tbuckley/cabot-search huggingface dataset:
Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion
Authors: Evan Udine, NiCole A. Finch, Mariely DeJesus-Hernandez, Jazmyne L. Jackson, Matthew C. Baker, Siva Arumugam Saravanaperumal, Eric Wieben, Mark T.W. Ebbert, Jaimin Shah, Leonard Petrucelli, Rosa Rademakers, Björn Oskarsson, Marka van Blitterswijk
Journal: Molecular Neurodegeneration (2024)

Abstract Background The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels. Methods We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat. Results For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value = 2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value = 1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value = 3.25E-04) as well as age at disease onset (P-Value = 0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~ 25 kb) and found that the expansion contains few interruptions in the blood. Conclusions Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.
Disrupting calcium homeostasis and glycometabolism in engineered lipid-based pharmaceuticals propel cancer immunogenic death
Authors: Qiuxia Peng, Xiaolong Li, Chao Fang, Chunyan Zhu, Taixia Wang, Binxu Yin, Xiulin Dong, Huaijuan Guo, Yang Liu, Kun Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

Homeostasis and energy and substance metabolism reprogramming shape various tumor microenvironment to sustain cancer stemness, self-plasticity and treatment resistance. Aiming at them, a lipid-based pharmaceutical loaded with CaO2 and glucose oxidase (GOx) (LipoCaO2/GOx, LCG) has been obtained to disrupt calcium homeostasis and interfere with glycometabolism. The loaded GOx can decompose glucose into H2O2 and gluconic acid, thus competing with anaerobic glycolysis to hamper lactic acid (LA) secretion. The obtained gluconic acid further deprives CaO2 to produce H2O2 and release Ca2+, disrupting Ca2+ homeostasis, which synergizes with GOx-mediated glycometabolism interference to deplete glutathione (GSH) and yield reactive oxygen species (ROS). Systematical experiments reveal that these sequential multifaceted events unlocked by Ca2+ homeostasis disruption and glycometabolism interference, ROS production and LA inhibition, successfully enhance cancer immunogenic deaths of breast cancer cells, hamper regulatory T cells (Tregs) infiltration and promote CD8+ T recruitment, which receives a considerably-inhibited outcome against breast cancer progression. Collectively, this calcium homeostasis disruption glycometabolism interference strategy effectively combines ion interference therapy with starvation therapy to eventually evoke an effective anti-tumor immune environment, which represents in the field of biomedical research.
Synergizing adaptive immunity and regenerative signals to enhance osteochondral defects repair
Authors: Changjian Lin, Chenting Ying, Yibo Xu, Yuxuan Zou, Ruihan Chen, Kaicheng Xu, Xiaoxiao Ji, Qihua Cao, Jiahui Weng, Lifeng Jiang, Chenyi Ye, Kai Xu, Yuzhe He, Weijun Li, Lidong Wu, Jisheng Ran, Yan Xiong, Xiaohua Yu, Jiapeng Bao
Journal: Bioactive Materials (2024)
Guselkumab for the treatment of moderate-to-severe plaque psoriasis in pediatric patients: results of the phase 3, randomized, placebo-controlled PROTOSTAR study
Authors: Vimal H Prajapati, Marieke M B Seyger, Dagmar Wilsmann-Theis, Erzsebet Szakos, Andrzej Kaszuba, Bart van Hartingsveldt, Meg Jett, Gigi Jiang, Shu Li, Vikash Sinha, Herta Crauwels, Cynthia M C DeKlotz, Amy S Paller
Journal: British Journal of Dermatology (2024)

