Citations

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.

Abstract Glioblastoma (GBM) is the most common form of malignant primary brain cancer in adults with a median survival of only 15 months. Therefore, new therapies to suppress malignant brain cancer are needed. Brain Tumor Initiating Cells (BTICs) are a GBM subpopulation of cells with a highly glycolytic profile that are thought to be responsible of the resistance of GBM to treatments. Metabolic reprogramming allows tumor cells to survive in unsupportive microenvironments. Manipulating tumor metabolism to counteract GBM resistance arises as a powerful approach with minimum effects in normal counterparts. At pharmacological concentrations, melatonin displays oncostatic properties. This is thought to be due to an increase in mitochondrial oxidative phosphorylation through the effects of melatonin in mitochondria, key organelle in metabolic homeostasis. We hypothesize that melatonin could alter BTIC metabolism, by inducing an anti-Warburg effect and as consequence, melatonin will decrease the viability of GBM cells and tumor growth. We found that treatment of GBM cell lines with 3mM melatonin significantly altered tumor cell metabolism. We observed that melatonin downregulated the lactate symporter MCT4 (p<0.002), inducing a significant intracellular accumulation of lactate (p<0.002) while decreasing it in the extracellular media (p<0.001). This was followed by a decrease in the internal pH (p<0.002). These effects were compensated by an increase in the oxygen consumption rate (OCR) followed by decay that leaded to an increase in ROS production (p<0.001). All these changes result in a depletion of cellular ATP (p<0.001) and eventually drove to a decrease in the proliferation (p<0.001) and cell death (p<0.001). When applied in vivo we observed a significant reduction in the tumor growth (p<0.001), volume (p<0.002) and weight (p<0.002), as well as a drop in the proliferation marker ki67 (p<0.001) and a fibrosis increase in treated tumors. These results position melatonin as a strong therapeutic candidate for GBM therapy.

Abstract Background En bloc spondylectomy is the gold standard for surgical resection of sacral chordomas (CHO), but the effect of extent of resection on recurrence and survival in patients with CHO of the cervical spine remains elusive. Methods MEDLINE, Embase, Scopus, and Cochrane were systematically reviewed. Patients with cervical CHO treated at three tertiary-care academic institutions were reviewed for inclusion. We performed an individual participant data meta-analysis to assess the overall survival (OS) and progression free survival (PFS) after en bloc-gross total resection (GTR) and intralesional-GTR compared to subtotal resection (STR). We then performed an intention-to-treat analysis including all patients with attempted en bloc resection in the en bloc group, regardless of the surgical margins. Results There was a total of 13 series including 161 patients with cervical CHO, including our current series of 22 patients. GTR (en bloc-GTR + intralesional-GTR) was associated with a significant decrease in the risk of local progression (pooled hazard ratio (PHR) = 0.22; 95% CI = 0.08–0.59; p = 0.003) and risk of death (PHR = 0.31; 95%; CI:0.12–0.83; p = 0.020). A meta-regression analyses determined that intralesional-GTR improved PFS (PHR = 0.35; 95%CI = 0.16–0.76; p = 0.009) as well as OS (PHR = 0.25; 95%CI = 0.08–0.79; p = 0.019) when compared to STR. En bloc-GTR was associated with a significant reduction in the risk of local progression (PHR = 0.06; 95%CI = 0.01–0.77; p = 0.030), but not a decreased OS (PHR = 0.50; 95% CI = 0.19–1.27; p = 0.145). Our intention-to-treat analyses revealed a near significant improvement in OS for the en bloc group (PHR: 0.15; 95%CI:0.02–1.22; p = 0.054), and nearly identical improvement in PFS. Radiation data was not available for the studies included in the meta-analysis. Conclusion This is the first and only meta-analysis of patients with cervical CHO. We found that both en bloc-GTR and intralesional-GTR resulted in improved local tumor control when compared to STR.

AbstractClinical translation of polymer‐based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA‐mediated knockdown in both glioma and melanoma cells in high‐serum conditions compared to non‐crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue‐mediated siRNA delivery beyond the liver, unlike conventional nanoparticle‐based delivery. These attributes of XbNPs facilitate robust siRNA‐mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid‐based therapeutics.

Abstract A subset of stem-like cells in glioblastoma (GBM; GSC) underlies tumor propagation, therapeutic resistance, and tumor recurrence. Immune evasion is critical for GSCs to carry out these functions. However, the molecular mechanisms employed by GSCs to escape antitumor immunity remain largely unknown. The reprogramming transcription factors Oct4 and Sox2 function as core multipotency factors and play an essential role in the formation and maintenance of GSCs, but the roles of these transcription factors in GSC immune escape have not been well explored. Here we examine how Oct4/Sox2 coexpression contributes to the immunosuppressive phenotype of GSCs. Combined transcription profiling and functional studies of Oct4/Sox2 coexpressing GSCs and differentiated GBM cells demonstrated that Oct4 and Sox2 cooperatively induce an immunosuppressive transcriptome consisting of multiple immunosuppressive checkpoints (i.e., PD-L1, CD70, A2aR, TDO) and dysregulation of cytokines and chemokines that are associated with an immunosuppressive tumor microenvironment. Mechanistically, induction and function of BRD/H3k27Ac-dependent immunosuppressive genes played a role in the immunosuppressive phenotype of GSCs. Pan-BET bromodomain inhibitors (e.g., JQ1) and shBRD4 constructs significantly inhibited the immunosuppressive transcriptome and immunosuppressive biological responses induced by Oct4/Sox2. Our findings identify targetable mechanisms by which tumor-propagating GSCs contribute to the immunosuppressive microenvironment in GBM. Significance: This report identifies mechanisms by which the reprogramming transcription factors Oct4 and Sox2 function to drive the immunomodulatory transcriptome of GSCs and contribute to the immunosuppressive microenvironment in GBM.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Currently, treatment is focused on achieving maximal safe resection, followed by chemo- and radiotherapy. Although surgery remains the most important therapeutic component, complete surgical resection is virtually impossible, as GBM cells readily infiltrate the adjacent brain parenchyma. One fundamental mechanism for GBM cell migration is the ability of these cells to use cell volume regulation as a driving force of cell infiltration and potentially interfering with apoptosis and cell cycle progression. In this work, we targeted the master regulators of cell volume, the kinases STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and Oxidative stress-responsive kinase-1) (OSR1) by using a novel proprietary small molecule inhibitor. In order to study the effects of inhibiting SPAK and OSR1, we analyzed cell proliferation and migration. First, we determined the IC50 using six different patient-derived GBM cell lines; we found IC50 values ranging from 0.2–2μM. Next, cell proliferation was determined by cell cycle analysis through Edu labeling. We found a significant decrease in S phase and cell cycle arrest in G2M (p= 0.001, n=6). In addition, cell migration was determined using boyden chamber assay. We found a dose-dependent reduction in cell migration (p=0.001, n=3). These results correlated with the phenomenon observed in an orthotopic murine model of GBM, in which the inhibitor showed a decrease in tumor growth (p=0.0026, n=4) and greater survival rates in vivo (p=0.0046, n=8). When used in combination with radiation therapy, this small molecule inhibitor was capable of radio-sensitizing GBM cells decreasing clonogenicity (p=0.01, n=3) were observed in vitro. In summary, by targeting the SPAK/OSR1 kinases with a small molecule inhibitor, GBM cells become less aggressive, mainly by interfering with cell migration and proliferation and becoming more sensitive to radiation.

Objetivo: Evaluar una serie de biomarcadores que permiten medir el proceso de cicatrización de las heridas e identificar los materiales que fueron utilizados para realizar dicha medición, teniendo en cuenta su incorporación en apósitos inteligentes. Método: Se realizó una revisión sistemática a partir de PubMed, Medline, CINAHL y Embase, sobre estudios que evaluaran el uso de materiales sensibles a biomarcadores. Se incluyeron estudios en inglés, sin tomar en cuenta el estado o fecha de publicación. No se incluyeron artículos de revisión ni sinopsis de conferencias. Resultados: La búsqueda mostró 296 estudios. Un investigador seleccionó 19 artículos para su inclusión. Todos los estudios fueron experimentales. Se encontraron artículos que evaluaron pH, tensión de oxígeno, temperatura, presión, ácido úrico, y glucosa. Los materiales utilizados fueron hidrogeles, fibras y tintas conductivas. Conclusión: El biomarcador más estudiado fue el pH. Los materiales que evalúan biomarcadores por medio de métodos colorimétricos podrían ser los más adecuados para su incorporación en apósitos inteligentes. Conflicto de interés: Este estudio fue respaldado, en parte, por el centro de Medicina Individualizada de Mayo Clinic, y por la Fundación de Cirugía Plástica (Plastic Surgery Foundation).

Abstract Background Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

Abstract We describe the clinical case of a 62-year-old man with an atypical grade II meningioma, invading bone and scalp, and present a step-by-step video description of a modified technique for cranioplasty and scalp reconstruction with latissimus dorsi flap. By using this technique, we aim to minimize the space between the dura and the flap, which would decrease the risk of fluid collections and infections.