bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Risk Signature of m6A Regulators, KIAA1429, YTHDF1, YTHDF2, METTL3 and Its Relationship with Immune Infiltration in Hepatocellular Carcinoma
Authors: Guo Jingjing , Wang Liwei , Xu Hanfeng , Zhu Chuandong , Wang Jianning , Zheng Qin
Published: July 2020

Background: Hepatocellular carcinoma (HCC) is a tumor of the digestive system with high mortality. N6-methyladenosine (m6A) is one of the most common forms of mRNA modification. Tumor neoantigens play an important role in anti-tumor immune response and predict the clinical response of immunotherapy. There are few studies on the relationship between m6A regulators and immune infiltrating cells. The objective of this study was to determine the gene expression and prognostic value of m6A regulators in hepatocellular carcinoma. Further, we explored the relationship between m6A regulators and immune-infiltrating cells.Methods: 13 m6A regulators expressions in 374 cancer tissues and 50 normal tissues were analyzed using RNA-seq data and clinical information in the TCGA database. Survival package was used to analyze the survival of patients in the two groups, and the corresponding clinical characteristics and gene expression were analyzed using univariate and multivariate Cox regression. We evaluated the expression of KIAA1429, YTHDF1, YTHDF2, and METTL3 in HCC and its correlation with TIICs using TIMER and CIBERSORT.Results: Most m6A regulators had higher expression levels in 374 cancer tissues. We confirmed two groups of HCC patients using a consensus clustering method. The prognosis of the cluster 1 group was poor compared with that of the cluster 2 group. The m6A regulators, KIAA1429, YTHDF1, YTHDF2, and METTL3 are highly expressed in the high-risk group of HCC. Furthermore, it was found that four m6A regulators (KIAA1429, YTHDF1, YTHDF2, and METTL3) are closely related to the clinicopathological characteristics and poor prognostic marker of hepatocellular carcinoma. We analyzed the correlation between KIAA1429, YTHDF1, YTHDF2, and METTL3 expression and the level of immune invasion of HCC.Conclusion: KIAA1429, YTHDF1, YTHDF2, and METTL3 as m6A regulators may regulate the tumor microenvironment through tumor immune infiltration cells to exert immune anti-tumor effects. KIAA1429, YTHDF1, YTHDF2, and METTL3 as molecular markers providing a new target for therapy of HCC in the further.
Hassle Faced with Induced Mania in Elderly Female While Treating for OC Symptoms. A Case Report.
Authors: BHARTI POONAM , singh Angad harshbir , Gupta Parul
Published: July 2020

Background- Obsessive-compulsive disorder (OCD) is one of the most frequently associated comorbidities in bipolar disorder (BD). While this presents a challenge in understanding the phenomenology and also the treatment aspect of co occurrence of mania with OCD. Case history- The index case is of an elderly female who presented with OC symptoms and while on treatment had mania episodes. The mania episodes presented challenges while managing underlying OC symptoms. Conclusion- The common neurobiological mechanism for the co-morbid illness and treatment lacunae are discussed. The serotonin, dopamine, and glutamate having important role in BD-OCD were evaluated to understand the neurobiological basis of BD-OCD. The index case presented with the challenge of understanding the phenomenology of the illness but also presented with opportunity to learn and successfully manage patients with such co-morbidity. Divalproex and risperidone combo was found to be effective in controlling mania in OCD patients.
An Affordance-based Approach for The Design of Customized Product Non-standard Part
Authors: Lemiao QIU , Heng LI , Guodong YI , Xiaojian LIU , Peng ZHANG , Shuyou ZHANG , Jianrong TAN
Published: July 2020

In this paper we develop an affordance-integrated approach to support design of the customized product non-standard part from conceptual period to detailed period. Firstly, the part affordances are identified by geometrical correlation analysis and shown by liaison graph. Secondly, a force transmission based method is developed to identify the main design parameters of a part, at the same time the design parameters and user requirements both can be mapped into the affordances. In turn, these affordances can be used as a bridge to construct the mapping relationship between the user requirements and the design parameters. In the end, both the force transmission method and the mapping relations are used to construct the detailed model of the non-standard part. A rear platen from the injection molding machine is employed to demonstrate the proposed approach and the result shows that this method can be feasible and useful in product design.
Community-Based Survey On Reported Increased Mortality In Kano State
Authors: Gambo Yusuf Yau
Published: July 2020

Objectives: The main objectives of the study were to use data to corroborate the reported mysterious deaths being recorded in Kano state of Nigeria and find possible explanations to the causes. Study design: This was a cross-sectional study. Methods: With total lockdown in force at the time of conducting the survey, it was not possible to get data through one-on-one interview. Instead, an online survey form was developed and shared widely among residents in the state. The form captured quantitative data about symptoms and circumstances for the deceased and the respondents were only the state residents that witnessed the death cases in their respective communities. Results: A total of 260 responses from various local government areas (LGAs) were received within a period of four days beginning from April 21, 2020. About half of the respondents affirmed that the death toll in their communities within the last two weeks before the survey were in multiples and most of the deaths started to occur from April 13 2020. Moreover, since then, the rate of deaths reported did not decline during the period of the research. Conclusion: There was a sudden increase in the number of deaths due to acute illness suggestive of a disease. Highest number of deaths was recorded among senior adults, affecting males than females. The most affected area was Kano Municipal which was one of the populous LGA in the state. Although it was hard to point out the possible cause of death based on the data, however, the possibility of linking the situation to the current COVID-19 pandemic could not be ruled out. This was because the data strongly aligned with the pandemic in terms of symptoms, incubation period, age group affected and other demographic characteristics.
MiR-125b-5p Inhibited The Progression of Hepatoblastoma As A Shared miRNA of The lncRNA NEAT1 and YES1
Authors: Jin Zhu , Chen Yutong , Mao Yuchen , Gao Mingjuan , Zheng Zebing , Tang Chengyan , Huang Lu , Qu Yan , Liu Yuanmei
Published: July 2020

