AKR7A3 modulates the metastasis of pancreatic ductal adenocarcinoma through regulating PHGDH-suppressed autophagy.

AKR7A3 is a member of the aldo-keto reductase (AKR) protein family, whose primary purpose is to reduce aldehydes and ketones to generate primary and secondary alcohols. It has been reported that AKR7A3 is downregulated in pancreatic cancer (PC). However, the mechanism underlying the effects of AKR7A3 in PC remains largely unclarified. Here, we explored the biological function, molecular mechanism and clinical relevance of AKR7A3 in pancreatic ductal adenocarcinoma (PDAC). AKR7A3 expression was downregulated in PDAC compared with adjacent normal tissues, and the lower AKR7A3 expression was related to poor prognosis. In addition, our results demonstrated that AKR7A3 could be a potential diagnostic marker for PDAC, especially in the early stages. Knockdown of AKR7A3 promoted PDAC progression and chemoresistance, while inhibiting autophagy flux. Mechanistically, AKR7A3 affected the metastasis, autophagy, and chemoresistance of PDAC by regulating PHGDH. Overall, the present study suggests that AKR7A3 inhibits PDAC progression by regulating PHGDH-induced autophagy. In addition, AKR7A3 inhibits chemoresistance via regulating PHGDH and may serve as a new therapeutic target for PDAC.

NUCKS1 promotes the progression of colorectal cancer via activating PI3K/AKT/mTOR signaling pathway.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.

TMEM43 promotes pancreatic cancer progression by stabilizing PRPF3 and regulating RAP2B/ERK axis.

BACKGROUND: Transmembrane protein 43 (TMEM43), a member of the transmembrane protein subfamily, plays a critical role in the initiation and development of cancers. However, little is known concerning the biological function and molecular mechanisms of TMEM43 in pancreatic cancer. METHODS: In this study, TMEM43 expression levels were analyzed in pancreatic cancer samples compared with control samples. The relationship of TMEM43 expression and disease-free survival (DFS) and overall survival (OS) were assessed in pancreatic cancer patients. In vitro and in vivo assays were performed to explore the function and role of TMEM43 in pancreatic cancer. Coimmunoprecipitation (co-IP) followed by protein mass spectrometry was applied to analyze the molecular mechanisms of TMEM43 in pancreatic cancer. RESULTS: We demonstrated that TMEM43 expression level is elevated in pancreatic cancer samples compared with control group, and is correlated with poor DFS and OS in pancreatic cancer patients. Knockdown of TMEM43 inhibited pancreatic cancer progression in vitro, decreased the percentage of S phase, and inhibited the tumorigenicity of pancreatic cancer in vivo. Moreover, we demonstrated that TMEM43 promoted pancreatic cancer progression by stabilizing PRPF3 and regulating the RAP2B/ERK axis. CONCLUSIONS: The present study suggests that TMEM43 contributes to pancreatic cancer progression through the PRPF3/RAP2B/ERK axis, and might be a novel therapeutic target for pancreatic cancer.

HSPA5 repressed ferroptosis to promote colorectal cancer development by maintaining GPX4 stability.

Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown. Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. In this study, erastin was used to induce ferroptosis in CRC cells. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. The CRC datasets were analyzed using the R software, GEPIA2, and TIMER2.0. The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increased during ferroptosis. HSPA5 was found to attenuate erastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bound directly to GPX4 and the interaction between HSPA5 and GPX4 increased when treated with erastin for a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down the GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to the immune microenvironment in CRC patients. Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.

Stromal cell-derived factor-1 regulates the secretion of interleukin-1ß in the temporomandibular joint of rats with synovial inflammation.

