Современный подход к компьютерно-томографической диагностике аденокарциномы легкого

The classification of tumors of the lung, pleura, thymus and heart was published by the World Health Organization (WHO) in 2015. It presents a completely different approach to adenocarcinoma compared to the 2004 WHO classification.Adenocarcinoma is the most common histological type of lung cancer.The interdisciplinary classification is based on consensus among oncologists, thoracic surgeons, pulmonologists, pathologists, molecular biologists, radiologists, radiologists and identifies a wide range of adenocarcinoma types and subtypes with varying prognosis and treatment. They are accompanied by a variety of manifestations and features on computed tomography, which usually correlate with histopathological findings, highlighting one of the key roles of the radiologist in the diagnosis and treatment of such patients.The aim of the work is to familiarize radiologists with the WHO 2015 classification, terminology and computed tomographic diagnostic criteria for various types of lung adenocarcinoma.Классификация опухолей легкого, плевры, тимуса и сердца опубликована Всемирной организации здравоохранения (ВОЗ) в 2015 г. В ней представлен совершенно иной подход к аденокарциноме по сравнению с классификацией ВОЗ 2004 г.Аденокарцинома – наиболее распространенный гистологический тип рака легких.Междисциплинарная классификация основана на консенсусе между онкологами, торакальными хирургами, пульмонологами, патологами, молекулярными биологами, рентгенологами, радиологами и определяет широкий спектр типов аденокарциномы и подтипов с различным прогнозом и лечением. Они сопровождаются разнообразными проявлениями и особенностями при компьютерной томографии, которые обычно коррелируют с гистопатологическими данными, подчеркивая одну из ключевых ролей врача-рентгенолога в диагностике и лечении таких пациентов.Целью работы является ознакомление врачей-рентгенологов с классификацией ВОЗ 2015, терминологией и компьютерно-томографическими диагностическими критериями различных типов аденокарциномы легкого.

The CUGBP2 Splicing Factor Regulates an Ensemble of Branchpoints from Perimeter Binding Sites with Implications for Autoregulation

Alternative pre-mRNA splicing adjusts the transcriptional output of the genome by generating related mRNAs from a single primary transcript, thereby expanding protein diversity. A fundamental unanswered question is how splicing factors achieve specificity in the selection of target substrates despite the recognition of information-poor sequence motifs. The CUGBP2 splicing regulator plays a key role in the brain region-specific silencing of the NI exon of the NMDA R1 receptor. However, the sequence motifs utilized by this factor for specific target exon selection and its role in splicing silencing are not understood. Here, we use chemical modification footprinting to map the contact sites of CUGBP2 to GU-rich motifs closely positioned at the boundaries of the branch sites of the NI exon, and we demonstrate a mechanistic role for this specific arrangement of motifs for the regulation of branchpoint formation. General support for a branch site-perimeter–binding model is indicated by the identification of a group of novel target exons with a similar configuration of motifs that are silenced by CUGBP2. These results reveal an autoregulatory role for CUGBP2 as indicated by its direct interaction with functionally significant RNA motifs surrounding the branch sites upstream of exon 6 of the CUGBP2 transcript itself. The perimeter-binding model explains how CUGBP2 can effectively embrace the branch site region to achieve the specificity needed for the selection of exon targets and the fine-tuning of alternative splicing patterns

The Caenorhabditis elegans Gene mfap-1 Encodes a Nuclear Protein That Affects Alternative Splicing

RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre–mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing.National Natural Science Foundation (China) (Grant 30971639)United States. National Institutes of Health (Grant GM24663

H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast

<p>Abstract</p> <p>Background</p> <p>The packaging of DNA into chromatin regulates transcription from initiation through 3' end processing. One aspect of transcription in which chromatin plays a poorly understood role is the co-transcriptional splicing of pre-mRNA.</p> <p>Results</p> <p>Here we provide evidence that H2B monoubiquitylation (H2BK123ub1) marks introns in <it>Saccharomyces cerevisiae</it>. A genome-wide map of H2BK123ub1 in this organism reveals that this modification is enriched in coding regions and that its levels peak at the transcribed regions of two characteristic subgroups of genes. First, long genes are more likely to have higher levels of H2BK123ub1, correlating with the postulated role of this modification in preventing cryptic transcription initiation in ORFs. Second, genes that are highly transcribed also have high levels of H2BK123ub1, including the ribosomal protein genes, which comprise the majority of intron-containing genes in yeast. H2BK123ub1 is also a feature of introns in the yeast genome, and the disruption of this modification alters the intragenic distribution of H3 trimethylation on lysine 36 (H3K36me3), which functionally correlates with alternative RNA splicing in humans. In addition, the deletion of genes encoding the U2 snRNP subunits, Lea1 or Msl1, in combination with an <it>htb-K123R </it>mutation, leads to synthetic lethality.</p> <p>Conclusion</p> <p>These data suggest that H2BK123ub1 facilitates cross talk between chromatin and pre-mRNA splicing by modulating the distribution of intronic and exonic histone modifications.</p

