EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.

Background: EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge.

Translocator protein (TSPO) is a biomarker of Zika virus (ZIKV) infection-associated neuroinflammation.

Zika is a systemic inflammatory disease caused by infection with Zika virus (ZIKV). ZIKV infection in adults is associated with encephalitis marked by elevated expression of pro-inflammatory cytokines and chemokines, as well as increased brain infiltration of immune cells. In this study, we demonstrate that ZIKV encephalitis in a mouse infection model exhibits increased brain TSPO expression.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

Background: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype.

Methods: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells and public clinical datasets to identify key protein kinases implicated in temozolomide resistance.

Repurposing of Zika virus live-attenuated vaccine (ZIKV-LAV) strains as oncolytic viruses targeting human glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer affecting the adult population. Median overall survival for GBM patients is poor (15 months), primarily due to high rates of tumour recurrence and the paucity of treatment options. Oncolytic virotherapy is a promising treatment alternative for GBM patients, where engineered viruses selectively infect and eradicate cancer cells by inducing cell lysis and eliciting robust anti-tumour immune response.

TSPO expression in a Zika virus murine infection model as an imaging target for acute infection-induced neuroinflammation.

Introduction: Zika virus (ZIKV) is a neurotropic human pathogen that causes neuroinflammation, whose hallmark is elevated translocator protein (TSPO) expression in the brain. This study investigates ZIKV-associated changes in adult brain TSPO expression, evaluates the effectiveness of TSPO radioligands in detecting TSPO expression, and identifies cells that drive brain TSPO expression in a mouse infection model.

Methods: The interferon-deficient AG129 mouse infected with ZIKV was used as neuroinflammation model.

Preclinical evaluation of [F]FDG-PET as a biomarker of lymphoid tissue disease and inflammation in Zika virus infection.

Purpose: Zika (ZIKV) is a viral inflammatory disease affecting adults, children, and developing fetuses. It is endemic to tropical and sub-tropical countries, resulting in half the global population at risk of infection. Despite this, there are no approved therapies or vaccines against ZIKV disease.

Integrative multi-omics approach to targeted therapy for glioblastoma.

This review describes recent technological advances applied to glioblastoma (GBM), a brain tumor with dismal prognosis. International consortial efforts suggest the presence of molecular subtypes within histologically identical GBM tumors. This emphasizes that future treatment decisions should no longer be made based solely on morphological analyses, but must now take into consideration such molecular and cellular heterogeneity.

Plasmodium vivax binds host CD98hc (SLC3A2) to enter immature red blood cells.

More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia. P. vivax preferentially invades reticulocytes (immature red blood cells).

Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers for In Situ Live-Cell Molecular Imaging of Dengue Virus Replication.

Current methods to detect and monitor pathogens in biological systems are largely limited by the tradeoffs between spatial context and temporal detail. A new generation of molecular tracking that provides both information simultaneously involves in situ detection coupled with non-invasive imaging. An example is antisense imaging that uses antisense oligonucleotide probes complementary to a target nucleotide sequence.

In vivo fate of liposomes after subconjunctival ocular delivery.

Subconjunctival administration of nanocarriers presents an alternative drug delivery strategy to overcome blood-ocular barriers to enhance drug bioavailability to specific parts of the eye. Using fiberoptic Confocal Laser Microendoscopy (CLM) and radiotracing, we describe the effects of charge, size, cholesterol content and lipid saturation on the ocular and corporal distribution of liposome nanocarriers in live mouse models. Positively charged or large (>250 nm) liposomes exhibit sustained ocular residence times in and around the injection site; cholesterol loading slows down this clearance, whereas lipid saturation accelerates clearance.

Cysteine Deprivation Targets Ovarian Clear Cell Carcinoma Oxidative Stress and Iron-Sulfur Cluster Biogenesis Deficit.

Current treatment options for ovarian clear cell carcinoma (OCCC) are limited to combination of platinum-based and other cytotoxic agents to which patients respond poorly due to intrinsic chemoresistance. There is therefore an urgent need to develop alternative therapeutic strategies for OCCC. Cysteine deprivation suppresses OCCC growth and with no apparent toxicity.

Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death.

Slow and continuous release of HS by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death.

MLL5 (KMT2E): structure, function, and clinical relevance.

The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A-2D and 2F-2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates.

Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents.

Hydrogen sulfide (HS) has been investigated for its potential in therapy. Recently, we reported novel HS donor molecules based on a thiophosphorus core, which slowly release HS and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied HS donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic HS donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line.

Discovery of New H2S Releasing Phosphordithioates and 2,3-Dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes with Improved Antiproliferative Activity.

Hydrogen sulfide (H2S) is now recognized as a physiologically important gasotransmitter. Compounds which release H2S slowly are sought after for their potential in therapy. Herein the synthesis of a series of phosphordithioates based on 1 (GYY4137) are described.