Correlation Analysis Between Tumor Deposit and Clinicopathologic Characteristics and Prognosis of Gastric Cancer: A Multicenter Retrospective Study.

BACKGROUND: The mechanism underlying the formation of gastric tumor deposits (TDs) is unclear. We aimed to explore the risk factors for the formation and prognostic value of TDs. METHODS: This retrospective analysis included 781 locally advanced gastric cancer (LAGC) patients from four medical institutions in China, from June 2014 to June 2018. The risk factors for TD formation and prognostic value were determined through univariate and multivariate analyses. RESULTS: Univariate analysis revealed that TD positivity was closely related to tumor diameter, Borrmann classification, differentiation degree, pT stage, pN stage, pTNM stage, and nerve and vascular invasion (p < 0.05). Multivariate logistic regression revealed that tumor diameter ≥ 5 cm (odds ratio [OR] 1.836, 95% confidence interval [CI] 1.165-2.894, p = 0.009) and vascular invasion (OR 2.152, 95% CI 1.349-3.433, p = 0.001) were independent risk factors for TD positivity. Multivariate Cox analysis revealed that TD positivity (OR 1.533, 95% CI 1.101-2.134, p = 0.011), tumor diameter ≥ 5 cm (OR 1.831, 95% CI 1.319-2.541, p < 0.001), pT4a stage (OR 1.652, 95% CI 1.144-2.386, p = 0.007), and vascular invasion (OR 1.458, 95% CI 1.059-2.008, p = 0.021) were independent risk factors for GC prognosis. The 5-year overall and disease-free survival of the TD-positive group showed significant effects among patients in the pT4a and pN3b stages (p < 0.05). CONCLUSIONS: TDs are closely related to tumor diameter and vascular invasion in LAGC patients, and TD positivity is an independent prognostic factor for LAGC patients, especially those at pT4a and pN3b stages.

Identification of key eRNAs for intervertebral disc degeneration by integrated multinomial bioinformatics analysis.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a common degenerative condition leading to abnormal stress distribution under load, causing intervertebral stenosis, facet joint degeneration, and foraminal stenosis. Very little is known about the molecular mechanism of eRNAs in IVDD. METHODS: Gene expression profiles of 38 annulus disc samples composed of 27 less degenerated discs (LDs) and 11 more degenerated discs (MDs) were retrieved from the GEO database. Then, differentially expressed enhancer RNAs (DEeRNAs), differentially expressed target genes (DETGs), and differentially expressed transcription factors (DETFs), hallmark of cancer signalling pathways according to GSVA; the types and quantity of immune cells according to CIBERSORT; and immune gene sets according to ssGSEA were analysed to construct an IVDD-related eRNA network. Then, multidimensional validation was performed to explore the interactions among DEeRNAs, DETFs and DEGs in space. RESULTS: A total of 53 components, 14 DETGs, 15 DEeRNAs, 3 DETFs, 5 immune cells, 9 hallmarks, and 7 immune gene sets, were selected to construct the regulatory network. After validation by online multidimensional databases, 21 interactive DEeRNA-DEG-DETF axes related to IVDD exacerbation were identified, among which the C1S-CTNNB1-CHD4 axis was the most significant. CONCLUSION: Based upon the results of our study, we theorize that the C1S-CTNNB1-CHD4 axis plays a vital role in IVDD exacerbation. Specifically, C1S recruits CTNNB1 and upregulates the expression of CHD4 in IVDD, and subsequently, CHD4 suppresses glycolysis and activates oxidative phosphorylation, thus generating insoluble collagen fibre deposits and leading to the progression of IVDD. Overall, these DEeRNAs could comprise promising therapeutic targets for IVDD due to their high tissue specificity.

The short- and long-term effect of membrane anatomy-guided laparoscopic D2 lymphadenectomy plus regional complete mesogastrium excision for locally advanced gastric cancer.

