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A 21-day-old baby with transposition of the great arteries with intact ventricular septum, infradiaphragmatic totally anomalous pulmonary venous connection, and atrial septum defect underwent combined arterial switch operation, totally anomalous venous connection repair, and atrial septum defect closure, using a right-sided approach and temporary pulmonary veins occlusion, with no postoperative and 6-months follow-up complications. Complete anatomical correction is the most conceivable treatment for this unusual pathology; right-sided approach instead lifting the heart toward the right pleural cavity to perform left atrium-to-pulmonary veins anastomosis limits heart displacement and avoids nonphysiological three-dimensional alterations; moreover, ligation and division of vertical vein allow to obtain more tissue for anastomosis; temporary occlusion of pulmonary veins while performing anastomosis is a simple procedure that allows to avoid deep hypothermic circulatory arrest or low flow systemic perfusion. Combination of these details facilitates intra- and postoperative management, especially in combined demanding cases. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p = 0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM. [ABSTRACT FROM AUTHOR]

Advanced head and neck squamous cell cancer (HNSCC) is currently treated with taxane-based chemotherapy. We have previously shown that docetaxel (DTX) induces a ras-dependent survival signal that can be antagonized by farnesyl transferase inhibitors (FTI) such as tipifarnib (TIP). Here we show that the synergistic TIP/DTX combination determines synergistic apoptotic conditions but, at the same time, it modulates the expression of the components of the multichaperone complex that is, in turn, involved in the regulation of the stability of members of the ras-mediated pathway. Therefore, we have stably transfected HNSCC KB and Hep-2 cells with a plasmid encoding for HSP90. The expression of the protein was increased in both transfected cell lines but its activation status was increased in Hep-2 clones and decreased in KB clones. On the basis of these results, we have treated both parental and HSP90-transfected cells with a HSP90 inhibitor geldanamycin (GA). We have found that the antiproliferative activity of GA is dependent upon the activation status of HSP90 and that it is strongly synergistic when added in combination with TIP but not with DTX in cells overexpressing HSP90 and even more in cells with increased HSP90 activity. These data were paralleled by the decreased expression and activity of the components belonging to the ras→mediated signal transduction pathway. The present results suggest that multichaperone complex activation could be a resistance mechanism to the anti-proliferative and apoptotic effects induced by TIP and that the combination of FTIs such as TIP with GA could be a suitable therapeutic strategy in the treatment of HSP90-overexpressing HNSCC. J. Cell. Physiol. 228: 130-141, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Adipose tissue is a readily available source of multipotent adult stem cells for use in tissue engineering/regenerative medicine. Various growth factors have been used to stimulate acquisition of endothelial characteristics by adipose-derived stem cells (ADSC). Herein, we study the growth and endothelial differentiation potential of ADSC seeded onto a porous polycaprolactone (PCL) scaffold. The objective of this study is to demonstrate that PCL is a good material to be used as a scaffold to support reconstruction of new endothelial tissue using adipose stem cells. We found that undifferentiated ADSC adhere and grow on PCL. We show that, after culture in endothelial differentiation medium, ADSC were positive to LDL uptake and expressed molecular markers characteristic of endothelial cells (CD31; eNOS and vWF). In addition, our study defines the time required for the differentiation of ADSC directly onto PCL. This study suggests that PCL can be used as a scaffold to generate endothelial tissue in vitro. PLC has excellent mechanical properties and a slow degradation rate. Moreover, based on our results, we propose that PCL could be used to graft scaffolds coated with endothelial cells derived from ADSC stem cells. Endothelial cells-coated PCL could find several applications to replace damaged area of the body; for example, a possible use could be the generation of vascular grafts. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012. [ABSTRACT FROM AUTHOR]

The methyl ester prodrug of Nω-nitro-L-arginine (L-NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L-NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of Nω-nitro-L-arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82-W-1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L-NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L-NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS-II expression by NAGAL. Finally, by using the LC–MS technique, we found that NAGAL elicited a higher increase in Nω-nitro-L-arginine (NA) concentration than did L-NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma. J. Cell. Physiol. 221: 440–447, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We study a Dirichlet problem for the heat equation in C- domain D X (0, T) with boundary data in h, a subspace of L. We derive our results using, in the representation of the solution, the kernel function associated to the caloric measure dω [ABSTRACT FROM AUTHOR]

Background: In recent years, an increasing number of individuals affected by neglected tropical diseases (NTDs) have been observed in Italy, due to migration, international travels and climate changes. Reliable data on the current NTD epidemiology in Italy and the health system preparedness on this issue are not available.Methods: We report the results of a survey on selected NTDs (schistosomiasis, strongyloidiasis, echinococcosis, Chagas disease, leishmaniasis, cysticercosis, filariasis and scabies) in nine Italian sentinel centres, in order to investigate their occurrence throughout the country and identify which ones are a priority for public health interventions, development of protocols for case management, and training activities. To explore the preparedness of the centres, we investigate the availability of specific diagnostic tools and drugs, needed for the management of the most common NTDs. We also reviewed and summarized the available national policies, recommendations and guidelines on NTDs in Italy.Results: Overall, 4123 NTDs cases were diagnosed in nine Italian centres within a 7-year period (2011-2017). Schistosomiasis and strongyloidiasis were the most common NTDs, accounting for about one-third each of all the diagnosed cases, followed by Chagas disease. The number of cases showed a significant trend to increase over time, mainly due to foreign-born subjects. Serology for Schistosoma spp. and Strongyloides stercoralis was available in seven and five centres, respectively. Agar plate stool culture for S. stercoralis was available in three sites. Ivermectin and praziquantel were always available in six centres. Six national policies, recommendations and guidelines documents were available, but for the most part, they are not fully implemented yet.Conclusions: This survey showed how some NTDs, such as schistosomiasis and strongyloidiasis, are becoming more common in Italy, due to multiple components. A list of seven key actions was proposed, in order to improve diagnosis, management and control of NTDs in Italy. [ABSTRACT FROM AUTHOR]

The effective management of patients with breast cancer (BC) depends on the early diagnosis of the disease. Currently, BC diagnosis is based on diagnostic imaging and biopsy, while the use of non-invasive circulating biomarkers for diagnosis remains an unmet need. Among the plethora of proposed non-invasive biomarkers, circulating microRNAs (miRNAs) have been considered promising diagnostic molecules because they are very stable in biological fluids and easily detectable. Although the discovery of miRNAs has opened a new avenue for their clinical application, the clinical translatability of these molecules remains unclear. This review analyses the role of circulating miRNAs as BC diagnostic biomarkers and focuses on two essential requirements to evaluate their clinical validity: i) Specificity and ii) consistent expression between the blood and tissue. These two issues were analyzed in depth using the Human miRNA Disease Database (HMDD v3.0) and the free search engine PubMed. One hundred and sixty three BC-associated miRNAs were selected and analyzed for their specificity among all human pathologies that shared deregulation (291) and consistent expression in the bloodstream and the tissue. In addition, we provide an overview of the current clinical trials examining miRNAs in BC. In conclusion, we highlight pitfalls in the translatability of circulating miRNAs into clinical practice due to the lack of specificity and a consistent expression pattern between the tissue and blood. [ABSTRACT FROM AUTHOR]

The article discusses the use of knife-edge scanning microscope to chart out the connectome of an octopus at submicron resolution. It mentions that large portions of the subesophageal mass and the optic lobe were imaged. It concludes that the approach would contribute to the understanding of the computational architecture of invertebrates, and would provide insights on the different cognitive capabilities of invertebrates and vertebrates.

The vasculature of each organ expresses distinct molecular signatures critically influenced by the pathological status. The heterogeneous profile of the vascular beds has been successfully unveiled by the in vivo phage display, a high-throughput tool for mapping normal, diseased, and tumor vasculature. Specific challenges of this growing field are targeted therapies against cancer and cardiovascular diseases, as well as novel bioimaging diagnostic tools. Tumor vasculature-homing peptides have been extensively evaluated in several preclinical and clinical studies both as targeted-therapy and diagnosis. To date, results from several Phase I and II trials have been reported and many other trials are currently ongoing or recruiting patients. In this review, advances in the identification of novel peptide ligands and their corresponding receptors on tumor endothelium through the in vivo phage display technology are discussed. Emphasis is given to recent findings in the clinical setting of vascular-homing peptides selected by in vivo phage display for the treatment of advanced malignancies and their altered vascular beds. [ABSTRACT FROM AUTHOR]

