Loss of p19Arf Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms

The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms

SCN2A and Its Related Epileptic Phenotypes

Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A -related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A -benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A -BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A -related epilepsies have not shown a clear genotype-phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no standardized treatment for SCN2A -related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital)

Battling Bacteria with Free and Surface-Immobilized Polymeric Nanostructures

With the discovery of antibiotics, bacterial infections and previously fatal diseases suddenly became curable. During the golden era of antibiotics, new classes of antibiotics were discovered. However, antibiotic-resistant bacteria rapidly evolved while fewer new antimicrobial drugs were discovered and marketed. Today, a growing number of infections are becoming harder to treat as the bacterial resistance is spreading and antibiotics become less effective. Evidently, there is an urgent demand for new strategies that efficiently battle pathogenic bacteria. Among emerging technologies, those involving polymeric nanostructures, especially polymersomes, offer many features that make them attractive candidates for battling infections. Polymersomes can be designed to be biocompatible and respond to various environmental signals. They are more robust than liposomes and can host hydrophobic and hydrophilic antimicrobial compounds, which can be released and act locally. Last but not least, they are biodegradable. Moreover, platforms comprising polymeric nanostructures can be designed as sensors for diagnosing infections. Many of these approaches require the immobilization of the antimicrobial nanostructures on a surface whereby the activity is localized to a specific region. Several recent examples of polymeric nanostructures with antimicrobial activity, both free in solution or immobilized on surfaces, are highlighted and discussed in this chapter