Boron phosphide under pressure: in situ study by Raman scattering and X-ray diffraction

Cubic boron phosphide BP has been studied in situ by X-ray diffraction and Raman scattering up to 55 GPa at 300 K in a diamond anvil cell. The bulk modulus of B0 = 174(2) GPa has been established, which is in excellent agreement with our ab initio calculations. The data on Raman shift as a function of pressure, combined with equation-of-state data, allowed us to estimate the Gr\"uneisen parameters of the TO and LO modes of zinc-blende structure, {\gamma}GTO = 1.16 and {\gamma}GLO = 1.04, just like in the case of other AIIIBV diamond-like phases, for which {\gamma}GTO > {\gamma}GLO = 1. We also established that the pressure dependence of the effective electro-optical constant {\alpha} is responsible for a strong change in relative intensities of the TO and LO modes from ITO/ILO ~0.25 at 0.1 MPa to ITO/ILO ~2.5 at 45 GPa, for which we also find excellent agreement between experiment and theory

The impact of demographic, anthropometric and athletic characteristics on left atrial size in athletes.

The structural adaptations of the “athlete’s heart” include left atrial (LA) enlargement. A literature search was performed based on PubMed listings up to 2nd November 2019 using "athletes AND left atrium", "athletes AND left atrial", "sports AND left atrium", "sports AND left atrial", “exercise AND left atrium” and “exercise AND left atrial” as the search terms. Eligible studies included those reporting the influence of demographic, anthropometric and athletic characteristics on left atrial size in athletes. A total of 58 studies were included in this review article. Although LA volume has been reported to be greater in males compared to females when indexed for body surface area (BSA), there was no difference between sexes. The positive association between LA size and age in athletes may reflect the increase in body size with maturation in nonadult athletes and the training age of endurance athletic activity in adult athletes. Caucasian and black athletes have been demonstrated to exhibit similar LA enlargement. The positive association of LA size with lean body mass possibly accounts for the relationship of LA size with BSA. LA enlargement has been reported only in endurance-trained, but not in strength-trained athletes. LA size appears to increase with an increase in both the volume and intensity of endurance training. LA size correlates independently with the training age of endurance athletes. The athlete’s characteristics that independently determine LA size include lean body mass, endurance training and training age

Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation.

Myeloid cell interactions with cells of the adaptive immune system are an essential aspect of immunity. A key aspect of that interrelationship is its modulation by the microenvironment. Oxygen is known to influence myelosuppression of T cell activation in part via the Hypoxia inducible (HIF) transcription factors. A number of drugs that act on the HIF pathway are currently in clinical use and it is important to evaluate how they act on immune cell function as part of a better understanding of how they will influence patient outcomes. We show here that increased activation of the HIF pathway, either through deletion of the negative regulator of HIF, the von Hippel-Lindau (VHL) gene, in myeloid cells, or through pharmacological inhibitors of VHL-mediated degradation of HIF, potently suppresses T cell proliferation in myeloid cell/T cell culture. These data demonstrate that both pharmacological and genetic activation of HIF in myeloid cells can suppress adaptive cell immune response

Acute and chronic hypoxia differentially predispose lungs for metastases

Abstract: Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression

The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG-treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG-treated CD19-CAR-T cells in patients with B-cell malignancies

Cutaneous exposure to hypoxia does not affect skin perfusion in humans.

$\textbf{Aim:}$ Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O$_2$ availability. Specifically, a reduction in skin-surface PO$_2$ attenuates transcutaneous O$_2$ diffusion, and hence epidermal O$_2$ supply. In response, epidermal HIF-1$\alpha$ expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide-dependent vasodilation. Here, we investigated whether the same mechanism exists in humans. $\textbf{Methods:}$ In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O$_2$-enriched (42%) breathing gas (Hypoxia$_\text{Skin}$), and once barometric pressure and inspired O$_2$ fraction were normal (Control$_1$). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O$_2$ was expelled from one bag by nitrogen flushing (Anoxia$_\text{Skin}$), whereas the other bag was flushed with air (Control$_2$). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF-1$\alpha$ expression was determined by immunohistochemical staining in forearm skin biopsies. $\textbf{Results:}$ Skin blood flux during Hypoxia$_\text{Skin}$ and Anoxia$_\text{Skin}$ remained similar to the corresponding Control trial ($P$ = 0.67 and $P$ = 0.81). Immunohistochemically stained epidermal HIF-1$\alpha$ was detected on 8.2 ± 6.1 and 5.3 ± 5.7% of the analysed area during Hypoxia$_\text{Skin}$ and Control$_1$ ($P$ = 0.30) and on 2.3 ± 1.8 and 2.4 ± 1.8% during Anoxia$_\text{Skin}$ and Control$_2$ ($P$ = 0.90) respectively. $\textbf{Conclusion:}$ Reductions in skin-surface PO$_2$ do not affect skin perfusion in humans. The unchanged epidermal HIF-1$\alpha$ expression suggests that epidermal O$_2$ homoeostasis was not disturbed by Hypoxia$_\text{Skin}$/Anoxia$_\text{Skin}$, potentially due to compensatory increases in arterial O$_2$ extraction.Gösta Fraenckel Foundatio

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

Funder: Vetenskapsrådet; FundRef: http://dx.doi.org/10.13039/501100004359Funder: Cancerfonden; FundRef: http://dx.doi.org/10.13039/501100002794Funder: Barncancerfonden; FundRef: http://dx.doi.org/10.13039/501100006313Funder: Svenska Läkaresällskapet; FundRef: http://dx.doi.org/10.13039/501100007687Funder: Cancer Research UK; FundRef: http://dx.doi.org/10.13039/501100000289Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy

The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia.

Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia

Glycolytic Response to Inflammation Over Time: Role of Myeloid HIF-1alpha

The in vivo response to lipopolysaccharide (LPS) occurs rapidly and has profound physiological and metabolic effects. The hypoxia inducible (HIF) transcription factor is an intrinsic and essential part of inflammation, and is induced by LPS. To determine the importance of the HIF response in regulating metabolism following an LPS response, glucose uptake was quantified in a time dependent manner in mice lacking HIF-1α in myeloid cells. We found that deletion of HIF-1α has an acute protective effect on LPS-induced hypoglycemia. Furthermore, reduced glucose uptake was observed in the heart and brown fat, in a time dependent manner, following loss of HIF-1α. To determine the physiological significance of these findings, cardiovascular, body temperature, and blood pressure changes were subsequently quantified in real time using radiotelemetry measurements. These studies reveal the temporal aspects of HIF-1α as a regulator of the metabolic response to acute LPS-induced inflammation