Cancer cells reprogram their metabolism to meet the requirement for survival and rapid growth. One hallmark of cancer metabolism is elevated aerobic glycolysis and reduced oxidative phosphorylation. ...Emerging evidence showed that most glycolytic enzymes are deregulated in cancer cells and play important roles in tumorigenesis. Recent studies revealed that all essential glycolytic enzymes can be translocated into nucleus where they participate in tumor progression independent of their canonical metabolic roles. These noncanonical functions include anti-apoptosis, regulation of epigenetic modifications, modulation of transcription factors and co-factors, extracellular cytokine, protein kinase activity and mTORC1 signaling pathway, suggesting that these multifaceted glycolytic enzymes not only function in canonical metabolism but also directly link metabolism to epigenetic and transcription programs implicated in tumorigenesis. These findings underscore our understanding about how tumor cells adapt to nutrient and fuel availability in the environment and most importantly, provide insights into development of cancer therapy.
Background
The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral ...infiltrating immune/inflammatory cells (IICs) in patients after surgery.
Methods
Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort.
Results
CD15+ neutrophils, CD20+ B cells and CD206+ tumour‐associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence‐predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence‐free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound‐guided fine‐needle aspiration.
Conclusion
PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy.
Surgical relevance
The immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4.
This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.
Immunosuppressive phenotype has poor prognosis
Crystal lattices with tetragonal or hexagonal structure often exhibit structural transitions in response to external stimuli
. Similar behaviour is anticipated for the lattice forms of topological ...spin textures, such as lattices composed of merons and antimerons or skyrmions and antiskyrmions (types of vortex related to the distribution of electron spins in a magnetic field), but has yet to be verified experimentally
. Here we report real-space observations of spin textures in a thin plate of the chiral-lattice magnet Co
Zn
Mn
, which exhibits in-plane magnetic anisotropy. The observations demonstrate the emergence of a two-dimensional square lattice of merons and antimerons from a helical state, and its transformation into a hexagonal lattice of skyrmions in the presence of a magnetic field at room temperature. Sequential observations with decreasing temperature reveal that the topologically protected skyrmions remain robust to changes in temperature, whereas the square lattice of merons and antimerons relaxes to non-topological in-plane spin helices, highlighting the different topological stabilities of merons, antimerons and skyrmions. Our results demonstrate the rich variety of topological spin textures and their lattice forms, and should stimulate further investigation of emergent electromagnetic properties.
DNA damage is a deleterious threat, but occurs daily in all types of cells. In response to DNA damage, poly(ADP-ribosyl)ation, a unique post-translational modification, is immediately catalyzed by ...poly(ADP-ribose) polymerases (PARPs) at DNA lesions, which facilitates DNA damage repair. Recent studies suggest that poly(ADP-ribosyl)ation is one of the first steps of cellular DNA damage response and governs early DNA damage response pathways. Suppression of DNA damage-induced poly(ADP-ribosyl)ation by PARP inhibitors impairs early DNA damage response events. Moreover, PARP inhibitors are emerging as anti-cancer drugs in phase III clinical trials for BRCA-deficient tumors. In this review, we discuss recent findings on poly(ADP-ribosyl)ation in DNA damage response as well as the molecular mechanism by which PARP inhibitors selectively kill tumor cells with BRCA mutations.
Purpose
The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality.
Materials and Methods
The QbD was ...described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone.
Results
The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include:
Defining target product quality profile
Designing product and manufacturing processes
Identifying critical quality attributes, process parameters, and sources of variability
Controlling manufacturing processes to produce consistent quality over time
Conclusions
Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.
A magnetic skyrmion is a topologically stable particle-like object that appears as a vortex-like spin texture at the nanometer scale in a chiral-lattice magnet. Skyrmions have been observed in ...metallic materials, where they are controllable by electric currents. Here, we report the experimental discovery of magnetoelectric skyrmions in an insulating chiral-lattice magnet Cu₂OSeO₃ through Lorentz transmission electron microscopy and magnetic susceptibility measurements. We find that the skyrmion can magnetically induce electric polarization. The observed magnetoelectric coupling may potentially enable the manipulation of the skyrmion by an external electric field without losses due to joule heating.
There is considerable evidence for relationship between gut microbiota and osteoarthritis (OA), but no studies have investigated their causal relationship.
This study utilized large-scale genome-wide ...association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and OA risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for OA. Comprehensively sensitive analyses were performed to validate the robustness of results and novel multivariable MR analyses were further conducted to ensure the independence of causal association. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations. Finally, enrichment analyses were used to investigate the biofunction.
After correction, three microbial taxa were identified to be causally associated with diverse joint OA (PFDR < 0.100), namely Methanobacteriaceae family for knee OA (PFDR = 0.043) and any OA (PFDR = 0.028), Desulfovibrionales order for knee OA (PFDR = 0.045) and Ruminiclostridium5 genus for knee OA (PFDR = 0.063). In addition, we also identified five suggestive microbial taxa that were significant with three different methods under the nominal significance (P < 0.05). Sensitive analysis excluded the influence of heterogeneity and horizontal pleiotropy and multivariable MR analysis ruled out the possibility of horizontal pleiotropy of BMI. GO enrichment analysis illustrates the protective mechanism of the identified taxa against OA.
This study found that several microbial taxa were causally associated with diverse joint OA. The results enhanced our understanding of gut microbiota in the pathology of OA.
IgA nephropathy is the most common primary glomerulonephritis worldwide, and genetic factors may play an important role in its pathogenesis. Following candidate gene association analysis and ...genome-wide linkage study, genome-wide association studies (GWAS) have found multiple susceptibility genes related to the pathogenesis and clinical phenotype of IgA nephropathy. Meanwhile, structural variation and epigenetic changes are also closely related to IgA nephropathy. Genetic variants have been found to explain about 11% of its heritability. In the current era of genomic medicine, how to find more susceptible genes/loci, whole genome sequencing studies (WGS) provide clues to further understand the genetic variation of IgA nephropathy. How to find the cell type-specific susceptibility genes associated with IgA nephropathy, multi-omics studies will conduct comprehensive analysis via single-cell sequencing, expression quantitative trait locus (eQTL) and genomics to find the pathogenic genes and offer insights into t
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