CAD/CAM design and 3D printing of a personalised rapid palatal expander for maxillary transverse deficiency.

Bone -borne ra pid ma xilla ry expansion appliances can achieve skeletal expansion while avoiding the undesirable dental side effec ts caused by a conventional rapid palatal expansion appliance. Typically, t hese (bone-bo rne appliances) included prefabricated devices, which can have limitations such as inadequate palatal adaptation leading to anch orage los s. In addit ion, a s bone thickness is not accounted for, prefabricated expanders cannot ensure the primary stability of the mini-implants. These disadvantages can be overcom e by customisation. This repor t aims to describe the digital design and three-dimensional printing workflow for constructing a personali sed M iniscrewassisted rapid palatal expansion (pMARPE) and present a case depicting its application in a 27-year-old female with 5.0 mm t ransverse discrepancy b etween the maxilla and the mandible. The result demonstrated that the pMARPE could be manufactured without the need for conventional impre s sion or laborator y p rocedures and effec tively e xpanded the palate of an ad ult pat ient with maxillar y transverse deficiency.

Skeletal and dentoalveolar modifications in adults with different sagittal facial patterns after personalized miniscrew-assisted rapid palatal expansion: A prospective cone-beam computed tomography study.

INTRODUCTION: This study aimed to compare the skeletal and dental modifications in adults with different sagittal facial patterns by a personalized miniscrew-assisted rapid palatal expander (pMARPE). METHODS: Forty subjects (aged 18-28 years; 15 females and 25 males) with maxillary transverse deficiency were assigned to 1 of 3 groups (Class I, II, and III relationship) on the basis of their sagittal facial patterns. Each patient was treated with an individually customized expander. A similar expansion protocol was used for all patients. Cone-beam computed tomography scans were obtained before and after expansion. One-way analysis of variance was used to analyze differences among 3 groups in skeletal, dentoalveolar, and periodontal changes (P <0.05). RESULTS: The success rates of expansion were higher in patients with a Class I or II relationship than those with a Class III relationship. Patients with a Class I or II relationship had greater changes in the anterior nasal spine and maxillary basal bone widths. A more parallel sutural opening in the anteroposterior direction was seen in those with a Class II relationship. The tipping of the maxillary first molar increased, and the buccal alveolar bone thickness decreased in all groups after expansion, especially in patients with a Class III relationship. CONCLUSIONS: The pMARPE effectively split the midpalatal suture among adults. However, midpalatal suture expansion was more difficult, and there were more dentoalveolar side effects and fewer orthopedic effects in patients with a Class III relationship than in those with Class I or II relationships.

Knockdown of TRPM2 promotes osteogenic differentiation of human periodontal ligament stem cells by modulating NF-κB /NLRP3 pathway.

Periodontitis is characterized by periodontal destruction triggered by chronic inflammation. The optimal treatment for periodontitis is to improve the periodontal microenvironment, reduce inflammation and achieve periodontal regeneration. Recently, the role of TRPM2 in inflammatory diseases has been reported. However, the function of TRPM2 in periodontal disease and the biological mechanism remain elusive. Therefore, this study aimed to identify the role and explore the underlying mechanisms of TRPM2 in periodontal disease. Here, we first identified the characterization of human periodontal ligament stem cells (PDLSCs). Oil Red O Staining and Alizarin Red mineralized matrix were used to evaluate the multi-differentiation capacity of cells. Flow cytometry was employed to detect MSC-specific surface markers of hPDLSCs. hPDLSCs were treated with 0, 5, 10 or 40 µg/mL of TNF-α for 72 h. Western blot assay were performed to examine the expression of Transient receptor potential cation channel, subfamily M, member 2 (TRPM2) in hPDLSCs. CCK8 and colony formation assays were used to detect the cell viability and proliferation of hPDLSCs, which revealed that TRPM2 knockdown promoted hPDLSCs proliferation. Then, ALP activity in hPDLSCs was detected by ALP activity detection kit. Next, the expression of ALP and Runx2 in hPDLSCs was detected by immunofluorescence staining. The result showed that TRPM2 knockdown promoted osteogenic differentiation and affected the genes expression of osteogenic. Finally, the expressions of p-p65, p65, p-IκBα, IκBα and NLRP3 in hPDLSCs were detected by western blot assay. Together, these results suggested that knockdown of TRPM2 accelerated osteogenic differentiation of hPDLSCs through mediating NF-κB /NLRP3 pathway.

Long-term survival outcome of locally advanced gastric cancer patients who achieved a pathological complete response to neoadjuvant chemotherapy.

