Adjacent Tissues Research Articles

SMAD4 Limits PARP1 dependent DNA Repair to Render Pancreatic Cancer Cells Sensitive to Radiotherapy.

Dysregulation of SMAD4 (i.e. somatic mutation) is strongly associated with poor pancreatic ductal adenocarcinoma (PDAC) prognosis, yet the molecular mechanisms remain underlying this relationship obscure. Previously, we discovered that SMAD4 mutation renders pancreatic cancer resistant to radiotherapy via promotion of autophagy. In the current work, we observed a downregulation of the protein level of SMAD4 in PDAC as compared with adjacent normal tissue, and that such SMAD4low PDAC failed to benefit from chemotherapy. Furthermore, we observed that SMAD4 depletion dramatically enhanced DNA repair capacity in response to irradiation (IR) or a radiomimetic chemical. Interestingly, we found the radiomimetic chemical having induced a robust translocation of SMAD4 into the nucleus, where a direct interaction was shown to occur between the MH1 domain of SMAD4 and the DBD domain of PARP1. Functionally, the SMAD4-PARP1 interaction was found to perturb the recruitment of PARP1 to DNA damage sites. Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.

ANGI-14. DRUGGABLE GENOME CRISPR SCREEN IN 3D HYDROGEL DEVICES REVEALS TARGETABLE KINASES AND PHOSPHATASES IMPLICATED IN CYTOSKELETAL REORGANIZATION IN INVADING GBM CELLS

Abstract The invasive nature of glioblastoma cells into adjacent brain tissues is a key factor in its unfavorable prognosis. To decipher the mechanisms driving glioblastoma invasion, we developed microdissectable biomimetic 3D hydrogel invasion devices containing hyaluronic acid hydrogels decorated with integrin-binding peptides (RGD) and crosslinked with protease-cleavable crosslinkers. The ability to disassemble these devices and interrogate cells in the core vs. invasive fraction allows for high throughput screens. We thus performed a screen in GBM43 cells expressing CRISPR/Cas9 and a 13,250 gRNA library targeting the 2550 genes in the druggable human genome. Of seven initial hits from this screen, only two could be validated by single gene CRISPR and use of a drug to target the hit - ACP1 (also known as LMW-PTP) and Aurora Kinase B (AURKB). Integration of ChIP-seq and RNA-seq revealed no plausible transcriptional targets of ACP1 and AURKB that could drive invasion. Proximity labeling with the TurboID system identified CTTN (cortactin), an actin binding protein whose phosphorylation is integral to the formation of lamellipodia and invadopodia, as phosphorylated by AURKB and Ephrin A2 (EPHA2), whose dephosphorylation controls cell morphology, adhesion, migration and invasion by modifying the organization of the actin cytoskeleton and influencing the activities of integrins and intercellular adhesion molecules, as dephosphorylated by ACP1. These findings underscore the delicate balance between kinase and phosphatase activities in regulating the actin cytoskeleton broadly and at the cell’s front or “leading edge,” offering new therapeutic targets to disrupt the invasion that is a hallmark of glioblastoma.

EXTH-13. COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T-CELLS IN LUNG CANCER BRAIN METASTASES

Abstract BACKGROUND Metastatic lung cancer, especially when it spreads to the brain, shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Evaluation of the potential synergy between anti-angiogenetic drugs and CAR T-cells in this context are an ongoing investigation. METHODS Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally. RESULTS Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T-cell and GFPT-cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T-cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T-cell persistence resulting in a survival benefit. CONCLUSION Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T-cell persistence and reduce tumor growth.

Head-to-head study of [18F]FAPI-04 PET/CT and [18F]FDG PET/CT for non-invasive assessment of liver cancer and its immunohistochemical markers.

