Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.

Background: Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic.

Monitoring the sleep health of adults: a scoping review of routine national surveillance systems.

Study Objectives: The aims of this review were to identify existing national surveillance systems monitoring one or more domains of sleep health in adults, and to describe the specific sleep health indicators used.

Methods: We systematically searched the gray and peer-reviewed literature for routinely conducted cross-sectional and longitudinal nationally representative health surveys that included the assessment of at least one domain of sleep health. The methodology involved: (1) targeted searches of the websites of national and international health agencies and statistics departments for 199 countries, (2) country-specific customized internet searches, and (3) country-specific electronic database searches of PubMed.

The enzymatic oxygen sensor cysteamine dioxygenase binds its protein substrates through their N-termini.

The non-heme iron-dependent dioxygenase 2-aminoethanethiol (aka cysteamine) dioxygenase (ADO) has recently been identified as an enzymatic oxygen sensor that coordinates cellular changes to hypoxia by regulating the stability of proteins bearing an N-terminal cysteine (Nt-cys) through the N-degron pathway. It catalyzes O-dependent Nt-cys sulfinylation, which promotes proteasomal degradation of the target. Only a few ADO substrates have been verified, including regulators of G-protein signaling (RGS) 4 and 5, and the proinflammatory cytokine interleukin-32, all of which exhibit cell and/or tissue specific expression patterns.

A comparison of cardiovascular disease associations of time-domain oximetry parameters in sleep apnoea cases from the Sleep Heart Health Study.

Polysomnograms (PSGs) contain a wealth of physiological information that is routinely recorded but not utilised in sleep studies. Intermittent hypoxia arising from obstructive sleep apnoea (OSA) events is an important risk in the later development of cardiovascular disease (CVD). Analysis of oximetry patterns from PSG studies may enable early assessment of CVD risk.

Overexpression of VIRMA confers vulnerability to breast cancers via the mA-dependent regulation of unfolded protein response.

Virilizer-like mA methyltransferase-associated protein (VIRMA) maintains the stability of the mA writer complex. Although VIRMA is critical for RNA mA deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is amplified and overexpressed in 15-20% of breast cancers.

Clinical Efficacy of the Oral Health System by Fresh Health Inc. in Adults on Gingivitis and Plaque in a 3-Arm, 30-Day Study as Compared to String Floss and Manual Brushing.

Objective: To evaluate the safety and efficacy of the Oral Health System by Fresh Health Inc., used in conjunction with manual toothbrushing (Fresh + MTB) as compared to string floss and manual toothbrushing (floss + MTB) and manual toothbrushing (MTB) alone, as measured by clinical signs of gingivitis, plaque reduction, pocket depth, and bleeding.

Methods: One hundred ninety-two (192) generally healthy adults exhibiting signs of gingivitis completed this 30-day randomized, controlled, examiner-blinded, three-group parallel study design.

Sodium Propionate or Sodium Butyrate Promotes Fatty Acid Oxidation in HepG2 Cells Under Oxidative Stress.

The beneficial effects of sodium butyrate (NaB) and sodium propionate (NaP) on fatty acid oxidation (FAO) genes and production of proinflammatory cytokines related to nonalcoholic fatty liver disease (NAFLD) were evaluated using HepG2 human liver hepatocellular carcinoma cells exposed to palmitate/oleate or lipopolysaccharides (LPSs) as a model. The results showed that NaP or NaB was able to promote FAO, regulate lipolysis, and reduce reactive oxygen species production by significantly increasing the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1), peroxisome proliferator-activated receptor alpha (PPAR), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 alpha (CPT1), fibroblast growth factor 21 (FGF21), and uncoupling protein 2 (UCP2) in HepG2 cells. Together, NaP and NaB may produce greater effects by increasing CPT1, PPAR, and UCP2 mRNA expression in LPS-treated HepG2 cells and by increasing CPT1 and ATGL mRNA expression in palmitate-/oleate-treated HepG2 cells.

Intermittent hypoxia enhances the expression of hypoxia inducible factor HIF1A through histone demethylation.

The cellular response to hypoxia is regulated through enzymatic oxygen sensors, including the prolyl hydroxylases, which control degradation of the well-known hypoxia inducible factors (HIFs). Other enzymatic oxygen sensors have been recently identified, including members of the KDM histone demethylase family. Little is known about how different oxygen-sensing pathways interact and if this varies depending on the form of hypoxia, such as chronic or intermittent.

Comparative associations of oximetry patterns in Obstructive Sleep Apnea with incident cardiovascular disease.

Study Objectives: Intermittent hypoxia is a key mechanism linking Obstructive Sleep Apnea (OSA) to cardiovascular disease (CVD). Oximetry analysis could enhance understanding of which OSA phenotypes are associated with CVD risk. The aim of this study was to compare associations of different oximetry patterns with incident CVD in men and women with OSA.

Improving the synergistic combination of programmed death-1/programmed death ligand-1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment.

Immune checkpoint inhibition with PD-1/PD-L1 blockade is a promising area in the field of anti-cancer therapy. Although clinical data have revealed success of PD-1/PD-L1 blockade as monotherapy or in combination with CTLA-4 or chemotherapy, the combination with radiotherapy could further boost anti-tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD-1/PD-L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia.

Predicting Cardiovascular Outcomes Using the Respiratory Event Desaturation Transient Area Derived from Overnight Sleep Studies.

A new method for calculation of an overnight oximetry signal metric which is predictive of cardiovascular disease (CVD) outcomes in individuals undergoing an overnight sleep test is presented. The metric - the respiratory event desaturation transient area (REDTA) - quantifies the desaturation associated with respiratory events. Data from the Sleep Heart Health Study, which includes overnight oximetry signals and long-term CVD outcomes, was used to develop and test the parameter.

Metabolite signatures of heart failure, sleep apnoea, their interaction, and outcomes in the community.

Aims: Sleep apnoea and congestive heart failure (CHF) commonly co-exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome.

Methods And Results: We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively.

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy.

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer.

Circadian rhythms regulate many physiological and behavioral processes, including sleep, metabolism and cell division, which have a 24-h oscillation pattern. Rhythmicity is generated by a transcriptional-translational feedback loop in individual cells, which are synchronized by the central pacemaker in the brain and external cues. Epidemiological and clinical studies indicate that disruption of these rhythms can increase both tumorigenesis and cancer progression.

Is Cumulative Time of Oxygen Desaturation a Better Predictor of Cardiovascular Mortality than Apnoea Hypopnoea Index?

In this paper, we explored the link between sleep apnoea and cardiovascular disease (CVD) using a time-series statistical measure of sleep apnoea-related oxygen desaturation. We compared the performance of a hypoxic measure derived from the polysomnogram with the Apnoea Hypopnoea Index (AHI) in predicting CVD mortality in patients of the Sleep Heart Health Study.We estimated the relative cumulative time of SpO below 90% (T90) using pulse oximetry signals from polysomnogram recordings as the hypoxic measure of desaturation patterns.

Out of breath, out of time: interactions between HIF and circadian rhythms.

Humans have internal circadian clocks that ensure that important physiological functions occur at specific times of the day. These molecular clocks are regulated at the genomic level and exist in most cells of the body. Multiple circadian resetting cues have been identified, including light, temperature, and food.

A zebrafish model of tuberculosis comorbidity and the effects of HIF-activating intervention.

Comorbidities are an important factor in tuberculosis pathophysiology and treatment but are understudied in animal models. Schild et al. present a zebrafish model of Mycobacterium marinum infection and wound comorbidity that retains responsiveness to protective hypoxia-inducible factor-1α activation as an example of a host-directed therapy.

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas.

Radiotherapy is the cornerstone of treatment of high-grade gliomas (HGGs). It eradicates tumor cells by inducing oxidative stress and subsequent DNA damage. Unfortunately, almost all HGGs recur locally within several months secondary to radioresistance with intricate molecular mechanisms.

A Cell Culture Model that Mimics Physiological Tissue Oxygenation Using Oxygen-permeable Membranes.

Dissolved oxygen and its availability to cells in culture is an overlooked variable which can have significant consequences on experimental research outcomes, including reproducibility. Oxygen sensing pathways play key roles in cell growth and behavior and pericellular oxygen levels should be controlled when establishing models. Standard cell culture techniques do not have adequate control over pericellular oxygen levels.

C-Terminal HSP90 Inhibitors Block the HIF-1 Hypoxic Response by Degrading HIF-1α through the Oxygen-Dependent Degradation Pathway.

Background/aims: Hypoxia Inducible Factor-1α (HIF-1α) is involved in cancer progression and is stabilized by the chaperone HSP90 (Heat Shock Protein 90), preventing degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90, which blocks binding to HIF-1α and induces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments partially because they induce a heat shock response.

Determining the Redox Potential of a Protein Disulphide Bond.

The redox potential of a protein disulphide bond is one of the most important factors for determining the role of a disulphide bond. Disulphide bonds can have a stabilizing role for the structure of a protein or they can play a functional role which can regulate protein bioactivity. Determining the redox potential of disulphides can help distinguish the functional from the structural disulphide bonds.

Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells.

Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression.

Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models.

Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients.