Accumulating evidence suggests that dysregulation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) pathway resulting in constitutively active Nrf2 and ...increased expression of cytoprotective Nrf2 target genes, has a pivotal role in cancer. Cancer cells are able to hijack the Keap1-Nrf2 system via multiple mechanisms leading to enhanced chemo- and radio-resistance and proliferation via metabolic reprogramming as well as inhibition of apoptosis. In this mini-review, we will describe the mechanisms leading to increased Nrf2 activity in cancer with a focus on the information achieved from large-scale multi-omics projects across various cancer types.
Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms ...of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between SQSTM1/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM.
It is generally agreed to centralise treatment of childhood cancers (CCs). We analysed (1) the degree of centralisation of CCs in European countries and 2) the relations between centralisation and ...survival.
The analysis comprised 4415 CCs, diagnosed between 2000 and 2007 and followed up to the end of 2013, from Belgium, Bulgaria, Finland, Ireland, the Netherlands and Slovenia. All these countries had national population-based cancer registries and were able to provide information on diagnosis, treatment, treatment hospitals, and survival. Each case was then classified according to whether the patient was treated in a high- or a low-volume hospital among those providing CC treatment. A Cox proportional hazard model was used to calculate the relation between volume category and five-year survival, adjusting by age, sex and diagnostic group.
The number of hospitals providing treatment for CCs ranged from six (Slovenia) to slightly more than 40 (the Netherlands and Belgium). We identified a single higher volume hospital in Ireland and in Slovenia, treating 80% and 97% of cases, respectively, and three to five major hospitals in the other countries, treating between 65% and 93% of cases. Outcome was significantly better when primary treatment was given in high-volume hospitals compared to low-volume hospitals for central nervous system tumours (relative risk RR = 0.71), haematologic tumours (RR = 0.74) and for all CC combined (RR = 0.83).
Treatment centralisation is associated with survival benefits and should be further strengthened in these countries. New plans for centralisation should include ongoing evaluation.
•The degree of centralisation of childhood cancers varied across six European countries.•Survival was higher for children treated at high-volume hospitals, especially for central nervous system tumours.•Centralisation of treatment should be improved.•Plan of centralisation, including evaluation, is needed.
Large-scale data on type-specific HPV prevalences and disease burden are needed to monitor the impact of HPV vaccination and to plan for HPV-based cervical screening.
33 043 women (aged 25-65) were ...screened for HPV by a Hybrid Capture 2 (HC2) in a population-based programme. HPV-positive women (n=2574) were triaged by cytology and HPV genotyped using PCR-Luminex. Type-specific prevalence of HPV infection and its correlation to findings in cytology triage and histology as well as Population Attributable Fractions for a referral to colposcopy and findings in histology were calculated.
Among HC2-positive women, 61.5% had normal, 23.1% had ASC-US and 15.5% had LSIL or more severe (LSIL+) results in cytology. Out of HC2-positive samples, 57% contained the 13 Group 1/2A HPV types, which were targeted by the HC2, 15% contained Group 2B types, 8.5% Group 3 types and 30% were found to be negative in HPV genotyping. The proportion of samples positive for HPV by the HC2, but negative in HPV genotyping increased with age and decreased with increasing cytological abnormality. The most frequent types were HPV 16 (0.9% of screened women and 12.1% of the HC2-positive women), HPV 31 (0.7% and 8.9%, respectively) and HPV 52 (0.5% and 6.3%, respectively). The prevalence of Group 1/2A HPV types increased with increasing CIN grade and attributed 78.3% (95% CI 53.4-89.9) of the CIN 3+ lesions, while HPV 16 attributed 55.8% (40.0-67.5) of them.
The type-specific prevalence of HPV were slightly lower than the average in international meta-analyses. Genotyping for HPV 16 better identified women with CIN 3+ than cytology triage at the threshold of LSIL+. The high proportion of women that were HC2-positive but HPV-negative in genotyping suggests that HPV genotyping may be useful also for validation of results in HPV screening. The large-scale HPV genotyping data were found to be directly useful for planning further preventive efforts for cervical cancer.
Federated Learning from Big Data Over Networks Sarcheshmehpour, Y.; Leinonen, M.; Jung, A.