OBJECTIVE: Retrospectively analyzed the short- and long-term efficacy between laparoscopic D2 lymphadenectomy plus regional complete mesogastrium excision (D2 + rCME) and traditional laparoscopic D2 in the treatment of patients with locally advanced gastric cancer (LAGC), in order to obtain more evidence for D2 + rCME gastrectomy. METHODS: A total of 599 LAGC patients who underwent laparoscopy-assisted radical gastrectomy from January 2014 to December 2019, including 367 cases in the D2 + rCME group and 232 cases in the D2 group. Intraoperative and postoperative clinicopathological parameters, postoperative complications and long-term survival in the two groups were statistically analyzed. RESULTS: No significant differences in the positive rate of mesogastric tumor deposits, the number of positive lymph nodes and postoperative length of stay were found between the two groups (P > 0.05). In the D2 + rCME group, intraoperative blood loss was significantly reduced (84.20 ± 57.64 ml vs. 148.47 ± 76.97 ml, P < 0.001), the time to first postoperative flatus and first liquid diet intake were significantly shortened (3[2-3] days vs. 3[3-3] days, P < 0.001; 7[7-8] days vs. 8[7-8] days, P < 0.001), and the number of lymph nodes dissected was greater (43.57 ± 16.52 pieces vs. 36.72 ± 13.83 pieces, P < 0.001). The incidence of complications did not significantly differ between the D2 + rCME group (20.7%) and D2 group (19.4%) (P > 0.05). Although there was no statistically difference in 3-year OS and DFS between the two groups. However, the trend was better in D2 + rCME group. In subgroup analysis, patients with positive tumor deposits (TDs) in the D2 + rCME group had significantly better 3-year DFS compared With D2 group (P < 0.05). CONCLUSION: Laparoscopic D2 + rCME is safe and feasible for the treatment of LAGC and is characterized by less bleeding, greater lymph node dissection and rapid recovery, without increasing postoperative complications. D2 + rCME group showed a better trend of long-term efficacy, especially significant beneficial for LAGC patients who with positive TDs.

Vimentin affects colorectal cancer proliferation, invasion, and migration via regulated by activator protein 1.

Uncontrolled recurrence and metastasis are important reasons for the high mortality rate of malignant tumors. Vimentin is positively correlated with the degree of malignancy of cancer cells. Vimentin is also highly expressed in colorectal cancer (CRC) cells and plays a critical role in the metastasis and prognosis of CRC. However, the molecular mechanism of vimentin in the progression of CRC is incompletely understood. Therefore, the most active regions (nucleotides: 785-1085 nt) of the vimentin promoter in CRC were identified using luciferase experiments. By transcription factor sequence search and mutation analysis, the activator protein 1 (AP-1) binding site in the region of 785-1085 nt was confirmed. The vimentin promoter activity was enhanced by overexpression of AP-1. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed that the binding site was recognized by AP-1. By cell proliferation assay, colony-forming assay, scratch-wound assay, cell migration assay, and cell invasion assay, we demonstrated that the AP-1 overexpression increased CRC cell proliferation, migration, and invasion. However, when vimentin was knocked down by vimentin small hairpin RNA in the CRC cell of AP-1 overexpression, this trend disappeared. Animal experiments and immunohistochemistry showed that AP-1 promoted tumor growth by regulating the vimentin gene. In summary, AP-1 affected metastasis, invasion of CRC cells in vitro, and tumor growth in vivo by activating the vimentin promoter. This study might provide new insights into the molecular mechanisms of the development of CRC and provide potential therapeutic targets for CRC.

Abdominal Oblique Internal and External Muscles Gap Colostomy for Lower Incidence of Parastomal Hernia and Higher Quality of Life: A Retrospective Cohort Study.

BACKGROUND: Parastomal hernia and fecal incontinence cause severe distress to the rectal cancer patients with stoma after abdominoperineal resection. We attempted a new colostomy technique through the gap between the abdominal oblique internal and external muscles to prevent parastomal hernia and improve quality of life. METHODS: This cohort study retrospectively examined clinical data from a total of 114 consecutive rectal cancer patients who underwent laparoscopic abdominoperineal resection in our center from March 2016 to March 2018 after propensity score matching. Group A included 57 patients who underwent colostomy through the gap between the abdominal oblique internal and oblique external muscles, while group B included 57 patients who underwent extraperitoneal colostomy. Patients' quality of life was evaluated using Fecal Incontinence Quality of Life (FIQL) Scale. RESULTS: Group A had a lower incidence of parastomal hernia (0% vs. 15.7%, p = 0.004) and higher quality of life, especially in lifestyle, coping/behavior and embarrassment domains (all p values < 0.05) than group B both during the follow-up period. The incidence of other outcomes did not differ between the groups. CONCLUSIONS: Colostomy through the gap between the abdominal oblique internal and oblique external muscle is a new technique showing both safety and effectiveness for preventing parastomal hernia and improving quality of life after laparoscopic abdominoperineal resection.

m6 A RNA methylation regulators contribute to malignant progression in rectal cancer.

