Search Results (236)

Background: Gastric cancer (GC) represents a significant global health burden with considerable heterogeneity in clinical and molecular behavior. The anatomical site of tumor origin—proximal versus distal—has emerged as a determinant of prognosis and response to therapy. The aim of this paper is to elucidate the transcriptional and regulatory differences between proximal gastric cancer (PGC) and distal gastric cancer (DGC) through master regulator (MR) analysis. Methods: We analyzed RNA-seq data from TCGA-STAD and microarray data from GEO (GSE62254, GSE15459). Differential gene expression and MR analyses were performed using DESeq2, limma, corto, and RegEnrich pipelines. A harmonized matrix of 4785 genes was used for MR inference following normalization and batch correction. Functional enrichment and survival analyses were conducted to explore prognostic associations. Results: Among 364 TCGA and 492 GEO patients, PGC was associated with more aggressive clinicopathological features and poorer outcomes. We identified 998 DEGs distinguishing PGC and DGC. PGC showed increased FOXM1 (a key regulator of cell proliferation), STAT3, and NF-κB1 activity, while DGC displayed enriched GATA6, CDX2 (a marker of intestinal differentiation), and HNF4A signaling. Functional enrichment highlighted proliferative and inflammatory programs in PGC, and differentiation and metabolic pathways in DGC. MR activity stratified survival outcomes, reinforcing prognostic relevance. Conclusions: PGC and DGC are governed by distinct transcriptional regulators and signaling networks. Our findings provide a biological rationale for location-based stratification and inform targeted therapy development. Full article

This study presents the first successful generation and comprehensive characterization of trophoblastic organoids (TOs) and the derivation of three-dimensional cavity- or sac-like structures—termed lacunoids/cystoids—from sheep intracytoplasmic sperm injection (ICSI) embryos. TOs were generated from sheep ICSI embryos for the first time and were shown to express trophoblastic markers at levels comparable to those in embryonic tissue. Detailed morphological characterization was conducted for both the TOs and the derived lacunoids/cystoids. Additionally, the TOs’ interactions with endometrial organoids (EOs), as well as those with preimplantation embryos, were investigated through co-culture experiments. The TOs expressed key trophoblastic markers, including CDX2, GATA3, syncytin-1, KRT18, KRT7, and Sox2, confirming their validity as a model for studying sheep trophoblast biology. The generation of lacunoids/cystoids from the TOs further revealed their structural and developmental characteristics, contributing valuable insights into early placental development and trophoblast-related pathologies. The TOs also supported extended embryonic development, and their co-culture with EOs induced dynamic changes in gene expression, particularly in angiogenesis-related genes, in both organoid types. This novel and reproducible in vitro model offers a reliable platform to study early placental development, effectively recapitulating the biological crosstalk between the trophectoderm and endometrium. The in-depth characterization of TOs and lacunoids/cystoids highlights their potential to advance our understanding of trophoblast differentiation and related developmental disorders. Full article

Background/Objectives: The neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode tyrosine kinase receptors, and their fusion genes are known as the oncogenic driver genes for cancer. This study aimed to compare the diagnostic ability of NTRK fusion among five types of multi-cancer genome profiling tests (multi-CGP tests) and determine a useful multi-CGP test for NTRK fusion, recorded in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to compare the diagnostic results for NTRK fusions among the five different CGP tests. Methods: A total of 88,688 tumor cases were enrolled in the C-CAT profiling database from 2019 to 2024. The detection frequency of NTRK fusion genes was compared to the results for five multi-CGP tests: NCC Oncopanel, FoundationOne CDx (F1), FoundationOne Liquid (F1L), GenMineTOP (GMT), and Guardant360. Results: NTRK fusion genes were detected in 175 (0.20%) of the 88,688 total cases. GMT, which is equipped with RNA sequencing function, frequently detected NTRK fusion genes (20 of 2926 cases; 0.68%) in comparison with the other four multi-CGP tests that do not have RNA sequencing analysis. GMT showed significantly (p < 0.05) higher diagnostic ability for NTRK fusions compared with the other four multi-CGP tests. Especially, NTRK2 fusion was significantly (p < 0.001) more highly determined by GMT than it was by the other four multi-CGP tests. The detection rates for FGFR1 and FGFR3 were significantly higher in GMT than in other multi-CGP tests. In contrast, the detection rates of the ALK and RET fusion genes were significantly higher in F1L. Conclusions: GMT, which is equipped with RNA sequencing analysis, might show a useful diagnostic ability for NTRK fusions, especially for NTRK2 fusion genes. Full article