To compare the performance of [18F]FDG and [18F]FAPI-04 in PET/CT evaluation for liver cancer lesions, with a further exploration of the associations between PET semiquantitative data and immunohistochemical markers to liver cancer. Patients with suspected malignant liver lesions (MLL) underwent [18F]FDG and [18F]FAPI-04 PET/CT scanning. Liver lesions were visually classified as positive or negative based on their uptake level exceeding that of adjacent normal liver tissue. SUVmax and tumor-to-background ratio (TBR) were recorded for semi-quantitative analysis. Sensitivity, specificity and accuracy of each tracer were determined using pathological findings as the gold standard. Furthermore, immunohistochemical analysis provided the molecular characteristics of all MLLs. Comprehensive analysis explored correlations between these molecular markers and PET semiquantitative parameters (SUVmax andTBR) to identify potential associations. The study enrolled 44 patients, with 39 confirmed cases of MLL, comprising 28 hepatocellular carcinomas (HCC) and 11 intrahepatic cholangiocarcinomas (ICC). For MLL detection, [18F]FAPI-04 and [18F]FDG exhibited sensitivities of 84.6% (33/39) and 76.9% (30/39), specificitiesy of 60% (3/5) and 100%(5/5), and accuracy of 81.8% (36/44) and 79.5%(35/44). Across all liver lesions, [18F]FAPI-04 significantly surpassed [18F]FDG in SUVmax(10.54 ± 6.72 VS. 7.68 ± 6.79) and TBR(4.35 ± 3.78 Vs. 3.17 ± 3.05). Notably, [18F]FAPI-04 displayed markebly elevated SUVmax in benign liver lesions (BLLs) (P = 0.032), HCCs (P = 0.005), and ICCs (P = 0.011). Lesions with hepatocyte negativity (P = 0.023), CD34 negativity(P = 0.044), and high Ki67 expression (> 30%) (P = 0.001) had higher SUVmax on [18F]FAPI-04. Additionally, ARG-1-negative lesions demonstrated higher TBR on [18F]FAPI-04 than ARG-1-positive lesions(P = 0.018). No significant SUVmax/TBR differences were observed with [18F]FDG based on these markers. A linear relationship was identified between Ki67 scores and SUVmax of [18F]FAPI-04 (R = 0.603, P < 0.001). [18F]FAPI-04 exhibits superior performance over [18F]FDG in PET/CT evaluation of liver cancer, characterized by increased sensitivity and SUVmax/TBR. Significant correlations with molecular markers, including Ki67, suggest [18F]FAPI-04's potential for characterizing liver cancer subtypes and assessing tumor proliferation. However, further research is required to validate these findings and their clinical significance. NCT05485792, Registered 01 August 2022.

Evaluation of training models for intraventricular neuroendoscopy.

Structured surgical education has become increasingly important in recent years. Intraventricular neuroendoscopic procedures have been widely established. However, training surgical skills with these techniques is crucial for young residents due to the potential harm to adjacent tissue. Therefore, we evaluated two different training models.Participants in two different international workshops were trained on a prefixed cadaver model and on a living murine intraabdominal model. Crucial neuroendoscopic techniques such as membrane perforation and tissue biopsy were performed. A blinded questionnaire evaluated both models.Sixty-three participants were trained on the animal model. Forty of these were trained on the cadaver model. The training effect was evaluated almost equally, with 8.5/10 for the animal model and 8.9/10 for the cadaver model. The tissue properties were rated higher regarding realism in the animal model, whereas the anatomic realism was rated higher in the cadaver model.The animal model is a valid alternative to cadaver models for teaching endoscopic neurosurgical skills. This model benefits from the simulation of real surgical tissue properties, including bleeding. The low costs and availability of this technique make it more ubiquitous and can help train further generations of neurosurgeons.

