Патоморфологические и молекулярно-генетические особенности диффузного типа рака желудка

 Gastric cancer (GC) is the 5th most common type of cancer in the world and the third leading cause of death from cancer. GC is a multi-factorial and morphologically heterogeneous disease. Currently, several morphological classifications of GC are used, however, for diagnosis, it is necessary to take into  account not only the morphological type of the tumor, but also its molecular subtype. According to the literature, the intestinal type of GC is most often associated with effects of environmental factors and is usually found in older  age groups in men, while diffuse gastric cancer (DGC) is a genetically determined disease which is more common in younger patients, with the same frequency among men and women.This review covers in detail GC, its classification by P.A. Lauren (1965), and its molecular subtypes characterized during the Cancer Genome Atlas project and examines the impact of certain risk factors on the pathogenesis of the disease, such as: H. pylori infection or Epstein – Barr virus. A separate section in this analytical work is dedicated to expression of the PD-L1 marker by tumor cells and the use of this parameter for prognosis and therapy of this disease. An essential part of the work is discussion of the features of intestinal and diffuse types of gastric cancer, which reflect not only the differences in classifications used in modern diagnosis, but also the relationship between the pathological pattern and the molecular subtype of gastric cancer.  Рак желудка (РЖ) занимает пятое место в мире по распространенности среди всех злокачественных новообразований и является третьей по значимости причиной смертности от онкологических заболеваний. РЖ является мультифакториальным, морфологически  неоднородным заболеванием. В настоящее время используется несколько морфологических классификаций  РЖ, однако для постановки диагноза требуется учитывать не только морфологический тип опухоли, но и ее  молекулярный подтип. По данным литературы, РЖ  интестинального типа чаще всего ассоциирован с  действием факторов окружающей среды и, как правило, встречается в старших возрастных группах у мужчин.  Диффузный тип рака желудка (ДТРЖ) является в большей степени генетически детерминированным заболеванием и чаще встречается у более молодых пациентов, при этом с одинаковой частотой среди мужчин и женщин.В данном обзоре подробно освещается тема РЖ, его  классификация по P.A. Lauren (1965), его молекулярным  подтипы, охарактеризованные в Атласе ракового генома  (The Cancer Genome Atlas), а также рассматривается влияние  определенных факторов риска на патогенез  заболевания, таких как инфицирование H. pylori или вирусом Эпштейна – Барр. Отдельную роль в данной  аналитической работе занимает вопрос экспрессии опухолевыми клетками маркера PD-L1 и использование  данного параметра для прогнозирования и терапии этого  заболевания. Немаловажной частью работы является  обсуждение особенностей интестинального и диффузного  типов рака желудка, которые отражают не только различия  используемых в современной диагностике классификаций,  но и взаимосвязь патоморфологической картины с  молекулярным подтипом рака желудка.

Applying bioinformatic analysis for prognostic assessment of the <i>HS3ST6</i> missense mutations clinical significance in the development of hereditary angioedema

Hereditary angioedema (HAE) is a genetically determined disease characterized by recurrent attacks of edema affecting the subcutaneous and/or submucosal layers of tissue, face, lips, neck, extremities of the body,  oral cavity,  intestine and/or larynx. In the latter case, the disease becomes life-threatening.    The majority of HAE cases are associated with decreased levels of C1 (C1-esterase inhibitor), there are also descriptions of HAE with dysfunctional C1 inhibitor and HAE with normal C1 inhibitor. In the first and second variants, mutations in the C1NH gene are the cause of the disease. HAE with normal quantitative  and functional levels of C1-inhibitor has the same clinical manifestations but with mutations in other genes, including F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6. Currently, mutations in the HS3ST6 gene remain poorly understood; only one missense mutation (p.Thr144Ser, rs746467957) associated with the development of HAE has been described.The aim of our work was to study new mutations in the HS3ST6 gene and analyze in silico their prognostic nature and clinical significance for the development of hereditary angioedema.The material was whole blood samples obtained from 13 patients with symptoms of hereditary angioedema without reduced levels and function of C1-INH.Whole exome sequencing of patients, bioinformatic analysis of HS3ST6 gene mutations using a number of databases and Web resources to predict the effect of mutations on the protein and assess the conservatism of the positions of the mutations detected was involved in study methods.Mutations in the HS3ST6 gene were identified in four patients, including two cases with two mutations simultaneously. Application of bioinformatic analysis allowed us to obtain new data on four missense mutations in the studied gene. Potential pathogenetic significance was determined for three of them. The mutation NC_000016.9:g.1962132G&gt;A (p.A163V) is most likely to be involved in pathogenesis of HAE by indirect disruption of heparan sulfate O-sulfation directly within the protein. The NC_000016.9:g.1962024G&gt;A mutation (p.P199L) appears to lead to the development of the disease through disruption of docking with SDC2 heparan sulfate. In the NC_000016.9:g.1962046C&gt;T (p.A192T) mutation, destabilization of the 192 amino acid position next to PAPS, may contribute to disruption of heparan sulfate O-sulfation through disruption of protein functional activity and, therefore, catalysis transfer of sulfo group to heparan sulfate syndecan-2. Thus, in all three cases, the formation of HAE appears to be possible due to disruption of the O-sulfation steps of heparan sulfate syndecan-2.Considering that in silico methods offer new opportunities to assess the pathogenetic significance of mutations, the application of bioinformatic analysis can contribute to a detailed investigation of the causes of hereditary angioedema. The present work convincingly demonstrates that rare mutations in the HS3ST6 gene may be involved in the pathogenesis of HAE and provoke edema due to increased bradykinin release

