The model for predicting the central lymph node metastasis in cN0 papillary thyroid microcarcinoma with Hashimoto's thyroiditis.

Background: The relationship between Hashimoto's thyroiditis (HT) and papillary thyroid microcarcinoma (PTMC) is controversial. These include central lymph node metastasis (CLNM), which affects the prognosis of PTMC patients. This study aimed to establish a predictive model combining ultrasonography and clinicopathological features to accurately evaluate latent CLNM in PTMC patients with HT at the clinical lymph node-negative (cN0) stage. Methods: In this study, 1102 PTMC patients who received thyroidectomy and central cervical lymph node dissection (CLND) from the First Affiliated Hospital of Shandong First Medical University from January 2021 to December 2022 and the 960th Hospital of PLA from January 2021 to December 2022 were jointly collected. The clinical differences between PTMCs with HT and those without HT were compared. A total of 373 PTMCs with HT in cN0 were randomly divided into a training cohort and a validation cohort. By analyzing and screening the risk factors of CLNM, a nomogram model was established and verified. The predictive performance was measured by the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA). Results: The ratio of central lymph node metastasis (CLNMR) in PTMCs with HT was 0.0% (0.0%, 15.0%) and 7.7% (0.0%, 40.0%) in the non-HT group (P<0.001). Multivariate logistic regression analysis showed that age, gender, calcification, adjacent to trachea or capsule, and TPOAB were predictors of CLNM in PTMCs with HT. The areas under the curve (AUC) of the prediction models in the training cohort and the validation cohort were 0.835 and 0.825, respectively, which showed good differentiation ability. DCA indicates that the prediction model also has high net benefit and clinical practical value. Conclusion: This study found that CLN involvement was significantly reduced in PTMC patients with HT, suggesting that different methods should be used to predict CLNM in PTMC patients with HT and without HT, to more accurately assist preoperative clinical evaluation. The actual CLNM situation of PTMCs with HT in cN0 can be accurately predicted by the combination of ultrasonography and clinicopathological features.

Surgical restabilization reduces the progression of post-traumatic osteoarthritis initiated by ACL rupture in mice.

OBJECTIVE: People who sustain joint injuries such as anterior cruciate ligament (ACL) rupture often develop post-traumatic osteoarthritis (PTOA). In human patients, ACL injuries are often treated with ACL reconstruction. However, it is still unclear how effective joint restabilization is for reducing the progression of PTOA. The goal of this study was to determine how surgical restabilization of a mouse knee joint following non-invasive ACL injury affects PTOA progression. DESIGN: In this study, 187 mice were subjected to non-invasive ACL injury or no injury. After injury, mice underwent restabilization surgery, sham surgery, or no surgery. Mice were then euthanized on day 14 or day 49 after injury/surgery. Functional analyses were performed at multiple time points to assess voluntary movement, gait, and pain. Knees were analyzed ex vivo with micro-computed tomography, RT-PCR, and whole-joint histology to assess articular cartilage degeneration, synovitis, and osteophyte formation. RESULTS: Both ACL injury and surgery resulted in loss of epiphyseal trabecular bone (-27-32%) and reduced voluntary movement at early time points. Joint restabilization successfully lowered OA score (-78% relative to injured at day 14, p < 0.0001), and synovitis scores (-37% relative to injured at day 14, p = 0.042), and diminished the formation of chondrophytes/osteophytes (-97% relative to injured at day 14, p < 0.001, -78% at day 49, p < 0.001). CONCLUSIONS: This study confirmed that surgical knee restabilization was effective at reducing articular cartilage degeneration and diminishing chondrophyte/osteophyte formation after ACL injury in mice, suggesting that these processes are largely driven by joint instability in this mouse model. However, restabilization was not able to mitigate the early inflammatory response and the loss of epiphyseal trabecular bone, indicating that these processes are independent of joint instability.

Integration of ultrasound-based radiomics with clinical features for predicting cervical lymph node metastasis in postoperative patients with differentiated thyroid carcinoma.