Neoplasias mamária e esplênica em cadela

Regarding mammary and splenic neoplasms in dogs, the surgical therapeutic approach is often the method of choice, given its curative potential and the possibility of subsequent histopathological analysis. In veterinary medicine, the incidence of mammary neoplasms is high, especially in unneutered female dogs. Breast carcinoma in situ, with its histological particularities and clinical behavior, requires a careful diagnosis and a precise therapeutic approach, carrying out additional tests such as cytopathology and ultrasound to adequately define the treatment. Surgical excision, associated with the evaluation of adjacent healthy breast tissue, is essential to ensure complete removal of neoplastic tissue, plus it is also indicated to perform ovariohysterectomy (OVH) together with mastectomy. Spleen tumors are similarly common in dogs, especially hemangiosarcoma, which is notable for its aggressiveness and high metastatic rate. Therefore, early diagnosis and precise interventions are essential for a good prognosis, with the affected organ being often removed in its entirety. Therefore, we report the case of a female Shih-Tzu dog, 7 years old and weighing 4kg, who presented, upon palpation, a nodule in the left M3 measuring &lt;1cm with absence of nodular secretion, change in color, itching local or galactorrhea. The patient was referred for regional mastectomy and OVH after cytological examination compatible with carcinoma and, in a pre-operative ultrasound examination, a singular hypoechoic nodular formation, discretely heterogeneous, vascularized on Doppler and in close contact with the splenic capsule was noted in the spleen in its medial parietal portion, measuring 0.96 cm in its longest axis. Thus, during intraoperative visual inspection after OVH and upon approval from the owner, it was decided to perform total splenectomy and, after histopathological examination, it was known that the organ was affected by hemangiosarcoma. The canine was discharged from the hospital a few hours after the end of the surgery, without the subsequent use of adjuvant therapies.

The effects of disease lesions and amoxicillin treatment on the physiology of SCTLD-affected corals

Metrics of coral physiology can be used to identify changes in coral health due to environmental stressors or management actions. One of the most unprecedented stressors to Caribbean corals is the spread of stony coral tissue loss disease (SCTLD), which also resulted in the novel management action of in-water amoxicillin treatments on active disease lesions. Though highly effective at halting lesions and preventing coral mortality, possible unintended consequences of topical application of amoxicillin to coral tissue were unknown. We used in-water instrumentation to measure and compare photosynthesis (P), respiration (R), P/R ratios, and calcification of corals that were visually healthy, actively diseased, and diseased but treated with amoxicillin paste. Measurements occurred across three time points and two species – Orbicella faveolata and Montastraea cavernosa. Across all metrics, treatment type did not cause significant differences, indicating that neither SCTLD lesions nor amoxicillin treatments impacted the physiology of adjacent tissues. There were significant variations among time points, which may have resulted from changes to coral health across the reef, variations due to environmental variables, or other unknown factors. We suggest that physiological metrics could be an interesting way to fate track coral health across short- and long-term timeframes. We also conclude that amoxicillin treatments as a tool to halt SCTLD are not detrimental to respiration, photosynthesis, or calcification rates of adult corals.

Mesenchymal stromal cells and platelet-riach fibrin membrane for the treatment of osteochondral defect in the rabbit

Cartilage has limited self-repair ability due to its complex structure and chondrocytes' relatively low metabolic activities. Functional repair of articular cartilage defects is a significant challenge for cartilage tissue engineering. Mesenchymal stromal cells (MSC) and platelet-rich fibrin membrane (PRFM) in repairing damaged articular cartilage in rabbit. They were subjected to osteochondral lesion and randomly into five groups: Group A, evaluated immediately after injury; Group B, natural evolution the injury; Group C, MSC; Group D, PRFM and Group E, MSC+ PRFM. Animals in Group A were euthanized after removing the cartilaginous flap, while animals in Groups B, C, D, and E were euthanized 60 days. The regeneration of the lesion was evaluated by analyzing its residual extension, as well as the density of chondrocytes and chondroblasts in the regenerated tissue adjacent to the lesion. Results, the Group E (MSC + PRFM) showed a greater reduction in the lesion size and a greater density of chondrocytes and chondroblasts in the regenerated and adjacent tissue compared to the other groups. Our results indicate that the combination of MSC and PRFM can successfully resurface the defect with cartilage and restore the subchondral bone in the specie studied, being effective in reducing hyaline cartilage defects; however, the combination of MSC and PRFM products might be more or less appropriate for treating different types of tissues and pathologies. The clinical efficacy of PRP remains under debate. Therefore, further research is needed at both the basic science and clinical levels.

Oxygen consumption measurements at ultra-high dose rate over a wide LET range.