We have previously reported on a novel monoclonal antibody (mAb) we designated F5, which was raised against a glycopeptide derived from the tandem repeat (TR) region of Mucin-4 (MUC4), a heavily O-glycosylated protein that is overexpressed in many pancreatic cancer cells. This mAb was highly specific for the MUC4 glycopeptide antigen in glycan microarrays, ELISA and SPR assays, selectively stained tissue derived from advanced-stage tumors, and bound MUC4⁺ tumor cells in flow cytometry assays. The mAb was also unique in that it did not cross-react with other commercial anti-MUC4 mAbs that were raised in a similar but non-glycosylated TR sequence. Here we describe the selective conjugation of a novel near-infrared dye to this mAb and in vivo biodistribution of this labeled mAb to various MUC4-expressing tumors in mice. The labeled mAb were selectively distributed to both cell-derived xenograft (CDX) flank tumors and patient-derived xenograft (PDX) tumors that expressed MUC4 compared to those that were MUC4-negative. Organ distribution analysis showed high uptake in MUC4⁺ relative to MUC4⁻ tumors. These results suggest that mAb F5 may be used to develop MUC4-targeted, passive antibody-based immunotherapies against Pancreatic Ductal Adenocarcinomas (PDACs) which are notorious for being refractory to many chemo- and radiotherapies Full article

Compared to the traditional flip-chip bonded focal plane array, in high-density vertically integrated photodiode (HDVIP) focal plane technology, the thickness of the mercury cadmium telluride (MCT or Hg_1−xCd_xTe) layer serves as a more critical parameter. This parameter not only influences the efficiency of photon energy absorption but also defines the pn junction area, thereby affecting the magnitude of the dark current. Furthermore, it significantly impacts the manufacturability of via-hole etching and formation processes. This paper investigated the photonic crystal resonances and coherent perfect absorption (CPA) effect of a thin MCT layer in HDVIP by using COMSOL Multiphysics^® 4.3b and optimized the structure of the loop-hole photodiode device. The CPA, which is formed by this structure, achieves high absorption of illumination in a very thin MCT film. It is demonstrated that an absorption rate of infrared radiation of more than 95% with a wavelength during the 8 µm–10 µm range can be achieved in Hg_1−xCd_xTe (x = 0.225) with a thickness of only 1.5 µm–3 µm. The benefit of thinner MCT film is that it decreases the dark current of pn junction and reduces the technical difficulty of etching and metallization of the loop-hole photodiode. Full article

Objectives: This study aims to identify clinical characteristics and biomarkers influencing survival outcomes in colorectal cancer (CRC) patients with spinal metastases. Methods: We conducted a retrospective cohort study involving 27 patients treated for CRC-derived spinal metastases at Johns Hopkins Hospital. Data on demographics, biomarker profiles of the primary colorectal tumor site, surgical outcomes, and survival were collected. Neurological function was assessed pre- and postoperatively using Frankel scores. Survival outcomes included overall survival (OS) and post-metastasis survival. Results: The median age of the patients was 58 years, with 63% being women. The sacral spine was the most frequently involved site (59.3%), followed by the thoracic and lumbar regions. Most patients (89%) already had extraspinal metastases, predominantly in the lungs. Biomarker analysis showed microsatellite stability in 63% of patients and CDX2 (Caudal-type homeobox 2) expression in 37%. Laminectomy was performed in 85% of cases and sacrectomy in 55.6%, leading to postoperative improvements in ambulatory function and neurological status. The main indications included local recurrence of the tumor and neurological deficits attributed to the impinging tumor. The median overall survival was 4.9 years, while the median post-metastasis survival was 3.0 years. Univariable analysis revealed that CK20 expression (p = 0.041) and spinal tumor recurrence (p = 0.045) were significantly associated with shorter post-metastasis survival. Conclusions: This study highlights the prognostic importance of CK20 expression and spinal tumor recurrence in CRC patients diagnosed with spinal metastases. Surgical intervention significantly improved neurological outcomes, enhancing patient quality of life. Further research with larger cohorts is needed to confirm these findings and optimize treatment strategies for this challenging patient population. Full article

