Search Results (70)

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts. Full article

Background/Objectives: An increasing number of apparently healthy individuals are adhering to a gluten-free lifestyle without any underlying medical indications, although the evidence for the health benefits in these individuals remains unclear. Although it has already been shown that a low- or gluten-free diet alters the gut microbiota, few studies have examined the effects of this diet on healthy subjects. Therefore, our aim was to evaluate whether and how a prolonged low-gluten diet impacts gut microbiota composition and function in healthy adults, bearing in mind its intimate link to the host’s health. Methods: Forty healthy volunteers habitually consuming a gluten-containing diet (HGD, high-gluten diet) were included in a randomised control trial consisting of two successive 8-week dietary intervention periods on a low-gluten diet (LGD). After each 8-week period, gut microbiota composition was assessed by 16S rRNA gene sequencing, molecular quantification by qPCR, and a cultural approach, while its metabolic capacity was evaluated through measuring faecal fermentative metabolites by ¹H NMR. Results: A prolonged period of LGD for 16 weeks reduced gut microbiota richness and decreased the relative abundance of bacterial species with previously reported potential health benefits such as Akkermansia muciniphila and Bifidobacterium sp. A decrease in certain plant cell wall polysaccharide-degrading species was also observed. While there was no major modification affecting the main short-chain fatty acid profiles, the concentration of the intermediate metabolite, ethanol, was increased in faecal samples. Conclusions: A 16-week LGD significantly altered both composition and metabolic production of the gut microbiota in healthy individuals, towards a more dysbiotic profile previously linked to adverse effects on the host’s health. Therefore, the evaluation of longer-term LDG would consolidate these results and enable a more in-depth examination of its impact on the host’s physiology, immunity, and metabolism. Full article

Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is essential. Hence, in this study, the metabolic capacity of the seminal vesicle using in vitro assays was investigated. Methods: The aim was to assess whether selected doping-relevant substances—stanozolol, LGD-4033, GW1516, trimetazidine, and anastrozole—are metabolised in seminal vesicle cellular fractions (SV-S9) and how that metabolism compares to biotransformations induced by human liver S9 fractions (HL-S9). Liquid chromatography coupled to high-resolution/accurate mass spectrometry (LC HRAM MS) enabled the sensitive detection and identification of metabolites, revealing a limited metabolic activity of SV-S9. Results: For LGD-4033, GW1516, and trimetazidine, minor metabolic transformations were observed, whereas no metabolites of stanozolol or anastrozole were detected. Gene expression analysis using digital polymerase chain reaction (dPCR) confirmed transcripts of CYP2D6, CYP2E1, and CYP2C9 in SV-S9, though no enzymatic activity was detected. Gene expression and enzymatic activity in CYP3A4 and CYP1A2—major hepatic enzymes—were absent in SV-S9. Conclusions: Overall, these pilot study results suggest that the seminal vesicle has only a low capacity for xenobiotic metabolism, which translates into a limited role in the biotransformation of drugs and, hence, the metabolic pattern. Full article

The explosive demand for high-performance secondary power sources in artificial intelligence (AI) has brought significant opportunities for low-voltage GaN devices. This paper focuses on research on high-efficiency and high-reliability low-voltage p-GaN gate HEMTs with a gate–drain distance, L_GD, of 1 to 3 μm in our pilot line, manufactured on 6-inch Si using a CMOS-compatible process, with extraordinary wafer-level uniformity. Specifically, these fabricated p-GaN gate HEMTs with an L_GD of 1.5 μm demonstrate a blocking voltage of over 180 V and a high V_TH of 1.6 V and exhibit a low R_ON of 2.8 Ω·mm. It is found that device structure optimization can significantly enhance device reliability. That is, through the dedicated optimization of source field plate structure and interlayer dielectric (ILD) thickness, the dynamic ON-resistance, R_ON, degradation of devices with an L_GD of 1.5 µm was successfully suppressed from 60% to 20%, and the V_TH shift was significantly reduced from 1.1 to 0.5 V. Further, the devices also passed preliminary gate bias stress and high-voltage OFF-state stress tests, providing guidance for preparing high-performance, low-voltage p-GaN gate HEMTs in the future. Full article

