Multinational companies increasingly focus on subsistence marketplaces, given their enormous market potential. Nevertheless, their potential is untapped because subsistence consumers face extreme ...constraints. The authors contend that subsistence consumers need marketplace literacy to participate effectively and beneficially in marketplaces. Marketplace literacy entails the knowledge and skills that enable them to participate in a marketplace as both consumers and entrepreneurs. This is crucial for subsistence consumers, as they often must function in both roles to survive. Previous research, however, has not empirically examined the influence of marketplace literacy on well-being or marketing outcomes related to well-being. To address this gap, the authors implemented three large-scale field experiments with approximately 1,000 people in 34 remote villages in India and Tanzania. They find that marketplace literacy causes an increase in psychological well-being and consumer outcomes related to well-being (e.g., consumer confidence, decision-making ability), especially for subsistence consumers with lower marketplace access, and it causes an increase in entrepreneurial outcomes related to well-being (e.g., starting a microenterprise) for those with higher marketplace access. Overall, this research generates practical implications for the use of marketplace literacy as a pathway to a better world.
Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic ...fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism among the top deregulated pathways. Ablation of farnesoid X receptor dramatically increases enterohepatic bile acid levels and jet-lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.
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•Chronic circadian disruption induces NAFLD and spontaneous hepatocarcinogenesis•Circadian dysfunction promotes global gene deregulation and metabolic disruption•The nuclear receptor CAR drives NAFLD to NASH, fibrosis, and HCC progression•Circadian disruption activates CAR via sympathetic dysfunction and cholestasis
Kettner et al. show that experimental chronic jet lag induces persistent deregulation of liver gene expression and metabolism, culminating in the development of hepatocellular carcinoma. The bile acid receptor FXR and xenobiotic receptor CAR play an important role in this process.
Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that ...define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.
This work presents detailed life cycle assessment (LCA) of a novel process to produce ethanol from rice straw in India. The process has been successfully demonstrated and proposed to be scaled-up, ...and detailed LCA of that process is the key novel contribution of this work. Cradle-to-gate system boundary is considered, which includes rice farming, transportation, and processing at the biorefinery. 1 l of ethanol is used as the functional unit. The process data are based on the demonstration-scale plant as well as the scale-up plant of 100 kilo litres per day being designed based on the same process. The life cycle inventory data are taken from the Ecoinvent® database. OpenLCA 1.6 is used to develop the LCA model, and impact assessment is performed using ILCD 2011 midpoint indicators. The GWP was 2.82 kg of CO
2
eq. per liter of ethanol using economic impact allocation. Electricity contributed 86% of the total impact, and use of hydroelectricity reduced the impact to 0.07 kg of CO
2
eq. per liter of ethanol. If additional benefits due to this process are considered, the impact reduced to − 0.392 kg of CO
2
eq. per liter of ethanol indicating considerable relative reduction in the GWP. Without allocation and implementing system expansion, the impact was 3.35 kg of CO
2
eq. per liter of ethanol. The energy return on investment was 1.59, indicating that the process was net energy positive. The lower bound on the life cycle water use was 507.4 l per liter of ethanol. The integrated nature of the process producing various value-added chemicals provided significant benefits from the perspective of environmental impacts.
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Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of ...cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC.
The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover ...dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.
Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the ...loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.
Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). ...Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.
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•Metastatic TNBC is dependent on mitochondrial FAO energy metabolism•FAO activates c-Src via autophosphorylation at residue Y419•CPT genes are critical in TNBC tumor progression and metastasis•Reduction of fat or FAO may provide clinical benefit to TNBC patients
Park et al. show that mitochondrial fatty acid β oxidation is an important energy pathway in metastatic triple-negative breast cancer. Their results uncover the significance of mitochondrial energy reprogramming in the tumor properties of triple-negative breast cancer and regulation of the Src cancer pathway by post-translational modification.
An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. ...Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.
Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. In this study, these 2 epigenetic mutations cooperated to induce leukemia. ...Leukemia-initiating cells from Dnmt3a−/− mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor–like immunophenotype, activate a stem-cell–like gene signature, and repress differentiated progenitor genes. We observed an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). HDAC inhibitors rapidly reversed the H3K9 methylation/acetylation imbalance in diseased mouse HSPCs while reducing the leukemia burden. In addition, using targeted metabolomic profiling for the first time in mouse leukemia models, we also showed that prostaglandin E2 is overproduced in double-mutant HSPCs, rendering them sensitive to prostaglandin synthesis inhibition. These data revealed that Dnmt3a and Idh2 mutations are synergistic events in leukemogenesis and that HSPCs carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC, which may reveal new therapeutic opportunities for patients carrying IDH1/2 mutations.
•Dnmt3a loss and IDH2 neomorphic mutation synergistically induce hematopoietic malignancy.•Dnmt3aKO-IDH2 mutant mouse leukemia is sensitive to HDAC inhibition and overproduces prostaglandin E2, to maintain abnormal self-renewal.
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