Reconstruction of the heart and the aorta for radical resection of lung cancer.

INTRODUCTION: We report a single-center experience of resection and reconstruction of the heart and aorta infiltrated by lung cancer in order to prove that involvement of these structures is no longer a condition precluding surgery. METHODS: Twenty-seven patients underwent surgery for lung cancer presenting full-thickness infiltration of the heart (n = 6) or the aorta (n = 18) and/or the supra-aortic branches (subclavian n = 3). Cardiac reconstruction was performed in 6 patients (5 atrium, 1 ventricle), with (n = 4) or without (n = 2) cardiopulmonary bypass, using a patch prosthesis (n = 4) or with deep clamping and direct suture (n = 2). Aortic or supra-aortic trunk reconstruction (n = 21) was performed using a heart-beating crossclamping technique in 14 cases (8 patch, 4 conduit, 2 direct suture), or without crossclamping by placing an endovascular prosthesis before resection in 7 (4 patch, 3 omental flap reconstruction). Neoadjuvant chemotherapy was administered in 13 patients, adjuvant therapy in 24. RESULTS: All resections were complete (R0). Nodal staging of lung cancer was N0 in 14 cases, N1 in 10, N2 in 3. No intraoperative mortality occurred. Major complication rate was 14.8%. Thirty-day and 90-day mortality rate was 3.7%. Median follow-up duration was 22 months. Recurrence rate is 35.4% (9/26: 3 loco-regional, 6 distant). Overall 3- and 5-year survival is 60.9% and 40.6%, respectively. CONCLUSIONS: Cardiac and aortic resection and reconstruction for full-thickness infiltration by lung cancer can be performed safely with or without cardiopulmonary bypass and may allow long-term survival of adequately selected patients.

Learning models for classifying Raman spectra of genomic DNA from tumor subtypes.

An early and accurate detection of different subtypes of tumors is crucial for an effective guidance to personalized therapy and in predicting the ability of tumor to metastasize. Here we exploit the Surface Enhanced Raman Scattering (SERS) platform, based on disordered silver coated silicon nanowires (Ag/SiNWs), to efficiently discriminate genomic DNA of different subtypes of melanoma and colon tumors. The diagnostic information is obtained by performing label free Raman maps of the dried drops of DNA solutions onto the Ag/NWs mat and leveraging the classification ability of learning models to reveal the specific and distinct physico-chemical interaction of tumor DNA molecules with the Ag/NW, here supposed to be partly caused by a different DNA methylation degree.

Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone.

AIMS: Epithelioid haemangioma (EH) of bone remains a highly controversial entity. Indeed, the WHO classifies EHs of soft tissues as benign tumours, whereas bone EHs are considered intermediate-locally aggressive tumours due to common multifocal presentation and local destructive growth. To gain insights into the clinical behaviour and biology of EH of bone we retrospectively analysed 42 patients treated in a single institution from 1978 to 2021. METHODS AND RESULTS: Multifocal presentation was detected in 17 of 42 patients (40%) primarily as synchronous lesions. Patients were treated with curettage (57%), resection (29%) or biopsy, followed by radiotherapy or embolisation (14%). Follow-up (minimum 24 months) was available for 38 patients, with only five local recurrences (13%) and no death of disease. To clarify whether the synchronous bone lesions in multifocal EH represent multicentric disease or clonal dissemination, four cases were profiled by RNA-sequencing. Separate lesions from the same patient, which showed a similar transcriptional profile, expressed the same fusion transcript (involving FOS or FOSB) with identical gene breakpoints. CONCLUSIONS: These results indicate that, in EH of bone, multifocal lesions are clonally related and therefore represent the spread of a same neoplastic clone rather than simultaneous independent tumours. This finding is in apparent contradiction with the benign clinical course of the disease, and suggests that tumour dissemination in bone EH probably reflects a phenomenon of passive spreading, with tumour cells colonising distal sites while maintaining their benign biological nature.

Statistical Classification for Raman Spectra of Tumoral Genomic DNA.

We exploit Surface-Enhanced Raman Scattering (SERS) to investigate aqueous droplets of genomic DNA deposited onto silver-coated silicon nanowires, and we show that it is possible to efficiently discriminate between spectra of tumoral and healthy cells. To assess the robustness of the proposed technique, we develop two different statistical approaches, one based on the Principal Components Analysis of spectral data and one based on the computation of the ℓ2 distance between spectra. Both methods prove to be highly efficient, and we test their accuracy via the Cohen's κ statistics. We show that the synergistic combination of the SERS spectroscopy and the statistical analysis methods leads to efficient and fast cancer diagnostic applications allowing rapid and unexpansive discrimination between healthy and tumoral genomic DNA alternative to the more complex and expensive DNA sequencing.

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness.

Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.

Conformational consequences of NPM1 rare mutations: An aggregation perspective in Acute Myeloid Leukemia.