OBJECTIVE: The primary objective was to establish a radiomics model utilizing longitudinal +cross-sectional ultrasound (US) images of lymph nodes (LNs) to predict cervical lymph node metastasis (CLNM) following differentiated thyroid carcinoma (DTC) surgery. METHODS: A retrospective collection of 211 LNs from 211 postoperative DTC patients who underwent neck US with suspicious LN fine needle aspiration cytopathology findings at our institution was conducted between June 2021 and April 2023. Conventional US and clinicopathological information of patients were gathered. Based on the pathological results, patients were categorized into CLNM and non-CLNM groups. The database was randomly divided into a training cohort (n = 147) and a test cohort (n = 64) at a 7:3 ratio. The least absolute shrinkage and selection operator algorithm was applied to screen the most relevant radiomic features from the longitudinal + cross-sectional US images, and a radiomics model was constructed. Univariate and multivariate analyses were used to assess US and clinicopathological significance features. Subsequently, a combined model for predicting CLNM was constructed by integrating radiomics, conventional US, and clinicopathological features and presented as a nomogram. RESULTS: The area under the curves (AUCs) of the longitudinal + cross-sectional radiomics models were 0.846 and 0.801 in the training and test sets, respectively, outperforming the single longitudinal and cross-sectional models (p < 0.05). In the testing cohort, the AUC of the combined model in predicting CLNM was 0.901, surpassing that of the single US model (AUC, 0.731) and radiomics model (AUC, 0.801). CONCLUSIONS: The US-based radiomics model exhibits the potential to accurately predict CLNM following DTC surgery, thereby enhancing diagnostic accuracy.

MSC-Exos: Important active factor of bone regeneration.

Bone defect and repair is a common but difficult problem in restorative and reconstructive surgery. Bone tissue defects of different sizes caused by different reasons bring functional limitations and cosmetic deformities to patients. Mesenchymal stem cells (MSC), a major hotspot in the field of regeneration in recent years, have been widely used in various studies on bone tissue regeneration. Numerous studies have shown that the bone regenerative effects of MSC can be achieved through exosome-delivered messages. Although its osteogenic mechanism is still unclear, it is clear that MSC-Exos can directly or indirectly support the action of bone regeneration. It can act directly on various cells associated with osteogenesis, or by carrying substances that affect cellular activators or the local internal environment in target cells, or it can achieve activation of the osteogenic framework by binding to materials. Therefore, this review aims to summarize the types and content of effective contents of MSC-Exos in bone regeneration, as well as recent advances in the currently commonly used methods to enable the binding of MSC-Exos to the framework and to conclude that MSC-Exos is effective in promoting osteogenesis.

Enzyme and microwave co-assisted extraction, structural characterization and antioxidant activity of polysaccharides from Purple-heart Radish.

A novel method of simultaneous extraction and separation of diverse polysaccharides from Purple-heart Radish was developed by integrating EAE with MAATPE. The effects of different enzymes, the ATPS composition, extraction temperature, time etc. were investigated by single-factor experiments and RSM. Under the optimum conditions, the extraction yields of PTP, PBP and total polysaccharides were 9.107 ± 0.391%, 32.506 ± 0.046% and 41.613 ± 0.437%, respectively. By means of HPGPC and PMP-HPLC, Mw of PTP and Mw of PBP were 15935 Da and 27962 Da, respectively. PTP and PBP were mainly composed of mannose, glucuronic acid, aminogalactose, glucose, galactose and arabinose. Moreover, both polysaccharides exhibited stronger antioxidant activities for scavenging multiple radicals and anti-lipid peroxidation. Compared to the conventional extraction methods, EAE-MAATPE achieved higher extraction efficiency due to the synergistic effect between EAE and MAATPE leading to rupture and enzymolysis of cell. Thus, EAE-MAATPE provided an efficient alternative to simultaneous extraction of different polysaccharides from natural products.

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma.

BACKGROUND: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. METHODS: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. RESULTS: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. CONCLUSIONS: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

Prognostic and clinicopathological value of MUC1 expression in colorectal cancer: A meta-analysis.