Gastric intestinal metaplasia (GIM) is a precancerous lesion and the key risk factor in the development of gastric cancer (GC), but early detection and treatment remain challenging. The traditional endoscopic diagnosis of metaplastic lesions is complicated by an increased rate of inappropriateness and false negativity. Although early interventions with H. pylori eradication, as well as endoscopic therapy results, were promising, there is still a significant unmet need to control GIM progression and recurrences. Molecular alterations, such as an increased DNA methylation index, have been identified as a crucial factor in the downregulation of tumor suppressor genes, such as the caudal-type homeobox (CDX2) gene, which regulates epithelial cell proliferation and GIM progression and is associated with treatment failure. CDX2 is downregulated by promoter hypermethylation in the colonic-type epithelium, in which the methylation was correlated with reduced intake of dietary folate sources. Tumor cells alter to dietary methionine sources in the biosynthesis of S-Adenosylmethionine, a universal methyl donor for transmethylation, under the conditions of limited folate and B12 availability. The gut microbiota also exhibited a shift in microbial composition, which could influence the host’s dietary methionine metabolism. Meanwhile, activated oncogenic signaling via the PI3K/Akt/mTORC1/c-MYC pathway could promotes rewiring dietary methionine and cellular proliferation. Tumor methionine dependence is a metabolic phenotype that could be helpful in predictive screening of tumorigenesis and as a target for preventive therapy to enhance precision oncology. This review aimed to discuss the molecular alterations in GIM to shed light on the alteration of methionine metabolism, with insight into new diagnostic and treatment approaches and future research directions. Full article

The proliferation of trophoblast stem (TS) cells and their differentiation into multiple lineages are pivotal for placental development and functions. Various transcription factors (TFs), such as CDX2, EOMES, GATA3, TFAP2C, and TEAD4, along with their binding sites and cis-regulatory elements, have been studied for their roles in trophoblast cells. While previous studies have primarily focused on individual enhancer regions in trophoblast development and differentiation, recent attention has shifted towards investigating the role of super-enhancers (SEs) in different trophoblast cell lineages. SEs are clusters of regulatory elements enriched with transcriptional regulators, forming complex gene regulatory networks via differential binding patterns and the synchronized stimulation of multiple target genes. Although the exact role of SEs remains unclear, they are commonly found near master regulator genes for specific cell types and are implicated in the transcriptional regulation of tissue-specific stem cells and lineage determination. Additionally, super-enhancers play a crucial role in regulating cellular growth and differentiation in both normal development and disease pathologies. This review summarizes recent advances on SEs’ role in placental development and the pathophysiology of placental diseases, emphasizing the potential for identifying SE-driven networks in the placenta to provide valuable insights for developing therapeutic strategies to address placental dysfunctions. Full article

Small extracellular vesicles (sEVs) play a crucial role in intercellular communication and have demonstrated significant relevance in reproductive biotechnology, particularly in in vitro maturation (IVM) and bovine embryo production. This study evaluates the effects of bovine follicular fluid-derived extracellular vesicles (ffsEVs) isolated using two methods: ultracentrifugation (UC) and size-exclusion chromatography (SEC) on oocyte maturation and preimplantational embryonic development. Significant differences in the size of ffsEVs obtained by both isolation methods were noted, with UC-derived ffsEVs (UC ffsEVs) being smaller than those isolated by SEC (SEC ffsEVs). UC ffsEVs were more effective in upregulating critical oocyte quality genes, such as HSF1 and CPT1B. However, no significant differences were observed in embryonic developmental rates. Furthermore, the expression of genes associated with preimplantational embryonic quality revealed that only the SEC ffsEVs group exhibited a significant increase in IFNT1 and SOX2 levels, indicating an enhancement in embryonic quality. Notably, blastocysts derived from SEC ffsEVs also showed a higher total cell count compared to those from UC ffsEVs. No differences were found in other critical genes like GLUT1 and CDX2. These results suggest that the use of SEC ffsEVs could improve the in vitro embryo production process, highlighting the importance of the isolation method in determining the functional efficacy of ffsEVs according to research objectives. Full article

Colon adenocarcinoma (COAD) demonstrates significant clinical heterogeneity across disease stages, gender, and age groups, posing challenges for unified therapeutic strategies. This study establishes a multi-dimensional stratification framework through integrative analysis of miRNA–gene co-expression networks, employing the MRNETB algorithm coupled with Markov flow entropy (MFE) centrality quantification. Analysis of TCGA-COAD cohorts revealed stage-dependent regulatory patterns centered on CDX2-hsa-miR-22-3p-MUC13 interactions, with progressive dysregulation mirroring tumor progression. Gender-specific molecular landscapes have emerged, characterized by predominant SLC26A3 expression in males and GPA33 enrichment in females, suggesting divergent pathogenic mechanisms between genders. Striking age-related disparities were observed, where early-onset cases exhibited molecular signatures distinct from conventional COAD, highlighted by marked XIST expression variations. Drug-target network analysis identified actionable candidates including CEACAM5-directed therapies and differentiation-modulating agents. Our findings underscore the critical need for heterogeneity-aware clinical decision-making, providing a roadmap for stratified intervention paradigms in precision oncology. Full article