BACKGROUND: Synovitis is characterized by the infiltration of inflammatory cells and often accompanies the pathological progression of the clinical symptoms affecting the temporomandibular joint (TMJ), such as pain, snapping, and limited mouth opening. It has been suggested that the signal transduction pathway and resultant proinflammatory mediators play important roles in the pathogenesis of synovitis. Therefore, in this present research, we aimed to investigate the changes in the expressions of stromal cell-derived factor 1 (SDF-1) and interleukin (IL)-1ß in rats with occlusal interference. MATERIALS AND METHODS: We divided 36 male Wistar rats into the following groups: Group A (control group), Group B (occlusal interference group), and Group C (AMD3100 group). Synovial inflammation was induced in the rats in Groups B and C to establish the occlusal interference model. The inflammatory changes were detected, and the expressions of SDF-1 and IL-1ß in the synovium were assayed via immunostaining and a real-time quantitative polymerase chain reaction (PCR). RESULTS: In Group B, obvious inflammatory changes were observed in the synovial membranes; additionally, the SDF-1 and IL-1ß expression levels were significantly higher at the protein and mRNA levels. However, in Group C, these experimental results were inhibited by an injection with AMD3100. CONCLUSION: These results may indicate that SDF-1 regulates the expression level of inflammatory factors, such as IL-1ß, in the synovial membranes of rats with occlusal interference. Our findings suggest that the SDF-1 axis may contribute to the onset of synovitis during the development of TMJ joint disease.

Chaperone-Mediated Autophagy.

Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy (CMA) was the first lysosomal process to be discovered by which intracellular components are selectively degraded. This process involves the recognition of the substrate, the unfolding and translocation of the substrate, and the degradation of the substrate. By degrading specific target proteins in a timely manner, CMA is involved in a variety of cellular activities. In the past few years, we have acquired a better understanding of how CMA is regulated. It has been reported that peroxide accumulation, aging and/or other pathological signals interfere with CMA function, which in turn induces neurodegenerative diseases, cancer, and other diseases. Combining results from the current research, we summarize the basic processes, regulatory mechanisms, and physiological functions of CMA and discuss its critical role in the development of diseases.

MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.

Endoplasmic reticulum stress mediates distinct impacts of sevoflurane on different subfields of immature hippocampus.

Sevoflurane, a typical inhaled anesthetic, is widely used in patients of all ages during surgery. The negative effects, such as inducing cell death and damaging spatial memory, of sevoflurane on neurodevelopment have raised increasing concerns in recent years. However, the molecular mechanism remains unclear. This study focused on the crucial role of endoplasmic reticulum (ER) stress in sevoflurane-induced hippocampal injury. Three-week-old rats were exposed to sevoflurane or control air for 5 h with or without ER stress inhibitor (4-phenylbutyric acid, 4-PBA) injection. The hippocampus was harvested to measure the ER stress sensors by western immunoblotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining was used to detect cell apoptosis and electrophysiology was used to measure the intrinsic excitability of neurons in hippocampus. We measured learning and memory ability by Morris water maze tests 5 weeks after sevoflurane exposure. Interestingly, persistent sevoflurane exposure significantly increased the levels of ER stress sensors in hippocampus. But it resulted in different effects in CA1 and dentate gyrus. Greatly increased caspase-12-mediated apoptotic cells, which were proved to be the neural stem cells, were detected in the dentate gyrus. Meanwhile, CA1 pyramidal neurons exhibited significantly reduced intrinsic excitability. Furthermore, the administration of ER stress inhibitor attenuated the above mentioned detrimental effects evidently and prevented the following relevant learning and memory deficits. In conclusion, sevoflurane-mediated ER stress performs distinct effects on the different subfields of the immature hippocampus and inhibiting ER stress during sevoflurane anesthesia will be a potential method to prevent the following learning and memory deficits in adulthood.

Fish connectivity mapping: linking chemical stressors by their mechanisms of action-driven transcriptomic profiles.

