A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation.

Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.

Pyroptosis-related gene signature for predicting gastric cancer prognosis.

Gastric cancer (GC) is a prevalent form of malignancy characterized by significant heterogeneity. The development of a specific prediction model is of utmost importance to improve therapy alternatives. The presence of H. pylori can elicit pyroptosis, a notable carcinogenic process. Furthermore, the administration of chemotherapeutic drugs is often employed as a therapeutic approach to addressing this condition. In the present investigation, it was observed that there were variations in the production of 17 pyroptosis-regulating proteins between stomach tissue with tumor development and GC cells. The predictive relevance of each gene associated with pyroptosis was assessed using the cohort from the cancer genome atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) was utilized to enhance the outcomes of the regression approach. Patients with gastric cancer GC in the cohort from the TCGA were categorized into low-risk or high-risk groups based on their gene expression profiles. Patients with a low risk of gastric cancer had a higher likelihood of survival compared to persons classified as high risk (P<0.0001). A subset of patients diagnosed with GC from a Genes Expression Omnibus (GEO) cohort was stratified according to their overall survival (OS) duration. The statistical analysis revealed a higher significance level (P=0.0063) regarding OS time among low-risk individuals. The study revealed that the GC risk score emerged as a significant independent prognostic factor for OS in patients diagnosed with GC. The results of Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) research revealed that genes associated with a high-risk group had significantly elevated levels of immune system-related activity. Furthermore, it was found that the state of immunity was diminished within this particular group. The relationship between the immune response to cancer and pyroptosis genes is highly interconnected, suggesting that these genes have the potential to serve as prognostic indicators for GC.

Programming peptide-oligonucleotide nano-assembly for engineering of neoantigen vaccine with potent immunogenicity.

Background: Neoantigen nanovaccine has been recognized as a promising treatment modality for personalized cancer immunotherapy. However, most current nanovaccines are carrier-dependent and the manufacturing process is complicated, resulting in potential safety concerns and suboptimal codelivery of neoantigens and adjuvants to antigen-presenting cells (APCs). Methods: Here we report a facile and general methodology for nanoassembly of peptide and oligonucleotide by programming neoantigen peptide with a short cationic module at N-terminus to prepare nanovaccine. The programmed peptide can co-assemble with CpG oligonucleotide (TLR9 agonist) into monodispersed nanostructures without the introduction of artificial carrier. Results: We demonstrate that the engineered nanovaccine promoted the codelivery of neoantigen peptides and adjuvants to lymph node-residing APCs and instigated potent neoantigen-specific T-cell responses, eliciting neoantigen-specific antitumor immune responses with negligible systemic toxicity. Furthermore, the antitumor T-cell immunity is profoundly potentiated when combined with anti-PD-1 therapy, leading to significant inhibition or even complete regression of established melanoma and MC-38 colon tumors. Conclusions: Collectively, this work demonstrates the feasibility and effectiveness of personalized cancer nanovaccine preparation with high immunogenicity and good biosafety by programming neoantigen peptide for nanoassembly with oligonucleotides without the aid of artificial carrier.

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy.

The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.

Preliminary Study on the Clinical Significance and Methods of Using Carbon Nanoparticles in Endoscopic Papillary Thyroid Cancer Surgery.

Purpose: The purpose of this study was to find the clinical significance and methods of using CN in endoscopic treatment for PTC. Materials and Methods: A total of 108 cases were randomly enrolled and divided into two groups, with 50 cases in the CN injection group who were injected with CN and 58 cases in the control group with no CN injection. All cases were analyzed with the size of carcinoma, the number of lymph node, and parathyroid gland injury. Results: All operations were successfully completed. The lymph node dissection number was 274 for the control group and 322 (the rate of black stained was 87%) for the CN injection group. The average number of lymph nodes in the CN injection group was 6.44 ± 2.08, which was significantly higher than that in the control group (4.72 ± 1.89). The control group had a relatively higher incidence of incidental parathyroidectomy, compared to the CN injection group (27.6% in the control group vs. 12% in the CN injection group, P=0.045). However, the incidence of hypoparathyroidism failed to show the significant difference between the two groups. Conclusion: Using CN in endoscopic PTC surgery could increase the detection rate of lymph nodes and reduce the injury of parathyroid glands to a certain extent.

Analysis of Risk Factors for Surgical Complications of Endoscopic Thyroidectomy via Total Areola Approach.

BACKGROUND: Increased surgical technology has led broad acceptance endoscopic thyroidectomy and its application in the treatment of thyroid diseases, including thyroid carcinoma. Although the incidence of complications and mortality of thyroid surgery has been significantly reduced, serious complications still occur from time to time. The purpose of this retrospective study is to identify the factors that influence the complications of endoscopic thyroidectomy. METHODS: This study was carried out between January 2012 and December 2019, where a total of 630 patients undergoing endoscopic thyroidectomy via the total areola approach were retrospectively evaluated to identify the key influencing factors of complications. RESULTS: The study established that the common complications included recurrent laryngeal nerve injury (3.33%), superior laryngeal nerve injury (2.54%), hypocalcemia (8.57%), and the incidence of complications was acceptable. Both univariate and multivariate analysis showed that thyroid carcinoma (P = 0.041), operation time lasting more than 150 minutes (P = 0.034) and operation before 2017 (P = 0.001) were risk factors of recurrent laryngeal nerve injury. We established that operation after 2017 (P < 0.005) was the only protective factor of superior laryngeal nerve injury. Thyroid carcinoma (P=0.04), operation mode (P=0.001), and surgery before 2017 (P<0.001) are risk factors for parathyroid injury. Among the clinical groups, operation before 2017 was an independent risk factor for all complications. CONCLUSION: For thyroid specialists, after the early learning curve, with the continuous improvement of endoscopic operation technology, high-definition equipment and more sophisticated operation equipment can be used in clinical practice, which can prevent and reduce the occurrence of complications.

The learning curve of endoscopic thyroid surgery for papillary thyroid microcarcinoma: CUSUM analysis of a single surgeon's experience.

BACKGROUND: With the development of surgical technics, endoscopic thyroid surgery has been gradually accepted and utilized in thyroid disease treatment, including thyroid carcinoma. This study aimed to evaluate the learning curve for endoscopic hemithyroidectomy (EHT) with ipsilateral central neck dissection (CND) and investigate how many cases must be performed before a surgeon becomes competent and proficient in this approach. METHODS: Ninety-nine consecutive patients who underwent EHT with ipsilateral CND for papillary thyroid microcarcinoma by a single surgeon between June 2015 and October 2017 were analyzed. Multidimensional cumulative summation (CUSUM) analysis was performed to evaluate the learning curve. RESULTS: The CUSUM graph showed the learning curve ascended in the first 31 cases and declined in the following cases. The number of lymph nodes removed in phase 2 (the following 68 cases) was significantly more than that in phase 1 (the first 31 cases) (5.06 ± 1.44 vs. 4.19 ± 1.51, P = 0.001). The operation time in phase 2 was shorter than that in phase 1 (123.38 ± 12.71 min vs. 132.90 ± 13.95 min, P = 0.008) and the rate of accidental removal of parathyroid gland decreased from 35.5% in phase 1 to 16.2% in phase 2 (P = 0.040). There was a declining trend but no significant difference in the rate of postoperative complications (9.7% in phase 2 vs. 4.4% in phase 1, P = 0.309). CONCLUSION: EHT with ipsilateral CND performed by surgeons was mastered after 31 cases, and the safety and feasibility of this endoscopic approach can also be demonstrated.