The role of radiolytic oxygen consumption for the in-vitro "Ultra-High Dose Rate" (UHDR) sparing and in-vivo FLASH effect is subject to active debate, but data on key dependencies such as the radiation quality are lacking. The influence of "dose-averaged Linear Energy Transfer" (LETd) and dose rate on radiolytic oxygen consumption was investigated by monitoring the oxygen concentration during irradiation with electrons, protons, helium, carbon, and oxygen ions at UHDR and "Standard Dose Rates" (SDR). Sealed "Bovine Serum Albumin" (BSA) 5% samples were exposed to 15Gy of electrons and protons, and for the first time helium, carbon, and oxygen ions with LETd values of 1, 5.4, 14.4, 65, and 100.3keV/µm, respectively, delivered at mean dose rates of either 0.3-0.4Gy/s for SDR or approximately 100Gy/s for UHDR. The Oxylite (Oxford Optronics) system allowed measurements of the oxygen concentration before and after irradiation to calculate the oxygen consumption rate. The oxygen consumption rate was found to decrease with increasing LETd from 0.351mmHg/Gy for low LET electrons to 0.1796mmHg/Gy for high LET oxygen ions at SDR and for UHDR from 0.317 to 0.1556mmHg/Gy, respectively. A higher consumption rate for SDR irradiation compared to the corresponding UHDR irradiation persisted for all particle types. The measured consumption rates demonstrate a distinct LETd dependence. The obtained dataset, encompassing a wide range of LETd values, could serve as a benchmark for Monte Carlo simulations, which may aid in enhancing our comprehension of oxygen-related mechanisms after irradiations. Ultimately, they could help assess the viability of different hypotheses regarding UHDR sparing mechanisms and the FLASH effect. The found LETd dependence underscores the potential of heavy ion therapy, wherein elevated consumption rates in adjacent normal tissue offer protective benefits, while leaving tumor regions with generally higher "Linear Energy Transfer" (LET) vulnerable.

Integrative analysis based on ATAC-seq and RNA-seq reveals a novel oncogene PRPF3 in hepatocellular carcinoma.

Assay of Transposase Accessible Chromatin Sequencing (ATAC-seq) is a high-throughput sequencing technique that detects open chromatin regions across the genome. These regions are critical in facilitating transcription factor binding and subsequent gene expression. Herein, we utilized ATAC-seq to identify key molecular targets regulating the development and progression of hepatocellular carcinoma (HCC) and elucidate the underlying mechanisms. We first compared chromatin accessibility profiles between HCC and normal tissues. Subsequently, RNA-seq data was employed to identify differentially expressed genes (DEGs). Integrating ATAC-seq and RNA-seq data allowed the identification of transcription factors and their putative target genes associated with differentially accessible regions (DARs). Finally, functional experiments were conducted to investigate the effects of the identified regulatory factors and corresponding targets on HCC cell proliferation and migration. Enrichment analysis of DARs between HCC and adjacent normal tissues revealed distinct signaling pathways and regulatory factors. Upregulated DARs in HCC were enriched in genes related to the MAPK and FoxO signaling pathways and associated with transcription factor families like ETS and AP-1. Conversely, downregulated DARs were associated with the TGF-β, cAMP, and p53 signaling pathways and the CTCF family. Integration of the datasets revealed a positive correlation between specific DARs and DEGs. Notably, PRPF3 emerged as a gene associated with DARs in HCC, and functional assays demonstrated its ability to promote HCC cell proliferation and migration. To the best of our knowledge, this is the first report highlighting the oncogenic role of PRPF3 in HCC. Furthermore, ZNF93 expression positively correlated with PRPF3, and ChIP-seq data indicated its potential role as a transcription factor regulating PRPF3 by binding to its promoter region. This study provides a comprehensive analysis of the epigenetic landscape in HCC, encompassing both chromatin accessibility and the transcriptome. Our findings reveal that ZNF93 promotes the proliferation and motility of HCC cells through transcriptional regulation of a novel oncogene, PRPF3.

Hsa_circ_0109320 Serves as a Novel Circular RNA Biomarker in Non-small Cell Lung Cancer by Promoting Metastasis.