ICASSP 2021 - 2021 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP),
2021-June-6
Conference Proceeding
Odprti dostop
This paper formulates and studies a novel algorithm for federated learning from large collections of local datasets. This algorithm capitalizes on an intrinsic network structure that relates the ...local datasets via an undirected "empirical" graph. We model such big data over networks using a networked linear regression model. Each local dataset has individual regression weights. The weights of close-knit sub-collections of local datasets are enforced to deviate only little. This lends naturally to a network Lasso problem which we solve using a primal-dual method. We obtain a distributed federated learning algorithm via a message passing implementation of this primal-dual method. We provide a detailed analysis of the statistical and computational properties of the resulting federated learning algorithm.
Anxiety frequently accompanies low-grade inflammation-associated conditions like depression, insulin resistance, coronary heart disease and metabolic syndrome. The association between anxiety and ...low-grade inflammation is, unlike between depression and low-grade inflammation, a very sparsely studied area in general populations. The aim of the present study was to investigate whether anxiety symptoms as well as comorbid anxiety and depressive symptoms are associated with low-grade inflammation at population level.
The general population-based Northern Finland 1966 Birth Cohort was followed until age 31 (n=2688 males and 2837 females), when the highly sensitive CRP concentrations were measured. Anxiety and depressive symptoms were defined by Hopkins Symptom Checklist-25 (HSCL-25).
After adjusting for confounders, logistic regression analyses showed that anxiety symptoms alone increased the probability for elevated hs-CRP levels (>3.0mg/L) in males over two-fold (2.19 CI 95% 1.08-4.46), while comorbid anxiety and depressive symptoms caused a 1.7-fold (1.76 CI 95% 1.13-2.74) increase in the probability for elevated hs-CRP levels (1.0-3.0mg/L).
Our results support the hypothesis that anxiety as well as comorbid anxiety and depression can be associated with an increased risk for low-grade inflammation in males at population level.
The interest in lentiviral vectors (LVs) has increased prominently for gene therapy applications, but few have reached the later stages of clinical trials. The main challenge has remained in scaling ...up the manufacturing process for the fragile vector to obtain high titers for in vivo usage. We have previously scaled up the LV production to iCELLis 500, being able to produce up to 180 L of harvest material in one run with perfusion. The following challenge considers the purification and concentration of the product to meet titer and purity requirements for clinical use. We have developed a downstream process, beginning with clarification, buffer exchange, and concentration, by tangential flow filtration. This is followed by a purification step using single membrane-based anion exchange chromatography and final formulation with tangential flow filtration. Different materials and conditions were compared to optimize the process, especially for the chromatography step that has been the bottleneck in lentiviral vector purification scale-up. The final infectious titer of the lentiviral vector product manufactured using the optimized scale-up process was determined to be 1.97 × 109 transducing units (TU)/mL, which can be considered as a high titer for lentiviral vectors.
The concentration and purification of the LVs were optimized and scaled up to process a 180-L harvest, with the main optimization concentrating on anion exchange chromatography. The process yielded a high-titer LV product, with the majority of the impurities removed.
Natural derived or originated compounds still play a major role as drugs, and as lead structures for the development of synthetic molecules. About 50% of the drugs introduced to the market during the ...last 20 years are derived directly or indirectly from small biogenic molecules. In the future, natural products will continue to play a major role as active substances, model molecules for the discovery and validation of drug targets. A multidisciplinary approach to drug discovery involving the generation of truly novel molecular diversity from natural product sources, combined with total and combinatorial synthetic methodologies provides the best solution to increase the productivity in drug discovery and development. Screening for new drugs in plants implies the screening of extracts for the presence of novel compounds and an investigation of their biological activities. It is currently estimated that approximately 420 000 plant species exist in nature. For the purpose of lead discovery, or for the scientific validation of a traditional medicinal plant or a phytopharmaceutical, active principals in complex matrices need to be identified. Therefore, the interfacing of biological and chemical assessment becomes the critical issue. Drug discovery from plants can be guided by epidemiologic studies facilitated with computer assisted HPLC microfractionation and microplate technology. Epidemiologic studies have shown that high dietary flavonoid intake may be associated with decreased risk for cardiovascular disease. Chlamydia pneumoniae is a common human pathogen and epidemiological and clinical studies have shown a connection between chronic C. pneumoniae infection, atherosclerosis and the risk of myocardial infarction. We will present here the detection of natural compounds active against C. pneumoniae as an example.
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