Restrictions resulting from the COVID-19 pandemic abruptly reversed the slow decline of the diagnosis and mortality rates of gastric cancer (GC). This scenario highlights the importance of developing cost-effective methods for mass screening and evaluation of treatment response. In this study, we evaluated a non-invasive method based on the circulating methylated cell-free DNA (cfDNA) of Reprimo (RPRM), a tumor suppressor gene associated with the development of GC. Methylated RPRM cfDNA was analyzed in three de-identified cohorts: Cohort 1 comprised 81 participants with GC and 137 healthy donors (HDs); Cohort 2 comprised 27 participants with GC undergoing gastrectomy and/or chemotherapy analyzed at the beginning and after three months of treatment; and Cohort 3 comprised 1105 population-based participants in a secondary prevention program who underwent esophagogastroduodenal (EGD) endoscopy. This cohort includes 180 normal participants, 845 participants with premalignant conditions (692 with chronic atrophic gastritis [AG] and 153 with gastric intestinal metaplasia/low-grade dysplasia [GIM/LGD]), 21 with high-grade dysplasia/early GC [HGD/eGC], and 59 with advanced GC [aGC]). A nested case-control substudy was performed using a combination of methylated RPRM cfDNA and pepsinogens (PG)-I/II ratio. The dense CpG island of the promoter region of the RPRM gene was bisulfite sequenced and analyzed to develop a fluorescence-based real-time PCR assay (MethyLight). This assay allows the determination of the absolute number of copies of methylated RPRM cfDNA. A targeted sequence of PCR amplicon products confirmed the gastric origin of the plasma-isolated samples. In Cohort 1, the mean value of GCs (32,240.00 copies/mL) was higher than that of the HD controls (139.00 copies/mL) (p < 0.0001). After dividing this cohort into training–validation subcohorts, we identified an area under the curve of 0.764 (95% confidence interval (CI) = 0.683–0.845) in the training group. This resulted in a cut-off value of 87.37 copies/mL (sensitivity 70.0% and specificity 80.2%). The validation subcohort predicted a sensitivity of 66.67% and a specificity of 83.33%. In Cohort 2 (monitoring treatment response), RPRM levels significantly decreased in responders (p = 0.0042) compared to non-responders. In Cohort 3 (population-based participants), 18.9% %, 24.1%, 30.7%, 47.0%, and 71.2% of normal, AG, GIM/LGD, HGD/eGC, and aGC participants tested positive for methylated RPRM cfDNA, respectively. Overall sensitivity and specificity in distinguishing normal/premalignant conditions vs. GC were 65.0% (95% CI 53.52% to 75.33%) and 75.9% (95% CI 73.16% to 78.49%), respectively, with an accuracy of 75.11% (95% CI 72.45% to 77.64%). Logistic regression analyses revealed an OR of 1.85 (95% CI 1.11–3.07, p = 0.02) and an odds ratio (OR) of 3.9 (95% CI 1.53–9.93, p = 0.004) for the risk of developing GIM/LGD and HGD/eGC, respectively. The combined methylated RPRM cfDNA and PG-I/II ratio reached a sensitivity of 78.9% (95% CI 54.43% to 93.95%) and specificity of 63.04% (95% CI 52.34% to 72.88%) for detecting HGD/eGC vs. three to six age- and sex-matched participants with premalignant conditions. Our results demonstrate that methylated RPRM cfDNA should be considered a direct biomarker for the non-invasive detection of GC and a predictive biomarker for treatment response. Full article