Background: microRNAs have been studied widely in hepatoblastoma. However, the role of miR-125b-5p and its relationship with the lncRNA sNEAT1 and YES1 in hepatoblastoma have not been reported previously. We aimed to reveal the role of NEAT1/miR-125b-5p/YES1 in the progression of hepatoblastoma.Methods: We collected tumor tissues and their adjacent tissues from 12 hepatoblastoma patients. qRT-PCR was applied to detect the expression of miR-125b-5p, and the relationship of miR-125b-5p with clinicopathological characteristics was analyzed. Dual luciferase reporter assays and RNA pull down assays were used to identify the relationships among NEAT1, miR-125b-5p and YES1. CCK8, Transwell assays and wound healing assays were used to examine cell viability, invasion and migration. In vivo experiments were also applied to detect the effect of miR-125b-5p on hepatoblastoma.Results: miR-125b-5p was significantly downregulated in hepatoblastoma tissue and cells. The higher the PRETEXT grade, the lower the miR-125b-5p level. NEAT1 could bind to miR-125b-5p and inhibit its expression. miR-125b-5p could target YES1 and inhibit its expression. Overexpression of miR-125b-5p decreased the proliferation, invasion, and migratory ability of hepatoblastoma cells. YES1 could rescue the above effects. At the same time, overexpression of miR-125b-5p resulted in decreased YES1 and tumor growth inhibition in vivo.Conclusion: miR-125b-5p acted as a shared miRNA of NEAT1 and YES1 in hepatoblastoma. Overexpression of miR-125b-5p could target YES1 and inhibit its expression, therefore inhibiting the progression of hepatoblastoma.
Prognostic Significance of COVID-19 Receptor ACE2 and Recommendation For Anti-Hypertensive Drug in Renal Cell Carcinoma
Authors: Kim Kihun , Ko Yeji , Ko Dai Sik , Kim Yun Hak
Published: July 2020

Background: Owing to its worldwide spread, the coronavirus disease (COVID-19) epidemic was declared a pandemic by the World Health Organization on March 11, 2020. Angiotensin-converting enzyme 2 (ACE2) is the outer surface protein of the cell membrane that is abundantly distributed in the heart, lungs, and kidneys, and plays an important role in molecular docking of the severe acute respiratory syndrome coronavirus 2. In this study, we aimed to analyze the difference in the survival rate according to ACE2 expressions in pan-cancer. Methods: The clinical and genomic data of pan-cancer patients were accessed from The cancer Genome Atlas. To identify the prognostic significance of ACE2, we used Kaplan-Meier with log-rank test, and the Cox proportional hazards regression to analyze prognostic significance. Results: In the Kaplan-Meier curve, clear cell renal cell carcinoma (ccRCC), uveal melanoma, and prostate adenocarcinoma showed statistically significant. In the Cox regression, thyroid carcinoma and glioblastoma multiforme, and ccRCC showed significant results. Only ccRCC had statistically significant, and high ACE2 expression is related to good prognosis. Conclusions: It is known that ACE inhibitor, a primary antihypertensive agent, increases ACE2 expression. Based on these results, we believe that the ACE inhibitor will be important to increase the lifespan of ccRCC patients. This study is the first research to offer a recommendation on the use of anti-hypertensive drugs to ccRCC patients.
Biological characteristics of rt181T/sW172* HBV are similar among distinct genotypes
Authors: Huaqiang Wang , Jun Ai , Jiajuan Zhang , Wenkai Zheng , Maorong Wang , Li Ping
Published: July 2020

Background: The influence of genotypes on disease progression and clinical outcome of HBV infection is noted. The impact of HBV genotypes on rtA181T/sW172* mutation remains unclear. Patients and Methods: Clinical characteristics of 69 patients with rtA181T/sW172* mutation and 39 patients with rtA181V mutation were analyzed in this study. Fifteen serum specimens with rtA181T/sW172* mutation from different genotypes were collected for cloning and sequence analysis. HBV markers in HepG2 cells encoding different proportions of rtA181T/sW172* mutation and wild type strains were detected in genotype A, B, C and D, respectively.Results: No statistically difference was detected between rtA181T and rtA181V group regarding mean age, sex ratio, liver functions, HBV DNA load and HBeAg positive rate, except for HBsAg level (rtA181T group = 3.07±0.54 lg IU/ml vs rtA181V group = 3.29±0.43 lg IU/ml, P=0.037). Among 69 patients with rtA181T/sW172* mutation, HBV genotypes B and C accounted for 17.0% and 83.0%, respectively. The rate of genotype B was lower in rtA181T group (10.1%) than that in rtA181V group (29.7%), whereas genotype C was higher in rtA181T group (89.9%) than that in rtA181V group (70.3%). HBV rtA181T/sW172* mutant coexisted with wild type strains, accounted for 25% to 90% in all HBV strains. The distribution proportion showed no statistical difference between genotype B and C (59.2%±24.3% vs. 61.2%±19.1% , P=0.86). In transfection experiments, the level of HBV DNA was the highest for genotype B, while HBsAg was expressed in the highest level for genotype A. HBsAg and virus particle were barely detected in the supernatants of rtA181T/sW172* HBV clones in all genotypes. As the proportion of wild type HBV plasmid increased, deficiency of rt181T/sW172* mutation was complemented in all genotypes. No significant difference of the relative expression was found among distinct genotypes (P >0.05).Conclusions: HBV rtA181T/sW172* mutational pattern may be influenced by genotypes, but biological characteristics of this mutation is similar among distinct genotypes.
Boosting effects of MiR-4262 on acute myeloid leukemia advancement via governing KLF6
Authors: Qu Hong , Chen Yongfang , Zeng Wenjing , Huang Xiaohua , Cheng Shuqin
Published: July 2020