Abstract Background No currently approved treatment for pediatric plaque psoriasis selectively targets interleukin (IL)-23. In adults, guselkumab (a selective IL-23 inhibitor targeting the p19 subunit) demonstrated substantial efficacy with a favorable safety profile in treating moderate-to-severe plaque psoriasis. Objective PROTOSTAR (NCT03451851) evaluated the efficacy and safety of guselkumab in pediatric patients with moderate-to-severe plaque psoriasis. Methods This phase 3, randomized, placebo-controlled study enrolled patients ≥6 to &amp;lt;18 years of age with moderate-to-severe plaque psoriasis. In Part 1 (Week [W]0–W16), patients were randomized to receive guselkumab, placebo, or open-label etanercept (active reference arm). At W16, Part 1 patients entered a guselkumab withdrawal/retreatment period or continued/crossed over to receive guselkumab (W16–W52). Co-primary endpoints were Investigator’s Global Assessment (IGA) 0/1 and Psoriasis Area and Severity Index (PASI)75 (or United States Food and Drug Administration-required PASI90 co-primary endpoint) responses at W16 of Part 1. Part 2 evaluated continuous open-label guselkumab treatment (W0–W52). Results Of 92 and 28 patients enrolled in Parts 1 and 2, respectively, 86% and 96% continued treatment through W52. In Part 1, at W16, significantly higher proportions of guselkumab-treated than placebo-treated patients achieved IGA 0/1 (66% vs 16%; P&amp;lt;0.001), PASI75 (76% vs 20%; P&amp;lt;0.001), and PASI90 (56% vs 16%; P&amp;lt;0.01). More than one-third of guselkumab-treated patients achieved clear skin (IGA 0: 39% vs 4% placebo; PASI100: 34% vs 0% placebo; both P&amp;lt;0.01). In Part 2, at W52, 86%, 93%, and 82% of guselkumab-treated patients achieved IGA 0/1, PASI75, and PASI90, respectively. Through W16 of Part 1, 42%, 68%, and 58% of guselkumab-, placebo-, and etanercept-treated patients, respectively, had adverse events (AEs). Rates of AEs with guselkumab were similar through W52 in Parts 1 and 2; common AEs included nasopharyngitis, upper respiratory tract infection, and COVID-19. No serious or opportunistic infections occurred. Conclusions Guselkumab demonstrated significant and clinically meaningful responses in pediatric patients with moderate-to-severe plaque psoriasis and all co-primary and major secondary endpoints were met. Guselkumab safety outcomes were similar to placebo; no new safety signals were identified. These findings support the use of guselkumab to treat pediatric patients with moderate-to-severe plaque psoriasis.
Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets
Authors: Chun Dou, Dong Liu, Lijie Kong, Mingling Chen, Chaojie Ye, Zheng Zhu, Jie Zheng, Min Xu, Yu Xu, Mian Li, Zhiyun Zhao, Jieli Lu, Yuhong Chen, Guang Ning, Weiqing Wang, Yufang Bi, Tiange Wang
Journal: Metabolism (2024)
NORAD exacerbates metabolic dysfunction-associated steatotic liver disease development via the miR-511-3p/Rock2 axis and inhibits ubiquitin-mediated degradation of ROCK2
Authors: Xu Zhang, Tianxing Chen, Zhenhan Li, Lingfeng Wan, Zhihang Zhou, Ying Xu, Dong Yan, Wei Zhao, Hao Chen
Journal: Metabolism (2024)
Effect of taking a dietary supplement containing Lactobacillus delbrueckii subsp. bulgaricus on clinical manifestations of functional dyspepsia and patients’ quality of life
Authors: I.G. Paliy, S.V. Zaika, O.O. Ksenchyn, I.V. Chernova
Journal: GASTROENTEROLOGY (2024)

Background. Functional dyspepsia is a common disorder that is difficult to treat and has a significant negative impact on the quality of life of patients. There is growing evidence that small intestinal microbiota plays a certain role in the pathophysiology of functional dyspepsia. Research aim: to study the effect of a product containing lyophilized lactic acid bacteria Lactobacillus delbrueckii subsp. bulgaricus strain 9702 (IMV B-7085) and its metabolic products on the clinical manifestations of the disease and quality of life of patients with functional dyspepsia. Materials and methods. Thirty-seven patients (16 men and 21 women) with functional dyspepsia were included in the study, their average age was (45.9 ± 2.5) years. The score on the Gastrointestinal Symptom Rating Scale was analyzed before treatment, after completing a 15-day course of taking the probiotic additive, which contained Lactobacillus delbrueckii subsp. bulgaricus, and 15 days after the end of the course. The dynamics of quality of life was evaluated based on the analysis of the SF-36 questionnaires, completed by patients before treatment and on day 30 of observation. Statistical calculations were performed using MedCalc® software, version 12.5.0.0. Results. On day 15 of taking the drug and 15 days after the end of the course, a significant (p &lt; 0.05) decrease in the severity of clinical manifestations on the Gastrointestinal Symptom Rating Scale was found compared to the baseline. The analysis of the dynamics of responses to the SF-36 questionnaire revealed a significant increase (p &lt; 0.05) on all scales of the physical component of health and a significant increase (p &lt; 0.05) in social functioning on all scales of the psychological component of health on day 30 of observation. Conclusions. Taking a dietary supplement containing Lactobacillus delbrueckii subsp. bulgaricus strain 9702 (IMV B-7085) improves the clinical manifestations of functional dyspepsia, as evidenced by a reduction in the severity of gastrointestinal symptoms and increased quality of life of these patients.
Diagnostic value of interleukins 23 and 17 in the assessment of ulcerative colitis severity
Authors: M.V. Stoikevych, O.M. Tatarchuk, T.S. Tarasova
Journal: GASTROENTEROLOGY (2024)