Клинико-морфологические особенности немышечноинвазивного рака мочевого пузыря: влияние на лечение, прогноз и рецидив заболевания (обзор литературы)

This review of bladder cancer describes modern clinical and pathologic features of the neoplasm, reports new data about treatment and prognosis of this disease.В настоящем обзоре описаны современные клинические и патоморфологические особенности рака мочевого пузыря, а также приведены данные о современных принципах лечения этого заболевания и критериях прогноза

The \u201cblind age assessment\u201d: applicability of Greulich & Pyle, Demirjian and Mincer aging methods on a population of unknown ethnic origin

Purpose: Age estimation is one of the most crucial issues in case of unknown deceased as well as in the living and is very frequently of radiological interest. Three methods for age estimation have been designated as the most reliable among the others: Greulich and Pyle, Demirjian and Mincer. The literature provides several studies concerning their applicability in different geographic contexts. However, not always can ancestry be ascertained, for example, in the case of badly preserved corpses. In these cases, age assessment must be performed without the corrections suggested by the literature for different ethnic groups. One may therefore wonder how reliable the result of age assessment performed without knowing the racial group to which the subject belongs may be. This study aimed at testing the applicability of the Greulich and Pyle Atlas, the Demirjian and the Mincer methods on a mixed population to compare skeletal and dental methods of age estimation. Materials and methods: X-ray films of 167 subjects aged between 4 and 31 years from more than 18 countries were recruited. One hundred and nine orthopantomographs (OPG) of children aged between 4 and 15.5 years were evaluated by Demirjian's method; whenever the highest Demirjian score was reached (31 cases), the Mincer method was applied. The skeletal maturation of 54 subjects aged between 7 and 19 years was determined by the Greulich and Pyle method. Results: The lowest average variance from chronological age was shown by the Greulich and Pyle method, followed by Demirjian. The Mincer method showed very high mean variances. Conclusions: Mean variances from the different methods do not significantly differ from data reported in the literature and demonstrate that the reliability of Demirjian, and Greulich and Pyle as they stand may be applied satisfactorily to remains or individuals of unknown ethnic origin

Microscopic markers of trauma in decomposed bone and skin

The goal of this presentation is to detect the vitality of soft tissue and bone lesions in an advanced state of decomposition using a monoclonal anti-human Glycophorine A antibody in order to evaluate the presence and distribution of blood cells. This presentation will impact the forensic science community by showing an attempt at detecting a vital reaction in decomposed skin and bone in order to distinguish between antemortem and postmortem lesions in difficult situations. The diagnosis of the vitality of a wound, or rather the identification of a vital reaction that enables one to differentiate an intravital wound from a postmortem wound, is a crucial issue in forensic pathology and more so in forensic anthropology. In fresh skin the macroscopic examination of hemorrhage infiltration can be sufficient to reveal the vitality of the wound but in many other cases histological and histochemical analyses are required. Bone injuries may follow similar \u201claws\u201d as concerns the evolution of the macroscopic and histological picture. The scope of this study was to detect the vitality of soft tissue and bone lesions in an advanced state of decomposition using a monoclonal anti-human Glycophorine A antibody in order to evaluate the presence and distribution of blood cells. Six samples of bone fractures and two samples of skin wounds were taken from cadavers with a known time of survival between trauma and death, and then submitted to a simulated decomposition procedure. Negative controls were also included. The samples were left to decompose for 30 days in air and in water and analized at a time interval of 3-6-15 and 30 days. The bones were decalcified in a specific solution consisting of water, HCl, and Formic acid. Bone samples were stained with HE, Perls\u2019, PTAH, Weigert technique and PAS. Skin samples were stained with HE, Trichrome stain. Both bone and skin samples were stained with immunohistochemical technique. Skin and bone samples from four real cases of blunt and gunshot trauma were also included in the study. Results showed, in the bone samples, red blood cell residues on the fractured margins and within Haversian canals may contribute to the diagnosis of a vital reaction. In the skin samples, red blood cells were visible until the 6th day in air and granular deposits of glycophorin reactive material after six days in air and in all samples in water. The general microscopic structure of bone was assessed in order to verify traumatic alterations in osteons. In conclusion, this study may begin to shed some light on the issue of detecting a vital reaction in decomposed skin and bone in order to distinguish between antemortem and postmortem lesions in difficult situations