Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease

The Niemann-Pick type C1 (NPC1) is a rare genetic disease characterized by the accumulation of endocytosed cholesterol and other lipids in the endosome/lysosome compartments. In the brain, the accumulation/mislocalization of unesterified cholesterol, gangliosides and sphingolipids is responsible for the appearance of neuropathological hallmarks, and progressive neurological decline in patients. The imbalance of unesterified cholesterol and other lipids, including GM2 and GM3 gangliosides, alters a number of signaling mechanisms impacting on the overall homeostasis of neurons. In particular, lipid depletion experiments have shown that lipid rafts regulate the cell surface expression of dopamine transporter (DAT) and modulate its activity. Dysregulated dopamine transporter’s function results in imbalanced dopamine levels at synapses and severely affects dopamine-induced locomotor responses and dopamine receptor-mediated synaptic signaling. Recent studies begin to correlate dopaminergic stimulation with the length and function of the primary cilium, a non-motile organelle that coordinates numerous signaling pathways. In particular, the absence of dopaminergic D2 receptor stimulation induces the elongation of dorso-striatal neuron’s primary cilia. This study has used a mouse model of the NPC1 disease to correlate cholesterol dyshomeostasis with dorso-striatal anomalies in terms of DAT expression and primary cilium (PC) length and morphology. We found that juvenile Npc1nmf164 mice display a reduction of dorso-striatal DAT expression, with associated alterations of PC number, length-frequency distribution, and tortuosity

d-mannose treatment neither affects uropathogenic Escherichia coli properties nor induces stable FimH modifications

Abstract: Urinary tract infections (UTIs) are mainly caused by uropathogenic Escherichia coli (UPEC). Acute and recurrent UTIs are commonly treated with antibiotics, the efficacy of which is limited by the emergence of antibiotic resistant strains. The natural sugar d-mannose is considered as an alternative to antibiotics due to its ability to mask the bacterial adhesin FimH, thereby preventing its binding to urothelial cells. Despite its extensive use, the possibility that d-mannose exerts “antibiotic-like” activity by altering bacterial growth and metabolism or selecting FimH variants has not been investigated yet. To this aim, main bacterial features of the prototype UPEC strain CFT073 treated with d-mannose were analyzed by standard microbiological methods. FimH functionality was analyzed by yeast agglutination and human bladder cell adhesion assays. Our results indicate that high d-mannose concentrations have no effect on bacterial growth and do not interfere with the activity of different antibiotics. d-mannose ranked as the least preferred carbon source to support bacterial metabolism and growth, in comparison with d-glucose, d-fructose, and l-arabinose. Since small glucose amounts are physiologically detectable in urine, we can conclude that the presence of d-mannose is irrelevant for bacterial metabolism. Moreover, d-mannose removal after long-term exposure did not alter FimH’s capacity to bind to mannosylated proteins. Overall, our data indicate that d-mannose is a good alternative in the prevention and treatment of UPEC-related UTIs

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the 'supernumerary' group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in in the X-linked nuclear encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11 but all are associated to a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects

Chikungunya virus vaccine candidates with decreased mutational robustness are attenuated in vivo and have compromised transmissibility

Chikungunya virus (CHIKV) is a reemerged arbovirus, a member of the Togaviridae family. It circulates through mosquito vectors mainly of the Aedes family and a mammalian host. CHIKV causes chikungunya fever, a mild to severe disease characterized by arthralgia, with some fatal outcomes described. In the past years, several outbreaks mainly caused by enhanced adaptation of the virus to the vector and ineffective control of the contacts between infected mosquito populations and the human host have been reported. Vaccines represent the best solution for the control of insect-borne viruses, including CHIKV, but are often unavailable. We designed live attenuated CHIKVs by applying a rational genomic design based on multiple replacements of synonymous codons. In doing so, the virus mutational robustness (capacity to maintain phenotype despite introduction of mutations to genotype) is decreased, driving the viral population toward deleterious evolutionary trajectories. When the candidate viruses were tested in the insect and mammalian hosts, we observed overall strong attenuation in both and greatly diminished signs of disease. Moreover, we found that the vaccine candidates elicited protective immunity related to the production of neutralizing antibodies after a single dose. During an experimental transmission cycle between mosquitoes and naive mice, vaccine candidates could be transmitted by mosquito bite, leading to asymptomatic infection in mice with compromised dissemination. Using deep-sequencing technology, we observed an increase in detrimental (stop) codons, which confirmed the effectiveness of this genomic design. Because the approach involves hundreds of synonymous modifications to the genome, the reversion risk is significantly reduced, rendering the viruses promising vaccine candidates