Background. Ulcerative colitis (UC) is a chronic bowel disease with a complex aetiology that includes immune, genetic and environmental factors. Its progression and severity vary greatly, suggesting that different cytokine pathways may be responsible for the heterogeneity of clinical outcomes. The purpose of the study was to investigate the state of cytokine regulation of inflammation depending on the severity of UC. Materials and methods. We examined 32 patients with UC who were treated at the Department of Intestinal Diseases of the State Institution “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”. Patients were divided into groups depending on disease severity determined by the Mayo index: moderate UC — 24 individuals, severe UC — 8 patients. Serum levels of interleukin (IL) 17 and IL-23 were determined by enzyme-linked immunosorbent assay. The study was performed according to the instructions for each test kit. Statistical processing of the results was done using the Statistica 6.1 software package. Results. The content of proinflammatory cytokines in the examined patients with UC was significantly higher than in the control group: IL-17 — by 9.0 times (р &lt; 0.05), the median level of IL-23 — 8.6-fold (р &lt; 0.05). When analysing the data depending on the disease severity, it was found that IL-17 was significantly higher in patients with moderate (by 9.9 times, р &lt; 0.05) and severe UC (by 9.1 times, р &lt; 0.05) than in controls. The median level of IL-23 was significantly higher in moderate (by 8.3 times, р &lt; 0.05) and severe UC (by 13.2 times, р &lt; 0.05) compared to that of the control group. In addition, with severe UC, the concentration of IL-23 was 1.6 times than in moderate UC. A correlation was found between the levels of IL-17 and IL-23 in patients with UC (r = +0.361; p = 0.042). Conclusions. The content of proinflammatory cytokines in UC has reliable differences vs. control group: IL-17 is significantly higher, by 9.0 times (р &lt; 0.05), and IL-23 — by 8.6 times (р &lt; 0.05). It was found that among patients with UC, the level of IL-23 was higher in those with severe course. Thus, quantitative determination of IL-17 and IL-23 levels in the blood serum of patients with UC can be a useful clinical tool for stratification by disease severity and help choose therapy.
Current concepts of chronic gastritis and gastropathies: new international consensus RE.GA.IN
Authors: S.M. Tkach, N.V. Kharchenko, A.E. Dorofieiev, Yu.Z. Hurkalo, L.M. Ryzhiy
Journal: GASTROENTEROLOGY (2024)

