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The aim of the present study was to assess the cytotoxicity of manumycin, a specific inhibitor of farnesyl:protein transferase, as well as its effects on protein isoprenylation and kinase-dependent signal transduction in COLO320-DM human colon adenocarcinoma which harbours a wild-type K-ras gene. Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21 ras farnesylation with a 50% inhibitory concentration (IC50) of 2.51 +/- 0.11 microM and 2.68 +/- 0.20 microM, respectively, while the geranylgeranylation of p21 rhoA and p21rap1 was not affected. Manumycin dose-dependently inhibited (IC50 = 2.40 +/- 0.67 microM) the phosphorylation of the mitogen-activated protein kinase/extracellular-regulated kinase 2 (p42MAPK/ERK2), the main cytoplasmic effector of p21ras, as well as COLO320-DM cell growth (IC50 = 3.58 +/- 0.27 microM) without affecting the biosynthesis of cholesterol. Mevalonic acid (MVA, 100 microM), a substrate of the isoprenoid synthesis, was unable to protect COLO320-DM cells from manumycin cytotoxicity. Finally, manumycin 1-25 microM for 24-72 h induced oligonucleosomal fragmentation in a dose- and time-dependent manner and MVA did not protect COLO320-DM cells from undergoing DNA cleavage. The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity. [ABSTRACT FROM AUTHOR]

Thymic epithelial cells participate in the maturation and selection of T lymphocytes. This review explores recent insights from single-cell sequencing regarding classifying thymic epithelial cells in both normal and neoplastic thymus. Cortical thymic epithelial cells facilitate thymocyte differentiation and contribute to positive selection. Medullary epithelial cells are distinguished by their expression of AIRE. Cells progress from a pre-AIRE state, containing precursors with cortical and medullary characteristics, termed junctional cells. Mature medullary epithelial cells exhibit promiscuous gene expression and after that downregulate AIRE mRNA. Post-AIRE cells can adopt a Hassall corpuscle-like phenotype or exhibit distinctive differentiation characteristics including tuft cells, ionocytes, neuroendocrine cells, and myoid cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The stem cell niche in the bone marrow is a hypoxic environment, where the low oxygen tension preserves the pluripotency of stem cells. We have identified mesangiogenic progenitor cells (MPC) exhibiting angiogenic and mesenchymal differentiation capabilities in vitro. The effect of hypoxia on MPC has not been previously explored. In this study, MPCs were isolated from volunteers' bone marrow and cultured under both normoxic and hypoxic conditions (3% O2). MPCs maintained their characteristic morphology and surface marker expression (CD18 + CD31 + CD90-CD73-) under hypoxia. However, hypoxic conditions led to reduced MPC proliferation in primary cultures and hindered their differentiation into mesenchymal stem cells (MSCs) upon exposure to differentiative medium. First passage MSCs derived from MPC appeared unaffected by hypoxia, exhibiting no discernible differences in proliferative potential or cell cycle. However, hypoxia impeded the subsequent osteogenic differentiation of MSCs, as evidenced by decreased hydroxyapatite deposition. Conversely, hypoxia did not impact the angiogenic differentiation potential of MPCs, as demonstrated by spheroid-based assays revealing comparable angiogenic sprouting and tube-like formation capabilities under both hypoxic and normoxic conditions. These findings indicate that hypoxia preserves the stemness phenotype of MPCs, inhibits their differentiation into MSCs, and hampers their osteogenic maturation while leaving their angiogenic potential unaffected. Our study sheds light on the intricate effects of hypoxia on bone marrow-derived MPCs and their differentiation pathways., (© 2024. The Author(s).)

The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mental disorders account for one of the most prevalent categories of the burden of disease worldwide, with depression expected to be the largest contributor by 2030, closely followed by anxiety. The COVID-19 pandemic possibly exacerbated these challenges, especially amongst adolescents, who experienced isolation, disrupted routines, and limited healthcare access. Notably, the pandemic has been associated with long-term neurological effects known as "long-COVID", characterized by both cognitive and psychopathological symptoms. In general, psychiatric disorders, including those related to long-COVID, are supposed to be due to widespread inflammation leading to neuroinflammation. Recently, the endocannabinoid system (ECS) emerged as a potential target for addressing depression and anxiety pathophysiology. Specifically, natural or synthetic cannabinoids, able to selectively interact with cannabinoid type-2 receptor (CB2R), recently revealed new therapeutic potential in neuropsychiatric disorders with limited or absent psychotropic activity. Among the most promising natural CB2R ligands, the bicyclic sesquiterpene β-caryophyllene (BCP) has emerged as an excellent anti-inflammatory and antioxidant therapeutic agent. This review underscores BCP's immunomodulatory and anti-inflammatory properties, highlighting its therapeutic potential for the management of depression and anxiety.