Non-small cell lung cancer (NSCLC), including squamous cell carcinoma and adenocarcinoma, ranks among the top 10 cancers worldwide in terms of prevalence and mortality. NSCLC, a highly malignant tumor, exhibits distant invasion and migration as well as an unfavorable prognosis. As an innovative circular RNA, hsa _circ_0109320 (circ_0109320) has been recognized as a promising cancer modulator. However, our understanding of the influence of circ_0109320 in NSCLC remains insufficient. Our research explored the clinical significance and effects of circ_0109320 on oncogenic non-small cell lung cancer (NSCLC) phenotypes. Microarray analysis and qPCR indicated that circ_0109320 expression in NSCLC specimens increased relative to that in adjacent normal tissues and was further elevated in metastatic lymph nodes. The specimens acquired from 25 patients confirmed these findings. Additionally, circ_0109320 indicated a good score (AUC = 0.688, P = 0.013) on the ROC curves, which suggests its suitability as a promising biomarker for lung cancer. Meanwhile, circ_0109320 was noticeably upregulated in lung cancer (LC) cell lines compared to human bronchial epithelial cells. Next, we performed loss- and gain-of-function experiments to examine the role of circ_0109320 in the tumor phenotypes of the cell lines. We observed that depletion or overexpression of circ_0109320 did not alter cell viability. However, the ectopic removal of circ_0109320 repressed the migration and invasion of A549 and SK-MES-1 cells, whereas circ_0109320 overexpression promoted cell migration and invasion. Furthermore, the examination of epithelial-mesenchymal transition (EMT) markers indicated that circ_0109320 elevates cell EMT activity. In conclusion, circ_0109320 level was highly associated with increased tumor cell proliferation and metastasis. circ_0109320 could be a promising predictor of clinical outcomes and a reliable target to treat NSCLC by inhibiting metastasis.

The implication of TET1, miR-200, and miR-494 expression with tumor formation in colorectal cancer: through targeting Wnt signaling

ObjectiveColorectal cancer (CRC) is a diverse and multifaceted disease characterized by genetic and epigenetic changes that contribute to tumor initiation and progression. CRC pathophysiology has been linked to the deregulation of the Wnt signaling pathway and the ten-eleven translocation (TET) DNA demethylases. This study aimed to evaluate the expression level of selective miRNAs (miR-200 and miR-494), TET1, and Wnt1 in colorectal polyps, actual colorectal tumors, and normal adjacent tissues. We also evaluated the effect of 5-aza cytidine on the expression level of TET1 and wnt1 in the HT29 cell line.Materials and methodsIn this study, we assessed TET1 and Wnt1 expression in 5-azacytidine-treated HT29 cells, a demethylating agent commonly used in cancer therapy. Additionally, we enrolled 114 individuals who underwent radical surgical colon resection, including 47 with cancerous tissues and 67 with polyps. We utilized qRT-PCR to measure miR-200, miR-494, TET1, and Wnt1 mRNA levels in colorectal polyps, actual colorectal tumors, and normal adjacent tissues.ResultsOur study revealed that TET1 expression was notably lower in both polyps and CRC tissue compared to adjacent normal tissue, with higher TET1 expression in tumors than polyps. We also observed significant differences in miR-200 and miR-494 expression in tumor samples compared to adjacent normal tissue. Our in vitro experiments revealed that 5-azacytidine administration increased TET1 and decreased Wnt1 expression in CRC cell lines. This suggests that DNA-demethylating drugs may have a therapeutic role in modifying TET1 and Wnt signaling in the development of CRC.ConclusionsOverall, our findings shed light on the intricate interactions between TET1, Wnt1, and specific miRNAs in colorectal cancer (CRC) and their potential implications for diagnosis and treatment.

Living Therapeutics for Synergistic Hydrogen-Photothermal Cancer Treatment by Photosynthetic Bacteria.