Инвазивный аспергиллёз лёгких у больных COVID-19

A retrospective analysis of the medical data of 12 patients with COVID-19 was performed. For the diagnosis of invasive aspergillosis the international criteria ECMM/ISHAM 2020 were used. We analyzed the scientific literature data on the diagnosis and treatment of invasive aspergillosis in patients with COVID-19.Results. Among the 12 examined patients with a severe course of COVID-19, invasive aspergillosis was diagnosed in 5 patients. Four patients (80%) were treated in the ICU. Steroids or interleukin-6 inhibitors were used in 80% patients. Severe lymphocytopenia was in 80% patients, neutropenia 20%. A fever refractory to antibiotic therapy was noted in 80% patients, an increase in respiratory failure – 60%, acute respiratory distress syndrome – 60%. All patients showed negative dynamics of changes in the chest CT scan. Invasive aspergillosis was confirmed with a positive test for galactomannan in bronchoalveolar lavage and / or serum in 100% of cases. All patients received antifungal therapy with voriconazole and/or caspofungin. The overall 12-week survival rate was 80%.Conclusion. In ICU patients with severe COVID-19 and progressive pulmonary symptoms invasive aspergillosis should be excluded. Examination of substrates from the lower respiratory tract (BAL, tracheal aspirate, or nonbronchoscopic lavage) is necessary. Laboratory examination should include microscopy, culture and test for galactomannan. Voriconazole and isavuconazole are drugs of choice for the treatment of invasive aspergillosis in patients with COVID-19.Провели ретроспективный анализ медицинских данных 12 больных COVID-19. Для диагностики инвазивного аспергиллеза использовали международные критерии ECMM/ISHAM, 2020. Проанализировали данные научной литературы, посвященной диагностике и терапии инвазивного аспергиллеза у больных COVID-19.Результаты. Из 12 обследованных пациентов с тяжелым течением COVID-19 инвазивный аспергиллез был диагностирован у 5 больных, из них 4 пациента (80%) находились на лечении в ОРИТ. Глюкокортикостероиды или ингибиторы интерлейкина-6 применяли у 80% пациентов. Выраженная лимфоцитопения была у 80% больных, нейтропения – у 20%. Рефрактерную к антибиотикотерапии лихорадку отмечали у 80% пациентов, нарастание дыхательной недостаточности – у 60%, острый респираторный дистресс-синдром – у 60%. У всех пациентов выявляли отрицательную динамику изменений в легких при компьютерной томографии. Инвазивный аспергиллез был подтвержден положительным результатом теста на галактоманнан в бронхоальвеолярном лаваже и/или сыворотке крови в 100% случаев. Все больные получали антимикотическую терапию вориконазолом и/или каспофунгином. Общая 12-недельная выживаемость составила 80%.Заключение. У пациентов в ОРИТ с тяжелым течением COVID-19 и прогрессирующими симптомами поражения легких следует исключить инвазивный аспергиллёз. Необходимо исследование материала из нижних отделов респираторного тракта (БАЛ, трахеальный аспират или небронхоскопический лаваж), которое должно включать микроскопию, посев и тест на галактоманнан. Вориконазол и изавуконазол – препараты выбора для лечения инвазивного аспергиллеза у больных COVID-19

Maternity testing in a chimerical child

Abstract. Human congenital chimerism is due to the coexistence of two genetically different cell lines either in the whole body or limited to the blood. We present a case of maternity in which the alleged child has ambiguous genitalia, and chimerism was suspected. The maternity was dubious and the father was not available for the study. STR typing of the child revealed the presence of X an Y chromosomes at Amelogenin locus and a double maternal and paternal alleles contribution in certain autosomical loci. We could not exclude maternal relationship between the alleged mother and the child. Molecular analysis performed with highly discriminating STR systems allowed us to clarify the origin of a chimerical individual.

Specialized Yeast Ribosomes: A Customized Tool for Selective mRNA Translation

Evidence is now accumulating that sub-populations of ribosomes - so-called specialized ribosomes - can favour the translation of subsets of mRNAs. Here we use a large collection of diploid yeast strains, each deficient in one or other copy of the set of ribosomal protein (RP) genes, to generate eukaryotic cells carrying distinct populations of altered ‘specialized’ ribosomes. We show by comparative protein synthesis assays that different heterologous mRNA reporters based on luciferase are preferentially translated by distinct populations of specialized ribosomes. These mRNAs include reporters carrying premature termination codons (PTC) thus allowing us to identify specialized ribosomes that alter the efficiency of translation termination leading to enhanced synthesis of the wild-type protein. This finding suggests that these strains can be used to identify novel therapeutic targets in the ribosome. To explore this further we examined the translation of the mRNA encoding the extracellular matrix protein laminin ?3 (LAMB3) since a LAMB3-PTC mutant is implicated in the blistering skin disease Epidermolysis bullosa (EB). This screen identified specialized ribosomes with reduced levels of RP L35B as showing enhanced synthesis of full-length LAMB3 in cells expressing the LAMB3-PTC mutant. Importantly, the RP L35B sub-population of specialized ribosomes leave both translation of a reporter luciferase carrying a different PTC and bulk mRNA translation largely unaltered