Early detection of colorectal cancer (CRC) significantly improves overall prognosis and increases 5-year survival rates up to 90%. Current non-invasive screening methods for CRC, such as the Faecal Immunohistochemical Test (FIT), have some drawbacks, namely, low sensitivity and a high false-positive rate. The Sialyl-Tn (STn) antigen, frequently expressed in pre-malignant lesions and adenocarcinomas, has been shown to be detected by the novel monoclonal antibody L2A5. In this study, we explored the potential of L2A5 as a non-invasive CRC screening method in an attempt to overcome current limitations. The subjects were categorised into four groups based on colonoscopy findings: no lesion (NL), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and colorectal cancer (CRC). Slot blot analysis using the L2A5 antibody was performed on stool samples from 95 colonoscopy patients. Our findings showed a differential STn expression between the different clinical groups, evidencing excellent discrimination between NL and CRC (AUC, 0.8252; 95% CI: 0.6983–0.9521; sensitivity, 70%). Moreover, moderate discrimination between the NL+LGD and HGD+CRC groups was discerned (AUC, 0.7766; 95% CI: 0.6792–0.8740; sensitivity, 58%). These findings support the application of L2A5 as a tool for detecting STn, allowing for the identification of advanced lesions in non-invasive CRC screening. Full article

Background: Barrett’s esophagus (BE) is a known precursor to esophageal adenocarcinoma (EAC). However, reports on incidence and progression-to-neoplasm rates have been very variable and conflicting. The aims of the study were to evaluate the characteristics of BE and its progression to neoplasm in a large homogeneous population. Methods: This was a retrospective population-based study with patients identified from 11 institutions through the databases in two centralized pathology laboratories. Demographics and relevant clinicopathological features were obtained from medical records among patients with a pathologically confirmed BE by the presence of intestinal metaplasia between 2003 and 2022. Results: A total of 1388 patients were identified with BE: 948 were men (69%); the median age at diagnosis was 62 years (IQR, 53–72). The ratio of long-segment BE to short-segment BE was significantly higher in patients ≥ 60 years (1.15, 284/248) than those ≤ 60 years (0.77, 205/265) (p = 0.0025). At BE diagnosis, 9.4% had neoplasms: LGD (n = 65), HGD (n = 16), and EAC (n = 49). Among 1258 non-dysplastic BE (NDBE) patients, 4.6% developed a neoplasm—LGD (n = 35), HGD (n = 8), and EAC (n = 15)—with a median observation-period of 5 years (IQR, 3–7). Overall, 160 cases with neoplasms were diagnosed in this BE cohort; 130 (74%) were present at initial BE diagnosis, and 58 (26%) progressed to neoplasms from NDBE. Conclusions: The ratio of long-segment BE was found to be significantly higher in patients ≥ 60 years. Around 9% of the patients were diagnosed as harboring a neoplasm concomitantly with BE, accounting for approximately 74% of all neoplasms. After a median follow-up of 5 years, about 5% of BE showed dysplastic or malignant progression. Full article

The application of GaN HEMTs on silicon substrates in high-voltage environments is significantly limited due to their complex buffer layer structure and the difficulty in controlling wafer warpage. In this work, we successfully fabricated GaN power HEMTs on 6-inch sapphire substrates using a CMOS-compatible process. A 1.5 µm thin GaN buffer layer with excellent uniformity and a 20 nm in situ SiN gate dielectric ensured uniformly distributed V_TH and R_ON across the entire 6-inch wafer. The fabricated devices with an L_GD of 30 µm and W_G of 36 mm exhibited an R_ON of 18.06 Ω·mm and an off-state breakdown voltage of over 3 kV. The electrical mapping visualizes the high uniformity of R_ON and V_TH distributed across the whole 6-inch wafer, which is of great significance in promoting the applications of GaN power HEMTs for medium-voltage power electronics in the future. Full article

Glucagon receptor (GCGR) is a class B1 G-protein-coupled receptor that plays a crucial role in maintaining human blood glucose homeostasis and is a significant target for the treatment of type 2 diabetes mellitus (T2DM). Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. To predict binding sites for other small molecules, we utilized both the crystal structure of the GCGR and MK-0893 complex and dynamic conformations. We docked five small molecules and selected the best conformation based on binding mode, docking score, and binding free energy. We performed MD simulations to verify the binding mode of the selected small molecules. Moreover, when selecting conformations, results of competitive binding were referred to. MD simulation indicated that Bay 27-9955 exhibits moderate binding stability in Pocket 3. MK-3577, LY2409021, and PF-06291874 exhibited highly stable binding to Pocket 2, consistent with experimental results. However, LY2409021 may also bind to Pocket 5. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues’ bioavailability, providing a reference for the study of GCGR small molecules. Full article

