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Glioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF β1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.

Background\ud \ud Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events.\ud \ud \ud \ud Aims\ud \ud We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI).\ud \ud \ud \ud Methods\ud \ud This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm.\ud \ud \ud \ud Results\ud \ud Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12–1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92–1.19; pinteraction = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27–1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83–1.28; pinteraction = 0.008).\ud \ud \ud \ud Conclusions\ud \ud In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies.\ud \ud \ud \ud Clinical Trial Registration\ud \ud URL: https://clinicaltrials.gov

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine–kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.

Stability studies performed by the pharmaceutical industry are principally designed to fulfill licensing requirements. Thus, post-dilution or post-reconstitution stability data are frequently limited to 24 h only for bacteriological reasons, regardless of the true physicochemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require preparation in advance for administration, for example, on weekends, holidays, or in general when pharmacies may be closed. We report an innovative strategy for storing resuspended solutions of azacitidine, a well-known chemotherapic agent, for which the manufacturer lists maximum stability of 22 h. By placing the syringe with the azacitidine reconstituted suspension between two refrigerant gel packs and storing it at 4 °C, we found that the concentration of azacitidine remained above 98% of the initial concentration for 48 h, and no change in color nor the physicochemical properties of the suspension were observed throughout the study period. The physicochemical and microbiological properties were evaluated by HPLC–UV and UHPLC-HRMS analysis, FTIR spectroscopy, pH determination, visual and subvisual examination, and sterility assay. The HPLC-UV method used for evaluating the chemical stability of azacitidine was validated according to ICH. Precise control of storage temperature was obtained by a digital data logger. Our study indicates that by changing the storage procedure of azacitidine reconstituted suspension, the usage window of the drug can be significantly extended to a time frame that better copes with its use in the clinical environment.

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung's architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.

The original version of this Article contained an error in Affiliation 5, which was incorrectly given as ‘Department of Surgery, Oncology and Gastroenterology, University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy’. The correct affiliation is listed below: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy In addition, the original version of this Article omitted an affiliation for Pierfranco Conte. The correct affiliations for Pierfranco Conte are listed below: Medical Oncology 2, Veneto Institute of Oncology IOV, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy These errors have now been corrected in the HTML and PDF versions of this Article, and in the accompanying Supplementary Information.

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy., Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.

Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.