men are at an approximately 50% lower risk of being diagnosed with PCa than are fathers of at least one biological child; 3) variants in a number of genes may play a role in linking male subfertility with reduced PCa risk through their associations with impaired reproductive function. The findings support the hypothesis that alterations in sex steroid action, potentially via interaction with the AHR-ARNT signaling pathway, may contribute to the overall reduction in PCa risk in subfertile men