BACKGROUND: Long-term outcome of patients with locally advanced gastric cancer (LAGC) who achieved a pathological complete response (pCR) was scarcely discussed, and never had the factors affecting the prognosis of pCR patients been investigated. METHODS: We retrospectively reviewed all patients who achieved a pCR to neoadjuvant chemotherapy (NAC) in Jinling Hospital. The 3- and 5-year overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method. Meanwhile, univariate and multivariate COX regression analysis was applied to identify prognostic factors affecting patients' survival. RESULTS: A total of 37 consecutive LAGC patients with pCR were included. The 3- and 5-year OS rates were 88.8% and 78.6%, and the 3- and 5-year PFS rates were 86.5% and 75.8%. In the multivariate COX model, NAC duration of more than 3 cycles (HR 0.11 [0.02-0.62], P = 0.013) and poorly differentiated tumor at diagnosis (HR 0.17 [0.03-0.95], P = 0.043) were detected as protective factors for patients OS. Whereas for PFS, NAC duration (HR 0.12 [0.02-0.67], P = 0.015) was the only protective factor confirmed, with tumor differentiation at diagnosis exhibiting marginal significance (HR 0.21 [0.04-1.09], P = 0.063). CONCLUSIONS: Patients with LAGC who achieved a pCR displayed favorable long-term survival outcome, especially those with adequate cycles (≥ 3) of NAC. Besides, poor differentiation at diagnosis might also predict the better OS when pCR achieved.

Effects of oral immunonutritional supplement on 3-year disease-free survival in gastric cancer patients with pathological stage III after total gastrectomy (CRUCIAL): study protocol of a multicentre, randomised clinical trial.

INTRODUCTION: The nutritional status of patients with gastric cancer (GC) after total gastrectomy continues to deteriorate and lasts a long time after discharge, which is an independent risk factor for mortality. Recent guidelines have recommended appropriate nutritional support after discharge for cancer surgery patients with malnutrition or nutritional risk. The evidence on the efficacy of oral immunonutritional supplement (INS) and its effect on long-term disease-free survival (DFS) in patients with GC is limited. This study was designed to test the hypothesis that oral INS compared to diet alone may improve 3-year DFS of GC patients with pathological stage III after total gastrectomy (Nutrition Risk Screening 2002 score ≥3 at discharge). METHODS AND ANALYSIS: This is a pragmatic, open-label, multicentre, randomised controlled study. 696 eligible GC patients with pathological stage III after total gastrectomy will be randomised in a 1:1 ratio to oral INS group or normal diet group for 6 months. The primary endpoint is 3-year DFS after discharge. The following secondary endpoints will be evaluated: 3-year overall survival; unplanned readmission rate at 3 and 6 months after discharge; quality of life, body mass index and haematological index at 3, 6 and 12 months after discharge; incidence of sarcopenia at 6 and 12 months after discharge; and the tolerance to chemotherapy. The adverse events of oral INS will also be evaluated during the intervention. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of Jinling Hospital, Nanjing University (number 2021NZKY-069-01). The present study may validate the effectiveness of oral immunonutritional therapy in improving 3-year DFS for GC patients with pathological stage III after total gastrectomy for the first time. The results of this trial will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05253716.

LncRNA PCGEM1 promotes colorectal cancer cell proliferation and migration in positive feedback loop through PCGEM1/miR-433-3p/CTCF axis.

BACKGROUND AND OBJECTIVES: Prostate cancer gene expression marker 1 (PCGEM1) has been identified as an oncogenic long non-coding RNA (lncRNA) in diverse cancers, but it has never been linked with colorectal cancer (CRC). Former studies have shown the mutual regulation between lncRNAs and transcription factors (TFs) in cancer. CCCTC binding factor (CTCF) has been reported to transcriptionally activate lncRNAs in cancers. We predicted the binding of CTCF on PCGEM1 promoter through UCSC (https://genome.ucsc.edu/), but their relation has not been studied. We aimed to investigate whether and how PCGEM1 functioned in CRC cells and the interaction between PCGEM1 and CTCF. METHODS AND RESULTS: The impacts of PCGEM1 and CTCF inhibition on CRC cells were verified through loss-of-function experiments. Mechanism experiments were used to prove the binding between CTCF and PCGEM1 in CRC progression. PCGEM1 possessed a high expression level in CRC cells as well as tumors. CTCF transcriptionally activated PCGEM1 expression. Knockdown of PCGEM1 or CTCF impeded proliferation and migration and drove apoptosis of CRC cells. Moreover, PCGEM1 bound miR-433-3p to prevent miR-433-3p from targeting CTCF. CONCLUSION: We first revealed PCGEM1/miR-433-3p/CTCF positive feedback loop as an oncogenic axis in CRC cells, which potentially provides new clues for the advancement of CRC treatment.

Efficacy of intra-arterial chemotherapy with sequential anti-PD-1 antibody in unresectable gastric cancer: A retrospective real-world study.

