Second-line treatment in renal cell carcinoma: clinical experience and decision making

Currently, conventional treatments for metastatic RCC (mRCC) include immune-based combination regimens and/or targeted therapies, the latter mainly acting on angiogenesis, a key element of the process of tumor growth and spread. Although these agents proved able to improve patients’ outcomes, drug resistance and disease progression are still experienced by a substantial number of VEGFR-TKIs-treated mRCC patients. Following the inhibition of the VEGF/VEGFRs axis, two strategies have emerged: either specifically targeting resistance pathways, at the same time continuing to inhibit angiogenesis, or using a completely different approach aimed at re-activating the immune system through the use of inhibitors of specific negative immune checkpoints. These two approaches, practically represented by the use of either cabozantinib or nivolumab, seem to remain a rational therapeutic approach also when first-line immune-based combinations are used. The objective of this study is to design a preferential therapeutic pathway for the second-line treatment of mRCC. The procedure applied in this project was a group discussion, based on the Nominal Group Technique (NGT) method in a meeting session, aimed at defining the therapeutic choice for the second-line treatment of mRCC. The NGT process defined the most relevant parameters that, according to the interviewed panelists, clinicians should consider for the selection of the second-line therapy in the context of advanced renal cell carcinoma of mRCC. The algorithm developed for the treatment selection as a result of this process should thus be considered by clinicians as reference for therapy selection. Plain language summary: The result of this paper was the definition of an algorithm intended to suggest a preferential therapeutic pathway considering both the outputs of the Nominal Group Technique (NGT) process and the actual clinical practice and the experience of selected panelists. During the NGT process and the discussion phase, panelists defined the most important parameters to be included in the algorithm that are important for the treatment definition. Cabozantinib and nivolumab are identified as the most reasonable therapeutic options for patients progressing after first-line treatment and are the medication options included in the algorithm for therapy selection

The role of iron and copper on the oligomerization dynamics of DR_2577, the main S-layer protein of deinococcus radiodurans

Surface (S)-layers are cryptic structures that coat the external surface of the bacterial cell in many species. The paracrystalline regularity of the S-layer is due to the self-assembling of one or more protein units. The property of self-assembling seems to be mediated by specific topologies of the S-layer proteins as well as the presence of specific ions that provide support in building and stabilizing the bi-dimensional S-layer organization. In the present study, we have investigated the self-assembling mechanism of the main S-layer protein of Deinococcus radiodurans (DR_2577) finding an unusual role played by Fe3+ and Cu2+ in the oligomerization of this protein. These findings may trace a structural and functional metallo-mediated convergence between the role of these metals in the assembling of the S-layer and their well-known roles in protecting against oxidative stress in D. radiodurans

Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study

Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R26 as a salivary candidate biomarker of systemic mastocytosis (SM). Its C26 variant is able to form multiprotein complexes (mPCs) and since protein–protein interactions (PPIs) are crucial for studying disease pathogenesis, potential markers, and therapeutic targets, we aimed to define the protein composition of the salivary cystatin D-C26 interactome associated with SM. An exploratory affinity purification-mass spectrometry method was applied on pooled salivary samples from SM patients, SM patient subgroups with and without cutaneous symptoms (SM+C and SM−C), and healthy controls (Ctrls). Interactors specifically detected in Ctrls were found to be implicated in networks associated with cell and tissue homeostasis, innate system, endopeptidase regulation, and antimicrobial protection. Interactors distinctive of SM−C patients participate to PPI networks related to glucose metabolism, protein S-nitrosylation, antibacterial humoral response, and neutrophil degranulation, while interactors specific to SM+C were mainly associated with epithelial and keratinocyte differentiation, cytoskeleton rearrangement, and immune response pathways. Proteins sensitive to redox changes, as well as proteins with immunomodulatory properties and activating mast cells, were identified in patients; many of them were involved directly in cytoskeleton rearrangement, a process crucial for mast cell activation. Although preliminary, these results demonstrate that PPI alterations of the cystatin D-C26 interactome are associated with SM and provide a basis for future investigations based on quantitative proteomic analysis and immune validation

A regional audit system for stillbirth: A way to better understand the phenomenon

Background: Implementation of high-quality national audits for perinatal mortality are needed to improve the registration of all perinatal deaths and the identification of the causes of death. This study aims to evaluate the implementation of a Regional Audit System for Stillbirth in Emilia-Romagna Region, Italy. Methods: For each stillbirth ( 65 22 weeks of gestation, 65 500 g) occurred between January 1, 2014 to December 1, 2016 (n = 332), the same diagnostic workup was performed and a clinical record with data about mother and stillborn was completed. Every case was discussed in a multidisciplinary local audit to assess both the cause of death (ReCoDe classification) and the quality of care. Data were reviewed by the Regional Audit Group. Stillbirth rates, causes of death and the quality of care were established for each case. Results: Total stillbirth rate was 3.09 per 1000 births (332/107,528). Late stillbirth rate was 2.3 per 1000 (251/107,087). Sixteen stillbirths were not registered by the Regional Birth Register. The most prevalent cause of death was placental disorder (33.3%), followed by fetal (17.6%), cord (14.2%) and maternal disorders (7.6%). Unexplained cases were 14%. Compared to local audits, the regional group attributed different causes of death in 17% of cases. At multivariate analysis, infections were associated with early stillbirths (OR 3.38, CI95% 1.62-7.03) and intrapartum cases (OR 6.64, CI95% 2.61-17.02). Placental disorders were related to growth restriction (OR 1.89, CI95% 1.06-3.36) and were more frequent before term (OR 1.86, CI95% 1.11-3.15). Stillbirths judged possibly/probably preventable with a different management (10.9%) occurred more frequently in non-Italian women and were mainly related to maternal disorders (OR 6.64, CI95% 2.61-17.02). Conclusions: Regional Audit System for Stillbirth improves the registration of stillbirth and allows to define the causes of death. Moreover, sub-optimal care was recognized, allowing to identify populations which could benefit from preventive measures