MiR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma

10.1371/journal.pone.0086872PLoS ONE91-POLN

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients

BACKGROUND: : Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression. METHODS: : The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load. RESULTS: : Humoral responses to COVID-19 vaccination were observed in 41/103 (40%) LTR at 28 days after the second vaccination. 62/103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation. CONCLUSIONS: : This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response

Return to work after a workplace-oriented intervention for patients on sick-leave for burnout - a prospective controlled study

<p>Abstract</p> <p>Background</p> <p>In the present study the effect of a workplace-oriented intervention for persons on long-term sick leave for clinical burnout, aimed at facilitating return to work (RTW) by job-person match through patient-supervisor communication, was evaluated. We hypothesised that the intervention group would show a more successful RTW than a control group.</p> <p>Methods</p> <p>In a prospective controlled study, subjects were identified by the regional social insurance office 2-6 months after the first day on sick leave. The intervention group (n = 74) was compared to a control group who had declined participation, being matched by length of sick leave (n = 74). The RTW was followed up, using sick-listing register data, until 1.5 years after the time of intervention.</p> <p>Results</p> <p>There was a linear increase of RTW in the intervention group during the 1.5-year follow-up period, and 89% of subjects had returned to work to some extent at the end of the follow-up period. The increase in RTW in the control group came to a halt after six months, and only 73% had returned to work to some extent at the end of the 1.5-year follow-up.</p> <p>Conclusions</p> <p>We conclude that the present study demonstrated an improvement of long-term RTW after a workplace-oriented intervention for patients on long-term sick leave due to burnout.</p> <p>Trial registration</p> <p>Current Controlled Trials NCT01039168.</p

Modeling Core Metabolism in Cancer Cells: Surveying the Topology Underlying the Warburg Effect

BACKGROUND: Alterations on glucose consumption and biosynthetic activity of amino acids, lipids and nucleotides are metabolic changes for sustaining cell proliferation in cancer cells. Irrevocable evidence of this fact is the Warburg effect which establishes that cancer cells prefers glycolysis over oxidative phosphorylation to generate ATP. Regulatory action over metabolic enzymes has opened a new window for designing more effective anti-cancer treatments. This enterprise is not trivial and the development of computational models that contribute to identifying potential enzymes for breaking the robustness of cancer cells is a priority. METHODOLOGY/PRINCIPAL FINDINGS: This work presents a constraint-base modeling of the most experimentally studied metabolic pathways supporting cancer cells: glycolysis, TCA cycle, pentose phosphate, glutaminolysis and oxidative phosphorylation. To evaluate its predictive capacities, a growth kinetics study for Hela cell lines was accomplished and qualitatively compared with in silico predictions. Furthermore, based on pure computational criteria, we concluded that a set of enzymes (such as lactate dehydrogenase and pyruvate dehydrogenase) perform a pivotal role in cancer cell growth, findings supported by an experimental counterpart. CONCLUSIONS/SIGNIFICANCE: Alterations on metabolic activity are crucial to initiate and sustain cancer phenotype. In this work, we analyzed the phenotype capacities emerged from a constructed metabolic network conformed by the most experimentally studied pathways sustaining cancer cell growth. Remarkably, in silico model was able to resemble the physiological conditions in cancer cells and successfully identified some enzymes currently studied by its therapeutic effect. Overall, we supplied evidence that constraint-based modeling constitutes a promising computational platform to: 1) integrate high throughput technology and establish a crosstalk between experimental validation and in silico prediction in cancer cell phenotype; 2) explore the fundamental metabolic mechanism that confers robustness in cancer; and 3) suggest new metabolic targets for anticancer treatments. All these issues being central to explore cancer cell metabolism from a systems biology perspective

Effectiveness of the AS03-Adjuvanted Vaccine against Pandemic Influenza Virus A/(H1N1) 2009 – A Comparison of Two Methods; Germany, 2009/10