Abnormal epigenetic reprogramming of nuclear-transferred (NT) embryos leads to the limited efficiency of producing cloned animals. Trichostatin A (TSA), a histone deacetylase inhibitor, improves NT embryo development, but its role in histone acetylation in porcine embryos cloned with mesenchymal stem cells (MSCs) is not fully understood. This study aimed to compare the effects of TSA on embryo development, histone acetylation patterns, and key epigenetic-related genes between in vitro fertilization (IVF), NT-MSC, and 40 nM TSA-treated NT-MSC (T-NT-MSC). The results demonstrated an increase in the blastocyst rate from 13.7% to 32.5% in the T-NT-MSC, and the transcription levels of CDX2, NANOG, and IGF2R were significantly elevated in T-NT-MSC compared to NT-MSC. TSA treatment also led to increased fluorescence intensity of acH3K9 and acH3K18 during early embryo development but did not differ in acH4K12 levels. The expression of epigenetic-related genes (HDAC1, HDAC2, CBP, p300, DNMT3a, and DNMT1) in early pre-implantation embryos followed a pattern similar to IVF embryos. In conclusion, TSA treatment improves the in vitro development of porcine embryos cloned with MSCs by increasing histone acetylation, modifying chromatin structure, and enhancing the expression of key genes, resulting in profiles similar to those of IVF embryos. Full article

Cd_xMn_1−xS solid solutions were synthesized by incorporating Mn²⁺ into CdS and the optimal ratio of Mn²⁺ to Cd²⁺ was explored via photocatalytic degradation performance for tetracycline (TC). Subsequently, the composite catalyst C@Cd_xMn_1−xS was prepared by loading Cd_xMn_1−xS onto the biomass gasification carbon residue (C) by hydrothermal method and characterized by various characterization tests. The optimal TC photodegradation condition and degradation mechanism catalyzed by C@Cd_xMn_1−xS was investigated. The results showed Cd_0.6Mn_0.4S had the optimal photocatalytic degradation efficiency, which is about 1.3 times that of CdS. The TC photodegradation efficiency by C@Cd_0.6Mn_0.4S prepared at the mass ratio of C to Cd_0.6Mn_0.4S of 1:2 was the best, which was 1.24 times that of Cd_0.6Mn_0.4S and 1.61 times that of CdS. Under the optimal conditions (visible light irradiation for 60 min, C@Cd_0.6Mn_0.4S of 20 mg, 40 mL TC solution of 40 mg/L), the TC degradation efficiency was 90.35%. The degradation efficiencies of 20 mg/L levofloxacin, ciprofloxacin, and 40 mg/L oxytetracycline catalyzed by C@Cd_0.6Mn_0.4S range from 89.88% to 98.69%. In the photocatalytic reaction system, •O₂⁻ and h⁺ are the dominant active species, which directly participate in the photocatalytic degradation reaction of TC, and •OH contributes little. The work provides a strategy to improve the photocatalytic performance of CdS for photocatalytic degradation antibiotics, and opens an interesting insight to deal with solid waste from biomass gasification. Full article

Background: Gastric adenocarcinoma is a highly lethal neoplasm with a short survival especially when metastatic. Few effective treatments are available for the control of the disease and palliation of patients with metastatic gastric cancer. Although progress has been made in the elucidation of molecular pathways invoked in gastric carcinogenesis, this knowledge has not yet led to major breakthroughs, in contrast to several other types of cancer. The role of stem cell transcription factors SOX2 and CDX2 is of particular interest in the pathogenesis of gastric cancer. Methods: The cohort of gastric adenocarcinomas from The Cancer Genome Atlas (TCGA) was interrogated and two groups of gastric cancers, with CDX2 induction and SOX2 suppression on the one hand and with CDX2 induction and SOX2 maintained expression on the other hand were retained. The induction of expression of the two transcription factors was defined as a mRNA expression z score compared with normal samples above zero. The two groups were compared for clinical-pathologic and genomic differences. Results: Among gastric cancers with up-regulated CDX2 mRNA, cancers with suppressed SOX2 mRNA were slightly more numerous (55.9%) than those with a maintained SOX2 expression. The SOX2 suppressed group had a higher prevalence of MSI high cancers (30.9% versus 10%) and of cases with high tumor mutation burden (35% versus 12.4%) than cancers with a SOX2 maintained expression, which presented more frequently high Chromosomal Instability (CIN). The group with SOX2 suppression had higher rates of mutations in many gastric cancer-associated genes such as epigenetic modifiers ARID1A, KMT2D, KMT2C, and KMT2B, as well as higher rates of mutations in genes encoding for receptor tyrosine kinases ERBB4 and FGFR1. On the other hand, TP53 mutations and amplifications in MYC, ERBB2, and CCNE1 were more common in the group with a maintained expression of SOX2, approaching significance for MYC. Conclusions: Notable differences are present in the genomic landscape of CDX2-induced gastric cancer depending on the level of expression of SOX2 mRNA. Despite this, SOX2 mRNA expression levels were not prognostic. Full article