Hydrogen gas (H2) therapy, recognized for its inherent biosafety, holds significant promise as an anti-cancer strategy. However, the efficacy of H2 treatment modalities is compromised by their reliance on systemic gas administration or chemical reactions generation, which suffers from low efficiency, poor targeting, and suboptimal utilization. In this study, living therapeutics are employed using photosynthetic bacteria Rhodobacter sphaeroides for in situ H2 production combined with near-infrared (NIR) mediated photothermal therapy. Living R. sphaeroides exhibits strong absorption in the NIR spectrum, effectively converting light energy into thermal energy while concurrently generating H2. This dual functionality facilitates the targeted induction of tumor cell death and substantially reduces collateral damage to adjacent normal tissues. The findings reveal that integrating hydrogen therapy with photothermal effects, mediated through photosynthetic bacteria, provides a robust, dual-modality approach that enhances the overall efficacy of tumor treatments. This living therapeutic strategy not only leverages the therapeutic potential of both hydrogen and photothermal therapeutic modalities but also protects healthy tissues, marking a significant advancement in cancer therapy techniques.

Genome-wide DNA methylation profiling reveals a novel hypermethylated biomarker PRKCB in gastric cancer

Globally, gastric cancer (GC) ranks among the most prevalent forms of malignancy, posing a significant health burden. Epigenetic modifications, predominantly characterized by alterations in DNA methylation patterns, have been linked to a diverse array of neoplastic processes. Here, we undertake a comprehensive analysis of the DNA methylation signature in GC, with the aim to discover the potential diagnostic epigenetic biomarkers. Utilizing the Illumina 935 K BeadChip, we conducted a genome-wide exploration of DNA methylation patterns in four paired samples of GC tissues and adjacent non-cancerous counterparts. The bisulfite-pyrosequencing (n = 7) was employed to the quantification for methylated gene. The pubic databases including GWAS Catalog, TCGA and GEO were used. The immunohistochemistry and qRT-PCR analysis were performed. In contrast to adjacent tissues, GC tissues manifested pronounced hypermethylation patterns specifically within the promoter cytosine-phosphate-guanine (CpG) islands, indicating localized epigenetic alterations. DNA methylome analysis further revealed 4432 differentially-methylated probes (DMPs), with the gene PRKCB exhibited the most prominent average DNA methylation disparity (mean Δβ = 0.353). Pyrosequencing validation confirmed three DMPs within the PRKCB promoter (cg08406370, cg00735962, and cg18526361). Notably, the mean methylation levels of PRKCB were inversely correlated with mRNA expression levels in the GWAS Catalog. Furthermore, both mRNA and protein expression levels of PRKCB were significantly reduced in GCs when compared to their adjacent non-cancerous counterparts, verified by TCGA and GEO database. Our study reveals significant DNA methylation alterations in GC and emphasizes the pivotal role of PRKCB gene hypermethylation in conferring GC risk, which offers fresh perspectives for advancing diagnostic approaches and therapeutic strategies for GC.

Xenotropic and polytropic retrovirus receptor 1 (XPR1) promotes progression of papillary thyroid carcinoma via the BRAF-ERK1/2-P53 signaling pathway.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Xenotropic and polytropic retrovirus receptor 1 (XPR1), identified as a cellular receptor, plays roles in many pathophysiological processes. However, the underlying function and molecular mechanisms of XPR1 in PTC remain unclear. Therefore, this study aimed to elucidate the role of XPR1 in the process of PTC and the potential mechanisms. RNA-sequencing was performed for gene differential expression analysis in PTC patients' tissues. Immunohistochemical assay, real-time PCR, and western blotting assay were used to determine the expression of XPR1, BRAF, and P53 in PTC tissues. The function of XPR1 on the progression of PTC was explored using in vitro and in vivo experiments. The molecular mechanism of XPR1 was investigated using gene silencing, ELISA, immunofluorescence, western blotting, and real-time PCR assays. We found that XPR1 was markedly upregulated in PTC tissues compared to adjacent noncancerous tissues, suggesting that high expression of XPR1 could be correlated with poor patient disease-free survival in PTC. In addition, the expression of BRAF and P53 in PTC tissues was substantially higher than in adjacent noncancerous tissues. Silencing of XPR1 reduced the proliferation, migration, and invasion capacities of TPC-1 cells in vitro and effectively inhibited the tumorigenecity of PTC in vivo. More importantly, silencing of XPR1 in TPC-1 cells significantly decreased the expression of XPR1, BRAF, and P53 both in vitro and in vivo. Interestingly, we demonstrated that XPR1 may positively activate the BRAF-ERK-P53 signaling pathway, further promoting PTC progression. The findings reveal a crucial role of XPR1 in PTC progression and prognosis via the BRAF-ERK1/2-P53 signaling pathway, providing potential therapeutic targets for treating PTC.

