HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer.

Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest.

Engraftment of a surrogate antigen onto tumor cell surface via pHLIP peptide to universally target CAR-T cell therapy to solid tumors.

CAR-T cells and monoclonal antibodies (mAbs) are immunotherapeutics that have shown efficacies against certain malignancies. However, their broad application is hindered by the scarcity of tumor-associated antigens on tumor cell surfaces. Previous investigations unveiled the unique capacity of pH-low insertion peptide (pHLIP) to anchor to plasma membranes under acidic conditions.

ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer.

DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR.

Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment.

Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity.

Unveiling the intricate dance: Obesity and TNBC connection examined.

Amid the dynamic field of cancer research, various targeted therapies have proven crucial in combating breast cancer, the most prevalent cancer among women globally. Triple Negative Breast Cancer (TNBC) stands out from other types of breast cancer due to the absence of three key receptors on the cell surface (progesterone, estrogen, and HER2). Researchers are working on finding ways to address TNBC's elusive biomarkers and minimize the damage caused by the disease through treatments like chemotherapies and targeted pathway receptors.

The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation.

STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells.

Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes.

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source.

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation.

Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca(A138T) mice, a PA model, reveals surprising outcomes.

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein.

A mitochondrial surveillance mechanism activated by mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator to remove a poison intron, increasing the stability and abundance of mRNA and protein.

Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential.

Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP-TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer.

ursaPGx: a new R package to annotate pharmacogenetic star alleles using phased whole-genome sequencing data.

Long-read sequencing technologies offer new opportunities to generate high-confidence phased whole-genome sequencing data for robust pharmacogenetic annotation. Here, we describe a new user-friendly R package, ursaPGx, designed to accept multi-sample phased whole-genome sequencing data VCF input files and output star allele annotations for pharmacogenes annotated in PharmVar.

Star allele search: a pharmacogenetic annotation database and user-friendly search tool of publicly available 1000 Genomes Project biospecimens.

Here we describe a new public pharmacogenetic (PGx) annotation database of a large (n = 3,202) and diverse biospecimen collection of 1000 Genomes Project cell lines and DNAs. The database is searchable with a user friendly, web-based tool ( www.coriell.

MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer.

Background: Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor.

Methods: In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models.

Use of genome-wide DNA methylation analysis to identify prognostic CpG site markers associated with longer survival time in dogs with multicentric high-grade B-cell lymphoma.

Background: DNA methylation analysis might identify prognostic CpG sites in CHOP-treated dogs with multicentric high-grade B-cell lymphoma (MHGL) with heterogenous prognosis.

Objective: To identify prognostic CpG sites of MHGL through genome-wide DNA methylation analysis with pyrosequencing validation.

Animals: Test group: 24 dogs.

Expansion of human hematopoietic stem cells by inhibiting translation.

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal.

Unraveling therapeutic targets in acute myeloid leukemia through multiplexed genome editing CRISPR screening.

Acute Myeloid Leukemia (AML) is a complex condition driven by genetic changes that disrupt the normal functioning of myeloid cells. Despite progress in treatments, AML prognosis remains challenging, emphasizing the need for innovative therapeutic approaches. CRISPR gene editing, known for its simplicity, efficiency, and cost-effectiveness, surpasses other techniques.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

Background: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction.

Postmortem toxicology findings from the Camden Opioid Research Initiative.

The United States continues to be impacted by decades of an opioid misuse epidemic, worsened by the COVID-19 pandemic and by the growing prevalence of highly potent synthetic opioids (HPSO) such as fentanyl. In instances of a toxicity event, first-response administration of reversal medications such as naloxone can be insufficient to fully counteract the effects of HPSO, particularly when there is co-occurring substance use. In an effort to characterize and study this multi-faceted problem, the Camden Opioid Research Initiative (CORI) has been formed.

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear.