Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory.
View Article and Find Full Text PDFWe show that a physical correspondence between Brownian motion and quantum mechanics can be established by formal analytic continuation if Wick rotation ( ) is replaced by the mirror symmetric, time transformation . Invariance of the square modulus of the wave function under this transformation reveals a tight connection between Born's interpretation of the probability density and the time , as being both the result of a time symmetry breaking in the informational content of the microscopic (quantum) world, which takes place as we move to a macroscopic level. We find that under the transformation , the Schrödinger equation and its complex conjugate conforms with a stochastic-mechanical model of the Brownian motion of a particle.
View Article and Find Full Text PDFIntroduction: About 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR).
View Article and Find Full Text PDFThe flow of water through a horizontal small-scale Venturi tube of rectangular cross-section is simulated using a modified version of the open-source code DualSPHysics, which is based on Smoothed Particle Hydrodynamics (SPH) methods. Water is simulated using the Murnaghan-Tait equation of state so that weak compressibility is allowed. The hydrodynamics is coupled to a Large-Eddy Simulation (LES) turbulence model.
View Article and Find Full Text PDFNon-extensive statistical mechanics (or -statistics) is based on the so-called non-additive Tsallis entropy. Since its introduction by Tsallis, in 1988, as a generalization of the Boltzmann-Gibbs equilibrium statistical mechanics, it has steadily gained ground as a suitable theory for the description of the statistical properties of non-equilibrium complex systems. Therefore, it has been applied to numerous phenomena, including real seismicity.
View Article and Find Full Text PDFBackground And Purpose: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome.
View Article and Find Full Text PDFCutaneous melanoma (CM) is a very aggressive disease, often characterized by unresponsiveness to conventional therapies and high mortality rates worldwide. The identification of the activating BRAF mutations in approximately 50% of CM patients has recently fueled the development of novel small-molecule inhibitors that specifically target BRAF -mutant CM. In addition, a major progress in CM treatment has been made by monoclonal antibodies that regulate the immune checkpoint inhibitors.
View Article and Find Full Text PDFMitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAF-mutant cutaneous melanoma (CM) pathogenesis. In the last years, Spry1 has been frequently described as an upstream regulator of MAPK signaling pathway. However, its specific role in BRAF-mutant CM is still poorly defined.
View Article and Find Full Text PDFPurpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab.
Patients And Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles.
Aberrant DNA methylation of cell-free circulating DNA (cfDNA) has recently gained attention for its use as biomarker in cancer diagnosis, prognosis, and prediction of therapeutic response. Quantification of cfDNA methylation levels requires methods with high sensitivity and specificity due to low amounts of cfDNA available in plasma, high degradation of cfDNA, and/or contamination with genomic DNA. To date, several approaches for measuring cfDNA methylation have been established, including quantitative methylation-specific PCR (qMSP), which represents a simple, fast, and cost-effective technique that can be easily implemented into clinical practice.
View Article and Find Full Text PDFBackground: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse.
View Article and Find Full Text PDFIn recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas.
View Article and Find Full Text PDFMantle cell lymphoma (MCL) is an aggressive haematological malignancy in which the response to therapy can be limited by aberrantly activated molecular and cellular pathways, among which autophagy was recently listed. Our study shows that the 9-cis-retinoic acid (RA)/Interferon(IFN)-α combination induces protective autophagy in MCL cell lines and primary cultures reducing the extent of drug-induced apoptosis. The treatment significantly up-regulates phospholipid scramblase 1 (PLSCR1), a protein which bi-directionally flips lipids across membranes.
View Article and Find Full Text PDFMantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a still undefined etiology. Several lines of evidence are consistent with the possible involvement of peculiar microenvironmental stimuli sustaining tumor cell growth and survival, as the activation of Toll-like receptors (TLR) 4 and 9. However, little is known about the contribution of other TLRs of pathogenic relevance in the development of MCL.
View Article and Find Full Text PDFA smoothed particle hydrodynamics (SPH) model is presented for simulating the decay chain transport of radionuclides in confined aqueous solutions. The SPH formulation is based on the open-source parallel code DualSPHysics extended to solve the advective-diffusion equation for the evolution of the concentration field coupled to the fluid-dynamic equations, including the effects of radioactive decay of the tracer contaminants. The performance of the method is demonstrated for environmental engineering problems dealing with the transport of contaminants in still and flowing water.
