Driving innovation for rare skin cancers: utilizing common tumours and machine learning to predict immune checkpoint inhibitor response

Metastatic Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC) are rare and both show impressive responses to immune checkpoint inhibitor treatment. However, at least 40% of patients do not respond to these expensive and potentially toxic drugs. Development of predictive biomarkers of response and rational, effective combination treatment strategies in these rare, often frail patient populations is challenging. This review discusses the pathophysiology and treatment of MCC and cSCC, with a particular focus on potential biomarkers of response to immunotherapy, and discusses how transfer learning using big data collected from patients with common tumours can be used in combination with deep phenotyping of rare tumours to develop predictive biomarkers and elucidate novel treatment targets

Dioxin Revisited: Developments Since the 1997 IARC Classification of Dioxin as a Human Carcinogen

In 1997 the International Agency for Research on Cancer (IARC) classified 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD; the most potent dioxin congener) as a group 1 carcinogen based on limited evidence in humans, sufficient evidence in experimental animals, and extensive mechanistic information indicating that TCDD acts through a mechanism involving the aryl hydrocarbon receptor (AhR), which is present in both humans and animals. The judgment of limited evidence in humans was based primarily on an elevation of all cancers combined in four industrial cohorts. The group 1 classification has been somewhat controversial and has been challenged in the literature in recent years. In this article we review the epidemiologic and mechanistic evidence that has emerged since 1997. New epidemiologic evidence consists primarily of positive exposure–response analyses in several of the industrial cohorts, as well as evidence of excesses of several specific cancers in the Seveso accident cohort. There are also new data regarding how the AhR functions in mediating the carcinogenic response to TCDD. The new evidence generally supports the 1997 IARC classification

Решение задач многокритериальной оптимизации с использованием генетических алгоритмов

В данной работе представлены существующие подходы и методы применения генетических алгоритмов для решения задач многокритериальной оптимизации. Предложены математическая модель и алгоритмы решения многокритериальной задачи выбора стратегии развития производственной системы. Представлены также результаты применения для решения этой задачи метода присваивания рангов Голдберга и гибридного генетического алгоритма.Представлені існуючи підходи і методи застосування генетичних алгоритмів для рішення залач багатокритеріальної оптимізації. Запропоновано математичну модель і алгоритми розв’язку багатокритеріальної задачі вибору стратегії розвитку виробничої системи. Навелено результати застосування для розв’язку цієї задачі методу надання рангів Голдберга і гібридного генетичного алгоритму.This paper describes the existing approaches and methods of application of genetic algorithms for multiobjective optimization. The mathematical model and algorithms for solving multiobjective optimization problems in management have been proposed. Experimental results of application of the hybrid genetic algorithms for solving combinatorial optimization problems have been presented

Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein

The multidrug resistance protein MRP1 and its isoform MRP2 are involved in ATP-dependent glutathione S-conjugate transport and have similar substrate specificities. MRP2 mediates hepatic organic anion transport into bile. The physiological function of MRP1 in hepatocytes is unknown. Previous results show that MRP1 expression is low in quiescent hepatocytes but increased after SV40 large T antigen immortalization, suggesting a relationship with cell proliferation. Therefore, we determined mrp1 and mrp2 expression in rat hepatocytes in relation to the cell cycle. By varying cell density we obtained cultures that are mainly in G(1) (high density) or have progressed into the S-phase or beyond (low density). In both cultures mrp1 mRNA and protein levels are increased, concomitantly with the disappearance of mrp2, This switch from mrp2 to mrp1 occurs in the G(1) phase of the cell cycle and is associated with a decreased cell polarity, Mrp1 is located on lateral membranes or on intracellular vesicles, depending on whether cell-cell contact is established. In both locations mrp1 contributes to cellular glutathione S-conjugate efflux and protects against oxidative stress-inducing quinones. We conclude that a switch in expression from the apically located mrp2 to the basolaterally located mrp1 preserves glutathione S-conjugate transport in hepatocytes entering the cell cycle and protects against certain cytotoxic agents

An evidence synthesis approach to estimating the incidence of seasonal influenza in the Netherlands.

OBJECTIVES: To estimate, using Bayesian evidence synthesis, the age-group-specific annual incidence of symptomatic infection with seasonal influenza in the Netherlands over the period 2005-2007. METHODS: The Netherlands population and age group distribution for 2006 defined the base population. The number of influenza-like illness (ILI) cases was estimated from sentinel surveillance data and adjusted for underascertainment using the estimated proportion of ILI cases that do not consult a general practitioner. The estimated number of symptomatic influenza (SI) cases was based on indirect evidence from the surveillance of ILI cases and the proportions of laboratory-confirmed influenza cases in the 2004/5, 2005/6 and 2006/7 respiratory years. In scenario analysis, the number of SI cases prevented by increasing vaccination uptake within the 65 +  age group was estimated. RESULTS: The overall symptomatic infection attack rate (SIAR) over the period 2005-2007 was estimated at 2·5% (95% credible interval [CI]: 2·1-3·2%); 410 200 SI cases (95% CI: 338 500-518 600) were estimated to occur annually. Age-group-specific SIARs were estimated for <5 years at 4·9% (2·1-13·7%), for 5-14 years at 3·0% (2·0-4·7%), for 15-44 years at 2·6% (2·1-3·2%), for 45-64 years at 1·9% (1·4-2·5%) and for 65 +  years at 1·7% (1·0-3·0%). Under assumed vaccination uptake increases of 5% and 15%, 1970 and 5310 SI cases would be averted. CONCLUSIONS: By synthesising the available information on seasonal influenza and ILI from diverse sources, the annual extent of symptomatic infection can be derived. These estimates are useful for assessing the burden of seasonal influenza and for guiding vaccination policy