Background: Purpose of this study was to explore the influence of miR-4262 on the progression of acute myeloid leukemia (AML) and its molecular mechanism.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to assess the expression of miR-4262 in AML serum and cell lines. MTT, Transwell assays and flow cytometry were adopted to investigate the effect of miR-4262 on cell proliferation, invasion, migration and apoptosis abilities of HL-60 cells respectively. Luciferase reporter assay was conducted to reveal the target relationship of miR-4262 and KLF6. Western blot analysis was utilized to evaluate the expression level of proteins.Results: Relative expression of miR-4262 was up-regulated in AML serum and cell lines (P<0.05). miR-4262 expression was closely related to FAB classification (P=0.002) of AML patients. miR-4262 mimics could promotes the proliferation, invasion and migration of HL-60 cells, while miR-4262 inhibitor is obviously weakened these biological behaviors. Luciferase assay illustrated that miR-4262 can directly interact with KLF6 3’UTR. Up-regulation of miR-4262 could decrease KLF6 level, and increase EGFR level, while the down-regulation of miR-4262 showed the opposite results. Moreover, KLF6 gene knockdown reversed the results caused by miR-4262 inhibitor (P<0.05). Inhibition of KLF6 could significantly promoted the proliferation, invasion and migration of HL-60 cells which is caused by miR-4262 inhibitor.Conclusions: miR-4262 was obviously increased in AML serum and cells, it promotes the progression of AML by regulating KLF6.
Homozygous RRM2 Variant Might Lead to Early Embryo Developmental Arrest: A Case Report
Authors: Wang Xiong , Liu Zhen-teng , Sha Yan-wei , Liu Xiao-yan , Wang Hai-long , Hao Cui-fang , Wu Jian-feng , Wang Jiahui
Published: July 2020

Background: Early embryonic developmental stagnation is one of the reasons that affect the outcome of in vitro fertilization-embryo transfer, leading to the depletion of available embryos or failure after transplantation. It has been shown that defects in the ribonucleotide-reductase lead to cell cycle arrest, developmental delay, and high mutation rates.Case presentation: Two female patients, who were siblings from an inbreeding family, suffered primary infertility of unknown causes and early embryonic developmental arrest during IVF treatment. A total of 39 oocytes were obtained from the patients in collectively 5 IVF/ICSI cycles, of which 37 were mature eggs, only 2 transplantable embryos were formed, and no pregnancy was achieved. Whole genome sequencing and Sanger sequencing were adopted to identify and confirm variations that might cause early embryo developmental stagnation in this family. We identified a homozygous variant c.262C>T:p.His88Tyr in ribonucleotide-diphosphate reductase subunit M2 (RRM2) in both patients and their parents each carried a heterozygous allele. Pedigree analysis showed an autosomal recessive inheritance pattern. Function of this variant was predicted by online databases, which indicated it to be a potential pathogenic mutation. Conclusions: We identified RRM2 as a potential causative gene for early embryonic developmental stagnation. It was also suggested that RRM2 might be a maternal effect gene.
The incidence, risk factors and prognosis of acute kidney injury in severe and critically ill patients with COVID-19 in mainland China: a retrospective study
Authors: Sang Ling , Chen Sibei , Zheng Xia , Guan Weijie , Zhang Zhihui , Liang Wenhua , Zhong Ming , Jiang Li , Pan Chun , Zhang Wei , Xia Jiaan , Chen Nanshan , Wu Wenjuan , Wu Hongkai , Xu Yonghao , Liu Xuesong , Liu Xiaoqing , He Jianxing , Li Shiyue , Zhang Dingyu , Zhong Nanshan , Li Yimin
Published: July 2020

