Targeting developmental pathways: the Achilles Heel of cancer?

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways

Interleukin 1 activates jun N-terminal kinases JNK1 and JNK2 but not extracellular regulated MAP kinase (ERK) in human glomerular mesangial cells

AbstractInterleukin 1 (IL-1) potently activates human glomerular mesangial cells (HMC). In cytosolic extracts of IL-1-stimulated HMC or in anion exchange chromatography fractions we could not find any change in phosphorylation of myelin basic protein (MBP), a good substrate for extracellular regulated kinase (ERK). In contrast, IL-1 stimulated GST-jun kinase activity at least 10-fold. The jun kinase activity could be characterised as JNK1 and JNK2 at the protein and mRNA level. IL-1, TNF, UV light and osmotic stress, but not PMA, LPS, IL-3, IL-4, IL-6, IL-8, IL-10, IL-13, GM-CSF, PDGF, bFGF, TGF-β and interferon-γ were able to stimulate jun kinase activity in HMC, suggesting that jun kinase is selectively mediating signal transduction of the proinflammatory cytokines IL-1 and TNF as well as of cellular stress in HMC

Проектирование системы электроснабжения цементного завода

Проектирование системы электроснабжения Топкинского цементного завода. На основе исходных данных был произведен эффективный метод расчета, проделан поэтапный расчет электрических нагрузок Топкинского цементного завода и ремонтно-механического цеха, проведен выбор кабельных линий и проверка при нормальном и послеаварийном режиме работы.Design of power supply system Topkinsky cement plant. Based on the initial data, an effective method of calculation, a step-by-step calculation of electrical loads Topkinsky cement plant and mechanical repair shop, a selection of cable lines and a check at the normal and after-accident operation

Изучение процессов неравновесного выхода водорода из металлических образцов (Ni,Ti) различной толщины различных видах стимуляции

Рассмотрены особенности неравновесного выхода водорода из образцов (Ni, Ti ) при различных способах насыщения материалов водородом ( электролиз, метод Сивертса, плазма ВЧ разряда) и стимуляции (термическая и стимуляция с высокой эффективной температурой). Проанализированы современные подходы теоретического рассмотрения данных процессов, включая обратный эффект Мессбауэра. Результаты работы актуальны для решения проблемы водородного охрупчивания конструкционных материалов в ядерной и водородной энергетике и предотвращения пассивирования примесных центров свечения в светодиодах.The features of the nonequilibrium hydrogen output from samples (Ni, Ti) at various methods of hydrogen saturation with materials (electrolysis, Sievert method, high-frequency discharge plasma) and stimulation (thermal and stimulation with high effective temperature) are considered.     Modern approaches to theoretical consideration of these processes, including the inverse Mossbauer effect, are analyzed.     The results of the work are relevant for the solution of the problem of hydrogen embrittlement of structural materials in nuclear and hydrogen energy and prevention of passivation of impurity centers of luminescence in light-emitting diodes

Rhinitis in the geriatric population

The current geriatric population in the United States accounts for approximately 12% of the total population and is projected to reach nearly 20% (71.5 million people) by 2030[1]. With this expansion of the number of older adults, physicians will face the common complaint of rhinitis with increasing frequency. Nasal symptoms pose a significant burden on the health of older people and require attention to improve quality of life. Several mechanisms likely underlie the pathogenesis of rhinitis in these patients, including inflammatory conditions and the influence of aging on nasal physiology, with the potential for interaction between the two. Various treatments have been proposed to manage this condition; however, more work is needed to enhance our understanding of the pathophysiology of the various forms of geriatric rhinitis and to develop more effective therapies for this important patient population

Immunosenescence of Polymorphonuclear Neutrophils

All immune cells are affected by aging, contributing to the high susceptibility to infections and increased mortality observed in the elderly. The effect of aging on cells of the adaptive immune system is well documented. In contrast, knowledge concerning age-related defects of polymorphonuclear neutrophils (PMN) is limited. During the past decade, it has become evident that in addition to their traditional role as phagocytes, neutrophils are able to secrete a wide array of immunomodulating molecules. Their importance is underlined by the finding that genetic defects that lead to neutropenia increase susceptibility to infections. Whereas there is consistence about the constant circulating number of PMN throughout aging, the abilities of tissue infiltration, phagocytosis, and oxidative burst of PMN from aged donors are discussed controversially. Furthermore, there are numerous discrepancies between in vivo and in vitro results, as well as between results for murine and human PMN. Most of the reported functional changes can be explained by defective signaling pathways, but further research is required to get a detailed insight into the underlying molecular mechanisms. This could form the basis for drug development in order to prevent or treat age-related diseases, and thus to unburden the public health systems