N6,2'-O-dimethyladenosine (m6 A) RNA methylation, which is correlated with cancer initiation and progression, is dynamically regulated by m6 A RNA methylation regulators, including writers, erasers, and readers. Two subgroups of rectal cancer, including cluster1 and cluster2, were identified based on consensus clustering to m6 A RNA methylation regulators. A protein-protein interaction network was constructed and hub genes were identified. The results demonstrated that the expression of WTAP was significantly associated with YTHDC1 and YTHDF2. The principal component analysis was used to compare the transcriptional profile between cluster1 and cluster2 subgroups. By using two identified m6 A RNA methylation regulators, we constructed a risk signature to predict the survival outcomes of rectal cancer. The results revealed that YTHDC2 and YTHDF2 were protective genes with HR < 1. The coefficients obtained from the least absolute shrinkage and selection operator algorithm were used to calculate the risk score. Patients were then divided into low- and high-risk groups based on the median risk score. The survival analysis demonstrated that there were significant differences in overall survival between these two groups (p < .05). The results of the univariate analysis showed that the risk score, AJCC stage, M stage, and age were associated with overall survival. The results of the multivariate Cox regression analysis showed that the risk score and age were still significantly associated with the overall survival (p < .05). To conclude, m6 A RNA methylation regulators can be regarded as potentially useful biomarkers for predicting the prognosis and designing a treatment strategy in rectal cancer.

TMEM100 expression suppresses metastasis and enhances sensitivity to chemotherapy in gastric cancer.

The gene encoding transmembrane protein 100 (TMEM100) was first discovered to be transcribed by the murine genome. It has been recently proven that TMEM100 contributes to hepatocellular carcinoma and non-small-cell lung carcinoma (NSCLC). This study investigates the impact of TMEM100 expression on gastric cancer (GC). TMEM100 expression was remarkably downregulated in GC samples compared to the surrounding non-malignant tissues (p < 0.01). Excessive TMEM100 expression prohibited the migration and invasion of GC cells without influencing their growth. However, TMEM100 knockdown restored their migration and invasion potential. Additionally, TMEM100 expression restored the sensitivity of GC cells to chemotherapeutic drugs such as 5-fluouracil (5-FU) and cisplatin. In terms of TMEM100 modulation, it was revealed that BMP9 rather than BMP10, is the upstream modulator of TM3M100. HIF1α downregulation modulated the impact of TMEM100 on cell migration, chemotherapy sensitivity and invasion in GC cells. Eventually, the in vivo examination of TMEM100 activity revealed that its upregulation prohibits the pulmonary metastasis of GC cells and increases the sensitivity of xenograft tumors to 5-FU treatment. In conclusion, TMEM100 serves as a tumor suppressor in GC and could be used as a promising target for the treatment of GC and as a predictor of GC clinical outcome.

Study on safety of laparoscopic total gastrectomy for clinical stage I gastric cancer: the protocol of the CLASS02-01 multicenter randomized controlled clinical trial.

BACKGROUND: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group recently launched a multicenter randomized clinical trial (CLASS02-01) to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG). METHODS: This CLASS02-01 trial is a prospective, multicenter, randomized, controlled, open, and non-inferiority trial. Two hundred patients who met the inclusion criteria and did not accord with the exclusion criteria will be randomly divided into LTG group (n = 100) and OTG group (n = 100). The primary purpose of this study is to evaluate the early operative morbidity and mortality of LTG compared with OTG for clinical stage I gastric adenocarcinoma. The second purpose is to evaluate the recovery course and compare the postoperative hospital stay of the patients enrolled in this study. DISCUSSION: This CLASS02-01 trial is the first prospective randomized two-arm controlled study to determine the safety of LTG compared with OTG. Through this trial, we hope to show that experienced surgeons can safely perform LTG with lymphadenectomy for gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03007550 . December 30, 2016.

ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway.

BACKGROUND: Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients' prognosis and its function in GC progression is unknown. METHODS: Clinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo. RESULTS: Downregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling. CONCLUSION: These findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.

Efficacy of Vitamin B Supplementation on Cognition in Elderly Patients With Cognitive-Related Diseases.

Increase in serum homocysteine is shown to be a potential risk factor for cognitive impairment. Evidence suggests that vitamin B supplementation may reduce cognitive decline by lowering the homocysteine levels. The current meta-analysis evaluated the efficacy of folic acid along with vitamin B12 and/or B6 in lowering homocysteine, thereby attenuating cognitive decline in elderly patients with Alzheimer disease or dementia. Randomized controlled trials (RCTs) comparing the efficacy of folate and B vitamin supplementation in patients with cognitive decline secondary to Alzheimer disease or dementia were identified using the keywords, "homocysteine, hyper-homocysteinemia, B vitamin, vitamin B6, B12, folic acid, cognitive, Alzheimer's disease, and dementia." The outcome measures analyzed were the Mini-Mental State Examination (MMSE) score and serum homocysteine. Of the 77 studies identified, 4 RCTs were included in the current meta-analysis. The baseline characteristics, age, and gender distribution of patients among the 2 groups (supplement vs placebo) were comparable. The results reveal that the intervention group achieved significantly greater reduction in homocysteine levels than the control (pooled difference in means = -3.625, 95% confidence interval [CI] = -5.642 to -1.608, P < .001). However, no significant difference in MMSE (pooled difference in means = 0.027, 95% CI = -0.518 to 0.573, P = 0.921) was observed between the groups. Taken together, vitamin B supplementation was effective in reducing serum homocysteine levels. However, it did not translate into cognitive improvement, indicating that the existing data on vitamin B-induced improvement in cognition by lowering homocysteine levels are conflicting.

LPS Upregulated VEGFR-3 Expression Promote Migration and Invasion in Colorectal Cancer via a Mechanism of Increased NF-κB Binding to the Promoter of VEGFR-3.

BACKGROUND AND AIM: Lipopolysaccharide(LPS) could promote the progression of colorectal cancer, but the specific regulatory mechanisms are largely unknown. So, this study aim to clarify the mechanisms that LPS upregulated VEGFR-3, which promotes colorectal cancer cells migration and invasion with a mechanism of increased NF-κB bind to the promoter of VEGFR-3. METHODS: The present study examined the VEGFR-3 expression in colorectal cancer tissues and analyzed the relationship between the VEGFR-3 expression with clinical parameters. PCR, Western blot, CCK-8, colone formation assay, and Transwell assay detected that LPS promoted the migration and invasion and the role of VEGFR-3 in the process of colorectal carcinoma in vitro. Used the methods of promoter analysis, EMSA assay and ChIP assay to explore the mechanisms LPS increased the expression of VEGFR-3. RESULTS: VEGFR-3 was significantly high expression in the colorectal cancer tissues. And the high expression was associated with the TNM stage and lymph node metastasis of colorectal cancer. LPS could promote the migration and invasion, which could be blocked by the neutralizing antibody IgG of VEGFR-3. And found that -159 nt to +65 nt was the crucial region of VEGFR-3 promoter. And detected that the NF-κB was important transcription factor for the VEGFR-3 promoter. And LPS could increase NF-κB binding to VEGFR-3 promoter and upregulated the expression of VEGFR-3 to exert biological functions. CONCLUSION: We have elucidated the relationship between LPS and the VEGFR-3 expression and revealed that VEGFR-3 play very important role in the process of LPS promoting the migration and invasion of colorectal cancer cells. Further illuminated the mechanism that LPS upregulated VEGFR-3 expression via increased NF-κB bind to the promoter of VEGFR-3.

Efficacy, safety, and tolerability of telcagepant in the treatment of acute migraine: a meta-analysis.