Background: Since the clinical correlates, prognosis and determinants of AKI in patients with Covid-19 remain largely unclear, we perform a retrospective study to evaluate the incidence, risk factors and prognosis of AKI in severe and critically ill patients with Covid-19.Methods: We reviewed medical records of all adult patients (>18 years) with laboratory-confirmed Covid-19 who were admitted to the intensive care unit (ICU) between January 23rd 2020 and April 6th 2020 at Wuhan JinYinTan Hospital and The First Affiliated Hospital of Guangzhou Medical University. The clinical data, including patient demographics, clinical symptoms and signs, laboratory findings, treatment [including respiratory supports, use of medications and continuous renal replacement therapy (CRRT)] and clinical outcomes, were extracted from the electronic records, and we access the incidence of AKI and the use of CRRT, risk factors for AKI, the outcomes of renal diseases, and the impact of AKI on the clinical outcomes.Results: Among 210 subjects, 131 were males (62.4%). The median age was 64 years (IQR: 56-71). Of 92 (43.8%) patients who developed AKI during hospitalization, 13 (14.1%), 15 (16.3%) and 64 (69.6%) patients were classified as stage 1, 2 and 3, respectively. 54 cases (58.7%) received CRRT. Age, sepsis, Nephrotoxic drug, IMV and elevated baseline Scr were associated with AKI occurrence. The renal recover during hospitalization among 16 AKI patients (17.4%), who had a significantly shorter time from admission to AKI diagnosis, lower incidence of right heart failure and higher P/F ratio. Of 210 patients, 93 patients deceased within 28 days of ICU admission. AKI stage 3, critical disease, greater age and minimum P/F <150mmHg independently associated with it.Conclusions: Among patients with Covid-19, the incidence of AKI was high. age , sepsis, nephrotoxic drug, IMV and baseline Scr were strongly associated with the development of AKI. Time from admission to AKI diagnosis, right heart failure and P/F ratio were independently associated with the potential of renal recovery. Finally, AKI KIDGO stage 3 independently predicted the risk of death within 28 days of ICU admission.
Entrepreneurship and Creative Destruction
Authors: Johnson Cathleen , Lusch Robert , Schmidt David
Published: July 2020

The study deals with reasons for the inefficient operation of the business sector in the economy through the analysis of the relationship between disruptive innovation and creative destruction. The research is carried out in the following logical sequence: the first stage presents William Baumol’s hypothesis about why entrepreneurship makes some societies richer and some poorer. There is entrepreneurship in every society, Baumol says, but background circumstances vary so that entrepreneurship can be productive, but depending on circumstances it also can be unproductive, or even downright destructive. The second stage substantiates the relationship between entrepreneurship, disruptive innovation, and creative destruction; the third stage investigates the role of entrepreneurs in society as integrators of resources and as managers of risk; the last stage defines possible problems in how the business sector functions in society. The study is based on the generalized works shown in the book “Commercial Society” and considers deep but no obvious links between ethics, economics, and entrepreneurship. In this work, the ethical question is how people have to live in order to make the world a better place. The economic question is what kind of society makes people willing and able to use their talents in ways that are good for themselves and for their communities. The entrepreneurial question is how people can bring services to the marketplace that can take a community to the next level of prosperity? The article offers tools for evaluating the interconnected effect of three business components: ethics, economics, and entrepreneurship. In the framework of entrepreneurship, the authors assess the central role of honesty not only in earning a community’s trust but also inaccurate self-assessment. For a corporation to flourish, its key decision-makers must be honest with themselves and each other about when their products, supply chains, or marketing strategies are not good enough and need to change. The role of the accountant in obtaining and processing information is likewise substantiated. Accounting calls for sophisticated forms of honesty and integrity: sorting through volumes of data so as to present a truth about a company’s cash flow that will not mislead the client.

Keywords: Creative Destruction, Entrepreneur, Innovation, Progress, Resource Integrator, Expectations, Value Proposition.
Is It Necessary a Renewal of the Theory of the Firm Based on Pandemic realities?
Authors: Trifu Alexandru
Published: July 2020

This paper deals with the study of the reverse impact made by the state regulation of entrepreneurial activity on economic development indicators and with substantiation of the expediency to develop new business management theories. According to the analysis of studies on “firm” definition and the peculiarities of its operation, these issues have been actively studied since Adam Smith when the firm was an important component of the marketplace, and until the legislative definition and certification of its operation. The article considers the firm a legal entity, an open economy institution operating under corporate law. The study is conducted based on a critical review of the literature in this field, including information and news of the pandemic period, the synthesis of which allows to draw conclusions about the possibility and need to update the theoretical basis for organizational management, based on the deduction method. According to the analysis results, today, the firm operates in conditions of increased competition and an open environment. Its main functions are the production of goods or services, making a profit and meeting the needs of the population, government agencies or other firms, and the basis of the activities of legislation and regulations approved by government agencies. One of the main problems in modern firms’ functioning is the coronavirus pandemic, which is the essential structural crisis in the economy after World War II. It caused rising unemployment, significant loss of profits, and bankruptcy of small and medium-sized enterprises. Thus, one of the most stable and efficient sectors of the pandemic economy is the IT business and the catering sector. The study shows the need to transform organizations’ existing management strategies in terms of their adaptation to the realities of the modern world economic system. The study results can be useful for managers and heads of enterprises in improving the efficiency of firms during the crisis.

Keywords: Lockdown, Pandemic, Profit, Public Authorities Support, Theory of the Firm, Wellbeing.
Ultrasonic characteristic of the liver in early congenital syphilis in children
Authors: Matyskina N. V. , Taranushenko T. E. , Goldshmidt A. V.
Published: July 2020

