Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives

Osteosarcoma (OS) is an aggressive osteoid-producing tumor of mesenchymal origin, which represents the most common primary bone malignancy. It is characterized by a complex and frequently uncertain etiology. The current standard care for high-grade OS treatment is neoadjuvant chemotherapy, followed by surgery and post-operative chemotherapy. In order to ameliorate survival rates of patients, new therapeutic approaches have been evaluated, mainly immunotherapy with antibody-drug conjugates or immunoconjugates. These molecules consist of a carrier (frequently an antibody) joined by a linker to a toxic moiety (drug, radionuclide, or toxin). Although several clinical trials with immunoconjugates have been conducted, mainly in hematological tumors, their potential as therapeutic agents is relatively under-explored in many types of cancer. In this review, we report the immunoconjugates directed against OS surface antigens, considering the in vitro and in vivo studies. To date, several attempts have been made in preclinical settings, reporting encouraging results and demonstrating the validity of the idea. The clinical experience with glembatumumab vedotin may provide new insights into the real efficacy of antibody-drug conjugates for OS therapy, possibly giving more information about patient selection. Moreover, new opportunities could arise from the ongoing clinical trials in OS patients with unconjugated antibodies that could represent future candidates as carrier moieties of immunoconjugates

Apoptosis and necroptosis induced by stenodactylin in neuroblastoma cells can be completely prevented through caspase inhibition plus catalase or necrostatin-1

Abstract Background Stenodactylin is a highly toxic plant lectin purified from the caudex of Adenia stenodactyla , with molecular structure, intracellular routing and enzyme activity similar to those of ricin, a well-known type 2 ribosome-inactivating protein. However, in contrast with ricin, stenodactylin is retrogradely transported not only in peripheral nerves but also in the central nervous system. Purpose Stenodactylin properties make it a potential candidate for application in neurobiology and in experimental therapies against cancer. Thus, it is necessary to better clarify the toxic activity of this compound. Study design We investigated the mechanism of stenodactylin-induced cell death in the neuroblastoma-derived cell line, NB100, evaluating the implications of different death pathways and the involvement of oxidative stress. Methods Stenodactylin cytotoxicity was determined by evaluating protein synthesis and other viability parameters. Cell death pathways and oxidative stress were analysed through flow cytometry and microscopy. Inhibitors of apoptosis, oxidative stress and necroptosis were tested to evaluate their protective effect against stenodactylin cytotoxicity. Results Stenodactylin efficiently blocked protein synthesis and reduced the viability of neuroblastoma cells at an extremely low concentration and over a short time (1 pM, 24 h). Stenodactylin induced the strong and rapid activation of apoptosis and the production of free radicals. Here, for the first time, a complete and long lasting protection from the lethal effect induced by a toxic type 2 ribosome-inactivating protein has been obtained by combining the caspase inhibitor Z-VAD-fmk, to either the hydrogen peroxide scavenger catalase or the necroptotic inhibitor necrostatin-1. Conclusion In respect to stenodactylin cytotoxicity, our results: (i) confirm the high toxicity to nervous cells, (ii) indicate that multiple cell death pathways can be induced, (iii) show that apoptosis is the main death pathway, (iv) demonstrate the involvement of necroptosis and (v) oxidative stress

Catching and monitoring clinical innovation through performance indicators. The case of the breast-conserving surgery indicator.

Background: The evolution in the surgical and diagnostic procedures, the attention to women’s preferences, the case mix, and di erences in professional practices may lead to a variability in the quality of breast cancer clinical pathway. To catch and manage this variability it is important to use valid measures. The aim of this paper is to examine the concurrent validity of the breast-conserving surgery (BCS) indicator and to provide evidence to guide the quality improvement process. Methods: The BCS indicator was calculated using hospital discharge records (HDRs) and was validated against surgi- cal registry (SR) data in a random sample of 336 women undergoing breast cancer surgery in 2012 in two Tuscan teaching hospitals. The concurrent validity of BCS was examined by cross-tabulating patients using the ICD-9 CM codes for breast surgery obtained from the two data sources. Results: The analysis, carried out involving breast cancer professionals, highlighted that the large majority of inter- ventions coded as “mastectomies” in HDRs are in fact reconstructing procedures, including nipple-sparing, skin- sparing and skin-reducing mastectomies in SR. These results led us to re ne the old algorithm, that calculates the proportion of breast-conserving surgery over the total number of breast interventions, and reclassify breast cancer surgical procedures into three categories: conservative, reconstructive and traditional mastectomy. Based on this new classi cation algorithm, the percentages of (I) reconstructive interventions were 16% at Florence TH and 38.3% at Pisa TH; (II) breast-conserving interventions were respectively 72.8 and 52.1%; and (III) mastectomies 11.2 and 9.6%. After adjusting for age in a logistic regression model, the percentages of reconstructive interventions at Florence and Pisa were respectively 22 and 34% and those of breast-conserving interventions 63 and 53%. Conclusions: Our results indicate that breast cancer care indicators should be re ned by distinguishing reconstruc- tive procedures (nipple/skin-sparing surgery with implant or breast tissue expander insertion) from traditional mas- tectomy. The involvement of breast care professionals in the choice of indicators proved to be crucial to capture the up-to-date breast cancer surgical practice and inform the quality improvement process. Keywords: Performance indicators, Breast cancer, Breast conserving surgery, Healthcare quality, Professional involvemen

GIANO and HARPS-N together: towards an Earth-mass detection instrument

This article describes the works we are doing for modifying the interface between the high resolution infrared spectrograph GIANO (0.97-2.4 micron) and the TNG telescope, passing from a fiber feed configuration to the original design of a direct light-feeding from the telescope to the spectrograph. So doing the IR spectrograph, GIANO, will work in parallel to HARPS-N spectrometer (0.38-0.70 micron), the visible high resolution spectrograph, thanks to a new telescope interface based on a dichroic window that simultaneously feeds the two instrumentes: this is GIARPS (GIAno and haRPS). The scientific aims of this project are to improve the radial velocity accuracy achievable with GIANO, down to a goal of 1 m/s, the value necessary to detect Earth-mass planets on habitable orbits around late-M stars, to implement simultaneous observations with Harps-N and GIANO optimizing the study of planets around cool stars. The very broad wavelengths range is particularly important to discriminate false radial velocity signals caused by stellar activity. We therefore include several absorption cells with different mixtures of gases and a stabilized Fabry Perot cavity, necessary to have absorption lines over the 0.97-2.4 microns range covered by GIANO. The commissioning of GIARPS is scheduled by the end of 2016

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K+ flux through the human ether-\ue0-gogo- related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the \u3b21 integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the \u3b21 integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with \u3b21 integrins as did closed channels, current flow through hERG1 channelswas necessary to activate the integrin-dependent phosphorylation of Tyr397 in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K+ flow, whereas metastasis of breast cancer cells was reduced when the hERG1/\u3b21 integrin interaction was disrupted. We conclude that the interaction of \u3b21 integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression

mAbs targeting CD20 and other lymphocyte CD markers in lymphoma treatment.

Lymphomas represent the seventh most common cancer in developed countries. The vascular nature of the majority of lymphomas represents a favorable situation for immunotherapy. Monoclonal antibodies against main lymphoma markers have been developed over the last three decades and some of them are commonly used in clinics. This chapter focuses on the main monoclonal antibodies directed against CD20 and other lymphoma markers and the results of the main clinical trials are summarized

Saporin-S6: A Useful Tool in Cancer Therapy

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