The Immune Response to Tumors as a Tool toward Immunotherapy

Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes

Second-line cabozantinib versus nivolumab in advanced renal cell carcinoma: Systematic review and indirect treatment comparison

Background: Nivolumab and cabozantinib, two new treatment options for previously-treated advanced/metastatic renal cell carcinoma (aRCC), have recently been approved. Methods: Two independent reviewers performed study selection, data extraction, and risk of bias assessment. Indirect treatment comparisons were carried out by directly assessing HR differences and statistical modeling of Kaplan-Meier curves from these two trials. Results: Publications identified showed that no head-to-head comparisons had been carried out. Two indirect treatment comparisons used agreed that there was no significant difference in OS between cabozantinib and nivolumab and that cabozantinib significantly improved PFS compared to nivolumab. Conclusions: The field of aRCC treatments is evolving rapidly, creating opportunities for individualized treatments and challenges for clinicians to keep up with the evidence. In lieu of availability of direct comparisons of all options, advanced modeling results presented herein can help to inform and improve personalized treatments

Right ventricular dysfunction parallels left ventricular functional involvement in women with breast cancer experiencing subclinical cardiotoxicity

Abstract Funding Acknowledgements Type of funding sources: None. Background Cancer therapy related cardiac toxicity disease (CRCTD) of the left ventricle (LV)can influence the outcome of oncologic patients. Little is known on CRCTD related right ventricular (RV)dysfunction even though RV involvement has been proven to be a remarkable prognosticator in heart failure. Purpose To analyse parallel changes in LV and RV function occurring during the course of cancer therapy in women affected by breast cancer by using both standard and speckle tracking echocardiography. Methods Fifty Her-2 positive breast cancer women (age = 53.6 ± 11.7 years) underwent sequential cancer therapy protocol including anthracycline (ANT) epirubicine + cyclophosphamide (4 cycles) followed by a total amount of 18 cycles with trastuzumab (TRZ) + paclitaxel. A complete echo-Doppler exam, including LV and RV global longitudinal strain (GLS)as well as RV septal and free wall longitudinal strain (SLS and FWLS respectively) assessment, was performed at baseline, after ANT end and after TRZ completion. Patients with overt heart failure and LV ejection fraction < 50%, coronary artery disease,atrial fibrillation, hemodinamically significant valve disease and inadequate echo were excluded. Overt CRCTD was defined according guidelines and both subclinical LV and RV CRCTD as a LV and RV GLS drop from baseline >15%. Results None of the patients experienced overt CTCRD but 6 patients (14%) showed subclinical LV dysfunction and 33 (66%) had a significant drop of RV longitudinal function.The comparison of standard echo-Doppler exam at baseline and after ANT and TRZ completion did not show significant changes of LV and RV systolic and diastolic parameters. Conversely, a progressive significant reduction of RV GLS (p < 0.002 after TRZ), SLS and FWLS and, with a lower extent, of LV GLS (p < 0.02 after TRZ) was observed after ANT and TRZ completion (Figure). Percentage reduction in RV GLS (DRV GLS) from baseline to ANT end correlated with LV GLS both at EC end (r=-0.40, p = 0.006) and after TRZ completion (r=-0.62, p < 0.0001). Conclusions Detrimental cardiac effects of cancer therapy involve both LV and RV systolic longitudinal function. Progressive RV dysfunction is evident through ANT and TRZ treatment. Early RV dysfunction parallels LV involvement and predicts subsequent LV subclinical dysfunction. A comprehensive LV and RV longitudinal function assessment might better predict the onset of CRCTD in breast cancer patients. Abstract Figure

Integrating traditional field methods with emerging digital techniques for enhanced outcrop analysis of deep water channel-fill deposits

The development of emerging digital technologies that allow the collection and analysis of field data represents a significant innovation in field-based geological studies. The integration of these digital techniques with traditional sedimentological field methods facilitates considerable improvements in outcrop characterization. An example of this integrated modern approach for geological data collection is employed for the detailed characterization of a turbidite channel-lobe system of the Gorgoglione Flysch Formation in Southern Italy. The study area, exposed above the village of Castelmezzano, has been measured and described in detailed stratigraphic sections, providing data for both sedimentological analysis and correlation of the stratigraphy. In order to gain a complete perspective on the exposure and stratigraphic elements, analysis of physical outcrop data was enhanced by the use of high-resolution Gigapixel imagery and 3D photogrammetric outcrop reconstructions. The Santa Maria section has been assessed in terms of vertical and lateral facies stacking arrangements and subdivided into two component facies associations separated by a prominent concave-up erosional boundary. The lower facies association, interpreted as a frontal lobe complex, consists of tabular, thick-bedded coarse sandstones interbedded with persistent heterolithic packages of thin-bedded sandstones and mudstones, and minor soft-sediment deformed strata. The upper facies association represents the infill of a channel-form and consists of a basal conglomerate, passing gradually upwards into massive amalgamated sandstones overlain by large-scale cross-laminated sandstones. The excellent exposure of the Santa Maria section records the complete evolution of a channel-lobe system, transitioning from frontal lobe deposition through channel incision and bypass, to progressive backfilling. This study shows how facies characterization, stratigraphic correlations and reconstruction of the depositional architectures have been substantially enhanced by the use of emerging digital techniques for geological data collection