Introduction. Liver lesion in congenital syphilis in infants in the first months of life is clinically observed in 74–86% of children in the form of enlargement and thickening during palpation. Pathological and anatomical studies reveal in 100% of cases typical changes in the liver, which are mainly due to diffuse round-cell infiltration, expansion of connective tissue and formation of gummas. Purpose of research. To analyze the indicators of ultrasound examination of the liver and spleen with the assessment of organ blood flow in children born to women with syphilitic infection and to identify the most significant signs associated with early congenital syphilis in the neonatal period.Materials and methods. The paper analyzes the data of a comprehensive survey of 397 newborns who were under observation from birth to 1 month of life, included in the study with the indication of the fact, born to women with a history of documented confirmed syphilitic infection.On the basis of the total sample, three groups of children from birth to 28 days of life were formed, taking into account the Federal clinical guidelines for the management of patients with syphilis (Moscow, 2015).The results of the study and their discussion. In 1 and 2 study groups found a significant increase in the oblique vertical size of the right lobe was 74.3 ± 0.7 mm (p < 0.05) and 73.9 ± 0.4 mm (p < 0.05), vs. 68.8 ± 0.3 mm in the control, as well as the thickness of the left lobe of the liver is 35.3 ± 0.4 mm (p < 0.05) and 34.8 ± 0.6 mm (p < 0.05), compared to 31.4 ± 0.7 mm in the control group. Along with this, in these groups, a higher index of the maximum blood flow velocity in the portal vein was noted, which in these 1 and 2 groups was 0.26 ± 0.02 m/s (p < 0.05) and 0.25 ± 0.02 m/s (p < 0.05), respectively, against 0.20 ± 0.02 m/s in the control. Along with sonographic signs, there was a significant prevalence of hyperbilirubinemia in groups 1 and 2 of newborns – 24.1% (p < 0.001) and 19.9%, respectively, against 9.0% in the control group (neonatal hepatitis was diagnosed in 11.4% of newborns with early congenital syphilis).Conclusion. The ultrasound features of the liver and early congenital syphilis include an increase in size, structural changes in the liver (only in PBC with symptoms) and hemodynamic features, characterized by increased blood flow by increasing the absolute value of linear velocities (maximum systolic and minimum diastolic) with a reduced resistance index.
Structure of the HLA-DR-DQ-genotype in children with coeliac disease
Authors: Dmitrieva Yu. A. , Roslavtseva E. A. , Kuryaninova V. A. , Zakharova I. N. , Borovik T. E. , Kasatkina E. N. , Klimov L. Ya. , Ivanova A. V. , Radchenko E. R. , Shuleshko O. V.
Published: July 2020

Introduction. Coeliac disease is a genetically determined disease associated with the HLA-DQ2 and DQ8 genes. According to European data, these alleles are detected in more than 95% of patients. The results of earlier studies in various regions of the Russian Federation and the constituent republics have shown a lower incidence of HLA-DQ2/DQ8 in children with coeliac disease (60–80%). These data served as a basis for discussion about regional genetic features and the potential for disease development in a significant proportion of patients without DQ2/DQ8 alleles.

Methods. Genetic screening was conducted on 275 children with coeliac disease. According to the results of the study, the patients were assigned to genetic risk groups.

Results. HLA-DQ2/DQ8-alleles were detected in 274 children (99.6%), with 86.9% of patients having DQ2 molecule in genotype and 12.7% having DQ8 molecule. Among 239 DQ2-positive patients, 33.5% were DQ2 homozygous. The remaining DQ2-positive patients had the following HLA-DR-DQ allele distribution: DR3-DQ2/DR5-DQ7 – 8.7%, DR7-DQ2/DR5-DQ7 – 13.4%, DR3-DQ2/ DRx-DQx – 22.2%, DR7-DQ2/DRx-DQx – 2.2%. In five children the incomplete DQ2 molecule was determined, represented by DQA1*0501 allele, while in four patients DQA1*501 was associated with DQB1*0301 allele forming DR5-DQ7 molecule. We found high and significant risk alleles in 29.1% and 22.2% of cases, while moderate and low risk alleles were found in 27.3% and 21.4% of cases respectively.

Conclusions: In Russian children with coeliac disease the prevalence of HLA-DQ2/DQ8 alleles corresponds to European data. Low detection frequency of HLA-DQ2/DQ8 molecules in Russian coeliac patients, which was reported earlier, may be due to peculiarities of the approach to the disease diagnostics, which do not correspond to modern Russian and international recommendations.
Intestinal microbiota as a key factor in the formation of immunity and tolerance. Probiotics capabilities
Authors: Kornienko E. A.
Published: July 2020

Introduction. The intestinal microbiome is an integral part of the health of its owner and performs several important functions: metabolic, coordinating, protective, epigenetic, which are closely interactive. In conditions of dysbiosis, disturbances of these functions contributes to different disorders.The intestinal immune system closely interacts with the microbiota. It is represented by all cells: T- and B-lymphocytes, T-regulatory, dendritic cells, macrophages. Micropresentation of antigens occurs through M-cells located between enterocytes. Toll-like receptors that recognize bacterial patterns are presented on the epithelial membrane. Dendritic cells present these antigens to T-cells and direct a further adaptive immune response.The immune system matures as a result of colonization of the intestine with microbiota, which is confirmed experimentally in gnotobiotic animals. Under physiological conditions, the immune system provides tolerance to its own microbiota through Tr-cells. Tolerogenic effects decrease in dysbiotic conditions, as a result, inflammation develops.

The state of the intestinal barrier. The intestinal barrier is maintained by microbiota, which stimulates the synthesis of mucin and claudine. In dysbiosis, permeability increases, and the immune system is attacked by microbes and their metabolites, which contributes to inflammation.Dysbiosis predisposes to the development of inflammatory bowel diseases, colorectal cancer, metabolic syndrome and obesity, food allergies. In these diseases, the microbiota loses its diversity and richness and has a predominantly pro-inflammatory effect.

The effect of probiotics on the immune system. Probiotics, due to adhesion to the mucous layer, enhance barrier functions, interact with the immune system, affect dendritic cells, promoting the formation of Tr and inhibiting the activation of NF-kB. Commensal metabolites (butyrate) increase the involvement of Tr cells in the colon, exerting a tolerogenic effect.