Recent decades have been marked by several important milestones in the field of gastritis. New epidemiological reports were received, especially from countries with a high incidence of gastric cancer, and H.pylori infection was recognized as the most important cause of gastritis, due to which it was quickly included in the primary infectious oncogenic agents. Clinical strategies for the detection and eradication of H.pylori infection were developed, the previously unsuspected clinical and pathological significance of gastric microbiota was established, and extraordinary progress was made in the technology of esophagogastroduodenoscopy. Histolo­gical determination of gastritis in terms of stage (that is, risk stratification of stomach cancer) was implemented into clinical practice. In addition to the Sydney and Houston gastritis classifications, the six editions of the Maastricht Consensus (1996–2022) and the Kyoto Global Consensus deserve special attention, thanks to which broad agreements and significant scientific achievements became possible in the most controversial issues of the entire spectrum of gastritis, with a special emphasis on H.pylori gastritis, which accounts for more than 90 % of all forms of gastritis worldwide. The Real-world Gastritis Initiative (RE.GA.IN) marks the next step in the ongoing search to achieve a better understanding of various gastric conditions. The RE.GA.IN consensus was concluded in Venice in November 2022 after 8 months of intensive global scientific reasonings. RE.GA.IN mission itself has been focused on critically reviewing, updating, sharing and building consensus on the current scientific knowledge of inflammatory gastric lesions. It includes eight sections on clinicopathological topics, each consisting of preamble, which presents brief statements and corresponding explanatory texts. For each statement, the level of evidence (assessed according to a predefined four-level scale) and the strength of recommendations on the GRADE system are reported. The following topics were considered in the consensus: 1) definition and classification issues of gastritis; 2) spectrum of H.pylori gastritis; 3) key diagnosis of H.pylori gastritis; 4) H.pylori gastritis: clinical results; 5) autoimmune gastritis; 6) gastritis of low prevalence; 7) gastritis and gastric microbiota; 8) epidemiology of gastritis and associated precancerous and neoplastic lesions. Thus, the most controversial aspects of gastritis were addressed, a comprehensive and diverse body of knowledge was brought together to use patient-oriented evidence to assist physicians in their real-world clinical practice.
The mystery of Taras Bilozerskyi, doctor and manufacturer
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2024)

The article explores the distinguished heritage of Taras Bilozerskyi, the son of close friends of the prominent Ukrainian poet Taras Shevchenko. It delves into Bilozerskyi’s medical career, highlighting his contribution to combating the cholera epidemic in the Caucasus and Crimea, as well as his role as a resident doctor at Obukhiv hospital. The article also presents a list of his scientific publications. Furthermore, it traces his journey from a doctor to a prominent oil producer, breeder and landlord. His life in exile is also shown.
Evaluation of global DNA methylation, homocysteine and vitamin B12 levels among patients with celiac disease
Authors: Farah Tareq Yaseen, Rakad M.Kh. Al-Jumaily
Journal: GASTROENTEROLOGY (2024)

Celiac disease (CD) is an immune-mediated disorder caused by gluten in genetically susceptible individuals characterized by chronic inflammation that essentially affects the small intestine. Objective: this study was designed to measure the potential role of some serological biomarkers including vitamin B12 and homocysteine (HCY) in the progression of CD as well as their relations to global DNA methylation (5mC). Materials and methods. Forty CD patients were enrolled in the study with an average age of (36.60 ± 2.03) years (range between 15 and 60). The diagnosis of the disease was confirmed by serological examinations and intestinal endoscopy in Gastroenterology and Liver Teaching Hospital in the Medical City Hospital in Baghdad city. Also, 40 healthy subjects were included in this study as control group with an average age of (32.22 ± 1.97) years (range between 16 and 59). The blood serum was checked for serological biomarker levels using an enzyme-linked immunosorbent assay. Also, DNA extracted from whole blood and the levels of 5mC were evaluated. Results. The analysis of serological biomarker data has shown that the mean vitamin B12 significantly decreases in CD patients compared to healthy controls: (109.80 ± 2.53) and (143.65 ± 2.36) pg/ml. Also, the results demonstrated a significant increase in HCY in CD patients compared to healthy controls — (10.60 ± 0.41) and (3.92 ± 0.23) umol. The results of global DNA methylation showed a highly significant decrease (P ≤ 0.01) in blood samples of patients with celiac disease (0.435 ± 0.020) vs. controls (0.594 ± 0.040). Conclusions. The findings of this study suggest that the differences in global DNA methylation levels may be used as a risk factor for developing CD, which indicates the involvement of vitamin B12 and HCY in CD progression.
Retrospective study of the frequency of diagnosing diffuse changes in the liver parenchyma according to the results of radiological studies
Authors: N.Yu. Ziuz, V.M. Bogomaz
Journal: GASTROENTEROLOGY (2024)

