Growth Factors and Synaptic Plasticity in Relapsing–Remitting Multiple Sclerosis

During multiple sclerosis (MS) inflammatory attacks, and in subsequent clinical recovery phases, immune cells contribute to neuronal and oligodendroglial cell survival and tissue repair by secreting growth factors. Animal studies showed that growth factors also play a substantial role in regulating synaptic plasticity, and namely in long-term potentiation (LTP). LTP could drive clinical recovery in relapsing patients by restoring the excitability of denervated neurons. We recently reported that maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and that the platelet-derived growth factor (PDGF) may play a key role in its regulation. We also reported that a Hebbian form of LTP-like cortical plasticity, explored by paired associative stimulation (PAS), correlates with clinical recovery from a relapse in MS. Here, we explored the role of PDGF in clinical recovery and in adaptive neuroplasticity in relapsing–remitting MS (RR-MS) patients. We found a correlation between the cerebrospinal fluid (CSF) PDGF concentrations and the extent of clinical recovery after a relapse, as full recovery was more likely observed in patients with high PDGF concentrations and poor recovery in subjects with low PDGF levels. Consistently with the idea that PDGF-driven synaptic plasticity contributes to attenuate the clinical consequences of tissue damage in RR-MS, we also found a striking correlation between CSF levels of PDGF and the amplitude of LTP-like cortical plasticity explored by PAS. CSF levels of fibroblast growth factor, granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor did not correlate with clinical recovery nor with measures of synaptic transmission and plasticity.     

Mutant KRAS is a druggable target for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.Pancreatic cancer is an aggressive disease that develops in a relatively symptom-free manner and in most cases, is already advanced at the time of diagnosis (1). It has one of the highest fatality rates of all cancers and is one of the leading causes of cancer-related deaths in the Western world (1, 2). Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases (3). Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases (4–6). KRAS mutations were shown to be an early event in the development of pancreatic cancer (5, 7, 8).The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D) (5, 9–11). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS (5, 11) and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation (12). Here, we aimed to harness the advantages of siRNA technology as a therapeutic modality for pancreatic cancer.Parenteral controlled drug delivery systems are used to improve and advance the therapeutic effects of drug treatments by providing optimized local drug concentrations over prolonged periods of time, reduction of side effects, and cost reduction (13). A prominent method of controlling the release rate of a drug in a pharmaceutical dosage is to embed the active agent within a polymeric matrix (14, 15). The polymer must be biocompatible, and in the case of parenteral administration, preferably biodegradable, to avoid the need to remove empty remnants.In the present study, we exploited the slow-release characteristics of the biodegradable polymer matrix, which we named local drug eluter (LODER) for the treatment of solid tumors.     

Sowing seeds of compassion: The case of a music therapy integration group

The purpose of this research was to examine whether, and in what ways, compassion developed within the integrating children in a music therapy integration group. The group included two integrated PDD boys and two integrating girls and met for 14 half-hour weekly sessions. The audio recordings and the verbal documentation of the sessions were analyzed according to qualitative (interpretative-phenomenology analysis) and quantitative methods. Qualitative analysis resulted in five distinct categories that could be organized hierarchically, from the most basic compassion (“pre-compassion”) to very high standard, compassionate behavior (“high compassion”), the higher levels containing the basic ones. Each of these categories diverged into variants, resulting in 11 additional sub-categories. Quantitative analysis showed that compassion developed gradually. As the process progressed, more compassion events were observed. Connections between compassion expressions and the use of music were found. Results of this research are discussed in light of the debate concerning integration for children with special needs. Recommendations for further therapeutic and research activity are provided.     

Expression of epithelial cell adhesion molecule in gallbladder carcinoma and its correlation with clinicopathologic variables

Gallbladder carcinoma is rare and fatal, and conventional therapies have been disappointing. Epithelial cell adhesion molecule (EpCAM) serves as a prognostic marker in various carcinomas and is a target of antibody-based therapies. Our purpose was to examine the expression of EpCAM in gallbladder carcinomas in relation to tumor grade, disease stage, and patient survival.Gallbladder carcinoma tissue specimens from 25 patients attending our center between 1991 and 2004 were immunohistochemically stained for EpCAM. The intensity and extent of staining were analyzed, and the specimens were classified accordingly: (1) weak, weak or no EpCAM expression in less than 10% of the selected area; (2) moderate, moderate expression in 10% to 49% of the selected area; or (3) strong, heavy staining in 50% or more of the selected area. The correlation between EpCAM expression and clinicopathologic variables was analyzed statistically.EpCAM overexpression predicted decreased survival (P = .005), but EpCAM expression did not correlate with tumor grade (P = .28) or disease stage (P = .10). EpCAM expression in gallbladder tumors may serve as a prognostic factor for poor survival. Its detection may help clinicians select patients likely to benefit from novel molecular therapies.