In recent years, advancements in the treatment of hematologic neoplasms have led to more effective and less toxic therapeutic schemes, resulting in prolonged patient life expectancy. However, the success of these treatments has also brought about an increased prevalence of cardiovascular adverse events, becoming a significant concern for the growing population of cancer survivors. Antineoplastic therapies, targeting both tumor and organ vessels, contribute to vascular toxicity, influenced by genetic factors and pre-existing vascular diseases. Chemotherapeutic agents and targeted treatments can induce cardiovascular toxicity by affecting endothelial cells and cardiomyocytes through various mechanisms, including hypoxia, vasculature abnormalities, and direct effects on cardiomyocytes. Cardiovascular adverse events encompass a wide range, from cardiac dysfunction to an elevated risk of arrhythmias. While early cardiac events are well-described in clinical trials, delayed toxicities are gaining relevance due to prolonged patient survival. The review focuses on the cardiac and vascular toxicity of antineoplastic drugs in hematological disorders, providing insights into the molecular physiopathology of cancer therapy-associated cardiotoxicity. Understanding how these drugs interact with the heart and blood vessels is essential for predicting, detecting, and managing chemotherapy-related heart issues.

Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most common thymic carcinomas. The acquisition of mutations in genes that control chromatin modifications and epigenetic regulation occurs in the advanced stages of thymic carcinomas. Anti-angiogenic drugs and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promising results for the treatment of unresectable tumors. Since thymic carcinomas are frankly aggressive tumors, this report presents insights into their oncogenic drivers, categorized under the established hallmarks of cancer.

With the improvement in cancer prognosis due to advances in antitumor therapeutic protocols and new targeted and immunotherapies, we are witnessing a growing increase in survival, however, at the same timeincrease in morbidity among cancer survivors as a consequences of the increased cardiovascular adverse effects of antineoplastic drugs. Common cardiovascular complications of antineoplastic therapies may include cardiac complications such as arrhythmias, myocardial ischemia, left ventricular dysfunction culminating in heart failure as well as vascular complications including arterial hypertension, thromboembolic events, and accelerated atherosclerosis. The toxicity results from the fact that these drugs not only target cancer cells but also affect normal cells within the cardiovascular system. In this article, we review the clinical features and main mechanisms implicated in antineoplastic drug-induced cardiovascular toxicity, including oxidative stress, inflammation, immunothrombosis and growth factors-induced signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Purpose of Review: Gliomas represent approximately 25% of all primary brain and other central nervous system (CNS) tumors and 81% of malignant tumors. Unfortunately, standard treatment approaches for most CNS cancers have shown limited improvement in patient survival rates., Recent Findings: The current drug development process has been plagued by high failure rates, leading to a shift towards human disease models in biomedical research. Unfortunately, suitable preclinical models for brain tumors have been lacking, hampering our understanding of tumor initiation processes and the discovery of effective treatments. In this review, we will explore the diverse preclinical models employed in neuro-oncology research and their contributions to translational science., Summary: By utilizing a combination of these preclinical models and fostering interdisciplinary collaborations, researchers can deepen their understanding of glioma brain tumors and develop novel therapeutic strategies to combat these devastating diseases. These models offer promising prospects for personalized and efficacious treatments for these challenging malignancies. Although it is unrealistic to fully replicate the complexity of the human body in vitro, the ultimate goal should be to achieve the closest possible resemblance to the clinical context., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Thymic epithelial tumors are rare malignant neoplasms that are frequently associated with paraneoplastic syndromes, especially myasthenia gravis. GTF2I is an oncogene mutated in a subgroup of thymomas that is reputed to drive their growth. However, for GTF2I wild-type tumors, the relevant mutations remain to be identified., Methods: We performed a meta-analysis and identified 4,208 mutations in 339 patients. We defined a panel of 63 genes frequently mutated in thymic epithelial tumors, which we used to design a custom assay for next-generation sequencing. We sequenced tumor DNA from 67 thymomas of patients with myasthenia gravis who underwent resection in our institution., Results: Among the 67 thymomas, there were 238 mutations, 83 of which were in coding sequences. There were 14 GTF2I mutations in 6 A, 5 AB, 2 B2 thymomas, and one in a thymoma with unspecified histology. No other oncogenes showed recurrent mutations, while sixteen tumor suppressor genes were predicted to be inactivated. Even with a dedicated assay for the identification of specific somatic mutations in thymic epithelial tumors, only GTF2I mutations were found to be significantly recurrent., Conclusion: Our evaluation provides insights into the mutational landscape of thymic epithelial tumors, identifies recurrent mutations in different histotypes, and describes the design and implementation of a custom panel for targeted resequencing. These findings contribute to a better understanding of the genetic basis of thymic epithelial tumors and may have implications for future research and treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pardini, Cucchiara, Palumbo, Tarrini, Di Vita, Coppedè, Nicolì, Guida, Maestri, Ricciardi, Aprile, Ambrogi, Barachini, Lucchi and Petrini.)

Pancreatic islet transplantation is a therapeutic option for achieving physiologic regulation of plasma glucose in Type 1 diabetic patients. At the same time, mesenchymal stem cells (MSCs) have demonstrated their potential in controlling graft rejection, the most fearsome complication in organ/tissue transplantation. MSCs can interact with innate and adaptive immune system cells either through direct cell-cell contact or through their secretome including exosomes. In this review, we discuss current findings regarding the graft microenvironment of pancreatic islet recipient patients and the crucial role of MSCs operation as cell managers able to control the immune system to prevent rejection and promote endogenous repair. We also discuss how challenging stressors, such as oxidative stress and impaired vasculogenesis, may jeopardize graft outcomes. In order to face these adverse conditions, we consider either hypoxia-exposure preconditioning of MSCs or human stem cells with angiogenic potential in organoids to overcome islets' lack of vasculature. Along with the shepherding of carbon nanotubes-loaded MSCs to the transplantation site by a magnetic field, these studies look forward to exploiting MSCs stemness and their immunomodulatory properties in pancreatic islet transplantation.

Autophagy is an evolutionarily conserved mechanism of cell adaptation to metabolic and environmental stress. It mediates the disposal of protein aggregates and dysfunctional organelles, although non-conventional features have recently emerged to broadly extend the pathophysiological relevance of autophagy. In baseline conditions, basal autophagy critically regulates cardiac homeostasis to preserve structural and functional integrity and protect against cell damage and genomic instability occurring with aging. Moreover, autophagy is stimulated by multiple cardiac injuries and contributes to mechanisms of response and remodeling following ischemia, pressure overload, and metabolic stress. Besides cardiac cells, autophagy orchestrates the maturation of neutrophils and other immune cells, influencing their function. In this review, we will discuss the evidence supporting the role of autophagy in cardiac homeostasis, aging, and cardioimmunological response to cardiac injury. Finally, we highlight possible translational perspectives of modulating autophagy for therapeutic purposes to improve the care of patients with acute and chronic cardiac disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor EVDV declared a past co-authorship with the author DS., (Copyright © 2023 Santovito, Steffens, Barachini and Madonna.)

Vascular progenitor cells are activated to repair and form a neointima following vascular damage such as hypertension, atherosclerosis, diabetes, trauma, hypoxia, primary cancerous lesions and metastases as well as catheter interventions. They play a key role not only in the resolution of the vascular lesion but also in the adult neovascularization and angiogenesis sprouting (i.e., the growth of new capillaries from pre-existing ones), often associated with carcinogenesis, favoring the formation of metastases, survival and progression of tumors. In this review, we discuss the biology, cellular plasticity and pathophysiology of different vascular progenitor cells, including their origins (sources), stimuli and activated pathways that induce differentiation, isolation and characterization. We focus on their role in tumor-induced vascular injury and discuss their implications in promoting tumor angiogenesis during cancer proliferation and migration.

