Abstract
The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would ...appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation.
Citation Format: Jiangbin Ye, Yang Li, Joshua J. Gruber, Ulrike M. Litzenburger, Yiren Zhou, Yu R. Miao, Edward L. LaGory, Albert M. Li, Zhen Hu, Lori S. Hart, John M. Maris, Howard Y. Chang, Amato J. Giaccia. Deciphering Warburg effect: hypoxia inhibits tumor cell differentiation through reducing acetyl-CoA generation and chromatin accessibility abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5708.
Individual, family and service level characteristics and outcomes are described for adult and adolescent patients receiving specialist inpatient or day patient treatment for anorexia nervosa (AN). ...Potential predictors of treatment outcome are explored.
Admission and discharge data were collected from patients admitted at 14 UK hospital treatment units for AN over a period of three years (adult units N = 12; adolescent N = 2) (patients N = 177).
One hundred and seventy-seven patients with a severe and enduring illness with wide functional impairment took part in the study. Following inpatient care, physical improvement was moderate/good with a large increase in BMI, although most patients continued to have a clinical level of eating disorder symptoms at discharge. The potentially modifiable predictors of outcome included confidence to change, social functioning and carer expressed emotion and control.
Overall, the response to inpatient treatment was modest particularly in the group with a severe enduring form of illness. Adolescents had a better response. Although inpatient treatment produces an improvement in physical health there was less improvement in other eating disorder and mood symptoms. As predicted by the carer interpersonal maintenance model, carer behaviour may influence the response to inpatient care, as may improved social functioning and confidence to change.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Applied Urban Ecology: A Global Frameworkexplores ways in which the environmental quality of urban areas can be improved starting with existing environmental conditions and their dynamics. Written by ...an internationally renowned selection of scientists and practitioners, the book covers a broad range of established and novel approaches to applied urban ecology. Approaches chosen for the book are placed in the context of issues such as climate change, green- and open-space development, flood-risk assessment, threats to urban biodiversity, and increasing environmental pollution (especially in the “megacities” of newly industrialized countries). All topics covered were chosen because they are socially and socio-politically relevant today.Further topics covered include sustainable energy and budget management, urban water resource management, urban land management, and urban landscape planning and design.Throughout the book, concepts and methods are illustrated using case studies from around the world. A closing synopsis draws conclusions on how the findings of urban ecological research can be used in strategic urban management in the future.Applied Urban Ecology: A Global Frameworkis an advanced textbook for students, researchers and experienced practitioners in urban ecology and urban environmental research, planning, and practice.
Background
Sleep problems (SP) are common in cancer patients but have not been previously assessed in patients receiving immune checkpoint inhibitors (ICI).
Methods
We collected questionnaire data on ...sleep apnea risk, insomnia, and general sleep patterns. We used an adjusted multivariate Poisson regression to calculate prevalence ratios (PRs) and associated 95% confidence intervals (CIs) for associations between these SP and metastatic versus localized cancer stage (M1 vs. M0), and adjusted logistic regression models to calculate ORs for associations between SP with the number of ICI infusions completed (6 + vs. < 6).
Results
Among 32 patients who received ICI treatment, the prevalence of low, intermediate, and high-risk OSA risk was 36%, 42%, and 21%, respectively. Overall, 58% of participants reported clinically significant insomnia. We did not find a significant association between intermediate or high risk OSA (vs. low risk) and metastatic cancer status (
PR
= 1.01 (95%
CI
: 0.28, 3.67)). Patients in the cohort who reported taking > 15 min to fall asleep were 3.6 times more likely to be diagnosed with metastatic cancer compared to those reporting shorter sleep latency (95%
CI
(1.74, 7.35)). We did not find a significant association between SP and number of ICI infusions completed.
Conclusion
Our data associating sleep apnea risk, insomnia, and sleep patterns with more advanced cancer encourages further exploration in larger-scale observational studies and suggests interventional clinical trials focused on sleep quality improvement that could result in better outcomes for these patients.
Clostridium difficile infection (CDI) is a leading cause of infectious diarrhea in solid organ transplant recipients (SOT). We aimed to assess incidence, risk factors, and outcome of CDI within the ...Swiss Transplant Cohort Study (STCS). We performed a case‐control study of SOT recipients in the STCS diagnosed with CDI between May 2008 and August 2013. We matched 2 control subjects per case by age at transplantation, sex, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors and evaluate outcome of CDI. Two thousand one hundred fifty‐eight SOT recipients, comprising 87 cases of CDI and 174 matched controls were included. The overall CDI rate per 10 000 patient days was 0.47 (95% confidence interval (CI 0.38‐0.58), with the highest rate in lung (1.48, 95% CI 0.93‐2.24). In multivariable analysis, proven infections (hazard ratio HR 2.82, 95% CI 1.29‐6.19) and antibiotic treatments (HR 4.51, 95% CI 2.03‐10.0) during the preceding 3 months were independently associated with the development of CDI. Despite mild clinical presentations, recipients acquiring CDI posttransplantation had an increased risk of graft loss (HR 2.24, 95% CI 1.15‐4.37; P = .02). These findings may help to improve the management of SOT recipients.
The authors demonstrate that despite mild clinical presentations and good clinical responses, Clostridium difficile infections are associated with an increased risk of graft loss in the Swiss Transplant Cohort Study.
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical ...efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo4,3-cpyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAFV600E xenograft model.
Curcumin is a natural product displaying a broad range of biological activities, including anticancer properties. It is, however, poorly absorbed by the human body and, as a so-called pan-assay ...interference compound, it exhibits non-specific activity leading to false positive results in biological assays. Nonetheless, different structural modifications of the curcumin scaffold have previously shown to lead to an improved biological and specificity profile without losing antiproliferative activity. In that respect, recent research in our group culminated in unprecedented benzothiazepane-based hit molecules with promising biological and drug-like properties. In the present hit expansion study, 14 new 2-aryl-4-(4-aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes were successfully synthesized through the implementation of various aromatic ring modifications and subsequently tested for cancer cell cytotoxicity using eight different cancer cell lines, revealing useful structure-activity relationship insights for this new class of compounds.
Display omitted
•14 New benzothiazepane-based curcuminoids were prepared, isolated and characterized by elaborate chemical synthesis work.•A cytotoxic assessment against 8 cancer cell lines revealed useful structure-activity relationship insights.•A para-hydroxy substitution on the two aromatic rings appeared to be essential for the anticancer activity.
The successful commercial scale deployment of carbon capture and storage (CCS) requires assurance of the confinement of the injected CO2 at each potential storage site. The critical elements of the ...confinement of CO2 are the caprock overlying the storage formation, and any faults or fractures which occur within the caprock. The most significant aspect of containment is the seal potential of the caprock, defined as the seal capacity, seal geometry and seal integrity. The seal capacity refers to the CO2 column height that the caprock can retain before capillary forces allow the migration of the CO2 into and possibly through the caprock. Determination of capacity is achieved primarily through petrophysical analyses such as mercury injection capillary pressure (MICP) tests. For storage in depleted fields, assessments of seal capacity can be made from empirical observations of actual hydrocarbon column heights and converting these to CO2 physical properties (density, temperature, pressure). Where these data sources are unavailable, the use of analogs can be a viable alternative. Seal geometry refers to the thickness and lateral extent of the caprock. The caprock must have sufficient lateral extent to cover whatever structural, stratigraphic or hydrodynamic storage reservoir in which the CO2 is trapped. In addition, its thickness should exceed the throw of any faults that cut so as to maintain an effective barrier despite faults through it. Seal geometry is evaluated through well data (stratigraphic, sedimentological and wireline log analyses) and seismic surveys, which are pre-requisites to any viable storage project. Seal integrity refers to the geomechanical properties of the caprock. These properties are controlled by caprock mineralogy, regional and local stress fields as well as any stress changes induced by injection or withdrawal of water or CO2. The modification of the stress field within a storage formation during and after injection of CO2 can lead to reservoir and caprock mechanical failure. This failure can result in the generation of new faults and fractures, reactivation of existing faults and/or bedding parallel slip. The key parameters determining whether faults might act as conduits or as seals are the juxtaposition relationships of rocks on either side of a fault plane, the properties of the fault zone itself or the reactivation potential of the fault. The greatest likelihood of fluid migration up faults is during or immediately after reactivation. Thus, the mere existence of faults does not automatically rule out a site for geological storage of carbon dioxide. On the contrary, sealing faults commonly trap hydrocarbons and compartmentalize oil and gas reservoirs and could also form suitable confining barriers at CO2 storage sites. Seal capacity, geometry and integrity interpretations must be tempered by the potential geochemical reactions between fluids and rocks and injected CO2 as well as by the hydrodynamic environment above and below the seal which may modify the calculated pressure regimes.
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to ...identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
PDF
