Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

BACKGROUND: Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been reported as possibly favorable prognostic factors in colorectal cancer (CRC). However, their longitudinal effect is unknown. METHODS: A pilot study was performed to investigate whether baseline PD-1/PD-L1 levels are associated with further laboratory changes and/or shorter survival. RESULTS: A total of 506 laboratory measurements from 37 metastatic CRC patients were analyzed. The baseline plasma PD-1 and PD-L1 levels were 27.73 ± 1.20 pg/mL and 16.01 ± 1.09 pg/mL, respectively. Disease progression (p = 0.0443) and baseline high-sensitivity C-reactive protein (p = 0.0011), aspartate transaminase (p = 0.0253), alanine transaminase (p = 0.0386), and gamma-glutamyl transferase (p = 0.0103) were associated with higher PD-L1 levels. Based on the baseline PD-1/PD-L1 levels, low and high PD-1/PD-L1 groups were created. Constant, pathological levels of complete blood count values, high-sensitivity C-reactive protein, serum albumin, high-density lipoprotein cholesterol, and lactate dehydrogenase were characteristic for patients with high baseline PD-L1. High PD-L1 levels were significantly associated with increased tumor burden. Disease-specific survival and progression-free survival were significantly shorter in patients with high PD-L1. CONCLUSIONS: Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found.

Longitudinal Analysis of 1α,25-dihidroxyvitamin D3 and Homocysteine Changes in Colorectal Cancer.

BACKGROUND: 1α,25-dihydroxycholecalciferol (1,25(OH)2D3) and homocysteine are known to play a role in the pathophysiology of colorectal cancer (CRC). In health, the two changes are inversely proportional to each other, but little is known about their combined effect in CRC. METHODS: The serum 1,25(OH)2D3 and the homocysteine levels of eighty-six CRC patients were measured, who were enrolled into four cohorts based on the presence of metastases (Adj vs. Met) and vitamin D3 supplementation (ND vs. D). RESULTS: 1,25(OH)2D3 was constant (Adj-ND), increased significantly (Adj-D, p = 0.0261), decreased (Met-ND), or returned close to the baseline after an initial increase (Met-D). The longitudinal increase in 1,25(OH)2D3 (HR: 0.9130, p = 0.0111) positively affected the overall survival in non-metastatic CRC, however, this effect was cancelled out in those with metastasis (p = 0.0107). The increase in homocysteine negatively affected both the overall (HR: 1.0940, p = 0.0067) and the progression-free survival (HR: 1.0845, p = 0.0073). Lower 1,25(OH)2D3 and/or higher homocysteine level was characteristic for patients with higher serum lipids, albumin, total protein, white blood cell and platelet count, male sex, and right-sided tumors. No statistically justifiable connection was found between the target variables. CONCLUSIONS: A measurement-based titration of vitamin D3 supplementation and better management of comorbidities are recommended for CRC.

Two Targets, One Hit: new Anticancer Therapeutics to Prevent Tumorigenesis Without Cardiotoxicity.

A serious adverse effect of cancer therapies is cardiovascular toxicity, which significantly limits the widespread use of antineoplastic agents. The promising new field of cardio-oncology offers the identification of potent anti-cancer therapeutics that effectively inhibit cancer cell proliferation without causing cardiotoxicity. Future introduction of recently identified cardio-safe compounds into clinical practice (including ERK dimerization inhibitors or BAX allosteric inhibitors) is expected to help oncologists avoid unwanted cardiological complications associated with therapeutic interventions.

Drugging the R-loop interactome: RNA-DNA hybrid binding proteins as targets for cancer therapy.

Unravelling the origin of genetic alterations from point mutations to chromosomal rearrangements was greatly enhanced by the discovery of RNA-DNA hybrids (R-loops) that behave as hotspots of genomic instability in a variety of organisms. Current models suggest that uncontrolled R-loops are a hazard to genome integrity, therefore, identifying proteins that are involved in recognising and signalling R-loop structures are of key importance. Herein we analysed key RNA-DNA hybrid binding proteins in humans taking advantage of large-scale gene expression, survival rate, and drug-sensitivity data from cancer genomics databases. We show that expression of RNA-DNA hybrid binding proteins in various cancer types is associated with survival and may have contrasting outcomes in responding to therapeutic treatments. Based on the revealed pharmacogenomic landscape of human RNA-DNA hybrid binding proteins, we propose that R-loops and R-loop binding proteins are potentially relevant new epigenetic markers and therapeutic targets in multiple cancers.

Histone H3 Lysine 56 Acetylation Is Required for Formation of Normal Levels of Meiotic DNA Breaks in S. cerevisiae.

Meiotic recombination is initiated by Spo11-catalyzed DNA double-strand breaks (DSBs) that are promoted by histone modifications and histone modifying enzymes. Herein we investigated the role of histone H3 lysine 56 acetylation (H3K56ac) located near the entry/exit points of the DNA in the globular H3 domain. We generated a series of mutant cells (asf1Δ, rtt109Δ, hst3/4Δ, and H3K56A) in which the endogenous level of H3K56ac was manipulated and tracked during meiotic growth. We show that complete loss or increased abundance of H3K56ac in these mutants allows timely entry into meiosis and sporulation and does not impair S phase progression, first and second meiotic cell divisions, and spore viability. In the asf1Δ, rtt109Δ, hst3/4Δ mutants, DSBs and crossovers form normal levels with a short (60-min) delay at the HIS4-LEU2 artificial recombination hotspot, however, DSB formation shows a ∼threefold decrease in the H3K56A mutant at the natural BUD23-ARE1 hotspot. The latter DSB phenotype, showing significant DSB reduction in the H3K56A mutant, was also observed at DSB sites using genome-wide mapping of Rfa1-coated single-stranded DNA flanking DSBs (RPA ChIP). Parallel mapping of H3K56-acetylated histones in wild type cells revealed strong depletion of the H3K56ac ChIP signal over Spo11-oligo DSBs, albeit most H3K56-acetylated histones were enriched adjacent to the identified RPA ChIP binding sites. Taken together, these associations demonstrate a prominent role of H3 lysine 56 acetylation in the formation of DNA breaks within recombination hotspot regions.

The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy.

Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.