Background. The prevalence of chronic liver pathology is high and increasing in most countries of the world. Objective: to evaluate the incidence rate of structural diffuse changes in the liver using radiological methods in different sex-age groups of the adult population. Materials and methods. 65,570 unique protocols of ultrasound examination and 1,212 magnetic resonance imaging (MRI) of the hepatobiliary system were studied in patients aged 18 years and older. During the statistical analysis of quantitative features, the distribution of indicators for normality was checked according to the Shapiro-Wilk test. The chi-square test was used to compare frequencies. To determine the relationship between the risk of diffuse liver changes and factor characteristics, we used the method of building logistic regression models. To assess the relationship between the factor traits and the resulting trait, the odds ratio (OR) and 95% confidence interval (CI) were calculated. To assess the quality of the model’s prediction, the area under the curve (AUC) and 95% CI were calculated. The level of statistical significance was chosen at 5 % (p = 0.05). The study was approved by the local ethics committee. Results. The frequency of diagnosing diffuse changes in the liver parenchyma during B-mode ultrasound examination in the total sample was 12.5 % (in women — 8.7 %, in men — 18.2 %). A statistically significant increase (p &lt; 0.01) in the risk of developing diffuse changes in the liver was found (OR = 1.01 (95% CI 1.01–1.02 %) with increasing age for each year. In the univariate logistic regression model, men had a 2.3 times higher chances of developing diffuse liver changes than wo­men (p &lt; 0.01), AUC = 0.604 (95% CI 0.598–0.61 %). In the gene­ral sample of patients who underwent MRI of the hepatobiliary system, the frequency of diagnosing fatty infiltration of the liver was 37 % (95% CI 34.3–39.8 %). In particular, among 700 women, the frequency of incidents was 34.1 % (95% CI 30.7–37.7 %), among 512 men — 41.0 % (95% CI 36.8–45.3 %). Conclusions. The prevalence of diffuse liver changes is high (12.5 % according to ultrasound and 37 % according to MRI) and increases with age among the adult population of working age. Given the variety of factors contributing to the progression of chronic liver diseases and the importance of identifying patients at high risk of developing liver cirrhosis, there is a need for widespread implementation of non-invasive diagnostic tests and technical upgrading of specialized healthcare facilities. The data obtained can serve as landmarks for calculating the needs for secondary care and improving clinical pathways for patients.
The latest diagnostic methods for esophageal and gastric examinations. High-resolution manometry is now available in Ukraine
Authors: Yu.M. Stepanov, N.V. Prolom, S.O. Tarabarov
Journal: GASTROENTEROLOGY (2024)

To date, there are several advanced methods for diagno­sing esophageal and gastric disorders that are actively used in clinical practice, among which high-resolution (HR) manometry stands out. This innovative study provides an opportunity to assess in detail the functional state of the esophagus, in particular the coordination of muscle contractions during swallowing and the function of the lower esophageal sphincter. HR manometry is an effective tool for detecting motility disorders such as achalasia, gastroesophageal reflux disease, diffuse esophageal spasm, as well as other functio­nal disorders that can affect the process of swallowing and moving food through the esophagus. One of the main advantages of HR manometry is accurate diagnosis of functional esophageal disorders due to the use of special catheters with numerous sensors located at a short distance from each other (about 1 cm). This allows you to create detailed topographic maps of pressure in the esophagus, which show the contraction of its muscles in real time. Thanks to this high resolution, it is possible to detect even minor motility disorders that previously went unnoticed when using traditional diagnostic methods. HR manometry has significantly improved the diagnosis of achalasia due to the ability to clearly identify three subtypes of this disease (classic achalasia, pan-esophageal pressure, and spastic achalasia). This allows doctors not only to make a more accurate diagnosis, but also to choose the optimal treatment strategy adapted to the specific type of disorder. In case of gastroesopha­geal reflux disease, HR manometry helps assess the function of the lower esophageal sphincter and diaphragm, which is important for detecting diaphragmatic weakness, which is one of the main causes of pathological reflux. In addition, this method makes it possible to diagnose concomitant peristalsis disorders that affect the ability of the esophagus to clear from acid reflux, thereby helping doctors better understand the mechanism of the disease and prescribe more effective treatment. Thus, HR manometry has a key place among modern methods for diagnosing esophageal disorders, allowing not only to accurately detect motility disorders, but also to optimize treatment. This significantly improves patients’ quality of life, as it helps doctors choose the most effective therapeutic strategies based on accurate data about esophageal function.