Plasma membrane receptor mediated MAPK signaling pathways are activated in human uterine cervix at parturition

BACKGROUND: Cervical ripening resembles an inflammatory reaction. Estrogens induce leukocyte migration into tissue and factors promoting cervical remodeling and labor, although the mechanisms are only partially known. The aim of this study was to investigate whether plasma membrane receptor mediated pathways, known to be activated by estrogens and proinflammatory compounds, are involved in cervical ripening before labor. METHODS: The expression and distribution of mitogen activated protein kinases (MAPK), which transduce extracellular signals into intracellular responses through phosphorylation, and their intracellular targets transcription factors c-Jun and c-Fos proteins (AP-1) were analysed in cervical biopsies from term pregnant women (TP), immediately after parturition (PP), and from non-pregnant women (NP). Immunohistochemistry and RT-PCR techniques were used. RESULTS: Cell-specific alterations in the immunostaining pattern for MAPK were observed. The expressions of activated, phosphorylated MAPK forms pERK1/2, pJNK and p38MAPK were significantly increased in cervical stroma until TP and pERK1/2 expression was significantly enhanced in PP group. c-Jun was significantly increased in cervical stroma and smooth muscle in TP as compared to NP group. c-Fos was significantly increased in stroma, squamous epithelium and glandular epithelium in PP as compared to TP group. CONCLUSION: We report, for the first time, cell-specific activation of pMAPKs and their targets transcription factors c-Fos and c-Jun (AP-1) proteins in human uterine cervix until term pregnancy, and immediately after parturition. These results suggest a role for MAPK activation in cervical ripening before labor

ПОСЛЕОПЕРАЦИОННЫЕ ОСЛОЖНЕНИЯ МАЛОИНВАЗИВНЫХ МЕТОДОВ ЛЕЧЕНИЯ РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ

Prostate cancer is the most common cancer among men. Radical prostatectomy (open, laparoscopic, or robotic) remains the main method of surgical treatment for prostate cancer. However, minimally invasive therapies for prostate cancer are becoming increasingly popular in recent years, because they have similar efficacy as open surgery. The most studied minimally invasive therapies are cryoablation, high intensity focused ultrasound (HIFU), and brachytherapy.Despite the minimization of damage to neighboring structures, minimally invasive procedures can cause a number of complications, like any other surgical interventions. Each method has specific limitations and the most typical complications. Since multiple minimally invasive methods are currently available, we can ensure an individual approach to each particular patient, thus using the advantages of the methods and avoiding possible complications. This article covers the most frequent and severe complications of minimally invasive therapies for prostate cancer, as well as the methods of their prevention and treatment.Рак предстательной железы (РПЖ) является наиболее распространенным онкологическим заболеванием среди мужчин. Радикальная простатэктомия (открытая, лапароскопическая, роботическая) считается основным хирургическим методом лечения РПЖ. Однако в последние годы все бόльшую популярность набирают малоинвазивные методы лечения РПЖ, которые не отстают по эффективности от радикальной операции (по данным последних исследований). К наиболее изученным малоинвазивным технологиям относятся криоаблация, HIFU-терапия (High Intensity Focused Ultrasound) и брахитерапия.Несмотря на минимизацию повреждения соседних структур, малоинвазивные методы лечения РПЖ, как и любые другие хирургические вмешательства, могут приводить к развитию ряда осложнений. Для каждого из методов существуют определенные ограничения, а также наиболее характерные и вероятные осложнения. Благодаря существованию на сегодняшний день целого ряда малоинвазивных методов лечения РПЖ возможен индивидуальный подход к конкретному пациенту, что позволяет избежать нежелательных осложнений и использовать сильные стороны каждого из методов. В настоящей работе рассмотрены наиболее частые и тяжелые осложнения, возникающие после малоинвазивного лечения РПЖ, а также методы их профилактики и лечения

Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity

The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GR(Cx30CreERT2) mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GR(Cx30CreERT2) mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-alpha and Il-1 beta as well as TNF-alpha protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+. The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTP-injected GR(Cx30CreERT2) mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of postmortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology

Возможность использования местной анестезии при чрескожной криоаблации почечно - клеточного рака под ультразвуковым контролем

Background. There is a category of patients with renal masses, due to severe concomitant diseases, can not perform the operation or may be associated with a threat to life. In addition, many patients with small tumor sites are extremely concerned about their disease and are negative about the tactics of active observation and insist on treatment. These patients can be offered alternative methods of treatment of renal cell carcinoma (RCC), the leading of which is cryoablation.Objective: to evaluate the effectiveness and safety of percutaneous cryoablation of the kidney tumor under ultrasound control.Materials and methods. In the Urology Clinic of the I.M. Sechenov First Moscow State Medical University during the period from 2015 to 2017 performed 23 percutaneous cryoablation of RCC, 7 (men – 4, women – 3) of which were performed under local anesthesia. In 4 patients due to severe concomitant diseases, general anesthesia was associated with an extremely high risk. Three patients refused from dynamic observation and from traditional surgical treatment; preferred an alternative treatment in the form of a percutaneous cryoablation under local anesthesia. In 4 cases, the formations were located in the lower segment along the posterior surface of the kidney, in 3 – along the lateral surface in the middle segment. The size of the formations was not used 4 cm (T1a). The age of the patients was 62.3 years (51 to 83 years). Right-sided localization of the tumor was noted in 3 patients, left-sided – in 4. One patient had a single kidney.At the preoperative stage and 6 months after the operation, all patients underwent ultrasound with dopplerography, multislice computerized tomography with contrast, and computer 3D modeling, which helped to clearly assess the size of the tumor, clarify the prevalence of the tumor process and the spatial ratio of the internal surface of the tumor node to the elements of the bowl-and-pelvis system. In all the observations, the formations were located along the posterior or lateral surface of the kidney; in the lower or middle segment; without invasion of the sine. We used a 3rd generation cryomash machine SeedNet gold (Galil Medical), cryoprobes IceSeed and IceRod. Intraoperative, immediately before cryoablation, a tumor biopsy was performed, the presence of RCC in all patients was confirmed morphologically.Results. According to the ultrasound examination with echodopplerography at 6 months after the operation, the size of the tumor node’s formations decreased on average by 6–8 mm, while there was no blood flow in them. When multislice computerized tomography with 3D modeling was performed, the formation was reduced and the accumulation of the contrast preparation was completely absent or their accumulation gradient did not exceed 10 HU (initially it was about 200 HU). There were no intraoperative complications. In 1 observation, a postoperative hematoma measuring 7 × 3 cm was resolved conservatively and did not require surgical treatment.Conclusions. Percutaneous cryodestruction under local anesthesia using ultrasound guidance seems to be an effective and safe technique for treating patients with stage T1a RCC with localization in the posterior or lateral surface in the lower or middle segments without invasion of the renal sinus and surrounding tissues. It is planned to continue monitoring patients to assess the long-term effectiveness of cryoablation.Введение. Существует категория пациентов c почечно-клеточным раком (ПКР), у которых в связи с тяжелыми сопутствующими заболеваниями операция не может быть выполнена или сопряжена с угрозой для жизни. Кроме того, многие пациенты с небольшим размером опухолевого узла крайне обеспокоены своим заболеванием и отрицательно относятся к тактике активного наблюдения, настаивая на лечении. Таким пациентам могут быть предложены альтернативные методы терапии ПКР, ведущим из которых является криоаблация.Цель исследования – оценить эффективность и безопасность чрескожной криоаблации опухоли почки под ультразвуковым контролем. Материалы и методы. В клинике урологии Первого Московского государственного медицинского университета им. И.М. Сеченова в период с 2015 по 2017 г. выполнены 23 чрескожные криоаблации ПКР, из них 7 (4 мужчин, 3 женщин) проводили под местной анестезией. У 4 пациентов ввиду тяжелых сопутствующих заболеваний общее обезболивание было сопряжено с крайне высоким риском. От динамического наблюдения и традиционного хирургического лечения отказались 3 пациента. Они предпочли альтернативное лечение в виде чрескожной криоаблации под местной анестезией. В 4 наблюдениях образования располагались в нижнем сегменте по задней поверхности почки, в 3 – в среднем сегменте по латеральной поверхности. Размер образований не превышал 4 см (стадия Т1a). Средний возраст пациентов составил 62,3 года (51–83 года). Правосторонняя локализация опухоли отмечена у 3 пациентов, левосторонняя – у 4. У 1 больного почка была единственной.На дооперационном этапе и через 6 мес после вмешательства всем пациентам проведены ультразвуковое исследование с допплерографией, мультиспиральная компьютерная томография с контрастированием и компьютерное трехмерное моделирование, что помогало четко оценить размер опухоли, уточнить распространенность опухолевого процесса и пространственное отношение внутренней поверхности опухолевого узла к элементам чашечно-лоханочной системы. Во всех наблюдениях образования располагались по задней или латеральной поверхности почки в нижнем или среднем сегменте без инвазии в синус.Мы использовали криомашину 3-го поколения SeedNet gold (Galil Medical), криозонды IceSeed и IceRod. За 3 нед до проведения операции выполняли биопсию опухоли. Наличие ПКР у всех больных было подтверждено морфологически.Результаты. По данным ультразвукового обследования с эходопплерографией через 6 мес после операции размер образований опухолевого узла уменьшился в среднем на 6–8 мм, при этом в них отсутствовал кровоток. При проведении мультиспиральной компьютерной томографии с трехмерным моделированием также отмечались уменьшение образований и полное отсутствие накопления контрастного препарата либо его градиент накопления не превышал 10 ед. HU (первоначально он составлял около 200 ед. HU). Интраоперационных осложнений не зарегистрировано. В 1 наблюдении выявлена послеоперационная гематома размером 7 × 3 см, разрешившаяся консервативно и не потребовавшая оперативного лечения.Заключение. Чрескожная криодеструкция под местной анестезией с использованием ультразвуковой навигации представляется эффективной и безопасной методикой лечения больных ПКР стадии Т1а с локализацией образования по задней или латеральной поверхности в нижнем или среднем сегменте без инвазии в почечный синус и окружающие ткани. Планируется продолжить наблюдение за пациентами для оценки долгосрочной эффективности криоаблации

Transcriptional Regulation of Human Dual Specificity Protein Phosphatase 1 (DUSP1) Gene by Glucocorticoids

Background: Glucocorticoids are potent anti-inflammatory agents commonly used to treat inflammatory diseases. They convey signals through the intracellular glucocorticoid receptor (GR), which upon binding to ligands, associates with genomic glucocorticoid response elements (GREs) to regulate transcription of associated genes. One mechanism by which glucocorticoids inhibit inflammation is through induction of the dual specificity phosphatase-1 (DUSP1, a.k.a. mitogen-activated protein kinase phosphatase-1, MKP-1) gene. Methodology/Principal Findings: We found that glucocorticoids rapidly increased transcription of DUSP1 within 10 minutes in A549 human lung adenocarcinoma cells. Using chromatin immunoprecipitation (ChIP) scanning, we located a GR binding region between 21421 and 21118 upstream of the DUSP1 transcription start site. This region is active in a reporter system, and mutagenesis analyses identified a functional GRE located between 21337 and 21323. We found that glucocorticoids increased DNase I hypersensitivity, reduced nucleosome density, and increased histone H3 and H4 acetylation within genomic regions surrounding the GRE. ChIP experiments showed that p300 was recruited to the DUSP1 GRE, and RNA interference experiments demonstrated that reduction of p300 decreased glucocorticoid-stimulated DUSP1 gene expression and histone H3 hyperacetylation. Furthermore, overexpression of p300 potentiated glucocorticoid-stimulated activity of a reporter gene containing the DUSP1 GRE, and this coactivation effect was compromised when the histone acetyltransferase domain was mutated. ChIP-reChIP experiments using GR followed by p300 antibodies showed significant enrichment of the DUSP1 GRE upon glucocorticoid treatment, suggesting that GR and p300 are in the same protein complex recruited to the DUSP1 GRE. Conclusions/Significance: Our studies identified a functional GRE for the DUSP1 gene. Moreover, the transcriptional activation of DUSP1 by glucocorticoids requires p300 and a rapid modification of the chromatin structure surrounding the GRE. Overall, understanding the mechanism of glucocorticoid-induced DUSP1 gene transcription could provide insights into therapeutic approaches against inflammatory diseases. © 2010 Shipp et al

An Integrated Pipeline for the Genome-Wide Analysis of Transcription Factor Binding Sites from ChIP-Seq

ChIP-Seq has become the standard method for genome-wide profiling DNA association of transcription factors. To simplify analyzing and interpreting ChIP-Seq data, which typically involves using multiple applications, we describe an integrated, open source, R-based analysis pipeline. The pipeline addresses data input, peak detection, sequence and motif analysis, visualization, and data export, and can readily be extended via other R and Bioconductor packages. Using a standard multicore computer, it can be used with datasets consisting of tens of thousands of enriched regions. We demonstrate its effectiveness on published human ChIP-Seq datasets for FOXA1, ER, CTCF and STAT1, where it detected co-occurring motifs that were consistent with the literature but not detected by other methods. Our pipeline provides the first complete set of Bioconductor tools for sequence and motif analysis of ChIP-Seq and ChIP-chip data

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido

Cytochrome c oxidase assembly factors with thioredoxin fold are conserved among prokaryotes and eukaryotes: Erratum

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41879/1/109-78-5-243_s001090000115.pd

Cytochrome c oxidase assembly factors with thioredoxin fold are conserved among prokaryotes and eukaryotes

Cytochrome c oxidase (COX) is a multi-subunit terminal oxidase of the eukaryotic respiratory chain involved in the reduction of oxygen to water. Numerous lines of evidence suggest that the assembly of COX is a multi-step, assisted process that depends on several assembly factors with largely unknown functions. Sco1/2 proteins have been isolated as high-copy number suppressors of a deletion of copper chaperone Cox17, implicating Sco1/2 in copper transport to COX subunits I or II. Here I report the similarity of Sco1/2 assembly factors to peroxiredoxins and thiol:disulfide oxidoreductases with a thioredoxin fold, suggesting that Sco-related proteins perform a catalytic rather than a copper transport function. Reported sequence similarities, together with the functional role of bacterial Sco-related proteins suggest that Sco-related proteins represent a new class of membrane-anchored thiol:disulfide oxidoreductases involved in COX maturation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41878/1/109-78-5-239_s001090000110.pd