Indications for the appointment of probiotics. Enterococcus faecium and Bifidobacterium longum have proven their activities similar to normal microbiota, and effectiveness in treatment of dysbiosis in children and adults.
Analysis of prognostic factors for survival in the Russian population of patients with disseminated gastric cancer, who received ramucirumab as secondline therapy in the RAMSELGA trial
Authors: Besova N. S. , Titova T. A. , Artamonova Е. V. , Tryakin A. A. , Stroyakovskiy D. L. , Perminova E. V. , Yukalchuk D. Yu. , Ponomarenko D. M. , Belyak N. P. , Orlova R. V. , Teletaeva G. M. , Ratner E. Yu. , Mochalova A. S. , Gordeeva O. O. , Zhabina A. S. , Gamayunov S. V. , Smolin A. V. , Povyshev A. Yu. , Andrievskikh M. I. , Stilidi I. S.
Published: July 2020

Background.Ramucirumab is a monoclonal antibody that inhibits the vascular endothelial growth factor receptor-2 (VEGFR2). The study is aimed to analyse prognostic factors for survival in patients with disseminated gastric cancer who received ramucirumab in the second-line therapy in ’real-life’ clinical setting of Russia (RAMSELGA).Methods.We retrospectively analysed the outcome of 163 patients aged 20–78 years from 11 oncological centres in Russia. Survival analysis was performed using the Kaplan – Meier model, and regression analysis was performed using the Cox model.Results.In a univariate analysis of overall survival, 5 factors were identified as independent factors of an unfavourable prognosis: 1) age <65 years (RR 0.542; 95% CI 0.302–0.971; p = 0.039); 2) time to tumour progression on the first-line therapy is not more than four months. (RR 0.161; 95% CI 0.105–0.246; p = 0.0000); 3) a low grade tumour or colloid cancer (RR 1,868; 95% CI 1,063–3,284; p = 0,030); 4) peritoneal metastasis (RR 1.549; 95% CI 1.026–2.339; p = 0.037); 5) ascites or pleurisy (RR 0.624; 95% CI 0.424–0.920; p = 0.017). In a multivariate analysis, favourable prognostic factors of overall survival of patients included age – 65 years or older (OS 2.288; 95% CI 1.240–4.220; p = 0.008) and time to tumour progression on the first-line therapy – more than 4 months (OS 6.650; 95% CI 4.221–10.477; p = 0.000).Conclusion.Despite an active search, prognostic factors for survival in patients that are universal for dGC have not yet been found. To build a universal prognostic model, a very thoughtful analysis considering not only clinical and laboratory, but also pathomorphological and molecular genetic characteristics is required.
Experience of using сrizotinib in patients with ALKpositive non-small cell lung cancer
Authors: Reutova E. V. , Laktionova L. V. , Marinov D. T. , Peregudov D. A. , Borisova T. N.
Published: July 2020

Introduction. Sufficient experience has been gained with the use of target drugs in patients with ALK-positive non-small cell lung cancer (NSCLC) over the past years. The multikinase inhibitor crizotinib was the first drug approved for use. The drug passed the accelerated registration in the United States, showing an indisputable advantage over standard chemotherapy both in untreated patients and patients, who had previously received cytostatic therapy. Brain metastasis is the manifestation of acquired resistance to crizotinib in almost half of patients, which requires local monitoring and/or prescription of the nextgeneration ALK inhibitors – ceritinib or alectinib. Experience has proven that it is sequential targeted therapy with the nextgeneration ALK inhibitors with a wider spectrum of anti-tumour activity and penetrating the blood-brain barrier that significantly improves the overall survival of these patients after disease progression on crizotinib. It appears then that the second generation drugs – ceritinib and particularly alectinib – show more impressive results when they are prescribed in the firstline therapy and have now replaced crisotinib in the clinical guidelines. Crizotinib has long remained the only target drug to treat ALK-positive patients in the Russian Federation. Material and methods. In our work, we analysed the crizotinib therapy outcomes in 104 patients with translocation in the ALK gene. The drug was prescribed in a standard dose of 250 mg orally twice per day. Treatment continued until disease progression or intolerable toxicity. Results. The objective response was 56.8%. The median time to progression was 13 months; the median overall survival was 46 months. Conclusion. The obtained data are consistent with previously published data and confirm the effectiveness of the drug in comparison with the previously available universal standard – combination chemotherapy.
Firsthand experience of chemoradiotherapy in patients with localized small cell lung cancer. Retrospective assessment
Authors: Kuzminov A. E. , Borisova T. N. , Breder V. V. , Reutova E. V. , Barbolina T. D. , Laktionov K. K.
Published: July 2020

