c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway

It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells. At the molecular level, we observed that c-Myc inhibition reduced the expression of mevalonate kinase (MVK), a molecule belonging to the mevalonate pathway that-according to previous findings-can control mutp53 stability, and thus contributes to cancer cell survival. In conclusion, this study unveils another criminal alliance between oncogenes, such as c-Myc and mutp53, that plays a key role in oncogenesis

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments. Previous studies have highlighted the role of IRE1 alpha and PERK UPR sensors on DDR, while the impact of ATF6 on this process remains under-investigated. This study shows for the first time that ATF6 sustains the expression level of BRCA-1 and protects colon cancer cells from the cytotoxic effect of ER stressors DPE and Thapsigargin. At molecular level, ATF6 activates mTOR to sustain the expression of HSP90, of which BRCA-1 is a client protein. Therefore, pharmacological or genetic inhibition of ATF6 promoted BRCA-1 degradation and increased DNA damage and cell death, particularly in combination with Adriamycin. All together this study suggests that targeting ATF6 may not only potentiate the cytotoxic effect of drugs triggering ER stress but may render colon cancer cells more sensitive to Adriamycin and possibly to other DNA damaging agents used to treat colon cancer

Unveiling the Thermoelectric Performances of Zn1−xFexSe Nanoparticles Prepared by the Hydrothermal Method

Fe2+-doped ZnSe nanoparticles, with varying concentrations of Fe2+ dopants, were prepared by the hydrothermal method and investigated using a multi-technique approach exploiting scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy, as well as measurement of the electrical transport properties and Seebeck coefficient (S). The doped nanoparticles appeared as variable-sized agglomerates on nanocrystallites upon SEM investigation for any doping level. Combined XRD and Raman analyses revealed the occurrence of a cubic structure in the investigated samples. Electric and thermoelectric (TE) transport investigations showed an increase in TE performance with an increase in Fe atom concentrations, which resulted in an enhancement of the power factors from 13 µWm−1K−2 to 120 µWm−1K−2 at room temperature. The results were also dependent on the operating temperature. The maximum power factor of 9 × 10−3 Wm−1K−2 was achieved at 150 °C for the highest explored doping value. The possible applications of these findings were discussed

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL

Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC50 values ¼ 0.015 and 0.005 lM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays

Thermoelectric and Structural Properties of Sputtered AZO Thin Films with Varying Al Doping Ratios

Nanomaterials can be game-changers in the arena of sustainable energy production because they may enable highly efficient thermoelectric energy conversion and harvesting. For this purpose, doped thin film oxides have been proven to be promising systems for achieving high thermoelectric performances. In this work, the design, realization, and experimental investigation of the thermoelectric properties exhibited by a set of five Al:ZnO thin films with thicknesses of 300 nm and Al doping levels ranging from 2 to 8 at.% are described. Using a multi-technique approach, the main structural and morphological features of the grown thin films are addressed, as well as the electrical and thermoelectrical transport properties. The results show that the samples exhibited a Seebeck coefficient absolute value in the range of 22-33 mu V/K, assuming their maximum doping level was 8 at.%, while the samples' resistivity was decreased below 2 x 10(-3) Ohm center dot cm with a doping level of 3 at.%. The findings shine light on the perspectives of the applications of the metal ZnO thin film technology for thermoelectrics

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

BACKGROUND: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31. METHODS: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients. RESULTS: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio. CONCLUSION: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.We thank Professor Franco Locatelli for critical reading this paper and for his suggestions. We would also like to thank the children ’ s parents, who gave their informed consent for publication and “Il cuore grande di Flavio ”Onlus. Dr. Marta Colletti is a post-doctoral fellow of the Umberto Veronesi Founda- tion. To Valentina Polcini for proofreading.S

Study of the effects of different biomaterials on osteogenic differentiation of oral-periosteal cells

Bone regeneration is currently one of the most important challenges for regenerative medicine and it is considered an ideal clinical strategy in the maxillo-facial area [1]. Bone resorption of alveolar crest occurring after tooth extraction leads to several risks for future treatments, including dental implants. For this reason, alveolar ridge preservation (ARP) has become a key component of contemporary clinical dentistry. Several clinical techniques and bone substitute materials can be used to fill the socket after tooth extraction. For all of them, the principle aim is to keep the shape and the size of the bone socket of the extracted tooth allowing inserting the dental implants [2]. The goal of our study was to compare different biocompatible scaffolds based on PLGA (Fisiograft®), Bioglass (Activioss®) and collagen (Sombrero®) in an in vitro model of tissue engineering for dental applications. The cells used in our study derived from Periosteum obtained from four different patients that underwent socket preservation selected by the School of Dentistry of the University of Pavia, previous informed consent. We created bio-complexes constituted by mesenchymal-periosteal cells seeded on different types of biomaterials and we performed adhesion, morphological, proliferative and bone differentiation analyses at different time points (7, 14 and 28 days of culture) in proliferative and osteogenic conditions. Bone differentiation was evaluated by qRT-PCR on genes involved in osteoblast development, like BMP-2, Osteocalcin and Periostin. Our results demonstrated that Sombrero® enhanced adhesion and proliferation of periosteal cells, as highlighted by Haematoxylin-Eosin staining and XTT test (3 and 7 days). Long-term studies (14 and 28 days) demonstrated that periosteal differentiation is about the same among the different materials tested. From these preliminary studies we can conclude that it could be advantageous the clinical use of both collagenic and PLGA scaffolds in order to ameliorate initial colonization and subsequent mechanical support in maxillo-bone regeneration. This work was supported by grant from NATO 2016 (“RAWINTS” (G-984961): RApid Skin Wound healing by INtegrated Tissue engineering and Sensing)

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy