Plasma Phospholipid Polyunsaturated Fatty Acid Associations with Neurocognition.

Neurocognitive deficits are implicated in major depressive disorder (MDD) and suicidal behavior, and cognitive function may be affected by blood levels of polyunsaturated fatty acids (PUFAs). Neuroprotective functions have been described for omega-3 (n-3) PUFAs, while omega-6 (n-6) PUFAs exhibit broadly opposing activities. Both classes of PUFAs are linked to MDD and suicidal behavior. However, few studies have investigated the relationships between PUFAs and neurocognitive function with respect to MDD or suicidal behavior. Among participants with MDD (n = 45) and healthy volunteers (HV, n = 30) we assessed performance on tasks of attentional capacity and executive function and its relationship to plasma phospholipid PUFA levels, expressed as a percentage of total plasma phospholipids, for eicosapentaenoic acid (EPA%), docosahexaenoic acid (DHA%), and arachidonic acid (AA%). Regression models tested the correlations between PUFA levels and task performance in three groups: MDD with a history of suicide attempt (SA, n = 20), MDD with no attempts (NA, n = 25), and HV. Interaction testing indicated a significant positive correlation of EPA% with continuous performance test scores in the NA group (F = 4.883, df = 2,72, p = 0.01), a measure of sustained attention. The AA% correlated negatively with performance on two executive function tasks, object alternation (beta = -3.97, z-score = -2.67, p = 0.008) and the Wisconsin card sort (beta = 0.80, t-score = -2.16, df = 69, p = 0.035), after adjustment for group and age, with no group effects. Our findings suggest a role for PUFA imbalance in attentional functioning and executive performance; however, no MDD-specific effect was observed.

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

BACKGROUND: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers uses telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology-directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult glioblastoma (GBM) patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood. METHODS: We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo. RESULTS: Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis. CONCLUSIONS: SMARCAL1 deficiency is permissive to ALT and promotes gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anticancer therapeutics that target the ALT phenotype.

Therapeutic Gene Editing in Inherited Retinal Disorders.

Since the development of CRISPR/Cas9 gene editing in 2012, therapeutic editing research has produced several phase 1-2a trials. Here we provide an overview of the mechanisms and applications of various gene-editing technologies including adeno-associated virus vectors, lentiviruses, CRISPR/Cas9 systems, base and prime editing, antisense oligonucleotides, short-hairpin RNAs, Cas13, and adenosine deaminase acting on RNA for the treatment of various inherited retinal diseases (IRDs). We outline the various stages of clinical trials using these technologies and the impacts they have made in advancing the practice of medicine.

Circular RNAs regulate cancer-related signaling pathways and serve as potential diagnostic biomarkers for human cancers.

Circular RNAs (circRNAs) are RNAs that have an important role in various pathological processes, including cancer. After the usage of high-throughput RNA sequencing, many circRNAs were found to be differentially expressed in various cancer cell lines and regulate cell signaling pathways by modulating particular gene expressions. Understanding their role in these pathways and what cancers they are found in can set the stage for identifying diagnostic and prognostic biomarkers and therapeutic targets of cancer. This paper will discuss which circRNAs are found in different cancers and what mechanisms they use to upregulate or downregulate certain cellular components.

BRD4 Prevents R-Loop Formation and Transcription-Replication Conflicts by Ensuring Efficient Transcription Elongation.

Effective spatio-temporal control of transcription and replication during S-phase is paramount to maintaining genomic integrity and cell survival. Dysregulation of these systems can lead to conflicts between the transcription and replication machinery, causing DNA damage and cell death. BRD4 allows efficient transcriptional elongation by stimulating phosphorylation of RNA polymerase II (RNAPII). We report that bromodomain and extra-terminal domain (BET) protein loss of function (LOF) causes RNAPII pausing on the chromatin and DNA damage affecting cells in S-phase. This persistent RNAPII-dependent pausing leads to an accumulation of RNA:DNA hybrids (R-loops) at sites of BRD4 occupancy, leading to transcription-replication conflicts (TRCs), DNA damage, and cell death. Finally, our data show that the BRD4 C-terminal domain, which interacts with P-TEFb, is required to prevent R-loop formation and DNA damage caused by BET protein LOF.

Phosphofructokinase 1 Platelet Isoform Promotes ß-Catenin Transactivation for Tumor Development.

Metabolism plays a critical role in direct regulation of a variety of cellular activities via metabolic enzymes and metabolites. Here, we demonstrate that phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis, promotes EGFR activation-induced nuclear translocation and activation of ß-catenin, thereby enhancing the expression of its downstream genes CCND1 and MYC in human glioblastoma cells. Importantly, we showed that EGFR-phosphorylated PFKP Y64 has a critical role in AKT activation and AKT-mediated ß-catenin S552 phosphorylation and subsequent ß-catenin transactivation and promotion of tumor cell glycolysis, migration, invasion, proliferation, and brain tumor growth. These findings highlight a novel mechanism underlying a glycolytic enzyme-mediated ß-catenin transactivation and underscore the integrated and reciprocal regulation of metabolism and gene expression, which are two fundamental biological processes in tumor development.

Prognostic value of receptor status conversion following neoadjuvant chemotherapy in breast cancer patients: a systematic review and meta-analysis.

Biomarkers of breast cancer such as hormone receptors (HR) and human epidermal growth factor 2 (HER2) can be altered after neoadjuvant chemotherapy (NAC). However, whether the conversion of these receptors affects the prognosis of patients remains to be determined. We sought to evaluate the prognostic value of HR and HER2 receptors before and after NAC and to analyze their clinical implications. Relevant studies were used to calculate the pooled hazard ratios, 95% confidence interval (95% CI). This meta-analysis included eight studies with 2847 patients. Compared to patients with HR+ → +, patients with HR+ → - have shorter disease free survival (DFS) (hazard ratio = 2.64, 95% CI 1.86-3.75) and overall survival (OS) (hazard ratio = 2.99, 95% CI 1.97-4.54). Furthermore, patients with HR- → + tend to achieve better DFS (hazard ratio = 0.83, 95% CI 0.60-1.17) compared to patients with HR- → -. Patients with HR- → + gain better OS (hazard ratio = 0.67, 95% CI 0.46-0.99) compared to patients exhibiting HR- → -. When comparing patients with HER2+ → - to patients with HER2+ → +, patients with HER2+ → - tended to achieve better DFS (hazard ratio = 1.65, 95% CI 1.08-2.53) though results for OS (hazard ratio = 1.16, 95% CI 0.54-2.49) were not statistically significant. Our data strongly support the need for redetection of HR and HER2 receptor status of surgical sample following neoadjuvant therapy. Changes in HR status induced by NAC can be used as a prognostic factor in breast cancer patients for predicting both OS and DFS. HER2 change may also be valuable for predicting prognosis. Further research should explore therapeutic strategies for those presenting receptor status conversion.