Introduction. In modern recommendations for the treatment of localized small cell lung cancer (SCLC), preference is given to socalled «early» chemoradiotherapy (CRT), which has a number of limitations due to its pronounced toxicity. With regard to prophylactic brain irradiation (PBI), although there is reliable evidence that it is necessary, PBI cannot be performed on all patients due to the frequent refusals of the patients themselves and the accompanying neurological pathology. The article presents own experience of therapy of patients with localized SCLC with the analysis of accumulated data. Materials and methods. Retrospective assessment of treatment results of patients with localized SCLC was carried out. The analysis included data on 63 patients. 47 patients received simultaneous CRT and 16 patients received consecutive CRT. The results of simultaneous CRT were evaluated first. 27 patients received “early” CRT, while 20 patients received “late” CRT. Results. The PFS median for the group of early CRT was 9.5 months (95% CI 4.2–14.9) and for the group of “late” CRT it was 11.8 months (6.4–17.1). The difference is statistically unreliable. The median of total survival rate was higher in the group of “early” CRT, despite the fact that PFS was lower. The OS median in the group of “early” CRT was 27.9 months (95% CI 2.1–53.7), and in the group of “late” – 24.8 months (95% CI 13.3–36.1). The difference is statistically unreliable. Prophylactic brain irradiation (PBI) in the group of patients with simultaneous CRT was received by 26 patients (55%). The results of overall survival show the crucial importance of PBI in patients with localized SCLC. The OS median in patients who received PBI was 45.9 months (95% CI 21.2–70.5), in patients who did not receive PBI – 21.7 months (95% CI 14.3–29). The difference is statistically significant, p = 0.01. As for complications, 2nd degree esophagitis was recorded more frequently in the group of early CRT – 57% in the group of early CRT and 42% in the group of late CRT, 3rd degree esophagitis was recorded in 1 patient in each group, the difference is not significant. Grade 3–4 hematological toxicity was observed in 5 patients in the group of early CRT and 2 patients in the group of late CRT, the difference is also unreliable. The OS median in the group of patients who received consecutive CRT was 27.1 months (95% CI 18.2–37.6), and the OS median in the group of patients who received simultaneous CRT was 27.9 months (95% CI 18.9–36.9). Conclusions. The obtained data show an unreliable advantage of the “early” CRT over the “late” CRT in terms of overall survival. However, no differences in median time before progression of both local and general ones were obtained. It is extremely important to perform PBI in patients with localized SCLC, as the survival rate in the assessed group of patients doubled.
Oncological care for the patients with hepatocellular carcinoma in COVID-19 pandemic
Authors: Petkau V. V. , Breder V. V. , Bessonova E. N. , Laktionov K. K. , Stilidi I. S.
Published: July 2020

On April 27, 2020, COVID-19 pandemic affected more than 2,5 million of people in more than 200 countries and caused 185 000 deaths. Healthcare systems have come under enormous stress. In COVID-19 pandemic oncological patients face two serious challenges: the risk of severe infectious disease course and the risk of malignant tumor progression. Forced correction of existing oncological standards of care is based on expert and professional community opinions, and daily gaining experience. The issue resumes the data on COVID-19 influence on liver function among the patients with chronic liver diseases and hepatocellular carcinoma. The guidance on HCC management in COVID-19 pandemic are provided. More than 1,5 million of people suffers from the liver pathology caused by chronic virus hepatitis, alcohol consumption, nonalcoholic fatty liver disease. Mild COVID-19 is often followed by transient liver function disorder which do not need specific treatment. Severe COVID-19 lids to the increase of aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), to the decrease of serum albumin in most cases. Regarding the HCC treatment preference should be given to telemedicine, limitation of contacts in health-care facilities, outpatient treatment, including oral medication (tyrosine kinase inhibitors), and if possible delay of invasive procedures with the help of bridge-therapy and active monitoring. Selecting the patients for surgery, ablation or transarterial chemoembolization (TACE) patients with minimal risk of decompensation, with maximum treatment benefit (on the base of prognostic scales), with lack of comorbid should be preferred. Selective and super selective TACE with drug-eluting beads or radioembolization should be used to reduce the risk of immunosuppression and postembolic syndrome. Live organ transplantation should be considered to be postponed. Targeted therapy could be a temporarily alternative to invasive procedures.
Clinical case of long-term use of atezolizumab and bevacizumab in the first-line treatment of recurrence of non-small cell lung cancer
Authors: Rozonova O. A. , Bazaeva I. Y. , Gorbunova V. A. , Artamonova E. V.
Published: July 2020

Lung cancer still holds the leading position in terms of morbidity and mortality, both among men and women. The five-year survival rate for lung cancer is one of the lowest among cancers and varies from 5% to 15% for different countries. The study of new directions in the treatment of this nosology is an extremely urgent problem at the present time. The most common histological variant is non-small cell lung cancer. The presence of driver mutations (EGFR, ALK, ROS1) makes it possible to use targeted therapy in these patients. However, in the absence of driver mutations, the treatment of disseminated non-small cell lung cancer is still based on chemotherapy, which has a low efficiency, making up only about 30% in the first line of treatment. A promising approach to the treatment of this group of patients is the use of immunotherapy, in particular anti-PD-1 and anti-PD-L1 checkpoint-inhibitors. In large randomized international clinical trials, pembrolizumab and atezolizumab were shown to be effective in the first line of treatment, and nivolumab in the second line of treatment. Moreover, according to meta-analyses on the effectiveness and safety of immunotherapy, PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab) have a lower toxicity profile compared to PD-1 inhibitors (pembrolizumab and nivolumab). This article presents a clinical observation of effective treatment of a patient with disseminated non-squamous non-small cell lung cancer with a combination of atezolizumab with bevacizumab and chemotherapy. The partial effect of treatment achieved in this patient is maintained for 3 years without the unacceptable toxicity.
Primary multiple BRCA associated breast cancer and ovarian cancer (clinical case)
Authors: Kononenko I. B. , Snegovoy A. V. , Bozhchenko Y. A. , Kravchenko D. N. , Selchuk Vladimir Yu. , Palchinskaia O. V.
Published: July 2020