During the autumn wave of the pandemic influenza virus A/(H1N1) 2009 (pIV) the German population was offered an AS03-adjuvanted vaccine. The authors compared results of two methods calculating the effectiveness of the vaccine (VE). The test-negative case-control method used data from virologic surveillance including influenza-positive and negative patients. An innovative case-series methodology explored data from all nationally reported laboratory-confirmed influenza cases. The proportion of reported cases occurring in vaccinees during an assumed unprotected phase after vaccination was compared with that occurring in vaccinees during their assumed protected phase. The test-negative case-control method included 1,749 pIV cases and 2,087 influenza test-negative individuals of whom 6 (0.3%) and 36 (1.7%), respectively, were vaccinated. The case series method included data from 73,280 cases. VE in the two methods was 79% (95% confidence interval (CI) = 35–93%; P = 0.007) and 87% (95% CI = 78–92%; P<0.001) for individuals less than 14 years of age and 70% (95% CI = −45%–94%, P = 0.13) and 74% (95% CI = 64–82%; P<0.001) for individuals above the age of 14. Both methods yielded similar VE in both age groups; and VE for the younger age group seemed to be higher

MUC1-C Oncoprotein Regulates Glycolysis and Pyruvate Kinase m2 Activity in Cancer Cells

Aerobic glycolysis in cancer cells is regulated by multiple effectors that include Akt and pyruvate kinase M2 (PKM2). Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed by human breast and other carcinomas. Here we show that transformation of rat fibroblasts by the oncogenic MUC1-C subunit is associated with Akt-mediated increases in glucose uptake and lactate production, consistent with the stimulation of glycolysis. The results also demonstrate that the MUC1-C cytoplasmic domain binds directly to PKM2 at the B- and C-domains. Interaction between the MUC1-C cytoplasmic domain Cys-3 and the PKM2 C-domain Cys-474 was found to stimulate PKM2 activity. Conversely, epidermal growth factor receptor (EGFR)-mediated phosphorylation of the MUC1-C cytoplasmic domain on Tyr-46 conferred binding to PKM2 Lys-433 and inhibited PKM2 activity. In human breast cancer cells, silencing MUC1-C was associated with decreases in glucose uptake and lactate production, confirming involvement of MUC1-C in the regulation of glycolysis. In addition, EGFR-mediated phosphorylation of MUC1-C in breast cancer cells was associated with decreases in PKM2 activity. These findings indicate that the MUC1-C subunit regulates glycolysis and that this response is conferred in part by PKM2. Thus, the overexpression of MUC1-C oncoprotein in diverse human carcinomas could be of importance to the Warburg effect of aerobic glycolysis

Perspectives on a ‘Sit Less, Move More’ Intervention in Australian Emergency Call Centres

Background: Prolonged sitting is associated with increased risk of chronic diseases. Workplace programs that aim to reduce sitting time (sit less) and increase physical activity (move more) have targeted desk-based workers in corporate and university settings with promising results. However, little is known about 'move more, sit less' programs for workers in other types of jobs and industries, such as shift workers. This formative research examines the perceptions of a 'sit less, move more' program in an Australian Emergency Call Centre that operates 24 hours per day, 7 days per week.  Methods: Participants were employees (N = 39, 72% female, 50% aged 36-55 years) recruited from Emergency Services control centres located in New South Wales, Australia. The 'sit less, move more' intervention, consisting of emails, posters and timer lights, was co-designed with the management team and tailored to the control centre environment and work practices, which already included electronic height-adjustable sit-stand workstations for all call centre staff. Participants reported their perceptions and experiences of the intervention in a self-report online questionnaire, and directly to the research team during regular site visits. Questionnaire topics included barriers and facilitators to standing while working, mental wellbeing, effects on work performance, and workplace satisfaction. Field notes and open-ended response data were analysed in an iterative process during and after data collection to identify the main themes.  Results: Whilst participants already had sit-stand workstations, use of the desks in the standing position varied and sometimes were contrary to expectations (e.g, less tired standing than sitting; standing when experiencing high call stress). Participants emphasised the "challenging" and "unrelenting" nature of their work. They reported sleep issues ("always tired"), work stress ("non-stop demands"), and feeling mentally and physically drained due to shift work and length of shifts. Overall, participants liked the initiative but acknowledged that their predominantly sitting habits were entrenched and work demands took precedence.  Conclusions: This study demonstrates the low acceptability of a 'sit less, move more' program in shift workers in high stress environments like emergency call centres. Work demands take priority and other health concerns, like poor sleep and high stress, may be more salient than the need to sit less and move more during work shifts

Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity