Photodisintegration of 4^4He into p+t

The two-body photodisintegration of $^4$He into a proton and a triton has been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at Jefferson Laboratory. Real photons produced with the Hall-B bremsstrahlung-tagging system in the energy range from 0.35 to 1.55 GeV were incident on a liquid $^4$He target. This is the first measurement of the photodisintegration of $^4$He above 0.4 GeV. The differential cross sections for the $\gamma$$^4$He$\to pt$ reaction have been measured as a function of photon-beam energy and proton-scattering angle, and are compared with the latest model calculations by J.-M. Laget. At 0.6-1.2 GeV, our data are in good agreement only with the calculations that include three-body mechanisms, thus confirming their importance. These results reinforce the conclusion of our previous study of the three-body breakup of $^3$He that demonstrated the great importance of three-body mechanisms in the energy region 0.5-0.8 GeV .Comment: 13 pages submitted in one tgz file containing 2 tex file and 22 postscrip figure

Exclusive Photoproduction of the Cascade (Xi) Hyperons

We report on the first measurement of exclusive Xi-(1321) hyperon photoproduction in gamma p --> K+ K+ Xi- for 3.2 < E(gamma) < 3.9 GeV. The final state is identified by the missing mass in p(gamma,K+ K+)X measured with the CLAS detector at Jefferson Laboratory. We have detected a significant number of the ground-state Xi-(1321)1/2+, and have estimated the total cross section for its production. We have also observed the first excited state Xi-(1530)3/2+. Photoproduction provides a copious source of Xi's. We discuss the possibilities of a search for the recently proposed Xi5-- and Xi5+ pentaquarks.Comment: submitted to Phys. Rev.

First measurement of target and double spin asymmetries for polarized e- polarized p --> e p pi0 in the nucleon resonance region above the Delta(1232)

The exclusive channel polarized proton(polarized e,e prime p)pi0 was studied in the first and second nucleon resonance regions in the Q2 range from 0.187 to 0.770 GeV2 at Jefferson Lab using the CEBAF Large Acceptance Spectrometer (CLAS). Longitudinal target and beam-target asymmetries were extracted over a large range of center-of-mass angles of the pi0 and compared to the unitary isobar model MAID, the dynamic model by Sato and Lee, and the dynamic model DMT. A strong sensitivity to individual models was observed, in particular for the target asymmetry and in the higher invariant mass region. This data set, once included in the global fits of the above models, is expected to place strong constraints on the electrocoupling amplitudes A_{1/2} and S_{1/2} for the Roper resonance N(1400)P11, and the N(1535)S11 and N(1520)D13 states.Comment: 13 pages, 13 figure

Efficacia antitumorale di un Antibody Drug Conjugate (B7-H3 ADC) come approccio innovativo di immunoterapia nel neuroblastoma

Introduzione: Vobra duo è un Antibody Drug Conjugate (ADC) composto da un anticorpo monoclonale umanizzato anti-B7-H3 coniugato alla duocarmicina, un agente alchilante del DNA. Vobra duo ha mostrato efficacia in studi clinici avanzati in tumori dell’adulto. B7-H3 è espresso in diversi tumori pediatrici, tra cui il neuroblastoma (NB), rappresentando un target di interesse in oncologia pediatrica. Risultati: Vobra duo riduce la vitalità cellulare di linee cellulari di NB coltivate sia in monostrato che sotto forma di sferoidi tumorali in maniera dose e tempo-dipendente e agisce attraverso un meccanismo di morte cellulare apoptotica. È inattivo contro una linea cellulare murina di NB non esprimente B7-H3 umano, mostrando, tuttavia, un effetto bystander se co-coltivata con cellule di NB esprimenti B7-H3 umano. In modelli murini ortotopici e metastatici di NB, la somministrazione settimanale di vobra duo per tre settimane consecutive ritarda significativamente la crescita del tumore e aumenta i tassi di sopravvivenza rispetto ai topi di controllo. Vobra duo somministrato per quattro settimane consecutive migliora ulteriormente la sopravvivenza in modelli ortotopici e in quelli in cui la massa primaria viene asportata chirurgicamente. Infine, cicli ripetuti di vobra duo sono in grado di controllare la ricaduta di malattia. Non si osservano né tossicità ematologica né alterazioni dei parametri di funzionalità epatica e renale nei topi trattati con vobra duo. Conclusioni: Vobra duo esercita una rilevante attività antitumorale in modelli preclinici di NB sia in vitro che in vivo e rappresenta un potenziale candidato per futuri studi clinici. Introduction: Vobra duo is an Antibody Drug Conjugate (ADC) composed of an anti-B7-H3 humanized monoclonal antibody conjugated to duocarmycin, a DNA alkylating agent. Vobra duo has shown efficacy in advanced clinical trials in adult tumors. B7-H3 is expressed in several pediatric tumors including neuroblastoma (NB), representing a target of interest in pediatric oncology. Results: Vobra duo reduces cell viability of NB cell lines, cultured in monolayer and as multicellular tumor spheroids, in a dose- and time-dependent manner, and acts through an apoptotic cell death mechanism. It is inactive against a murine NB cell line that does not express human B7-H3, showing, however, a bystander effect when co-cultured with NB cells expressing human B7-H3. In NB orthotopic and metastatic mouse models, weekly administration of vobra duo for three consecutive weeks significantly delays tumor growth and increases survival rates compared to control mice. Vobra duo administered for four consecutive weeks further improves survival in orthotopic models and in those subjected to surgical removal of the primary tumor mass. Finally, repeated cycles of vobra duo are able to control disease relapse. Neither hematological toxicity nor alterations in liver and kidney function parameters were observed in mice treated with vobra duo. Conclusions: Vobra duo exerts relevant antitumor activity in NB preclinical models both in vitro and in vivo and represents a potential candidate for future clinical studies

The Olive Leaves Extract Has Anti-Tumor Effects against Neuroblastoma through Inhibition of Cell Proliferation and Induction of Apoptosis

Neuroblastoma (NB) is the most common extra-cranial solid tumor of pediatric age. The prognosis for high-risk NB patients remains poor, and new treatment strategies are desirable. The olive leaf extract (OLE) is constituted by phenolic compounds, whose health beneficial effects were reported. Here, the anti-tumor effects of OLE were investigated in vitro on a panel of NB cell lines in terms of (i) reduction of cell viability; (ii) inhibition of cell proliferation through cell cycle arrest; (iii) induction of apoptosis; and (iv) inhibition of cell migration. Furthermore, cytotoxicity experiments, by combining OLE with the chemotherapeutic topotecan, were also performed. OLE reduced the cell viability of NB cells in a time- and dose-dependent manner in 2D and 3D models. NB cells exposed to OLE underwent inhibition of cell proliferation, which was characterized by an arrest of the cell cycle progression in G0/G1 phase and by the accumulation of cells in the sub-G0 phase, which is peculiar of apoptotic death. This was confirmed by a dose-dependent increase of Annexin V+ cells (peculiar of apoptosis) and upregulation of caspases 3 and 7 protein levels. Moreover, OLE inhibited the migration of NB cells. Finally, the anti-tumor efficacy of the chemotherapeutic topotecan, in terms of cell viability reduction, was greatly enhanced by its combination with OLE. In conclusion, OLE has anti-tumor activity against NB by inhibiting cell proliferation and migration and by inducing apoptosis.</jats:p

Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors

Retinoids are a class of natural and synthetic compounds derived from vitamin A. They are involved in several biological processes like embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. In light of their important functions, retinoids have been widely investigated for their therapeutic applications. Thus far, their use for the treatment of several types of cancer and skin disorders has been reported. However, these therapeutic agents present several limitations for their widespread clinical translatability, i.e., poor solubility and chemical instability in water, sensitivity to light, heat, and oxygen, and low bioavailability. These characteristics result in internalization into target cells and tissues only at low concentration and, consequently, at an unsatisfactory therapeutic dose. Furthermore, the administration of retinoids causes severe side-effects. Thus, in order to improve their pharmacological properties and circulating half-life, while minimizing their off-target uptake, various retinoids delivery systems have been recently developed. This review intends to provide examples of retinoids-loaded nano-delivery systems for cancer treatment. In particular, the use and the therapeutic results obtained by using fenretinide-loaded liposomes against neuroectodermal-derived tumors, such as melanoma, in adults, and neuroblastoma, the most common extra-cranial solid tumor of childhood, will be discussed.</jats:p

Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors

Retinoids are a class of natural and synthetic compounds derived from vitamin A. They are involved in several biological processes like embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. In light of their important functions, retinoids have been widely investigated for their therapeutic applications. Thus far, their use for the treatment of several types of cancer and skin disorders has been reported. However, these therapeutic agents present several limitations for their widespread clinical translatability, i.e., poor solubility and chemical instability in water, sensitivity to light, heat, and oxygen, and low bioavailability. These characteristics result in internalization into target cells and tissues only at low concentration and, consequently, at an unsatisfactory therapeutic dose. Furthermore, the administration of retinoids causes severe side-effects. Thus, in order to improve their pharmacological properties and circulating half-life, while minimizing their off-target uptake, various retinoids delivery systems have been recently developed. This review intends to provide examples of retinoids-loaded nano-delivery systems for cancer treatment. In particular, the use and the therapeutic results obtained by using fenretinide-loaded liposomes against neuroectodermal-derived tumors, such as melanoma, in adults, and neuroblastoma, the most common extra-cranial solid tumor of childhood, will be discussed