BACKGROUND: A very large and rapidly growing collection of transcriptomic profiles in public repositories is potentially of great value to developing data-driven bioinformatics applications for toxicology/ecotoxicology. Modeled on human connectivity mapping (Cmap) in biomedical research, this study was undertaken to investigate the utility of an analogous Cmap approach in ecotoxicology. Over 3500 zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) transcriptomic profiles, each associated with one of several dozen chemical treatment conditions, were compiled into three distinct collections of rank-ordered gene lists (ROGLs) by species and microarray platforms. Individual query signatures, each consisting of multiple gene probes differentially expressed in a chemical condition, were used to interrogate the reference ROGLs. RESULTS: Informative connections were established at high success rates within species when, as defined by their mechanisms of action (MOAs), both query signatures and ROGLs were associated with the same or similar chemicals. Thus, a simple query signature functioned effectively as an exposure biomarker without need for a time-consuming process of development and validation. More importantly, a large reference database of ROGLs also enabled a query signature to cross-interrogate other chemical conditions with overlapping MOAs, leading to novel groupings and subgroupings of seemingly unrelated chemicals at a finer resolution. This approach confirmed the identities of several estrogenic chemicals, as well as a polycyclic aromatic hydrocarbon and a neuro-toxin, in the largely uncharacterized water samples near several waste water treatment plants, and thus demonstrates its future potential utility in real world applications. CONCLUSIONS: The power of Cmap should grow as chemical coverages of ROGLs increase, making it a framework easily scalable in the future. The feasibility of toxicity extrapolation across fish species using Cmap needs more study, however, as more gene expression profiles linked to chemical conditions common to multiple fish species are needed.

Investigation of treatment methods in obstructive colorectal cancer.

PURPOSE: The aim of this study was to explore the treatment strategies for patients with obstructive colorectal cancer at different sites. METHODS: Treatment strategies were adopted according to the location of colorectal cancer and the condition of the patients when they were admitted to the hospital. Among a total of 134 patients, 29 patients were subjected to stent placement to relieve the obstruction before undergoing colorectal resection, 15 patients underwent per anum ileus catheterization to alleviate the symptoms of obstruction and waited for removal of the tumor within a limited time; 39 underwent intraoperative colonic lavage and colon resection with anastomosis and the remaining 51 patients were subjected to emergency surgery due to strangulation of the bowel, perforation, septic shock or other conditions before surgery. RESULTS: Stent placement was successfully performed on 23 patients, with a success rate of 79%. Ninety-five of 134 patients (71% had stage I anastomosis and only one case had anastomotic fistula. Infection of incision happened in 9 (7%) cases and 2 (1.5%) patients died of infection. CONCLUSIONS: Individualized treatment for patients with obstructive colorectal cancer can lead to tumor resection and stage I anastomosis, thereby avoiding the suffering of second-stage surgery or colostomy.

Anterior tibial artery perforator flap for reconstruction of intraoral defects.

PURPOSE: The present clinical study assessed the feasibility of using an anterior tibial artery perforator (ATAP) flap for the reconstruction of an intraoral defect after ablative surgery for oral cancer. PATIENTS AND METHODS: A cohort of consecutive patients with oral cancer requiring reconstruction of an intraoral defect using an ATAP flap were enrolled after ablative surgery for oral cancer and ipsilateral neck dissection. RESULTS: Twelve patients had primary oral squamous cell carcinoma (8 with tongue cancer and 4 with buccal cancer). All patients received intraoral defect repair using an ATAP flap from the lower left leg. The flap measured 7 × 4 to 8 × 6 cm(2). Flap thickness was approximately 4.8 mm (3 to 6 mm). Anastomosis of all ATAP flaps was straightforward because of the long and high-caliber vessel pedicle. All flaps survived and yielded excellent esthetic results for intraoral reconstruction. No major complications occurred in any patient. CONCLUSION: The main advantages of the ATAP flap included the thin and pliable tissue characteristics and a long and high-caliber pedicle. For small and medium-size intraoral defects, the ATAP flap is a reliable alternative to the radial forearm free flap.

Effects of HMGB1/TLR4 on secretion IL-10 and VEGF in human jaw bone-marrow mesenchymal stem cells.

OBJECTIVE: We aimed to investigate the regulatory effects of HMGB1/TLR4 signaling pathway on the expression of IL-10 and VEGF in human bone marrow mesenchymal stem cells. METHODOLOGY: Human JBMSCs were isolated and cultured. Then, HMGB1 was added into the JBMSCs culture medium, and the protein and mRNA expression levels of IL-10 and VEGF were assessed. Moreover, cells were pretreated with a specific TLR4 inhibitor (TAK-242), and the expression changes of IL-10 and VEGF were compared. RESULTS: Compared with the control group, exposure to HMGB1 in human JBMSCs up-regulated TLR4, IL-10, and VEGF secretion at both protein and mRNA levels (P<0. 05). In addition, the increased expression of IL-10 and VEGF could be restrained in TAK-242 group compared with the HMGB1 group (P<0.05). CONCLUSIONS: The results indicated that HMGB1 activate TLR4 signaling pathway in Human JBMSCs, which plays a regulatory role in cytokines expression.