Neural correlates of outcome of cognitive therapy compared to psychodynamic therapy in affective disorders. a meta-analysis

Anxiety and depression disorders are commonly associated with structural and functional changes in the fronto-limbic brain areas. However, it is still unexplored how different psychotherapeutic approaches affect the functional brain. The present meta-analysis aims to compare the neurobiological outcome of the cognitive therapies compared to the psychodynamic therapies in anxiety and depression disorders

Low serum total testosterone level as a predictor of upstaging and upgrading in low-risk prostate cancer patients meeting the inclusion criteria for active surveillance

Active surveillance (AS) is currently a widely accepted treatment option for men with clinically localized prostate cancer (PCa). Several reports have highlighted the association of low serum testosterone levels with high-grade, high-stage PCa. However, the impact of serum testosterone as a predictor of progression in men with low-risk PCa has been little assessed.In this study, we evaluated the association of circulating testosterone concentrations with a staging/grading reclassification in a cohort of low-risk PCa patients meeting the inclusion criteria for the AS protocol but opting for radical prostatectomy.Radical prostatectomy (RP) was performed in 338 patients, eligible for AS according to the following criteria: clinical stage T2a or less, PSApT2) and upgrading (GS≥7; primary Gleason pattern 4) disease. Unfavorable disease was defined as the occurrence of pathological stage>pT2 and predominant Gleason score 4. Total testosterone was measured before surgery.Low serum testosterone levels (<300 ng/dL) were significantly associated with upgrading, upstaging, unfavorable disease and positive surgical margins. The addition of testosterone to a base model, including age, PSA, PSA density, clinical stage and positive cancer involvement in cores, showed a significant independent influence of this variable on upstaging, upgrading and unfavorable disease.In conclusion, our results support the idea that total testosterone should be a selection criterion for inclusion of low-risk PCa patients in AS programs and suggest that testosterone level less than 300 ng/dL should be considered a discouraging factor when a close AS program is considered as treatment option

Liquid biopsy biomarkers in urine: a route towards molecular diagnosis and personalized medicine of bladder cancer

Bladder cancer (BC) is characterized by high incidence and recurrence rates together with genomic instability and elevated mutation degree. Currently, cystoscopy combined with cytology is routinely used for diagnosis, prognosis and disease surveillance. Such an approach is often associated with several side effects, discomfort for the patient and high economic burden. Thus, there is an essential demand of non-invasive, sensitive, fast and inexpensive biomarkers for clinical management of BC patients. In this context, liquid biopsy represents a very promising tool that has been widely investigated over the last decade. Liquid biopsy will likely be at the basis of patient selection for precision medicine, both in terms of treatment choice and real-time monitoring of therapeutic effects. Several different urinary biomarkers have been proposed for liquid biopsy in BC, including DNA methylation and mutations, protein-based assays, non-coding RNAs and mRNA signatures. In this review, we summarized the state of the art on different available tests concerning their potential clinical applications for BC detection, prognosis, surveillance and response to therap

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC. Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development. Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC

Artificial Intelligence and Machine Learning in Prostate Cancer Patient Management-Current Trends and Future Perspectives

Artificial intelligence (AI) is the field of computer science that aims to build smart devices performing tasks that currently require human intelligence. Through machine learning (ML), the deep learning (DL) model is teaching computers to learn by example, something that human beings are doing naturally. AI is revolutionizing healthcare. Digital pathology is becoming highly assisted by AI to help researchers in analyzing larger data sets and providing faster and more accurate diagnoses of prostate cancer lesions. When applied to diagnostic imaging, AI has shown excellent accuracy in the detection of prostate lesions as well as in the prediction of patient outcomes in terms of survival and treatment response. The enormous quantity of data coming from the prostate tumor genome requires fast, reliable and accurate computing power provided by machine learning algorithms. Radiotherapy is an essential part of the treatment of prostate cancer and it is often difficult to predict its toxicity for the patients. Artificial intelligence could have a future potential role in predicting how a patient will react to the therapy side effects. These technologies could provide doctors with better insights on how to plan radiotherapy treatment. The extension of the capabilities of surgical robots for more autonomous tasks will allow them to use information from the surgical field, recognize issues and implement the proper actions without the need for human intervention