PREPARATION AND CHARACTERIZATION OF LIPID NANOPARTICLE FORMULATIONS FOR siRNA DELIVERY BY A MICROFLUIDIC APPROACH

The marketing authorizations of vaccines against SARS-Cov-2 have speed up the application of Lipid Nanoparticles (LNPs) to nucleic acid delivery for the treatment of rare diseases, diabetes, and cancer. In comparison to non-viral vehicles, LNPs provide a safer and more effective tool with no immunogenic responses. Meanwhile, LNPs are able to encapsulate different genetic materials as small interfering RNA (siRNA), messenger RNA (mRNA), or plasmids and are extremely tuneable to changes in the formulation composition and chemical modification. Herein, LNPs encapsulating siRNA were manufactured through a microfluidic system, starting from a mixture of ionizable amino lipid DLin-MC3-DMA, DSPC, cholesterol, PEG-DMG in a molar ratio of 50:10:38.5:1.5, respectively, with a final total lipid concentration of 12.5 mM [1, 2]. The organic phase of lipids dissolved in ethanol and the aqueous phase containing siRNA in acetate buffer (pH 4) were combined at a 1:3 volume with a final flow rate of 12 mL/min. After testing different N/P (Nitrogen/nucleic acid Phosphate) charge ratios, the 3:1 proportion was selected as the best balance for formulating siRNA-loaded LNPs. The resultant siRNA-LNPs were then dialyzed against phosphate-buffered saline (PBS, pH 7.4) using GeBaFlex dialysis membranes (14 kDa MWCO) for 3 h at 4 °C to remove ethanol, and subsequently filtered through a 0.2 μm filters. Specifically, two different non-specific negative-control si-RNAs were employed leading to siRNA-NC1-LNPs and siRNA-NC2-LNPs. The two formulations, prepared under nuclease free conditions, showed comparable features with a mean particle size of about 50 nm, a polydispersity index of 0.127 and a near neutral surface charge at physiological pH of 7.4. Both the colloidal suspensions were stable up to 30 days during storage at 4 °C. Lipid concentration was determined by the measurement of cholesterol content using an enzymatic colorimetric method. To minimize the waste of expensive materials (i.e. RNA) and thus optimize the process in view of a manufacturing development, the encapsulation efficiency (EE%) was calculated taken into consideration the amount of RNA added in the preparative mixture (input RNA) rather than the total RNA amount measured after the processing steps, as traditionally reported [3]. RNA encapsulation efficiency (EE%) was calculated upon measurement by Quant-iT Ribogreen RNA assay of the whole LNPs (unencapsulated RNA) and the LNPs lysed with 0.1% Tryton (encapsulated RNA). EE% was calculated by taking the ratio of encapsulated RNA to the input RNA. The siRNA-NC1-LNP and siRNA-NC2-LNP formulations provided an EE% of about 90%. At selected time points (0-7-15-21-30 days) physical and chemical features of LNPs as well as a possible leakage of RNA from LNPs (unencapsulated RNA) were measured confirming a great stability of LNPs over time and siRNA retention. In conclusion, we demonstrated that for better guiding the design of future RNA therapeutics, an in-depth analysis of the synthesis parameters can provide a useful insight for process optimization to reduce RNA loss and the associated cost

Bone Marrow Environment in Metastatic Neuroblastoma

The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong attraction and possibility of survival; (iii) differently from adult cancers, NB metastases are available because the diagnostic procedures require morphological examination of BM; (iv) NB metastatic cells express surface antigens that allow enrichment of NB metastatic cells by immune–magnetic separation; and (v) patients with localized disease represent an internal control to discriminate specific alterations occurring in the metastatic niche from generic alterations determined by the neoplastic growth at the primary site. Here, we first review the information regarding the features of BM-infiltrating NB cells. Then, we focus on the alterations found in the BM of children with metastatic NB as compared to healthy children and children with localized NB. Specifically, information regarding all the BM cell populations and their sub-sets will be first examined in the context of BM microenvironment in metastatic NB. In the last part, the information regarding the soluble factors will be presented

Bone Marrow Environment in Metastatic Neuroblastoma

The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong attraction and possibility of survival; (iii) differently from adult cancers, NB metastases are available because the diagnostic procedures require morphological examination of BM; (iv) NB metastatic cells express surface antigens that allow enrichment of NB metastatic cells by immune–magnetic separation; and (v) patients with localized disease represent an internal control to discriminate specific alterations occurring in the metastatic niche from generic alterations determined by the neoplastic growth at the primary site. Here, we first review the information regarding the features of BM-infiltrating NB cells. Then, we focus on the alterations found in the BM of children with metastatic NB as compared to healthy children and children with localized NB. Specifically, information regarding all the BM cell populations and their sub-sets will be first examined in the context of BM microenvironment in metastatic NB. In the last part, the information regarding the soluble factors will be presented.</jats:p