TIPE2 regulates periodontal inflammation by inhibiting NF-κB p65 phosphorylation.

BACKGROUND: The roles and molecular mechanisms of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in periodontitis remain largely unknown. OBJECTIVE: This study aimed to determine the expression of TIPE2 and NF-κB p65 in rat Porphyromonas gingivalis-induced periodontics in vivo. METHODOLOGY: Periodontal inflammation and alveolar bone resorption were analyzed using western blotting, micro-computed tomography, TRAP staining, immunohistochemistry, and immunofluorescence. THP-1 monocytes were stimulated using 1 µg/ml Pg. lipopolysaccharide (Pg.LPS) to determine the expression of TIPE2 in vitro. TIPE2 mRNA was suppressed by siRNA transfection, and the transfection efficiency was proven using western blotting and real-time PCR. The NF-κB pathway was activated by treating the cells with 1 µg/ml Pg.LPS to explore related mechanisms. RESULTS: The expression of both TIPE2 and NF-κB p65 was increased in the gingival tissues of rat periodontitis compared with normal tissues. Positive expression of TIPE2 was distributed in inflammatory infiltrating cells and osteoclasts in the marginal lacunae of the alveolar bone. However, strong positive expression of TIPE2 in THP-1 was downregulated after Pg.LPS stimulation. TIPE2 levels negatively correlated with TNF-α and IL-1ß. Decreased TIPE2 in THP-1 further promoted NF-κB p65 phosphorylation. Mechanistically, TIPE2 knockdown upregulated NF-κB signaling pathway activity. CONCLUSIONS: Taken together, these findings demonstrate that TIPE2 knockdown aggravates periodontal inflammatory infiltration via NF-κB pathway. Interventions aimed at increasing TIPE2 may help in the therapeutic applications for periodontitis.

Machine learning-based integration develops a metabolism-derived consensus model for improving immunotherapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PAC) is one of the most malignant cancer types and immunotherapy has emerged as a promising treatment option. PAC cells undergo metabolic reprogramming, which is thought to modulate the tumor microenvironment (TME) and affect immunotherapy outcomes. However, the metabolic landscape of PAC and its association with the TME remains largely unexplored. METHODS: We characterized the metabolic landscape of PAC based on 112 metabolic pathways and constructed a novel metabolism-related signature (MBS) using data from 1,188 patients with PAC. We evaluated the predictive performance of MBS for immunotherapy outcomes in 11 immunotherapy cohorts from both bulk-RNA and single-cell perspectives. We validated our results using immunohistochemistry, western blotting, colony-formation assays, and an in-house cohort. RESULTS: MBS was found to be negatively associated with antitumor immunity, while positively correlated with cancer stemness, intratumoral heterogeneity, and immune resistant pathways. Notably, MBS outperformed other acknowledged signatures for predicting immunotherapy response in multiple immunotherapy cohorts. Additionally, MBS was a powerful and robust biomarker for predicting prognosis compared with 66 published signatures. Further, we identified dasatinib and epothilone B as potential therapeutic options for MBS-high patients, which were validated through experiments. CONCLUSIONS: Our study provides insights into the mechanisms of immunotherapy resistance in PAC and introduces MBS as a robust metabolism-based indicator for predicting response to immunotherapy and prognosis in patients with PAC. These findings have significant implications for the development of personalized treatment strategies in patients with PAC and highlight the importance of considering metabolic pathways and immune infiltration in TME regulation.

Progress in Pluronic F127 Derivatives for Application in Wound Healing and Repair.