BACKGROUND: Accumulating evidence supports the overexpression of mucin 1 (MUC1) in colorectal cancer (CRC), but the value of elevated MUC1 expression remains controversial. Here, we evaluated the prognostic and clinicopathological value of MUC1 expression in CRC. MATERIALS AND METHODS: The Web of Science, PubMed, Embase, Cochrane Library, and Wanfang databases, as well as the China Biology Medicine disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) were searched for studies on MUC1 expression and prognosis of CRC through July 20, 2018. The pooled relative risks (RRs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the prognostic and clinicopathological value of MUC1 expression in CRC. The Revman version 5.3 package and STATA, version 12 were employed for pooled analysis and analysis of publication bias. RESULTS: This meta-analysis included 16 published studies. The combined analysis showed that CRC patients with high MUC1 expression had a worse clinical outcome in overall survival (OS) (HR = 1.51, 95% CI = 1.30-1.75, P <.00001). In addition, high MUC1 expression was associated with higher TNM stage (RR = 1.44, 95% CI = 1.17-1.77, P = .0007), greater depth of invasion (RR = 1.30, 95% CI = 1.10-1.53, P = .002), and lymph node metastasis (RR = 1.47, 95% CI = 1.20-1.80, P = .0002) of CRC. However, the elevated MUC1 expression was not related to disease-free survival/recurrence-free survival (DFS/RFS) (HR = 1.51, 95% CI = 0.78-2.89, P = .22), histological grade (RR = 1.15, 95% CI = 0.96-1.38, P = .12), gender (RR = 0.95; 95% CI = 0.83-1.08, P = .44), tumor size (RR = 1.11, 95% CI = 0.85-1.44, P = .44), tumor site (RR = 1.01, 95% CI = 0.88-1.16, P = .84), or mucinous component (RR = 0.83, 95% CI = 0.60-1.14, P = .24) in CRC. CONCLUSION: Our findings indicated that high MUC1 expression represents a marker of poor prognosis in CRC. Meanwhile, elevated MUC1 expression was associated with advanced TNM stage, greater depth of invasion, and lymph node metastasis.

Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy.

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Prognostic Value of MUC2 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The reliability of MUC2 as a prognostic marker in colorectal cancer (CRC) is controversial. This study evaluated the association between MUC2 expression levels in CRC tissues and prognosis. METHODS: The PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine disc (CBMdisc), Wanfang Database, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies exploring the relationship between MUC2 expression in CRC tissues and overall survival (OS). Pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the associations between MUC2 expression levels and prognosis and MUC2 expression levels and CRC clinicopathological characteristics, respectively. RESULTS: The meta-analysis included 11 studies (2619 patients). Low MUC2 expression level was significantly associated with poor OS (HR, 1.67; 95% CI, 1.43-1.94; P < 0.00001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR, 1.60; 95% CI, 1.21-2.12; P = 0.001) in patients with CRC. Low MUC2 expression level was associated with advanced TNM stage (RR, 1.42; 95% CI, 1.26-1.60; P < 0.00001), lymph node metastasis (RR, 1.41; 95% CI, 1.25-1.60; P < 0.00001), lymphatic invasion (RR,1.64; 95% CI, 1.26-2.12; P = 0.0002), rectal tumor site (RR, 1.26; 95% CI, 1.09-1.46; P = 0.001), and large tumor size (RR,1.32; 95% CI, 1.02-1.70; P = 0.03). There were no associations between low MUC2 expression level and gender, histological grade, depth of invasion, and distant metastasis. CONCLUSION: The low levels of MUC2 in CRC tissues are poor prognostic factor independent of stage or other well-recognized markers of later-stage disease. Large well-designed cohort studies are required to validate MUC2 as a biomarker for poor prognosis in CRC.

The family of apoptosis-stimulating proteins of p53 is dysregulated in colorectal cancer patients.