Early colorectal cancer diagnosis: A novel methylated stool DNA model enhanced the diagnostic efficiency.

Methylated stool DNA (sDNA) is a reliable noninvasive biomarker for early colorectal cancer (CRC) diagnosis. However, there are barely any diagnostic panels that can achieve both a sensitivity and specificity exceeding 90% simultaneously. We aimed to identify a novel methylated sDNA panel and model for the early diagnosis of CRC. We conducted methyl-CpG binding domain isolated genome sequencing (MiGS) on CpG island methylation phenotype (CIMP)-positive (n=3) and CIMP-negative CRC tissues (n=3) and their corresponding normal adjacent tissues. Subsequently, by utilizing both the aforementioned data and public datasets, we identified a set of promising methylated sDNA markers for CRC. Next, we validated 5 of these genes using pyrosequencing in CRC patients (n=31). Then, we developed a combined diagnostic model (CDM) for CRC based on the methylation status of PRDM12, FOXE1, and SDC2 by a Training cohort (n=231). Finally, the performance of CDM was evaluated in an independent multicenter Validation cohort (n=800). A total of 1062 participants were included in this study. The area under the curve (AUC) of the CDM was 0.979 (95% CI: 0.960-0.997), and the optimal sensitivity and specificity were 97.35% and 99.05%, respectively, in the training cohort (n=231). In the independent validation cohort (n=800), the AUC was 0.950 (95% CI: 0.927-0.973), along with the optimal sensitivity of 92.75% and specificity of 97.21%. When CRC and advanced adenoma (AAD) were used as diagnostic targets, the model AUC was 0.945 (95% CI: 0.922-0.969), with an optimal sensitivity of 91.89% and a specificity of 95.21%. The model sensitivity for nonadvanced adenoma patients was 68.66%. The sDNA diagnostic model CDM, developed from both CIMP-P and CIMP-N, exhibited exceptional performance in CRC and could serve as a potential alternative strategy for CRC screening.

Contributions of Tissue Inhibitor of Metalloproteinase-1 Genotypes to the Risk of Metastasis in Gastric Cancer.

In gastric cancer (GCa) tissues, the mRNA and protein levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) are significantly elevated compared to adjacent non-cancerous tissues. Moreover, the abnormal up-regulation of TIMP-1 has been associated with a poor prognosis. However, the role of TIMP-1 genotypes in susceptibility to GCa has seldom been investigated. This study aimed to evaluate the influence of TIMP-1 genotypes on GCa susceptibility and their potential interactions with clinico-pathological factors, including age, sex, body mass index, smoking, alcohol consumption, Helicobacter pylori (H. pylori) infection, and metastasis status. TIMP-1 rs4898, rs6609533, and rs2070584 genotypes were analyzed in 161 patients with GCa and 483 non-cancer control subjects from a Taiwanese population using PCR-RFLP methodology and direct sequencing. The genotypic (p for trend=0.1987) and allelic (p=0.0733) frequencies of TIMP-1 rs4898 did not differ significantly between GCa cases and controls. Under the dominant model, combined CT+CC genotypes were not associated with GCa risk [odds ratio (OR)=0.74, 95% confidence interval (95%CI)=0.51-1.07, p=0.1272]. Similarly, no significant association was found for TIMP-1 rs6609533 or rs2070584 polymorphisms. Importantly, patients with GCa carrying the TIMP-1 rs4898 TT genotype exhibited a significantly enhanced risk of GCa when they had smoking (p=0.0140) and alcohol drinking habits (p=0.0011). Furthermore, the CC genotype of TIMP-1 rs4898 was linked to a lower risk of distant metastasis. The TIMP-1 rs4898 CC genotype may serve as a prognostic biomarker and could inform lifestyle modifications aimed at GCa prevention. Validation of TIMP-1 genotypic profile in diverse populations is warranted.