Pluronic F127 hydrogel biomaterial has garnered considerable attention in wound healing and repair due to its remarkable properties including temperature sensitivity, injectability, biodegradability, and maintain a moist wound environment. This comprehensive review provides an in-depth exploration of the recent advancements in Pluronic F127-derived hydrogels, such as F127-CHO, F127-NH2, and F127-DA, focusing on their applications in the treatment of various types of wounds, ranging from burns and acute wounds to infected wounds, diabetic wounds, cutaneous tumor wounds, and uterine scars. Furthermore, the review meticulously examines the intricate interaction mechanisms employed by these hydrogels within the wound microenvironment. By elucidating the underlying mechanisms, discussing the strengths and weaknesses of Pluronic F127, analyzing the current state of wound healing development, and expanding on the trend of targeting mitochondria and cells with F127 as a nanomaterial. The review enhances our understanding of the therapeutic effects of these hydrogels aims to foster the development of effective and safe wound-healing modalities. The valuable insights provided this review have the potential to inspire novel ideas for clinical treatment and facilitate the advancement of innovative wound management approaches.

Discovery and validation of gene classifiers for endocrine-disrupting chemicals in zebrafish (danio rerio).

BACKGROUND: Development and application of transcriptomics-based gene classifiers for ecotoxicological applications lag far behind those of biomedical sciences. Many such classifiers discovered thus far lack vigorous statistical and experimental validations. A combination of genetic algorithm/support vector machines and genetic algorithm/K nearest neighbors was used in this study to search for classifiers of endocrine-disrupting chemicals (EDCs) in zebrafish. Searches were conducted on both tissue-specific and tissue-combined datasets, either across the entire transcriptome or within individual transcription factor (TF) networks previously linked to EDC effects. Candidate classifiers were evaluated by gene set enrichment analysis (GSEA) on both the original training data and a dedicated validation dataset. RESULTS: Multi-tissue dataset yielded no classifiers. Among the 19 chemical-tissue conditions evaluated, the transcriptome-wide searches yielded classifiers for six of them, each having approximately 20 to 30 gene features unique to a condition. Searches within individual TF networks produced classifiers for 15 chemical-tissue conditions, each containing 100 or fewer top-ranked gene features pooled from those of multiple TF networks and also unique to each condition. For the training dataset, 10 out of 11 classifiers successfully identified the gene expression profiles (GEPs) of their targeted chemical-tissue conditions by GSEA. For the validation dataset, classifiers for prochloraz-ovary and flutamide-ovary also correctly identified the GEPs of corresponding conditions while no classifier could predict the GEP from prochloraz-brain. CONCLUSIONS: The discrepancies in the performance of these classifiers were attributed in part to varying data complexity among the conditions, as measured to some degree by Fisher's discriminant ratio statistic. This variation in data complexity could likely be compensated by adjusting sample size for individual chemical-tissue conditions, thus suggesting a need for a preliminary survey of transcriptomic responses before launching a full scale classifier discovery effort. Classifier discovery based on individual TF networks could yield more mechanistically-oriented biomarkers. GSEA proved to be a flexible and effective tool for application of gene classifiers but a similar and more refined algorithm, connectivity mapping, should also be explored. The distribution characteristics of classifiers across tissues, chemicals, and TF networks suggested a differential biological impact among the EDCs on zebrafish transcriptome involving some basic cellular functions.

Characterizations of alveolar repair after mandibular second molar extraction: an experimental study in rats.

BACKGROUND: Characterizations of rat mandibular second molar extraction socket with significantly different buccal and lingual alveolar ridge width remain unclear. OBJECTIVE: To observe alterations in the alveolar ridge after extraction of mandibular second molars, and to examine processes of alveolar socket healing in an experimental model of alveolar ridge absorption and preservation. METHODOLOGY: Eighteen Wistar rats were included and divided into six groups regarding healing time in the study. Bilateral mandibular second molars were extracted. The rats with tooth extraction sockets took 0, 1.5, 2, 3, 4 and 8 weeks of healing. Histological observation, tartrate-resistant acidic phosphatase (TRAP) staining, Masson's trichrome staining, immunohistochemical staining and micro-computed tomography (micro-CT) were applied to estimate alterations in the alveolar ridge. RESULTS: Different buccal and lingual alveolar ridge width led to different height loss. Lingual wall height (LH) decreased significantly two weeks after tooth extraction. Buccal wall height rarely reduced its higher ridge width. From two to eight weeks after extraction, bone volume (BV/TV), density (BMD), and trabecular thickness (Tb.Th) progressively increased in the alveolar socket, which gradually decreased in Tb.Sp and Tb.N. LH showed no significant change during the same period. Osteogenic marker OCN and OPN increased during bone repair from two to eight weeks. The reduced height of the lingual wall of the tooth extraction socket was rarely repaired in the later repair stage. Osteoclast activity led to absorption of the alveolar ridge of the alveolar bone wall within two weeks after operation. We observed positive expression of EMMPRIN and MMP-9 in osteoclasts that participated in the absorption of the spire region. CONCLUSION: Extraction of rat mandibular second molars may help the study of alveolar ridge absorption and preservation. The EMMPRIN-MMP-9 pathway may be a candidate for further study on attenuating bone resorption after tooth extraction.

Comprehensive Analysis of 5-Methylcytosine (m5C) Regulators and the Immune Microenvironment in Pancreatic Adenocarcinoma to Aid Immunotherapy.

Background: Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers and has a poor prognosis. As a critical RNA modification, 5-methylcytosine (m5C) has been reported to regulate tumor progression, including PAAD progression. However, a comprehensive analysis of m5C regulators in PAAD is lacking. Methods: In the present study, PAAD datasets were obtained from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and ArrayExpress databases. The expression pattern of m5C regulators were analyzed and patients were divided into different m5C clusters according to consensus clustering based on m5C regulators. Additionally, m5C differentially expressed genes (DEGs) were determined using Limma package. Based on m5C DEGs, patients were divided into m5C gene clusters. Moreover, m5C gene signatures were derived from m5C DEGs and a quantitative indicator, the m5C score, was developed from the m5C gene signatures. Results: Our study showed that m5C regulators were differentially expressed in patients with PAAD. The m5C clusters and gene clusters based on m5C regulators and m5C DEGs were related to immune cell infiltration, immune-related genes and patient survival status, indicating that m5C modification play a central role in regulating PAAD development partly by modulating immune microenvironment. Additionally, a quantitative indicator, the m5C score, was also developed and was related to a series of immune-related indicators. Moreover, the m5C score precisely predicted the immunotherapy response and prognosis of patients with PAAD. Conclusion: In summary, we confirmed that m5C regulators regulate PAAD development by modulating the immune microenvironment. In addition, a quantitative indicator, the m5C score, was developed to predict immunotherapy response and prognosis and assisted in identifying PAAD patients suitable for tailored immunotherapy strategies.

Role of TFRC as a Novel Prognostic Biomarker and in Immunotherapy for Pancreatic Carcinoma.

Objective: To explore the expression of the transferrin receptor (TFRC) gene in pancreatic cancer and to analyze the pathogenesis and immunotherapy of TFRC in patients using bioinformatics methods. Methods: We used public data from the cancer genome atlas (TCGA) and gene expression omnibus databases to explore the expression level of the TFRC gene in pancreatic cancer patients. At the same time, we analyzed the correlation between the TFRC gene expression and patient survival, and further analyzed the correlation between TFRC and survival time of patients with different clinicopathological characteristics. Co-expressed genes and pathway enrichment analyses were used to analyze the mechanism of the TFRC in the occurrence and development of pancreatic cancer. Ultimately, we used the R software to examine the relationship between TFRC and immune phenotypes and immune cell infiltration using the TCGA database. Results: The results of the study showed that TFRC is highly expressed in pancreatic cancer tissue. The upregulated expression of TFRC was negatively correlated with the survival in patients with pancreatic cancer. The bioinformatics analysis showed that TFRC plays a role in the occurrence and development of pancreatic cancer mainly through signaling pathways (including cell adhesion molecule binding, condensed chromosomes, chromosome segregation, and cell cycle checkpoints). Finally, TFRC is associated with immune phenotypes and immune cell infiltration, which may influence immunotherapy. Conclusion: TFRC is significantly increased in pancreatic cancer and is associated with a poor prognosis. Moreover, research on TFRC may generate new ideas for the immunotherapy of pancreatic cancer.