The apoptosis-stimulating protein of p53 (ASPP) family is a newly identified family protein including ASPP1, ASPP2 and inhibitor of ASPP (iASPP), by which the tumor protein 53 (TP53)-mediated apoptotic process is selectively regulated. Downregulation of ASPP1/ASPP2 and upregulation of iASPP were revealed to be associated with a poor prognosis and metastasis in several types of cancer. However, to the best of our knowledge, the expression of ASPP in colorectal cancer (CRC) has not previously been investigated. The present study analyzed ASPP expression in human CRC tissues with multiple clinical and pathological profiles. A total of 41 patients diagnosed with CRC were enrolled in the present study. The expression of ASPP was detected by immunohistochemistry, immunofluorescence and reverse transcription-quantitative polymerase chain reaction. In addition, the variation in ASPP expression was examined in a number of pathological groups. The associations among ASPP expression, and the expression of TP53, plasma carcinoembryonic antigen (CEA) levels and α-fetoprotein (AFP) levels were also investigated. ASPP1 and ASPP2 expression was significantly reduced, while iASPP expression was elevated in CRC samples compared with expression in adjacent non-cancerous tissues. Downregulation of ASPP1 was detected in the TP53-positive group compared with the TP53-negative group. The increase in iASPP expression was correlated with the grade of malignancy, but not with regional lymph node status or metastases. The expression of ASPP2 was negatively correlated with plasma CEA levels. The results of the present study, not only enrich CRC epidemic and pathological data, but also provide valuable indices for CRC clinical treatment and prognosis.

Circulating and tumor-infiltrating mucosal associated invariant T (MAIT) cells in colorectal cancer patients.

Mucosal associated invariant T (MAIT) cells are important for immune defense against infectious pathogens and regulate the pathogenesis of various inflammatory diseases. However, their roles in the development of colorectal cancer (CRC) are still unclear. This study examined the phenotype, distribution, clinical relevance and potential function of MAIT cells in CRC patients. We found that the percentages of circulating memory CD8(+) MAIT cells were significantly reduced while tumor infiltrating MAIT cells were increased, especially in patients with advanced CRC. The serum CEA levels were positively correlated with the percentages of tumor infiltrating MAIT cells in CRC patients, but negatively correlated with the percentages of circulating MAIT in advanced CRC patients. Activated circulating MAIT cells from CRC patients produced lower IFN-γ, but higher IL-17. Furthermore, higher levels of Vα7.2-Jα33, IFN-γ and IL-17A were expressed in the CRC tissues. Co-culture of activated MAIT cells with HCT116 cells enhanced IL-17 expression and induced HCT116 cell cycle arrest at G2/M phase in a contact- and dose-dependent manner, which was abrogated by treatment with anti-MR1. Therefore, MAIT cells preferably infiltrate into the solid tumor in CRC patients and may participate in the immune surveillance of CRC.

A Higher Frequency of CD14+ CD169+ Monocytes/Macrophages in Patients with Colorectal Cancer.

OBJECTIVE: Monocytes and macrophages can infiltrate into tumor microenvironment and regulate the progression of tumors. This study aimed at determining the frequency of different subsets of circulating monocytes and tumor infiltrating macrophages (TIMs) in patients with colorectal cancer (CRC). METHODS: The frequency of different subsets of circulating monocytes was characterized in 46 CRC patients and 22 healthy controls (HC) by flow cytometry. The frequency of different subsets of macrophages was analyzed in TIMs from 30 tumor tissues and in lamina propria mononuclear cells (LPMCs) from 12 non-tumor tissues. The concentrations of plasma cytokines and carcinoembryonic antigen (CEA) were determined. The potential association of these measures with the values of clinical parameters was analyzed. RESULTS: In comparison with that in the HC, the percentages of circulating CD14+ CD169+, CD14+ CD169+ CD163+ and CD14+ CD169+ CD206+ monocytes and TIMs CD14+ CD169+ as well as IL-10+ CD14+ CD169+, but not IL-12+ CD14+ CD169+ macrophages were significantly increased, accompanied by higher levels of plasma IL-10 in the CRC patients. The percentages of CD14+ CD169+ circulating monocytes and TIM macrophages were associated with the stage of disease and correlated positively with the levels of plasma IL-10 and CEA in CRC patients. CONCLUSION: Our data suggest that an increase in the frequency of CD14+ CD169+ cells may be associated with the development and progression of CRC and is concomitant rise of both, pro-tumor (M2-like, IL-10 producing) and anti-tumor (M1-like, IL-12 producing) monocytes and infiltrating macrophages. The frequency of CD14+ CD169+ circulating monocytes and infiltrating macrophages may serve as a biomarker for evaluating the pathogenic degrees of CRC.

Histone deacetylase HDAC4 promotes gastric cancer SGC-7901 cells progression via p21 repression.

Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5'-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer.