Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans.

Immunotherapy leads to cancer eradication despite the tumor's immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules.

Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.

Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an "eat-me" signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial "don't eat-me" signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance.

YY1-mediated enhancer-promoter communication in the immunoglobulin μ locus is regulated by MSL/MOF recruitment.

The rearrangement and expression of the immunoglobulin μ heavy chain (Igh) gene require communication of the intragenic Eμ and 3' regulatory region (RR) enhancers with the variable (V) gene promoter. Eμ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eμ wild-type enhancer and that of Eμ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network.

MSL2 ensures biallelic gene expression in mammals.

In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA. This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders. Whether and how a biallelic or monoallelic state is determined in a cell-type-specific manner at individual loci remains unclear.

Quality assurance of hematopoietic stem cells by macrophages determines stem cell clonality.

Tissue-specific stem cells persist for a lifetime and can differentiate to maintain homeostasis or transform to initiate cancer. Despite their importance, there are no described quality assurance mechanisms for newly formed stem cells. We observed intimate and specific interactions between macrophages and nascent blood stem cells in zebrafish embryos.

Epigenetic Regulators as the Gatekeepers of Hematopoiesis.

Hematopoiesis is the process by which both fetal and adult organisms derive the full repertoire of blood cells from a single multipotent progenitor cell type, the hematopoietic stem cells (HSCs). Correct enactment of this process relies on a synergistic interplay between genetically encoded differentiation programs and a host of cell-intrinsic and cell-extrinsic factors. These include the influence of the HSC niche microenvironment, action of specific transcription factors, and alterations in intracellular metabolic state.

Differential H4K16ac levels ensure a balance between quiescence and activation in hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are able to reconstitute the bone marrow while retaining their self-renewal property. Individual HSCs demonstrate heterogeneity in their repopulating capacities. Here, we found that the levels of the histone acetyltransferase MOF (males absent on the first) and its target modification histone H4 lysine 16 acetylation are heterogeneous among HSCs and influence their proliferation capacities.

Temporal expression of MOF acetyltransferase primes transcription factor networks for erythroid fate.

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are orchestrated by the combinatorial action of transcription factors and epigenetic regulators. Here, we have explored the mechanism by which histone H4 lysine 16 acetyltransferase MOF regulates erythropoiesis. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing uncovered that MOF influences erythroid trajectory by dynamic recruitment to chromatin and its haploinsufficiency causes accumulation of a transient HSC population.

Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells.

Aim: Considering the central role of dendritic cells (DCs) on the development of an antitumor immune response, in this study we used a murine model to evaluate how DC transfection with drug-treated tumor cell RNA changes their phenotype, and whether transfection enhances the in vivo effectiveness of a DC-based antitumor vaccine.

Materials And Methods: MC-38 colorectal tumor cells were pretreated with the minimum effective concentration of 5-fluorouracil (5-FU), then their total RNA was extracted and transfected into DCs. These DCs were inoculated into C57Bl/6 mice bearing subcutaneous MC-38 tumor.

End-to-side versus end-to-end neurorrhaphy at the peroneal nerve in rats.

Purpose: To evaluate three different kinds of neurorrhaphy of the peroneal nerve.

Methods: Eigthy rats were divided into 5 groups. Control: nerve had no intervention.

DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome.

Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome.

BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity.

Benzofuroxan is an interesting ring system, which has shown a wide spectrum of biological responses against tumor cell lines. We investigated, herein, the antitumor effects of benzofuroxan derivatives (BFDs) in vitro and in a melanoma mouse model. Cytotoxic effects of twenty-two BFDs were determined by MTT assay.

Tolerogenic IDO(+) Dendritic Cells Are Induced by PD-1-Expressing Mast Cells.

Mast cells (MCs) are tissue resident cells, rich in inflammatory mediators, involved in allergic reactions, and with an increasingly recognized role in immunomodulation. Dendritic cells (DCs), on the other hand, are central to the determination of immune response patterns, being highly efficient antigen-presenting cells that respond promptly to changes in their microenvironment. Here, we show that direct cell contact between immature monocyte-derived DCs (iDCs) and MC bends DCs toward tolerance induction.

Synergistic anti-tumor effects of the combination of a benzofuroxan derivate and sorafenib on NCI-H460 human large cell lung carcinoma cells.

Lung cancer is the most frequent and lethal human cancer in the world. Because is still an unsolved health issue, new compounds or therapeutic strategies are urgently needed. Furoxans are presented as potentials candidates for lung cancer treatment.