View Article and Find Full Text PDFThe multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination.
View Article and Find Full Text PDFEpigenetic regulation allows heritably modulating gene expression profiles without modifying the primary sequence of gDNA. Under physiologic conditions, epigenetic patterns determine tissue-specific gene expression landscapes, gene imprinting, inactivation of chromosome X, and preservation of genomic stability. The most characterized mediators of epigenetic inheritance are gDNA methylation and histone posttranslational modifications that cooperate to alter chromatin state and genome transcription.
View Article and Find Full Text PDFPhys Rev E Stat Nonlin Soft Matter Phys
July 2015
The rapid evaporation and explosive boiling of a van der Waals (vdW) liquid drop in microgravity is simulated numerically in two-space dimensions using the method of smoothed particle hydrodynamics. The numerical approach is fully adaptive and incorporates the effects of surface tension, latent heat, mass transfer across the interface, and liquid-vapor interface dynamics. Thermocapillary forces are modeled by coupling the hydrodynamics to a diffuse-interface description of the liquid-vapor interface.
View Article and Find Full Text PDFPhys Rev E Stat Nonlin Soft Matter Phys
July 2014
We study numerically liquid-vapor phase separation in two-dimensional, nonisothermal, van der Waals (vdW) liquid drops using the method of smoothed particle hydrodynamics (SPH). In contrast to previous SPH simulations of drop formation, our approach is fully adaptive and follows the diffuse-interface model for a single-component fluid, where a reversible, capillary (Korteweg) force is added to the equations of motion to model the rapid but smooth transition of physical quantities through the interface separating the bulk phases. Surface tension arises naturally from the cohesive part of the vdW equation of state and the capillary forces.
View Article and Find Full Text PDFContinuously improving knowledge of the fine mechanisms regulating cross-talk between immune cells, and of their multi-faceted interactions with cancer cells, has prompted the development of several novel immunotherapeutic strategies for cancer treatment. Among these, modulation of the host's immune system by targeting immunological synapses has shown notable clinical efficacy in different tumor types. Despite this, objective clinical responses and, more importantly, long-term survival are achieved only by a fraction of patients; therefore, identification of the mechanism(s) responsible for the differential effectiveness of immune checkpoint blockade in specific patient populations is an area of intense investigation.
View Article and Find Full Text PDFPrognostic molecular markers are urgently needed for allowing to discriminate the clinical course of disease of melanoma patients, which is highly heterogeneous and unpredictable also within a specific clinicopathological stage and substage of disease. Alterations in DNA methylation have been reported to be widely present in cutaneous melanoma, profoundly impacting its biology. In line with this notion, we have identified methylation markers as independent prognostic factors in stage IIIC melanoma patients.
View Article and Find Full Text PDFMalignant melanoma is a complex disease that arises and evolves due to a myriad of genetic and epigenetic events. Among these, the interaction between epigenetic alterations (i.e.
View Article and Find Full Text PDFPurpose: Pharmacologic DNA hypomethylation holds strong promises in cancer immunotherapy due to its immunomodulatory activity on neoplastic cells. Searching for more efficient DNA hypomethylating agents to be utilized to design novel immunotherapeutic strategies in cancer, we investigated the immunomodulatory properties of the new DNA hypomethylating agent SGI-110, that is resistant to in vivo inactivation by cytidine deaminase.
Experimental Design: Cutaneous melanoma, mesothelioma, renal cell carcinoma, and sarcoma cells were treated in vitro with SGI-110.
Background: The clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.
Methods: Genome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients.
Background: Epigenetic remodelling of cancer cells is an attractive therapeutic strategy and distinct DNA hypomethylating agents (DHA) are being actively evaluated in patients with hemopoietic or solid tumours. However, no studies have investigated the modulation of gene expression profiles (GEP) induced by DHA in transformed and benign tissues. Such information is mandatory to clarify the fine molecular mechanism(s) underlying the clinical efficacy of DHA, to identify appropriate therapeutic combinations, and to address safety issues related to their demethylating potential in normal tissues.
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