Scrotal cancer: Incidence, survival and second primary tumours in the Netherlands since 1989

Background: Since the 1970s there have been few epidemiological studies of scrotal cancer. We report on the descriptive epidemiology of scrotal cancer in the Netherlands. Methods: Data on all scrotal cancer patients were obtained from the Netherlands Cancer Registry (NCR) in the period 1989-2006 and age-standardised incidence rates were calculated also according to histology and stage. Relative survival was calculated and multiple primary tumours were studied. Results: The overall incidence rate varied around 1.5 per 1 000 000 person-years, most frequently being squamous cell carcinoma (27%), basal cell carcinoma (19%) and Bowen's disease (15%). Overall 5-year relative survival was 82%, being 77% and 95% for patients with squamous and basal cell carcinoma, respectively. In all, 18% of the patients were diagnosed with a second primary tumour. Conclusion: The incidence rate of scrotal cancer did not decrease, although this was expected; affected patients might benefit from regular checkups for possible new cancers

A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites

Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection

An Antagomir to MicroRNA Let7f Promotes Neuroprotection in an Ischemic Stroke Model

We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothesized that microRNAs (miRNAs) that target the IGF-1 signaling family for translation repression could be alternatively suppressed to promote IGF-1-like neuroprotection. Here, we report that two conserved IGF pathway regulatory microRNAs, Let7f and miR1, can be inhibited to mimic and even extend the neuroprotection afforded by IGF-1. Anti-mir1 treatment, as late as 4 hours following ischemia, significantly reduced cortical infarct volume in adult female rats, while anti-Let7 robustly reduced both cortical and striatal infarcts, and preserved sensorimotor function and interhemispheric neural integration. No neuroprotection was observed in animals treated with a brain specific miRNA unrelated to IGF-1 (anti-miR124). Remarkably, anti-Let7f was only effective in intact females but not males or ovariectomized females indicating that the gonadal steroid environment critically modifies miRNA action. Let7f is preferentially expressed in microglia in the ischemic hemisphere and confirmed in ex vivo cultures of microglia obtained from the cortex. While IGF-1 was undetectable in microglia harvested from the non-ischemic hemisphere, IGF-1 was expressed by microglia obtained from the ischemic cortex and was further elevated by anti-Let7f treatment. Collectively these data support a novel miRNA-based therapeutic strategy for neuroprotection following stroke

Concerning the application of the H-1 NMR ABX analysis for assignment of stereochemistry to aldols deriving from aldehydes lacking beta-branches

Attempts to apply the H-1 NMR ABX method for assignment of stereochemistry of beta-hydroxy ketones to aldols 4-10 deriving from a-methyl aldehydes lacking P-branches reveals that the presence of a beta-branch in the aldehyde reaction partner is necessary so that the average chemical environment of Ha and Hb is different for the Felkin and anti-Felkin aldols (see conformational pairs A/B and C/D, respectively). When the chiral alpha-methyl aldehyde lacks a beta-branch, as in the case of the aldehyde precursors to 4-10, the conformational energies of E and F (for the Felkin P-hydroxy ketone derivatives), and conformers G and H for the anti-Felkin aldols, are too close in energy (within each pair), such that the average chemical and magnetic environments of Ha and Hb in the two diastereomers cannot be easily distinguished. This analysis provides a rational basis for application of the H-1 NMR ABX pattern analysis to other beta-hydroxy ketone derivatives.7025104611046

Increased fecundity of malathion-specific resistant beetles in absence of insecticide pressure

Despite that resistance frequency is assumed to decline when selective pressure is relaxed, the stability of resistance frequency has been observed in some insects in the absence of insecticide. In the red flour beetle, Tribolium castaneum, the first case of malathion-resistance was reported in the early 1960s. The malathion-specific resistant phenotype has now almost completely replaced the susceptible one in red flour beetle populations. In the present study, several life-history traits that could influence the fitness of the insects were compared between insecticide-susceptible and malathion-specific resistant populations of the red flour beetle. On average, egg fertility and egg-to-adult development time did not differ between susceptible and resistant populations. However, the fecundity of resistant females was greater than that of susceptible ones. Generally, differences in development time between insecticide resistant and susceptible populations are considered as having more effect on fitness than do differences in fecundity. However, the observed increased female fecundity may participate, in combination with the previously observed increased male reproductive success, to the development and the stability of malathion-specific resistance in T. castaneum

Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hotspots

Meiotic recombination initiates following the formation of DNA double strand breaks (DSBs) by the Spo11 endonuclease early in prophase I at discrete regions in the genome coined hotspots. In mammals, meiotic DSB site selection is directed in part by sequence specific binding of PRDM9, a polymorphic histone H3 (H3K4Me3) methyltransferase. However, other chromatin features needed for meiotic hotspot specification are largely unknown. Here, we show that the recombinogenic cores of active hotspots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these open chromatin-associated histone marks is dynamic and is manifest at spermatogonia and/or pre-leptotene meiotic stage cells, which would facilitate PRDM9 binding and access for Spo11 to direct the formation of DSBs, which are initiated at leptotene. Importantly, manipulating histone acetylase and deacetylase activity established that histone acetylation marks are necessary for both hotspot activity and crossover resolution. We conclude there are functional roles for histone acetylation marks at mammalian meiotic recombination hotspots