Often proteins association is a physiological process used by cells to regulate their growth and to adapt to different stress conditions, including mutations. In the case of a subtype of Acute Myeloid Leukemia (AML), mutations of nucleophosmin 1 (NPM1) protein cause its aberrant cytoplasmatic mislocalization (NPMc+). We recently pointed out an amyloidogenic propensity of protein regions including the most common mutations of NPMc+ located in the C-terminal domain (CTD): they were able to form, in vitro, amyloid cytotoxic aggregates with fibrillar morphology. Herein, we analyzed the conformational characteristics of several peptides including rare AML mutations of NPMc+. By means of different spectroscopic, microscopic and cellular assays we evaluated the importance of amino acid composition, among rare AML mutations, to determine amyloidogenic propensity. This study could add a piece of knowledge to the structural consequences of mutations in cytoplasmatic NPM1c+.

Proteomimetics of Natural Regulators of JAK-STAT Pathway: Novel Therapeutic Perspectives.

The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein-protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK-STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

Perspectives in Peptide-Based Vaccination Strategies for Syndrome Coronavirus 2 Pandemic.

At the end of December 2019, an epidemic form of respiratory tract infection now named COVID-19 emerged in Wuhan, China. It is caused by a newly identified viral pathogen, the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which can cause severe pneumonia and acute respiratory distress syndrome. On January 30, 2020, due to the rapid spread of infection, COVID-19 was declared as a global health emergency by the World Health Organization. Coronaviruses are enveloped RNA viruses belonging to the family of Coronaviridae, which are able to infect birds, humans and other mammals. The majority of human coronavirus infections are mild although already in 2003 and in 2012, the epidemics of SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERS-CoV), respectively, were characterized by a high mortality rate. In this regard, many efforts have been made to develop therapeutic strategies against human CoV infections but, unfortunately, drug candidates have shown efficacy only into in vitro studies, limiting their use against COVID-19 infection. Actually, no treatment has been approved in humans against SARS-CoV-2, and therefore there is an urgent need of a suitable vaccine to tackle this health issue. However, the puzzled scenario of biological features of the virus and its interaction with human immune response, represent a challenge for vaccine development. As expected, in hundreds of research laboratories there is a running out of breath to explore different strategies to obtain a safe and quickly spreadable vaccine; and among others, the peptide-based approach represents a turning point as peptides have demonstrated unique features of selectivity and specificity toward specific targets. Peptide-based vaccines imply the identification of different epitopes both on human cells and virus capsid and the design of peptide/peptidomimetics able to counteract the primary host-pathogen interaction, in order to induce a specific host immune response. SARS-CoV-2 immunogenic regions are mainly distributed, as well as for other coronaviruses, across structural areas such as spike, envelope, membrane or nucleocapsid proteins. Herein, we aim to highlight the molecular basis of the infection and recent peptide-based vaccines strategies to fight the COVID-19 pandemic including their delivery systems.

Metal-Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis.

In metal-peptide interactions, cations form stable complexes through bonds with coordinating groups as side chains of amino acids. These compounds, among other things, exert a wide variety of antimicrobial activities through structural changes of peptides upon metal binding and redox chemistry. They exhibit different mechanisms of action (MOA), including the modification of DNA/RNA, protein and cell wall synthesis, permeabilization and modulation of gradients of cellular membranes. Nowadays, the large increase in antibiotic resistance represents a crucial problem to limit progression at the pandemic level of the diseases that seemed nearly eradicated, such as tuberculosis (Tb). Mycobacterium tuberculosis (Mtb) is intrinsically resistant to many antibiotics due to chromosomal mutations which can lead to the onset of novel strains. Consequently, the maximum pharmaceutical effort should be focused on the development of new therapeutic agents and antimicrobial peptides can represent a valuable option as a copious source of potential bioactive compounds. The introduction of a metal center can improve chemical diversity and hence specificity and bioavailability while, in turn, the coordination to peptides of metal complexes can protect them and enhance their poor water solubility and air stability: the optimization of these parameters is strictly required for drug prioritization and to obtain potent inhibitors of Mtb infections with novel MOAs. Here, we present a panoramic review of the most recent findings in the field of metal complex-peptide conjugates and their delivery systems with the potential pharmaceutical application as novel antibiotics in Mtb infections.

Interactions of cisplatin analogues with lysozyme: a comparative analysis.

The biophysical characterization of drug binding to proteins plays a key role in structural biology and in the discovery and optimization of drug discovery processes. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding of metal-based drugs to their final target is challenging, due to the physicochemical properties of these agents. Different cisplatin derivatives have shown different citotoxicities in most common cancer lines, suggesting that they exert their biological activity via different mechanisms of action. Here we carried out a comparative analysis, by studying the behaviours of three Pt-compounds under the same experimental conditions and binding assays to properly deepen the determinants of the different MAOs. Indeed we compared the results obtained using surface plasmon resonance, isothermal titration calorimetry, fluorescence spectroscopy and thermal shift assays based on circular dichroism experiments in the characterization of the formation of adducts obtained upon reaction of cisplatin, carboplatin and iodinated analogue of cisplatin, cis-Pt (NH3)2I2, with the model protein hen egg white lysozyme, both at neutral and acid pHs. Further we reasoned on the applicability of employed techniques for the study the thermodynamics and kinetics of the reaction of a metallodrug with a protein and to reveal which information can be obtained using a combination of these analyses. Data were discussed on the light of the existing structural data collected on the platinated protein.