Introduction.The study of mutation in BRCA1/2 genes was first initiated in the USA and Europe, and later in Russia. Statistics indicate that women with the BRCA1/BRCA2 mutation have a higher risk of breast and/or ovarian cancer than the general population. According to different authors, the average cumulative risk among BRCA1 carriers is 65% (range 44–78%) for breast cancerand 39% (range 18–54%) for ovarian cancer. For mutation carriers in the BRCA2 gene, the risk for breast cancer is 45–49%, whilethe risk for RNA is 11–18%. However, in patients already diagnosed with breast cancer or ovarian cancer, the risk of a second tumorpersists throughout life and may remain high even in old age. Treatment of BRCA-associated breast cancer and/or ovarian canceris almost the same as treatment for sporadic cancer, and includes surgical, radiation, and drug anticancer therapy. However, thereare some features that need to be considered in clinical practice.Clinical case.In this article we present the clinical experience of the treatment of a 32-year-old patient with BRCA1-associated primary multiple synchronous breast cancer and metachronous uterine tube cancer. In July 2015, the patient was diagnosed withsynchronous cancer of both breast (Luminal A right breast cancer and Luminal B left breast cancer).As part of a treatment and with the patient’s consent, a bilateral adnexectomy was performed. In the histological examination ofthe operating material, the uterine tube cancer was diagnosed in situ. From 16.03.2016 to the present time the patient receivesadjuvant endocrinotherapy without signs of disease progression.Conclusion.This clinical case study presents the importance of a combined approach to the treatment and prevention of BRCAassociated cancer.
Experience of long-term clinical observation of a patient with a rare type of stomach cancer – lymphoepithelioma-like carcinoma
Authors: Kogoniya L. M. , Gurevich L. E. , Mazurin V. S. , Markarova E. V.
Published: July 2020

Stomach cancer is one of the most frequently diagnosed cancers. The success of special methods of treatment are still disappointing in this disease, and stomach cancer has historically been considered a tumor refractory to treatment. Therefore, this category of patients, especially in the stage of dissemination, in most cases, palliative therapy is recommended. In recent years, the use of systemic chemotherapy and targeted therapy has led to a significant improvement in the quality of life and survival rates for stomach cancer compared to palliative therapy. However, significant progress in diagnostic methods over the past two decades has made it possible and possible to review approaches to the treatment of many cancer diseases that are refractory to chemotherapy. The last 2 decades, due to improved methods of diagnosis have allowed to revise approaches to the treatment of many refractory to chemotherapy of neoplastic diseases. In particular, the literature describes cases of revision and changes due to pre-existing diagnosis of IHC Research (carcinoid, NEO, stomach cancer, pancreatic cancer). This communication allows to share their own long experience of observation and treatment of a patient with a rare form of stomach cancer – lymphoepithelioma-like carcinoma.
Fulvestrant in the treatment of luminal metastatic breast cancer: the balance of effectiveness and safety
Authors: Koroleva I. A. , Kopp M. V.
Published: July 2020

The review presents the results of studies of fulvestrant in metastatic breast cancer (MBC). Hormone therapy is an effective method of treating hormone-positive metastatic breast cancer even in the presence of visceral metastases in the absence of a visceral crisis and without detected resistance to endocrine therapy. During the COVID-19 pandemic, hormone therapy is safer for patients with hormone-positive MBC than chemotherapy, since it does not lead to immunosuppression. Fulvestrant is a “pure antiestrogen”, it has a greater affinity for estrogen receptors than tamoxifen. Fulvestrant is both a competitive antagonist and a selective estrogen receptor degrader (SERD), this mechanism of action provides complete blocking of the estrogen signaling pathway. In the phase III CONFIRM study, the optimal dose of fulvestrate was determined to be 500 mg once every 28 days, with a loading dose of 500 mg on day 15 of the first month of therapy. In the FALCON phase III study (n = 462), which included postmenopausal MBC patients who had not previously received any endocrine therapy, fulvestrant 500 mg was compared with the aromatase inhibitor anastrozole. Significant improvement in PFS was achieved with fulvestrant therapy compared to anastrozole: 16.6 months in the fulvestrant group versus 13.8 months with anastrozole [OR = 0.797; 95% CI 0.637–0.999; p = 0.0486]. A subgroup analysis showed that patients without visceral metastases can benefit most from taking fulvestrant. In all studies fulvestrant 500 mg has demonstrated a good toxicity profile, so it is being studied as a component of combined endocrine therapy. In the PALOMA-3 study the combination of fulvestrant with palbociclib (CDK4/6 inhibitor) demonstrated a median PFS 9.5 months, compared with monotherapy with fulvestrant – 4.6 months (HR = 0.46, p < 0.0001). In the MONALEESA-3 study, the median PFS in patients receiving ribociclib with fulvestrant was significantly higher compared to those taking placebo with fulvestrant: 20.5 months and 12.8 months, respectively (HR = 0.593; 95% CI: 0.480–0.732; p < 0.001). In the MONARCH-2 study the combination of fulvestrant and abemaciclib was studied in the second line of therapy, the median PFS was 16.4 months in the group of fulvestrant and abemaciclib, and 9.3 months in the group of fulvestrant and placebo (HR = 0.553; 95% CI 0.449-0.681; p < 0.0001). Fulvestrant has a satisfactory toxicity profile, does not require supporting therapy, and is included in the clinical recommendations for monotherapy and combination therapy.