Precision fluoropyrimidines dosing in a compound heterozygous variant carrier of the DPYD gene: a case report

Background: Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging. Case presentation: We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up. Conclusion: Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs

p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling.

Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins.status: publishe

Prevalence of genital HPV infection in STI and healthy populations and risk factors for viral persistence

Human papillomavirus (HPV) is a well-established carcinogenic agent. This study aimed to assess prevalence and persistence rate of genital HPV infection in sexually transmitted infections (STIs) patients and healthy subjects. The risk factors influencing the persistence of genital HPV infection were also investigated. The samples were collected with the ThinPrep liquid-based cytology system. Among the HPV-positive patients, those consenting were retested after 12 months. Overall, 145/292 subjects proved HPV positive with a higher prevalence (51%) in STI than in healthy population (43%). The persistence of genital HPV infection was statistically associated with female gender, HR-HPV infection, smoking, andUreaplasma parvuminfection

Climate change hastens the urgency of conservation for range-restricted plant species in the central-northern Mediterranean region

With the consensus that human activities are leading to dangerous interference in Earth\u2019s climate, there has been growing policy pressure for clear quantification and attribution of the resulting biological impacts. Despite the exceptional diversity in the Mediterranean biome, largely due to the number of rare and endemic plant species, the effect of future climate change on present Mediterranean plant species has only been examined in a few studies. In this study we presented an analysis of the potential effects of climate change on 22 plant species whose range is restricted to central-northern Mediterranean region. We used species distribution modelling to test whether projected climate change may affect the current suitability of species\u2019 habitat; to evaluate possible future threats due to climate change; and to test any relationship between extinction risk and ecological and life-history predictors. The studied species were predicted to lose some 50% of their current range by 2020. Similarly, the probability of occurrence in known localities was predicted to drop drastically by 2020. Our results support a relationship between biological characteristics and range contractions. Although the Mediterranean species were projected to lose a lower amount of habitat than Alpine ones, species with restricted geographic range seem to be more prone to climate change effects than widespread ones. Our results emphasize the need for immediate monitoring and conservation actions and suggest that rare species might be useful for monitoring the conservation status of habitat in relationship to the effects of global warming in the Mediterranean region