Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). ...Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19.
We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ.
A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality.
One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients.
Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration.
Obstruction of justice is any "interference with the orderly administration of law and justice," and may consist of "a medley of crimes." This area of the law is governed principally by 18 U.S.C. § ...1501 through § 1520, which protect the integrity of proceedings before the federal judiciary and other governmental bodies. Here, Chao focuses on the provisions given the most expansive treatment by courts.
The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)
. Wild-type p53 accumulates in response to cellular stress, and ...regulates gene expression to alter cell fate and prevent tumour development
. Wild-type p53 is also known to modulate cellular metabolic pathways
, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase-an enzyme of the tricarboxylic acid cycle-specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine ...hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.
In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth.
Biodiversity experiments have shown that species loss reduces ecosystem functioning in grassland. To test whether this result can be extrapolated to forests, the main contributors to terrestrial ...primary productivity, requires large-scale experiments. We manipulated tree species richness by planting more than 150,000 trees in plots with 1 to 16 species. Simulating multiple extinction scenarios, we found that richness strongly increased stand-level productivity. After 8 years, 16-species mixtures had accumulated over twice the amount of carbon found in average monocultures and similar amounts as those of two commercial monocultures. Species richness effects were strongly associated with functional and phylogenetic diversity. A shrub addition treatment reduced tree productivity, but this reduction was smaller at high shrub species richness. Our results encourage multispecies afforestation strategies to restore biodiversity and mitigate climate change.
Current challenges in capturing naive human pluripotent stem cells (hPSCs) suggest that the factors regulating human naive versus primed pluripotency remain incompletely defined. Here we demonstrate ...that the widely used Essential 8 minimal medium (E8) captures hPSCs at a naive-to-primed intermediate state of pluripotency expressing several naive-like developmental, bioenergetic, and epigenomic features despite providing primed-state-sustaining growth factor conditions. Transcriptionally, E8 hPSCs are marked by activated lipid biosynthesis and suppressed MAPK/TGF-β gene expression, resulting in endogenous ERK inhibition. These features are dependent on lipid-free culture conditions and are lost upon lipid exposure, whereas short-term pharmacological ERK inhibition restores naive-to-primed intermediate traits even in the presence of lipids. Finally, we identify de novo lipogenesis as a common transcriptional signature of E8 hPSCs and the pre-implantation human epiblast in vivo. These findings implicate exogenous lipid availability in regulating human pluripotency and define E8 hPSCs as a stable, naive-to-primed intermediate (NPI) pluripotent state.
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•Essential 8 (E8) hPSCs exhibit naive-to-primed intermediate (NPI) pluripotency features•NPI traits are dependent on lipid-free E8 composition•Lipid deprivation triggers endogenous ERK inhibition despite exposure to high FGF2•De novo lipogenesis marks transcriptomes of E8 hPSCs and human pre-implantation epiblast
The regulation of human naive pluripotency remains incompletely understood. Cornacchia et al. show that lipid-free culture conditions are sufficient to skew human pluripotent stem cells toward a naive-to-primed intermediate state via endogenous ERK inhibition. Transcriptomic analyses suggest that pluripotency regulation via de novo lipogenesis mimics in vivo regulation during pre-implantation development.
Chalcogenide semiconductors offer excellent optoelectronic properties for their use in solar cells, exemplified by the commercialization of Cu(In,Ga)Se2- and CdTe-based photovoltaic technologies. ...Recently, several other chalcogenides have emerged as promising photoabsorbers for energy harvesting through the conversion of solar energy to electricity and fuels. The goal of this review is to summarize the development of emerging binary (Sb2X3, GeX, SnX), ternary (Cu2SnX3, Cu2GeX3, CuSbX2, AgBiX2), and quaternary (Cu2ZnSnX4, Ag2ZnSnX4, Cu2CdSnX4, Cu2ZnGeX4, Cu2BaSnX4) chalcogenides (X denotes S/Se), focusing especially on the comparative analysis of their optoelectronic performance metrics, electronic band structure, and point defect characteristics. The performance limiting factors of these photoabsorbers are discussed, together with suggestions for further improvement. Several relatively unexplored classes of chalcogenide compounds (such as chalcogenide perovskites, bichalcogenides, etc.) are highlighted, based on promising early reports on their optoelectronic properties. Finally, pathways for practical applications of emerging chalcogenides in solar energy harvesting are discussed against the backdrop of a market dominated by Si-based solar cells.
Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the “oncometabolite” D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block ...differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).
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•Mammalian cells selectively produce L-2-hydroxyglutarate in response to hypoxia•L-2HG arises from reduction of glutamine-derived α-ketoglutarate•Lactate dehydrogenase A represents the primary source of hypoxia-induced L-2HG•L-2HG is necessary and sufficient for enhanced H3K9me3 in response to hypoxia
The oncometabolite D-2-hydroxyglutarate (D-2HG) produced by mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) contributes to cancer pathogenesis. Intlekofer et al. and Oldham et al. now show that the enantiomer L-2HG is selectively produced in hypoxic cells to regulate histone methylation levels and to help mitigate cellular reductive stress through inhibition of glycolysis and electron transport.
Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown ...of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
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