Investigation of CST7 and hsa-miR-4793-5p gene expression in breast cancer

Breast cancer (BC) presents as a worldwide challenge, known as the most frequently diagnosed cancer in women. In 2022, BC was diagnosed in 2.3 million women with 670,000 deaths globally. In this research, our objective was to examine the CST7 and has-miR-4793-5p gene expression in BC tumor tissues and adjacent normal tissues.Using GSE57897 gene expression data from 422 BC samples and 31 breast samples from healthy controls which was based on the Platform GPL18722 (spotted oligonucleotide Homo sapiens microRNA (miRNA) array) in the Gene Expression Omnibus (GEO) and compare with miRNAs with a conserved target location on CST7 mRNA were found using databases. The study population included 60 fresh BC tissue samples and adjacent normal tissues as control. The Quantitative Real-Time PCR was used to evaluate the expression levels of CST7 and has-miR-4793-5p in the breast tissues.The present study, found that CST7 and hsa-miR-4793-5p were significantly increased in tumoral tissues in compare to normal tissues. Further analysis revealed a remarkable association between CST7 and hsa-miR-4793-5p gene expression alteration. ROC curve analysis demonstrated high accuracy for CST7 expression in BC tumors. Comparison of gene expression between different stages and patient family history showed significant findings. Due to the high sensitivity and specificity of the expression changes of these two genes, they are suitable candidates for further investigations to be considered as part of a diagnosis and prognosis panel.

Identification of Potential Biomarkers in Papillary Thyroid Carcinoma Based on Proteomics.

To identify biomarkers of papillary thyroid carcinoma (PTC) and explore the possible pathogenic mechanism. This study included five patients with PTC. Protein expression of cancer tissues and adjacent normal thyroid tissues from each patient were analyzed by TMT proteomics technology. Differentially expressed proteins were identified, and functional annotation of differentially expressed proteins was performed by bioinformatics and pathway enrichment analysis. A total of 639 differentially expressed proteins were identified, including 278 upregulated and 361 downregulated proteins. Six upregulated proteins were identified as potential specific markers of PTC. Differentially expressed proteins may represent new molecular markers of PTC. These differentially expressed proteins and the related pathways may provide new insights into the pathogenic mechanisms of PTC.

Odontogenic carcinosarcoma of the mandible: A case report.

Odontogenic carcinosarcoma, a rare and challenging diagnosis, was identified in a 60-year-old male through histopathology, revealing a biphasic neoplasm with malignant epithelial and mesenchymal components. Surgical resection is crucial for management, highlighting the importance of vigilant postoperative follow-up to ensure early detection of any recurrence. One rare mixed malignant odontogenic tumor is odontogenic carcinosarcoma, which comprises malignant epithelial and mesenchymal components. Diagnosing odontogenic carcinosarcoma is challenging due to its rarity and atypical clinical presentation. This study reports a 60-year-old male patient who presented with a painless swelling on the right side of his face and experienced facial asymmetry for 6 months, ultimately diagnosed with odontogenic carcinosarcoma. A biphasic neoplasm with malignant alterations in both epithelial and mesenchymal components was identified upon histopathological examination. MRI imaging showed an expansile multilobulated lytic lesion with cortical erosion and extraosseous extension in the posterior region of the right mandibular body and ramus. Following contrast administration, homogeneous lesion enhancement was observed, with a few small non-enhancing necrotic areas in central parts. The patient subsequently underwent a right hemi-mandibulectomy with resection of adjacent soft tissues and neck dissection due to lymph node involvement. The resulting defect was reconstructed using a pectoralis major flap. No recurrence or metastasis was reported during the 6-month follow-up, reinforcing the positive results. This case highlights the importance of recognizing odontogenic carcinosarcoma and underscores the challenges in diagnosing and managing this rare tumor. Early identification and aggressive treatment can lead to positive outcomes, as evidenced by the absence of recurrence or metastasis in this patient during the follow-up period.