Background: Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) treatment, and radiotherapy remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical approaches that do not fully respect the complexity of GB cell biology and fail to test efficiently anti-cancer treatments. Therefore, better treatment screening approaches are needed. In this study, we have developed a novel functional precision medicine approach to test the response to anticancer treatments in organoids derived from the resected tumors of glioblastoma patients., Methods: GB organoids were grown for a short period of time to prevent any genetic and morphological evolution and divergence from the tumor of origin. We chose metabolic imaging by NAD(P)H fluorescence lifetime imaging microscopy (FLIM) to predict early and non-invasively ex-vivo anti-cancer treatment responses of GB organoids. TMZ was used as the benchmark drug to validate the approach. Whole-transcriptome and whole-exome analyses were performed to characterize tumor cases stratification., Results: Our functional precision medicine approach was completed within one week after surgery and two groups of TMZ Responder and Non-Responder tumors were identified. FLIM-based metabolic tumor stratification was well reflected at the molecular level, confirming the validity of our approach, highlighting also new target genes associated with TMZ treatment and identifying a new 17-gene molecular signature associated with survival. The number of MGMT gene promoter methylated tumors was higher in the responsive group, as expected, however, some non-methylated tumor cases turned out to be nevertheless responsive to TMZ, suggesting that our procedure could be synergistic with the classical MGMT methylation biomarker., Conclusions: For the first time, FLIM-based metabolic imaging was used on live glioblastoma organoids. Unlike other approaches, ex-vivo patient-tailored drug response is performed at an early stage of tumor culturing with no animal involvement and with minimal tampering with the original tumor cytoarchitecture. This functional precision medicine approach can be exploited in a range of clinical and laboratory settings to improve the clinical management of GB patients and implemented on other cancers as well., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morelli, Lessi, Barachini, Liotti, Montemurro, Perrini, Santonocito, Gambacciani, Snuderl, Pieri, Aquila, Farnesi, Naccarato, Viacava, Cardarelli, Ferri, Mulholland, Ottaviani, Paiar, Liberti, Pasqualetti, Menicagli, Aretini, Signore, Franceschi and Mazzanti.)

Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN)., Material and Methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients' samples and in the Ty82 cell line., Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization ( n = 5/7) with a duration of 4.3 months (range 3-5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells., Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients' susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP).

Background: Ponatinib (PON), a third-generation tyrosine kinase inhibitor (TKI), has proven cardiovascular toxicity, with no known preventing agents usable to limit such side effect. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a new class of glucose-lowering agents, featuring favorable cardiac and vascular effects., Aims: We assessed the effects of the SGLT2 inhibitors empagliflozin (EMPA) and dapagliflozin (DAPA) on human aortic endothelial cells (HAECs) and underlying vasculo-protective mechanisms in an in vitro model of PON-induced endothelial toxicity., Methods and Results: We exposed HAECs to PON or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nmol/L) or dapagliflozin (DAPA) for 0-48 h exposure times. Compared with vehicle, incubations of HAECs with PON significantly reduced cell viability (0.56 ± 0.11 vs 0.23 ± 0.05 absorbance units, p < 0.01), increased the number of senescent cells at β-gal-assay (PON 9 ± 4 vs basal DMSO 3 ± 1 β-Gal + cells/field, p < 0.01), decreased tubulization in Matrigel (PON PON: 6 ± 1 vs basal DMSO 12 ± 1 tubuli number/field, p < 0.05) with a non-statistically significant trend of PON to decrease the number of autophagic cells at immunofluorescence assay and flow cytometry. EMPA reverted the effects of PON on cell viability (E 500 + PON 0.24 ± 0.05 vs PON 0.56 ± 0.11 absorbance units, p < 0.01) and induced autophagy (E 500 7 ± 4.3 vs basal DMSO 2.6 ± 2.3 mean fluorescence vs PON 2.6 ± 2.4 mean fluorescence, p < 0.05). EMPA and DAPA also reversed the effects of PON on cell senescence (E 500 + PON 4 ± 1 and DAPA 100 4 ± 2 vs PON 9 ± 4 β-Gal + cells/field, p < 0.01) and improved cell tubulization (E 500 + PON 21 ± 3 vs PON 6 ± 1 tubuli number/field, p < 0.05; DAPA 100 + PON 16 ± 2 vs PON 6 ± 1 tubuli number/field, p < 0.05)., Conclusion: EMPA and DAPA attenuate the vasculo-toxic effect exerted by PON by reverting endothelial cell senescence and dysfunction. These findings support the design of clinical studies exploring the vasculo-protective effects of EMPA or DAPA on PON-induced vascular toxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mesangiogenic progenitor cells (MPCs) have been isolated from human bone marrow (BM) mononuclear cells. They attracted particular attention for the ability to differentiate into exponentially growing mesenchymal stromal cells while retaining endothelial differentiative potential. MPC power to couple mesengenesis and angiogenesis highlights their tissue regenerative potential and clinical value, with particular reference to musculoskeletal tissues regeneration. BM and adipose tissue represent the most promising adult multipotent cell sources for bone and cartilage repair, although discussion is still open on their respective profitability. Culture determinants, as well as tissues of origin, appeared to strongly affect the regenerative potential of cell preparations, making reliable methods for cell isolation and growth a prerequisite to obtain cell-based medicinal products. Our group had established a definite consistent protocol for MPC culture, and here, we present data showing MPCs to be tissue specific., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barachini, Montali, Panvini, Carnicelli, Gatti, Piolanti, Bonicoli, Scaglione, Buda and Parchi.)