Obstructive sleep apnea and excessive daytime sleepiness among commercial motor vehicle drivers in Lusaka, Zambia.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a risk factor for a major public health problem, car crashes, due to excessive daytime sleepiness (EDS). Commercial vehicle driving (CVD) is a hazardous occupation, having a high fatality rate worldwide. There have been no studies on EDS and OSA in Zambia despite the high rate of annual road traffic accidents (RTAs). We aim to determine the prevalence of EDS and OSA risk among CVDs in Lusaka, Zambia, to assess the impact of OSA on high RTA rates. METHODS: This was a cross-sectional study. The STOP BANG questionnaire and the Epworth Sleepiness Scale were used. Consecutive sampling of drivers was done who were divided into low and high risk of OSA (HROSA). The risk factors associated with OSA in the bivariate analyses were subjected to a multivariate logistic regression model. RESULTS: One hundred thirty-six drivers participated in the study (all male) with a mean age of 48 ± 5 years. The prevalence of HROSA was 22.8% out of whom 67.7% also had a EDS. Only 9.6% of the total cohort had EDS without HROSA. Using Fisher's exact test, HROSA was significantly associated with older age (> 50 years, P < .001), obesity (body mass index >30, P < .001), neck circumference of > 40 cm (P = .032), and hypertension (P < .001). Snoring and EDS were significantly associated with RTAs (P < .0001 and P = .007, respectively). CONCLUSIONS: High risk of OSA and EDS are common among CMV drivers in Zambia and underdiagnosed. The risk factors for OSA are amenable to preventive interventions. CITATION: Simpamba K, May JL, Waghat A, Attarian H, Mateyo K. Obstructive sleep apnea and excessive daytime sleepiness among commercial motor vehicle drivers in Lusaka, Zambia. J Clin Sleep Med. 2023;19(7):1191-1198.

Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease.

Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring.

IDH3α regulates one-carbon metabolism in glioblastoma.

Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity, S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation.

Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.

Dual bioluminescence and near-infrared fluorescence monitoring to evaluate spherical nucleic acid nanoconjugate activity in vivo.

RNA interference (RNAi)-based gene regulation platforms have shown promise as a novel class of therapeutics for the precision treatment of cancer. Techniques in preclinical evaluation of RNAi-based nanoconjugates have yet to allow for optimization of their gene regulatory activity. We have developed spherical nucleic acids (SNAs) as a blood-brain barrier-/blood-tumor barrier-penetrating nanoconjugate to deliver small interfering (si) and micro (mi)RNAs to intracranial glioblastoma (GBM) tumor sites. To identify high-activity SNA conjugates and to determine optimal SNA treatment regimens, we developed a reporter xenograft model to evaluate SNA efficacy in vivo. Engrafted tumors stably coexpress optical reporters for luciferase and a near-infrared (NIR) fluorescent protein (iRFP670), with the latter fused to the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT). Using noninvasive imaging of animal subjects bearing reporter-modified intracranial xenografts, we quantitatively assessed MGMT knockdown by SNAs composed of MGMT-targeting siRNA duplexes (siMGMT-SNAs). We show that systemic administration of siMGMT-SNAs via single tail vein injection is capable of robust intratumoral MGMT protein knockdown in vivo, with persistent and SNA dose-dependent MGMT silencing confirmed by Western blotting of tumor tissue ex vivo. Analyses of SNA biodistribution and pharmacokinetics revealed rapid intratumoral uptake and significant intratumoral retention that increased the antitumor activity of coadministered temozolomide (TMZ). Our study demonstrates that dual noninvasive bioluminescence and NIR fluorescence imaging of cancer xenograft models represents a powerful in vivo strategy to identify RNAi-based nanotherapeutics with potent gene silencing activity and will inform additional preclinical and clinical investigations of these constructs.

Plasmonic gold and luminescent silicon nanoplatforms for multimode imaging of cancer cells.

The development of multimodal nanoparticle platforms is desirable for cancer nanotechnology applications. Creating single nanoplatforms with both plasmonic and photoluminescent optical properties has remained a challenge, because combining discrete entities each having one of these unique properties typically results in the attenuation of one of the desirable properties. Here, we overcome challenges associated with combining plasmonic gold with luminescent silicon nanocrystals for biological imaging applications by incorporating multiple silicon quantum dots into the core of a micelle and then depositing gold on the surface of the nanostructure. Within the newly developed nanoconstruct, the gold shell exhibits plasmonic light scattering properties useful for dark field imaging, while the silicon nanocrystals maintain their photoluminescence. The result is a nanoplatform with both plasmonic and luminescent properties in a useful form. Multimodal imaging of pancreatic cancer cells demonstrates overlap of luminescence from the silicon quantum dots with light scattering from the gold shell. This approach can be tailored to other formulations and address the challenge of fluorescence attenuation that is typically observed when quantum dots are combined with plasmonic materials. The usefulness of these particles may eventually extend beyond multimodal imaging to include photothermal treatment.

Bioconjugation of luminescent silicon quantum dots to gadolinium ions for bioimaging applications.

Luminescent imaging agents and MRI contrast agents are desirable components in the rational design of multifunctional nanoconstructs for biological imaging applications. Luminescent biocompatible silicon quantum dots (SiQDs) and gadolinium chelates can be applied for fluorescence microscopy and MRI, respectively. Here, we report the first synthesis of a nanocomplex incorporating SiQDs and gadolinium ions (Gd³âº) for biological applications. The nanoconstruct is composed of a PEGylated micelle, with hydrophobic SiQDs in its core, covalently bound to DOTA-chelated Gd³âº. Dynamic light scattering reveals a radius of 85 nm for these nanoconstructs, which is consistent with the electron microscopy results depicting radii ranging from 25 to 60 nm. Cellular uptake of the probes verified that they maintain their optical properties within the intracellular environment. The magnetic resonance relaxivity of the nanoconstruct was 2.4 mM⁻¹ s⁻¹ (in terms of Gd³âº concentration), calculated to be around 6000 mM⁻¹ s⁻¹ per nanoconstruct. These desirable optical and relaxivity properties of the newly developed probe open the door for use of SiQDs in future multimodal applications such as tumour imaging.