Gene expression of transporters and phase I/II metabolic enzymes in murine small intestine during fasting

<p>Abstract</p> <p>Background</p> <p>Fasting has dramatic effects on small intestinal transport function. However, little is known on expression of intestinal transport and phase I/II metabolism genes during fasting and the role the fatty acid-activated transcription factor PPARα may play herein. We therefore investigated the effects of fasting on expression of these genes using Affymetrix GeneChip MOE430A arrays and quantitative RT-PCR.</p> <p>Results</p> <p>After 24 hours of fasting, expression levels of 33 of the 253 analyzed transporter and phase I/II metabolism genes were changed. Upregulated genes were involved in transport of energy-yielding molecules in processes such as glycogenolysis (<it>G6pt1</it>) and mitochondrial and peroxisomal oxidation of fatty acids (<it>Cact</it>, <it>Mrs3/4</it>, <it>Fatp2</it>, <it>Cyp4a10</it>, <it>Cyp4b1</it>). Other induced genes were responsible for the inactivation of the neurotransmitter serotonin (<it>Sert</it>, <it>Sult1d1</it>, <it>Dtd</it>, <it>Papst2</it>), formation of eicosanoids (<it>Cyp2j6</it>, <it>Cyp4a10</it>, <it>Cyp4b1</it>), or for secretion of cholesterol (<it>Abca1 </it>and <it>Abcg8</it>). Cyp3a11, typically known because of its drug metabolizing capacity, was also increased. Fasting had no pronounced effect on expression of phase II metabolic enzymes, except for glutathione <it>S</it>-transferases which were down-regulated. Time course studies revealed that some genes were acutely regulated, whereas expression of other genes was only affected after prolonged fasting. Finally, we identified 8 genes that were PPARα-dependently upregulated upon fasting.</p> <p>Conclusion</p> <p>We have characterized the response to fasting on expression of transporters and phase I/II metabolic enzymes in murine small intestine. Differentially expressed genes are involved in a variety of processes, which functionally can be summarized as a) increased oxidation of fat and xenobiotics, b) increased cholesterol secretion, c) increased susceptibility to electrophilic stressors, and d) reduced intestinal motility. This knowledge increases our understanding of gut physiology, and may be of relevance for e.g. pre-surgery regimen of patients.</p

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression

<p>Abstract</p> <p>Background</p> <p>The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARα), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARα on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARα-null mice. Treatment with the synthetic PPARα agonist WY14643 served as reference.</p> <p>Results</p> <p>We identified 74 barrier genes that were PPARα-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARα regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense.</p> <p>Conclusion</p> <p>We identified intestinal barrier genes that were PPARα-dependently regulated after acute activation by fatty acids. This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARα as an important factor controlling this key function, and underscores the importance of PPARα for nutrient-mediated gene regulation in intestine.</p

Миф о "Братьях Карамазовых". Какой Достоевский нужен современной России?

В статье на основе текста романа «Братья Карамазовы» опровергается позиция И. Евлампиева, который видит в Ф.М. Достоевском по преимуществу гностического мыслителя, а также эксплицируются теоретические предпосылки тенденциозного подхода к творчеству русского писателя. Акцентируется внимание на связи романов Достоевского с православной традицией, а также значимости этой позиции для становления русского самосознания и истории России.У статті на основі тексту роману «Брати Карамазови» спростовується позиція І. Євлампієва, який вбачає у Ф.М. Достоєвському переважно гностичного мислителя, а також експлікуються теоретичні передумови тенденційного підходу до творчості російського письменника. Робиться акцент на зв’язку романів Достоєвського з православною традицією, а також на значимості цієї позиції для становлення російської самосвідомості та історії Росії.In the article the position of I. Evlampiev, who considers F.M. Dostoyevskiy, for the most part, as a gnostic thinker, is being disproved on the basis of the text of the novel “The Karamazov brothers”. Also, theoretical preconditions of tendentious understanding of the creative work of the Russian writer are being explicated. Besides, the relationship between Dostoyevskiy’s novels and orthodox tradition and the importance of this position for establishing Russian self-consciousness and the history of Russia are being indicated