Although triptans are widely used for treating acute migraine, they are contraindicated or not effective in a large proportion of patients. Hence, alternative treatments are needed. Calcitonin gene-related peptide receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. A meta-analysis of the efficacy of telcagepant vs. placebo and triptans (zolmitriptan or rizatriptan) was performed. Randomized controlled trials were indentified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant. The primary outcome measure was pain freedom 2 hours after first treatment. The secondary outcome measure was pain relief 2 hours after first treatment. Eight trials were included in the meta-analysis (telcagepant = 4011 participants). The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (odds ratio = 0.76, 95% confidence interval = 0.57-1.01, P = 0.061). These findings indicate that telcagepant can be effective for treating acute migraine. Calcitonin gene-related peptide receptor antagonists represent a potentially important alternative means of treating acute migraine.

Relation between LRG1 and CD4+ T cells, cognitive impairment and neurological function in patients with acute ischemic stroke.

Objective: To assess the relationship between LRG1 and CD4+ T cells, cognitive impairment and neurological function in acute ischemic stroke (AIS). Methods: Plasma LRG1 was detected by ELISA in 175 patients with AIS at baseline, day (D) 1, D7, month (M) 1 and M3. Results: LRG1 was negatively related to Th2 and Treg cells and positively linked to Th17 (all p < 0.05). LRG1 increased from baseline to D1, then decreased until M3 (p < 0.001). LRG1 at each assessment point was increased in patients with cognitive impairment or poor neurological function at M3 versus those without (all p < 0.05). Conclusion: LRG1 is linked to decreased Th2 and Tregs, increased Th17, cognitive impairment and nonideal neurological function recovery in patients with AIS.

Modulation of YBX1-mediated PANoptosis inhibition by PPM1B and USP10 confers chemoresistance to oxaliplatin in gastric cancer.

Gastric cancer (GC) is a common malignant tumor of the digestive tract, and chemoresistance significantly impacts GC patients' prognosis. PANoptosis has been associated with oxaliplatin-induced cell death. However, the direct regulatory role of YBX1 in cellular chemoresistance through PANoptosis remains unclear. In this study, we investigated the impact of YBX1 on regulating PANoptosis and its influence on the resistance of gastric cancer cells to oxaliplatin. Through overexpression and silencing experiments, we assessed YBX1's effect on proliferation and PANoptosis regulation in gastric cancer cells. Additionally, we identified PPM1B and USP10 as interacting proteins with YBX1 and confirmed their influence on YBX1 molecular function and protein expression levels. Our results demonstrate that YBX1 suppresses PANoptosis, leading to enhanced resistance of gastric cancer cells to oxaliplatin. Furthermore, we found that PPM1B and USP10 play critical roles in regulating YBX1-mediated PANoptosis inhibition. PPM1B directly interacts with YBX1, causing dephosphorylation of YBX1 at serine 314 residue. This dephosphorylation process affects the deubiquitination of YBX1 mediated by USP10, resulting in decreased YBX1 protein expression levels and impacting PANoptosis and oxaliplatin resistance in gastric cancer cells. Additionally, we discovered that the 314th amino acid of YBX1 has a profound impact on its own protein expression abundance, thereby affecting the functionality of YBX1. In conclusion, our study reveals the significance of PPM1B-mediated dephosphorylation of YBX1 and USP10-mediated deubiquitination in regulating PANoptosis and sensitivity to oxaliplatin in gastric cancer cells. These findings offer a potential therapeutic strategy for patients with oxaliplatin-resistant gastric cancer.

NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression.

Gastric cancer (GC) is an aggressive malignancy with poor patient outcomes. NAT10 is an acetyltransferase that has been reported to contribute to GC progression. In-depth investigation into the underlying molecular mechanisms driven by NAT10 could help identify therapeutic targets to improve GC treatment. Here, we found that NAT10 forms condensates to regulate RNA dynamics and promote GC progression. In GC patient samples, elevated NAT10 expression correlated with an unfavorable prognosis, advanced disease stage, and metastasis. NAT10 enhanced proliferation, migration, and invasion of GC cells, supported growth of patient-derived organoids, and accelerated tumor development. A C-terminal intrinsically disordered region mediated liquid-liquid phase separation (LLPS) of NAT10 and was essential for its tumor-promoting function in GC. Moreover, NAT10 interacted with the splicing factor SRSF2, leading to its acetylation and increased stability. Acetylated SRSF2 directly bound to the pre-mRNA of the m6A reader YTHDF1, resulting in enhanced YTHDF1 exon 4 skipping and upregulation of a short YTHDF1 transcript that could stimulate GC cell proliferation and migration. Furthermore, YTHDF1 exon 4 skipping correlated with NAT10 and SRSF2 expression and was associated with a more aggressive phenotype in GC patient samples. Together, this study uncovers the role of NAT10 LLPS in modulating YTHDF1 splicing through SRSF2 acetylation to drive GC progression, providing insights into the oncogenic mechanism of NAT10.