Context.--Fine-needle aspiration cytology (FNAC) of pulmonary nodules is usually guided by computed tomography (CT), whereas ultrasonography (US) is generally considered not applicable for such purposes. Objective.--To evaluate the clinical applicability and diagnostic utility of US-guided transthoracic FNAC of peripheral pulmonary nodules. Design.--Ultrasonography-guided transthoracic FNAC was obtained from 40 selected patients with peripheral, subpleural, and paravertebral pulmonary nodules. Airdried and Diff-Quik--stained smears were used for rapid on-site evaluation; additional smears were alcohol fixed for Papanicolaou staining. Cell blocks were set up for immunocytochemical and molecular studies; in 2 cases, a flow cytometry evaluation was also performed. The series was compared to 40 CT-guided pulmonary FNAC samples from patients with pleural, peripheral, and paravertebral pulmonary nodules, to evaluate differences in terms of diagnostic rate, time of execution, safety, and cost. Results.--The US-guided FNAC samples had results that were adequate and representative in 95% of cases. No significant differences were observed between the 2 groups in terms of diagnostic rate, number of passes, and cellularity of both smears and cell blocks. The mean time needed for the execution of US-guided FNAC was 13.1 minutes, whereas the mean time for CT-guided FNAC was 23.6 minutes. Thus, US-guided FNAC was significantly more rapid than CT-guided pulmonary FNAC. Because pneumothorax occurred in 1 individual who underwent US-guided FNAC and in 9 who underwent CT-guided FNAC, we might conclude that US-guided FNAC is a significantly safer procedure. Finally, comparing the costs of both procedures, US-guided FNAC is less expensive. Conclusions.--Our experience showed an elevated clinical applicability and diagnostic utility of US-guided transthoracic FNAC for selected pulmonary nodules. [ABSTRACT FROM AUTHOR]

• The rational design and polymer architecture influence the relaxivity of MRI media. • The presence of crosslinked hydrogel alters the longitudinal relaxation time. • The acquired knowledge can be used for development of a new generation of MRI probe. Nowadays, natural polysaccharides have given promising results as drug carriers. Among them, the hydrogels, thanks to their versatile properties, have been produced and engineered at the nano-scale in order to develop nanovectors for diagnostic and therapeutic purposes. Here, we investigate the contribution that a natural biopolymer, hyaluronic acid (HA), can give to the field of Magnetic Resonance Imaging (MRI). In addition, we study the relaxometric properties of crosslinked and non-crosslinked hydrogel networks and outline the impact of both HA concentration and crosslinker, Divinyl Sulfone (DVS), on the relaxivity of aqueous polymer solutions, even in the absence of Contrast Agents (CAs). Results show that proper HA concentration and the presence of the crosslinking agent can enhance the longitudinal relaxation time of the surrounding water, even in the absence of CAs. These findings could inspire the design of novel nanostructured hydrogels with enhanced relaxometric properties for MRI applications and not only. [ABSTRACT FROM AUTHOR]

Background: The aim of the present review is to discuss how the promising field of biobanking can support health care research strategies. As the concept has evolved over time, biobanks have grown from simple biological sample repositories to complex and dynamic units belonging to large infrastructure networks, such as the Pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI). Biobanks were established to support scientific knowledge. Different professional figures with varied expertise collaborate to obtain and collect biological and clinical data from human subjects. At same time biobanks preserve the human and legal rights of each person that offers biomaterial for research.Methods: A literature review was conducted in April 2019 from the online database PubMed, accessed through the Bibliosan platform. Four primary topics related to biobanking will be discussed: (i) evolution, (ii) bioethical issues, (iii) organization, and (iv) imaging.Results: Most biobanks were founded as local units to support specific research projects, so they evolved in a decentralized manner. The consequence is an urgent needing for procedure harmonization regarding sample collection, processing, and storage. Considering the involvement of biomaterials obtained from human beings, different ethical issues such as the informed consent model, sample ownership, veto rights, and biobank sustainability are debated. In the face of these methodological and ethical challenges, international organizations such as BBMRI play a key role in supporting biobanking activities. Finally, a unique development is the creation of imaging biobanks that support the translation of imaging biomarkers (identified using a radiomic approach) into clinical practice by ensuring standardization of data acquisition and analysis, accredited technical validation, and transparent sharing of biological and clinical data.Conclusion: Modern biobanks permit large-scale analysis for individuation of specific diseases biomarkers starting from biological or digital material (i.e., bioimages) with well-annotated clinical and biological data. These features are essential for improving personalized medical approaches, where effective biomarker identification is a critical step for disease diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced homeostasis passing through a network of structures, regulated principally via fission and fusion. Herein we discuss about the most advanced findings considering mitochondria as dynamic biophysical systems playing compelling roles in the regulation of energy metabolism in both physiologic and pathologic processes controlling cell death and survival. Precisely, we focus on the mitochondrial commitment to the onset, maintenance and counteraction of apoptosis, autophagy and senescence in the bioenergetic reprogramming of cancer cells. In this context, looking for a pharmacological manipulation of cell death processes as a successful route for future targeted therapies, there is major biotechnological challenge in underlining the location, function and molecular mechanism of mitochondrial proteins. Based on the critical role of mitochondrial functions for cellular health, a better knowledge of the main molecular players in mitochondria disfunction could be decisive for the therapeutical control of degenerative diseases, including cancer. [ABSTRACT FROM AUTHOR]

Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma. [ABSTRACT FROM AUTHOR]