Inhibition of the Nicotinic Acetylcholine Receptors by Cobra Venom α-Neurotoxins: Is There a Perspective in Lung Cancer Treatment?

Nicotine exerts its oncogenic effects through the binding to nicotinic acetylcholine receptors (nAChRs) and the activation of downstream pathways that block apoptosis and promote neo-angiogenesis. The nAChRs of the α7 subtype are present on a wide variety of cancer cells and their inhibition by cobra venom neurotoxins has been proposed in several articles and reviews as a potential innovative lung cancer therapy. However, since part of the published results was recently retracted, we believe that the antitumoral activity of cobra venom neurotoxins needs to be independently re-evaluated

Moving Towards Accountability for Reasonableness – A Systematic Exploration of the Features of Legitimate Healthcare Coverage Decision-Making Processes Using Rare Diseases and Regenerative Therapies as a Case Study

Background: The accountability for reasonableness (A4R) framework defines 4 conditions for legitimate healthcare coverage decision processes: Relevance, Publicity, Appeals, and Enforcement. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide decision-making towards legitimacy. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer therefore a useful case study. Methods: Features operationalizing each A4R condition as well as three different approaches to address these features (cost-per-QALY-focused and multicriteria-based) were defined and organized into a matrix. Seven experts explored these features during a panel run under the Chatham House Rule and provided general and RDRT-specific recommendations. Responses were analyzed to identify converging and diverging recommendations. Results: Regarding Relevance, recommendations included supporting deliberation, stakeholder participation and grounding coverage decision criteria in normative and societal objectives. Thirteen of 17 proposed decision criteria were recommended by a majority of panelists. The usefulness of universal cost-effectiveness thresholds to inform allocative efficiency was challenged, particularly in the RDRT context. RDRTs raise specific issues that need to be considered; however, rarity should be viewed in relation to other aspects, such as disease severity and budget impact. Regarding Publicity, panelists recommended transparency about the values underlying a decision and value judgements used in selecting evidence. For Appeals, recommendations included a life-cycle approach with clear provisions for re-evaluations. For Enforcement, external quality reviews of decisions were recommended. Conclusion: Moving coverage decision-making processes towards enhanced legitimacy in general and in the RDRT context involves designing and refining approaches to support participation and deliberation, enhancing transparency, and allowing explicit consideration of multiple decision criteria that reflect normative and societal objectives

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

Background: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. Methods: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. Results: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. Conclusion: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype

Involvement of cell surface TG2 in the aggregation of K562 cells triggered by gluten

Gluten-induced aggregation of K562 cells represents an in vitro model reproducing the early steps occurring in the small bowel of celiac patients exposed to gliadin. Despite the clear involvement of TG2 in the activation of the antigen-presenting cells, it is not yet clear in which compartment it occurs. Herein we study the calcium-dependent aggregation of these cells, using either cell-permeable or cell-impermeable TG2 inhibitors. Gluten induces efficient aggregation when calcium is absent in the extracellular environment, while TG2 inhibitors do not restore the full aggregating potential of gluten in the presence of calcium. These findings suggest that TG2 activity is not essential in the cellular aggregation mechanism. We demonstrate that gluten contacts the cells and provokes their aggregation through a mechanism involving the A-gliadin peptide 31-43. This peptide also activates the cell surface associated extracellular TG2 in the absence of calcium. Using a bioinformatics approach, we identify the possible docking sites of this peptide on the open and closed TG2 structures. Peptide docks with the closed TG2 structure near to the GTP/GDP site, by establishing molecular interactions with the same amino acids involved in stabilization of GTP binding. We suggest that it may occur through the displacement of GTP, switching the TG2 structure from the closed to the active open conformation. Furthermore, docking analysis shows peptide binding with the β-sandwich domain of the closed TG2 structure, suggesting that this region could be responsible for the different aggregating effects of gluten shown in the presence or absence of calcium. We deduce from these data a possible mechanism of action by which gluten makes contact with the cell surface, which could have possible implications in the celiac disease onset