From Melanoma Development to RNA-Modified Dendritic Cell Vaccines: Highlighting the Lessons From the Past

Although melanoma remains the deadliest skin cancer, the current treatment has not resulted in the desired outcomes. Unlike chemotherapy, immunotherapy has provided more tolerable approaches and revolutionized cancer therapy. Although dendritic cell-based vaccines have minor side effects, the undesirable response rates of traditional approaches have posed questions about their clinical translation. The immunosuppressive tumor microenvironment can be the underlying reason for their low response rates. Immune checkpoints and indoleamine 2,3-dioxygenase have been implicated in the induction of immunosuppressive tumor microenvironment. Growing evidence indicates that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Protein kinase B (PKB) (PI3K/AKT) pathways, as the main oncogenic pathways of melanoma, can upregulate the tumoral immune checkpoints, like programmed death-ligand 1. This study briefly represents the main oncogenic pathways of melanoma and highlights the cross-talk between these oncogenic pathways with indoleamine 2,3-dioxygenase, tumoral immune checkpoints, and myeloid-derived suppressor cells. Moreover, this study sheds light on a novel tumor antigen on melanoma, which has substantial roles in tumoral immune checkpoints expression, indoleamine 2,3-dioxygenase secretion, and stimulating the oncogenic pathways. Finally, this review collects the lessons from the previous unsuccessful trials and integrates their lessons with new approaches in RNA-modified dendritic cell vaccines. Unlike traditional approaches, the advances in single-cell RNA-sequencing techniques and RNA-modified dendritic cell vaccines along with combined therapy of the immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitor, and RNA-modified dendritic cell-based vaccine can overcome these auto-inductive loops and pave the way for developing robust dendritic cell-based vaccines with the most favorable response rate and the least side effects

Involvement of Central β-Adrenergic Circuitry in Food and Water Intake in Chickens

We examined the effects of intracerebroventricular (i.c.v.) microinjections of α, β-adrenergic agonist, isoproterenol (ISOP), and of a β₁,₂-adrenoceptor blocker, propranolol (PROP), on food and water intake in broiler cockerels deprived of food and water for 3 h. We found that ISOP, at a 200 nM concentration and not smaller, significantly (P ≤ 0.05) increased food intake but not water intake. PROP microinjected in different doses (20-80 mM) significantly (P ≤ 0.05) decreased food intake. These observation suggest a direct orexigenic role for the β₁ - and β-adrenergic systems in the regulation of food intake in chickens. The significant (P ≤ 0.05) effect of i.c.v. injections of PROP (transient increase in water intake) implies a role of the adrenergic system, possibly via α-adrenoceptors, in the regulation of water intake in broilers, which is food intake-independent.Було досліджено впливи інтрацеребровентрикулярних мікроін’єкцій агоніста β-адренорецепторів ізопротеренолу та блокатора β-адренорецепторів пропранололу на споживання їжі та води бройлерами-півниками, позбавленими їжі та питва протягом 3 год. Виявилося, що ізопротеренол у концентрації 200 нM (але не менше) істотно (P ≤ 0.05) посилював споживання їжі, але не води. Пропранолол, ін’єкований у різних дозах (20–80 мкM), вірогідно зменшував споживання їжі. Отримані дані свідчать на користь гіпотез про орексигенну роль β₁ - та β₂-адренергічних систем у регуляції споживання їжі курчатами. Істотний (P ≤ 0.05) ефект ін’єкцій пропранололу (тимчасове зростання споживання води) вказує на певну роль адренергічної системи щодо регуляції споживання води бройлерами; цей ефект, вірогідно, реалізується через α-адренорецептори та є незалежним від впливів на споживання їжі

Pancreatic cancer signaling pathways, genetic alterations, and tumor microenvironment: The barriers affecting the method of treatment

Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment

Exact symmetry breaking ground states for quantum spin chains

We introduce a family of spin-1/2 quantum chains, and show that their exact ground states break the rotational and translational symmetries of the original Hamiltonian. We also show how one can use projection to construct a spin-3/2 quantum chain with nearest neighbor interaction, whose exact ground states break the rotational symmetry of the Hamiltonian. Correlation functions of both models are determined in closed form. Although we confine ourselves to examples, the method can easily be adapted to encompass more general models.Comment: 4 pages, RevTex. 4 figures, minor changes, new reference

MiR-144: A new possible therapeutic target and diagnostic/prognostic tool in cancers

MicroRNAs (miRNAs) are small and non-coding RNAs that display aberrant expression in the tissue and plasma of cancer patients when tested in comparison to healthy individuals. In past decades, research data proposed that miRNAs could be diagnostic and prognostic biomarkers in cancer patients. It has been confirmed that miRNAs can act either as oncogenes by silencing tumor inhibitors or as tumor suppressors by targeting oncoproteins. MiR-144s are located in the chromosomal region 17q11.2, which is subject to significant damage in many types of cancers. In this review, we assess the involvement of miR-144s in several cancer types by illustrating the possible target genes that are related to each cancer, and we also briefly describe the clinical applications of miR-144s as a diagnostic and prognostic tool in cancers

Bound entanglement in quantum phase transitions

We investigate quantum phase transitions in which a change in the type of entanglement from bound entanglement to either free entanglement or separability may occur. In particular, we present a theoretical method to construct a class of quantum spin-chain Hamiltonians that exhibit this type of quantum criticality. Given parameter-dependent two-site reduced density matrices (with prescribed entanglement properties), we lay out a reverse construction for a compatible pure state for the whole system, as well as a class of Hamiltonians for which this pure state is a ground state. This construction is illustrated through several examples.Comment: 9 pages, 8 figure

Prognostic Role and Clinical Significance of Tumor-Infiltrating Lymphocyte (TIL) and Programmed Death Ligand 1 (PD-L1) Expression in Triple-Negative Breast Cancer (TNBC): A Systematic Review and Meta-Analysis Study

This meta-analysis aimed to evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1), their associations with the clinicopathological characteristics, and the association between their levels in patients with triple-negative breast cancer (TNBC). PubMed, EMBASE, Scopus, ProQuest, Web of Science, and Cochrane Library databases were searched to obtain the relevant papers. Seven studies with 1152 patients were included in this study. Like the level of TILs, there were no significant associations between PD-L1 expression and tumor size, tumor stage, lymph node metastasis, histological grade, and Ki67 (All p-values ≥ 0.05). Furthermore, there was no significant association between PD-L1 expression with overall survival (OS) and disease-free survival (DFS). In assessment of TILs and survival relationship, the results showed that a high level of TILs was associated with long-term OS (hazard ratios (HR) = 0.48, 95% CI: 0.30 to 0.77, p-value < 0.001) and DFS (HR = 0.53, 95% CI: 0.35 to 0.78, p-value < 0.001). The results displayed that tumoral PD-L1 expression was strongly associated with high levels of TILs in TNBC patients (OR = 8.34, 95% CI: 2.68 to 25.95, p-value < 0.001). In conclusion, the study has shown the prognostic value of TILs and a strong association between tumoral PD-L1 overexpression with TILs in TNBC patients

Acyloxylation of Cyclic Enones: Synthesis of Densely Oxygenated Guaianolides

The α′-acyloxylation of cyclic enones with linear carboxylic acids is described. The reaction is promoted by KMnO4 in the presence of a carboxylic acid and its corresponding carboxylic anhydride. The optimization of the reaction has been carried out using the statistical methodology known as design of experiments. The optimized reaction conditions have been evaluated in terms of substrate scope and compatibility with different functional groups. The methodology has been applied to the synthesis of densely oxygenated guaianes and guaianolides