Background and Objectives: Early-onset colorectal cancer (EO-CRC) has become a significant public health concern due to its alarming rise in incidence and the poor prognosis associated with this disease. The aim of our study was to identify epidemiological, clinical, and paraclinical characteristics that could explain the more aggressive evolution of EO-CRC compared to late-onset colorectal cancer (LO-CRC). Materials and Methods: We conducted a retrospective study over a two-year period, including 204 patients diagnosed with colorectal cancer (CRC). The patients were divided into two subgroups: those with EO-CRC and those with LO-CRC. Statistical analysis was performed using IBM SPSS Statistics, Version 29.0. Results: EO-CRC was identified in 11.3% of the patients included in the study. Compared to LO-CRC patients, EO-CRC patients exhibited a tendency for more distal tumor localization and a stenotic endoscopic appearance (43.5% vs. 29.3%). Regarding histopathological diagnosis, EO-CRC patients demonstrated a higher proportion of the mucinous histologic subtype (34.8% vs. 14.4%) and a significantly greater percentage of poorly differentiated tumors (39.1% vs. 14.5%; p = 0.010). Immunohistochemical results, available for a limited number of patients, revealed higher CDX2 positivity in LO-CRC patients (p = 0.012) and higher HER2 positivity in EO-CRC patients (p = 0.002). Smoking (p = 0.006) and hypertension (p = 0.002) were more prevalent in EO-CRC patients than in LO-CRC patients. Conclusions: Patients with EO-CRC exhibit distinct histopathological and molecular characteristics compared to those with LO-CRC, which may contribute to their poorer prognoses. The higher prevalence of the mucinous histological subtype, poor tumor differentiation, increased HER2 expression, and reduced CDX2 expression suggest potential molecular pathways driving the aggressive nature of EO-CRC. These findings highlight the need for tailored screening strategies and personalized therapeutic approaches in younger CRC patients. Future studies should further investigate the underlying mechanisms and potential biomarkers that could guide early diagnoses and targeted treatments. Full article

Complex RNA-seq signatures involving the transcription factors ASCL1, NEUROD1, and POU2F3 classify Small Cell Lung Cancer (SCLC) into four subtypes: SCLC-A, SCLC-N, SCLC-P, and SCLC-I (triple negative or inflamed). Preliminary studies suggest that identifying these subtypes can guide targeted therapies and potentially improve outcomes. This study aims to evaluate whether the expression levels of these three key transcription factors can effectively classify SCLC subtypes, comparable to the use of individual antibodies in immunohistochemical (IHC) analysis of formalin-fixed, paraffin-embedded (FFPE) tumor samples. We analyzed preclinical models of increasing complexity, including eleven human and five mouse SCLC cell lines, six patient-derived xenografts (PDXs), and two circulating tumor cell (CTC)-derived xenografts (CDXs) generated in our laboratory. RT-qPCR conditions were established to detect the expression levels of ASCL1, NEUROD1, and POU2F3. Additionally, protein-level analysis was performed using Western blot for cell lines and IHC for FFPE samples of PDX and CDX tumors, following our experience with patient tumor samples from the CANTABRICO trial (NCT04712903). We found that the analyzed SCLC cell line models predominantly expressed ASCL1, NEUROD1, and POU2F3, or showed no expression, as identified by RT-qPCR, consistently matching the previously assigned subtypes for each cell line. The classification of PDX and CDX models demonstrated consistency between RT-qPCR and IHC analyses of the transcription factors. Our results show that single-gene analysis by RT-qPCR from FFPE-extracted RNA simplifies SCLC subtype classification. This approach provides a cost-effective alternative to IHC staining or expensive multi-gene RNA sequencing panels, making SCLC subtyping more accessible for both preclinical research and clinical applications. Full article