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

Ethylenediamine functionalized-single-walled nanotube (f-SWNT)-assisted in vitro delivery of the oncogene suppressor p53 gene to breast cancer MCF-7 cells

A gene delivery concept based on ethylenediamine-functionalized single-walled carbon nanotubes (f-SWCNTs) using the oncogene suppressor p53 gene as a model gene was successfully tested in vitro in MCF-7 breast cancer cells. The f-SWCNTs-p53 complexes were introduced into the cell medium at a concentration of 20 μg mL−1 and cells were exposed for 24, 48, and 72 hours. Standard ethidium bromide and acridine orange assays were used to detect apoptotic cells and indicated that a significantly larger percentage of the cells (approx 40%) were dead after 72 hours of exposure to f-SWCNTs-p53 as compared to the control cells, which were exposed to only p53 or f-SWCNTs, respectively. To further support the uptake and expression of the genes within the cells, green fluorescent protein-tagged p53, attached to the f-SWCNTs was added to the medium and the complex was observed to be strongly expressed in the cells. Moreover, caspase 3 activity was found to be highly enhanced in cells incubated with the f-SWCNTs-p53 complex, indicating strongly induced apoptosis. This system could be the foundation for novel gene delivery platforms based on the unique structural and morphological properties of multi-functional nanomaterials

Atrophin proteins: an overview of a new class of nuclear receptor corepressors

The normal development and physiological functions of multicellular organisms are regulated by complex gene transcriptional networks that include myriad transcription factors, their associating coregulators, and multiple chromatin-modifying factors. Aberrant gene transcriptional regulation resulting from mutations among these elements often leads to developmental defects and diseases. This review article concentrates on the Atrophin family proteins, including vertebrate Atrophin-1 (ATN1), vertebrate arginine-glutamic acid dipeptide repeats protein (RERE), and Drosophila Atrophin (Atro), which we recently identified as nuclear receptor corepressors. Disruption of Atrophin-mediated pathways causes multiple developmental defects in mouse, zebrafish, and Drosophila, while an aberrant form of ATN1 and altered expression levels of RERE are associated with neurodegenerative disease and cancer in humans, respectively. We here provide an overview of current knowledge about these Atrophin proteins. We hope that this information on Atrophin proteins may help stimulate fresh ideas about how this newly identified class of nuclear receptor corepressors aids specific nuclear receptors and other transcriptional factors in regulating gene transcription, manifesting physiological effects, and causing diseases

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

Prognostic value of increase in transcript levels of Tp73 ΔEx2-3 isoforms in low-grade glioma patients

Glial tumours are a devastating, poorly understood condition carrying a gloomy prognosis for which clinicians sorely lack reliable predictive parameters facilitating a sound treatment strategy. Tp73, a p53 family member, expresses two main classes of isoforms – transactivatory activity (TA)p73 and ΔTAp73 – exhibiting tumour suppressor gene and oncogene properties, respectively. The authors examined their expression status in high- and low-grade adult gliomas. Isoform-specific real-time reverse transcription-polymerase chain reaction was used for the analysis of Tp73 isoform transcript expression in a series of 51 adult patients harbouring glial tumours, in order to compare tumour grades with each other, and with non-tumoural samples obtained from epileptic patients as well. Our data demonstrate increase of TAp73 and ΔTAp73 transcript levels at onset and early stage of the disease. We also show that ΔEx2–3 isoform expression in low-grade tumours anticipates clinical and imaging progression to higher grades, and correlates to the patients' survival. Expression levels of P1 promoter generated Tp73 isoforms – and particularly ΔEx2–3 – indeed allow for prediction of the clinical progression of low-grade gliomas in adults. Our data are the first such molecular biology report regarding low-grade tumours and as such should be of help for sound decision-making

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