Химиотерапия распространенного рака поджелудочной железы у пациентов старшей возрастной группы (обзор литературы)

Elderly patients with malignant neoplasms of the pancreas are poorly represented in large clinical trials. Thus, in the MPACT and ACCORD study, the median age of patients with malignant neoplasms of the pancreas was 61 years, and it remains unclear whether the results obtained can be extrapolated to older patients, whom we most often encounter in real clinical practice. The vast majority of studies that analyzed the efficacy and tolerability of systemic chemotherapy in elderly and senile patients showed good tolerability of gemcitabine monotherapy, the tolerability of combined chemotherapy regimens among older patients with pancreatic adenocarcinoma varied between studies, but was expectedly higher than with monotherapy. with regard to survival rates, the effectiveness of systemic chemotherapy has also been shown here, especially combined regimens among elderly patients. But almost all studies were retrospective or included a small number of patients, which does not allow assessing the reliability of the results. The question of the advisability of intensifying chemotherapy in elderly and senile patients remains open.Пациенты пожилого и старческого возраста со злокачественными новообразованиями поджелудочной железы в крупных клинических исследованиях представлены скупо. Так, в исследованиях MPACT и ACCORD медиана возраста пациентов со злокачественными новообразованиями поджелудочной железы составила 61 год, и остается неясным, можно ли экстраполировать полученные результаты на пациентов старшего возраста, которых мы чаще всего и встречаем в реальной клинической практике. Подавляющее большинство работ, где проводился анализ эффективности и переносимости системной химиотерапии у пациентов пожилого и старческого возраста, показали хорошую переносимость монотерапии гемцитабином; переносимость комбинированных режимов химиотерапии среди пациентов старшей возрастной группы с аденокарциномой поджелудочной железы различалась между исследованиями, но была ожидаемо выше, чем при монотерапии. Что касается показателей выживаемости у пожилых пациентов, здесь также была показана эффективность системной химиотерапии, особенно комбинированных режимов. Но практически все исследования были ретроспективными или включали малое число больных, что не позволяет оценить достоверность результатов. Таким образом, вопрос о целесообразности интенсификации химиотерапии у пациентов пожилого и старческого возраста остается открытым

MARCO, TLR2, and CD14 Are Required for Macrophage Cytokine Responses to Mycobacterial Trehalose Dimycolate and Mycobacterium tuberculosis

Virtually all of the elements of Mycobacterium tuberculosis (Mtb) pathogenesis, including pro-inflammatory cytokine production, granuloma formation, cachexia, and mortality, can be induced by its predominant cell wall glycolipid, trehalose 6,6′-dimycolate (TDM/cord factor). TDM mediates these potent inflammatory responses via interactions with macrophages both in vitro and in vivo in a myeloid differentiation factor 88 (MyD88)-dependent manner via phosphorylation of the mitogen activated protein kinases (MAPKs), implying involvement of toll-like receptors (TLRs). However, specific TLRs or binding receptors for TDM have yet to be identified. Herein, we demonstrate that the macrophage receptor with collagenous structure (MARCO), a class A scavenger receptor, is utilized preferentially to “tether” TDM to the macrophage and to activate the TLR2 signaling pathway. TDM-induced signaling, as measured by a nuclear factor-kappa B (NF-κB)-luciferase reporter assay, required MARCO in addition to TLR2 and CD14. MARCO was used preferentially over the highly homologous scavenger receptor class A (SRA), which required TLR2 and TLR4, as well as their respective accessory molecules, in order for a slight increase in NF-κB signaling to occur. Consistent with these observations, macrophages from MARCO−/− or MARCO−/−SRA−/− mice are defective in activation of extracellular signal-related kinase 1/2 (ERK1/2) and subsequent pro-inflammatory cytokine production in response to TDM. These results show that MARCO-expressing macrophages secrete pro-inflammatory cytokines in response to TDM by cooperation between MARCO and TLR2/CD14, whereas other macrophage subtypes (e.g. bone marrow–derived) may rely somewhat less effectively on SRA, TLR2/CD14, and TLR4/MD2. Macrophages from MARCO−/− mice also produce markedly lower levels of pro-inflammatory cytokines in response to infection with virulent Mtb. These observations identify the scavenger receptors as essential binding receptors for TDM, explain the differential response to TDM of various macrophage populations, which differ in their expression of the scavenger receptors, and identify MARCO as a novel component required for TLR signaling

The Rts1 Regulatory Subunit of Protein Phosphatase 2A Is Required for Control of G1 Cyclin Transcription and Nutrient Modulation of Cell Size

The key molecular event that marks entry into the cell cycle is transcription of G1 cyclins, which bind and activate cyclin-dependent kinases. In yeast cells, initiation of G1 cyclin transcription is linked to achievement of a critical cell size, which contributes to cell-size homeostasis. The critical cell size is modulated by nutrients, such that cells growing in poor nutrients are smaller than cells growing in rich nutrients. Nutrient modulation of cell size does not work through known critical regulators of G1 cyclin transcription and is therefore thought to work through a distinct pathway. Here, we report that Rts1, a highly conserved regulatory subunit of protein phosphatase 2A (PP2A), is required for normal control of G1 cyclin transcription. Loss of Rts1 caused delayed initiation of bud growth and delayed and reduced accumulation of G1 cyclins. Expression of the G1 cyclin CLN2 from an inducible promoter rescued the delayed bud growth in rts1Δ cells, indicating that Rts1 acts at the level of transcription. Moreover, loss of Rts1 caused altered regulation of Swi6, a key component of the SBF transcription factor that controls G1 cyclin transcription. Epistasis analysis revealed that Rts1 does not work solely through several known critical upstream regulators of G1 cyclin transcription. Cells lacking Rts1 failed to undergo nutrient modulation of cell size. Together, these observations demonstrate that Rts1 is a key player in pathways that link nutrient availability, cell size, and G1 cyclin transcription. Since Rts1 is highly conserved, it may function in similar pathways in vertebrates

Heterochromatin and the molecular mechanisms of 'parent-of-origin' effects in animals.

Twenty five years ago it was proposed that conserved components of constitutive heterochromatin assemble heterochromatinlike complexes in euchromatin and this could provide a general mechanism for regulating heritable (cell-to-cell) changes in gene expressibility. As a special case, differences in the assembly of heterochromatin-like complexes on homologous chromosomes might also regulate the parent-of-origin-dependent gene expression observed in placental mammals. Here, the progress made in the intervening period with emphasis on the role of heterochromatin and heterochromatin-like complexes in parent-of-origin effects in animals is reviewed

AREAL 50 MeV Electron Accelerator Project for THz and Middle IR FEL

Advanced Research Electron Accelerator Laboratory AREAL is an electron accelerator project based on photocathode RF gun. The first phase of the facility is a 5 MeV energy RF phototgun, which is currently under operation. The facility developments imply energy upgrade to 50 MeV with further delivery of the electron beam to the undulator sections for Free Electron Laser and coherent undulator radiation in MIR and THz frequency ranges, respectively. In this report the design study of AREAL 50 MeV facility main systems along with the beam dynamics and characteristics of expected radiation are presente