3D stem cell spheroids with urchin-like hydroxyapatite microparticles enhance osteogenesis of stem cells.

Cell therapy (also known as cell transplantation) has been considered promising as a next-generation living-cell therapy strategy to surpass the effects of traditional drugs. However, their practical clinical uses and product conversion are hampered by the unsatisfied viability and efficacy of the transplanted cells. Herein, we propose a synergistic enhancement strategy to address these issues by constructing 3D stem cell spheroids integrated with urchin-like hydroxyapatite microparticles (uHA). Specifically, cell-sized uHA microparticles were synthesized via a simple hydrothermal method using glutamic acid (Glu, E) as the co-template with good biocompatibility and structural antimicrobial performance (denoted as E-uHA). Combining with a hanging drop method, stem cell spheroids integrated with E-uHA were successfully obtained by culturing bone marrow mesenchymal stem cells (BMSCs) with a low concentration of the E-uHA suspensions (10 µg mL-1). The resulting composite spheroids of BMSCs/E-uHA deliver a high cellular viability, migration activity, and a superior osteogenic property compared to the 2D cultured counterpart or other BMSC spheroids. This work provides an effective strategy for integrating a secondary bio-functional component into stem cell spheroids for designing more cell therapy options with boosted cellular viability and therapeutic effect.

DNA Demethylation of Promoter Region Facilitates Atoh-1-Induced Interleukin-19 Expression Activation in Bone Marrow Monocytes of Old Mice.

With increasing age, there is a notable increase in the differentiation of bone marrow-derived mononuclear cells (BMMs) into osteoclasts, accompanied by a concurrent rise in both osteoclast quantity and activity. This escalation in osteoclastic activity accelerates bone resorption, which in turn contributes to age-related bone loss and metabolic bone disorders, notably osteoporosis. Our study confirms that elevated IL-19 expression promotes aging-induced bone loss in aged mice and sheds light on the regulatory mechanisms upstream of IL-19 expression and secretion. Primarily, it is the methylation status of the IL-19 gene's promoter region that impacts Atonal BHLH Transcription Factor 1 (Atoh1)'s ability to bind to the promoter. We found that this specific mechanism involves reduced expression and binding affinity of Dnmt1 to the IL-19 promoter region. The findings of our study suggest that targeting IL-19 could be a potential strategy for managing bone loss-related conditions and enhance the current understanding of how DNA methylation levels contribute to age-related bone loss.

Recombinant Salmonella-based 4-1BBL vaccine enhances T cell immunity and inhibits the development of colorectal cancer in rats: in vivo effects of vaccine containing 4-1BBL.

BACKGROUND: Immunotherapy with vaccines is attractive for the treatment of cancer. This study is aimed at determining the effect of recombinant Salmonella (SL3261)-based 4-1BB ligand (4-1BBL) vaccine on the development of colorectal cancers and the potential immune mechanisms in rats. RESULTS: In comparison with that in the PBS group, similar levels of 4-1BBL expression, the frequency of T cells, IFN-γ responses, and comparable numbers of tumors were detected in the SL3261 and SL3261C groups of rats. In contrast, significantly fewer numbers of tumors, increased levels of 4-1BBL expression in the spleens and colorectal tissues, higher frequency of peripheral blood and splenic CD3+CD25+ T cells, and stronger splenic T cell IFN-γ responses were detected in the SL3261R group of rats. CONCLUSION: Our results indicated that vaccination with recombinant attenuated Salmonella harboring the 4-1BBL gene efficiently enhanced T cell immunity and inhibited the development of carcinogen-induced colorectal cancers in rats.