Members of the LGD/CC2D1 protein family contain repeats of the family-defining DM14 domains. Via this domain, they interact with members of the CHMP family, which are essential for the ESCRT machinery-mediated formation of intraluminal vesicles during endosome maturation. Here, we investigate the requirement of the DM14 domains for the function of Lgd in detail. We found that although both odd-numbered DM14s can act in a functionally redundant manner, the redundancy is not complete and both contribute to the full function of Lgd. Our analysis indicates that some of the AAs that form the KARRxxR motif of the onDM14s are not exchangeable by similarly charged AAs without loss of function, indicating that they not only provide charge, but also fulfil structural roles. Furthermore, we show that the region of Lgd between DM14-4 and the C2 domain as well as its C-terminal region to the C2 domain are important for protein stability/function. Moreover, we analysed the importance of AAs that are conserved in all DM14 domains. Finally, our analysis of the C. elegans ortholog of Lgd revealed that it has only one DM14 domain that is functionally equivalent to the onDM14s. Altogether, the results further the understanding of how Lgd family members regulate the ESCRT machinery. Full article

Background: Barrett’s esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE–dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE–dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction. Full article

With the increasing complexity of integrated circuit design, the threat of a hardware Trojan (HT) is becoming more and more prominent. At present, the research mainly focuses on the detection of HTs, but the amount of research on the diagnosis of HTs is very small. The number of existing HT diagnosis methods is generally completed by detecting the HT nodes in the netlist. The main reason is the lack of consideration of the integrity of HTs, so the diagnosis accuracy is low. Based on the above reason, this paper proposes two implanted node search algorithms named layer-by-layer difference search (LDS) and layer-by-layer grouping difference search (LGDS). The LDS algorithm can greatly reduce the search time, and the LGDS algorithm can solve the problem of input node disorder. The two methods greatly reduce the number of nodes sorting and comparing, and therefore the time complexity is lower. Moreover, the relevance between implanted nodes is taken into account to improve the diagnosis rate. We completed experiments on an HT diagnosis; the HT implantation example is from Trust-Hub. The experimental results are shown as follows: (1) The average true positive rate (TPR) of the diagnosis using KNN, RF, or SVM with the LDS or LGDS algorithm is more than 93%, and the average true negative rate (TNR) is 100%. (2) The average proportion of implanted nodes obtained by the LDS or LGDS algorithm is more than 97%. The proposed method has a lower time complexity compared with other existing diagnosis methods, and the diagnosis time is shortened by nearly 75%. Full article

The polarization and elastrocaloric effect of chiral barium titanate (BaTiO₃) with an Ising–Bloch-type domain wall under stress was investigated using the Landau–Ginzburg–Devonshire (LGD) theory. It has been shown that tensile stresses increase the magnitude of the Ising polarization component in barium titanate, together with a decrease in the domain wall width. Compressive stresses cause a reduction in the Ising polarization component and an increase in the domain width. Under compressive stress, barium titanate exhibits a negative elastrocaloric effect and temperature changes with increasing stress, while BaTiO₃ exhibits a positive elastrocaloric effect under tensile stress. Bloch polarization shows angle-dependent polarization under external force, but the temperature change from the elastrocaloric effect is smaller than that of Ising polarization under stress. This work contributes to the understanding of polarization evolution under tension in ferroelectrics with chiral structure. Full article

Local government debt (LGD), an important financing tool for local governments to achieve high-quality development, especially through the expansion of urban investment bonds led by local investment and financing platforms, has a significant impact on green development efficiency (GDE). This article starts from LGD, selects data from 30 provinces from 2010 to 2019, and uses a two-way fixed-effect model and mediation-effect model to empirically analyze the impact of LGD on GDE. The research results show that LGD has a significant inhibitory effect on GDE, and LGD can indirectly affect GDE through the degree of industrialization and the number of the urban population. This article suggests that the government should make even fuller use of LGD funds, optimize the use of relevant funds, standardize the operation of local government investment and financing platforms, reduce debt risks, promote industrial structure upgrading, promote urban population resettlement measures, and improve China’s GDE. Full article

Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics. Full article