Background: The prognosis of unresectable gastric cancer is poor, while the efficacy of anti-PD antibodies has not been evaluated. Methods: Patients with unresectable gastric cancer who received intra-arterial chemotherapy (IAC) with sequential anti-PD-1 antibody as induction therapy in Jinling Hospital were retrospectively analyzed. The primary outcome is R0 resection rate. The secondary outcomes include safety, conversion surgery rate, overall survival (OS) and progression free survival (PFS) after postoperative IAC and anti-PD-1 treatments. Meanwhile, Tumor immunity in the microenvironment (TIME) before and after IAC was comprehensively dissected with multiplex immunofluorescence in order to detect possible mechanisms favoring anti-PD-1 treatment response. Results: Between May 2019 and October 2020, 36 patients received at least one cycle of IAC with sequential anti-PD-1 antibody in our institution. The objective response was achieved in 28 patients (77.8%). Thirty patients (83.3%) successfully underwent conversion surgery, among which R0 resection was managed in 25/30 patients, and 23.3% (7/30) was assessed as pathological complete remission. During the median follow-up period of 19.7 months, patients who underwent R0 resection displayed superior OS (HR 0.14 [95% CI 0.04-0.50], P < 0.0001) and PFS (HR 0.11 [0.03-0.44], P < 0.0001) than those who did not. Grade 3 adverse events (AEs) were only encountered in 19.4% patients, no grade 4 AEs observed. In TIME analysis, the number of tertiary lymphoid structures (TLSs) (P = 0.004) were greatly induced by IAC, as well as CD8+ T cells (P = 0.011) and PD-1+ cells (P = 0.025). Meanwhile, Tumor associated macrophages shifted towards anti-tumor M1-like subtypes, with CD68+CD163+ M2-like subpopulation significantly decreased (P = 0.04). Conclusion: Preoperative IAC with sequential anti-PD-1 antibody exhibited promising clinical benefit for unresectable gastric cancer with remarkable conversion rate and R0 resection rate, and also prolonged survival as postoperative regimen. TIME transformation induced by ICA might mediate the additive effect with the immune checkpoint inhibitor.

Targeting Long Non-Coding RNAs in Hepatocellular Carcinoma: Progress and Prospects.

Hepatocellular carcinoma is the fifth-ranked cancer worldwide with a relatively low five-year survival rate. Long non-coding RNAs are a group of RNAs with remarkable aberrant expression which could act on multiple bioprocesses and ultimately impact upon tumor proliferation, invasion, migration, metastasis, apoptosis, and therapy resistance in cancer cells including hepatocellular carcinoma cells. In recent years, long non-coding RNAs have been reported to be indispensable targets in clinical target therapy to stop the growth of cancer and prolong the lifespan of patients with hepatocellular carcinoma. In this review, we enumerate the signaling pathways and life activities affected by long non-coding RNAs in hepatocellular carcinoma cells to illustrate the role of long non-coding RNAs in the development and therapy resistance of hepatocellular carcinoma.

The role of Aurora-A in human cancers and future therapeutics.

Aurora-A is a mitotic serine/threonine-protein kinase and an oncogene. In normal cells, Aurora-A appears from G2 phase and localizes at the centrosome, where it participates in centrosome replication, isolation and maturation. Aurora-A also maintains Golgi apparatus structure and spindle assembly. Aurora-A undergoes ubiquitination-mediated degradation after the cell division phase. Aurora-A is abnormally expressed in tumor cells and promotes cell proliferation by regulating mitotic substrates, such as PP1, PLK1, TPX2, and LAST2, and affects other molecules through a non-mitotic pathway to promote cell invasion and metastasis. Some molecules in tumor cells also indirectly act on Aurora-A to regulate tumor cells. Aurora-A also mediates resistance to chemotherapy and radiotherapy and is involved in tumor immunotherapy. Clinical trials of Aurora-A molecular inhibitors are currently underway, and clinical transformation is just around the corner.

Phase II Study of Preoperative Intra-Arterial Epirubicin, Etoposide, and Oxaliplatin Combined with Oral S-1 Chemotherapy for the Treatment of Borrmann Type 4 Gastric Cancer.

PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of preoperative, intra-arterial perfusion of epirubicin, etoposide, and oxaliplatin combined with oral chemotherapy S-1 (SEEOX) for the treatment of type 4 gastric cancer. MATERIALS AND METHODS: A single-center, single-arm phase II trial was conducted on 36 patients with histologically proven type 4 gastric cancer without distant peritoneal or organ metastasis. Patients received 3, 21-day courses of SEEOX preoperative chemotherapy. The primary endpoint was overall survival (OS) and the secondary outcomes assessed were chemotherapeutic response, radical resection rate, pathological regression, toxicities, postoperative morbidity, and mortality. RESULTS: All patients were at an advanced stage of cancer (stage III or IV) and completed the entire course of treatment. Based on changes in tumor volume and peritoneal metastasis, the objective response rate was 55.6% (20/36; 95% confidence interval [CI], 38.5%-72.6%) and the disease control rate was 69.4% (25/36; 95% CI, 53.6%-85.3%). The radical resection rate was 75% (27/36; 95% CI, 60.1%-89.9%) and the proportion of R0 resections was 66.7% (21/36; 95% CI, 50.5%-82.8%). The pathological response rate was 33.3%, of which 13.9% showed complete pathological regression. The median survival was 27.1 months (95% CI, 22.24-31.97 months), and the 2-year OS was 48.5% (95% CI, 30.86%-66.1%). CONCLUSIONS: Preoperative SEEOX is a safe and effective treatment for type 4 gastric cancer. Based on these preliminary data, a phase III study will be conducted to confirm the superiority of this regimen over standard treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02949258.

Laparoscopic management of cholecystoenteric fistula: A single-center experience.

Aim To report our experience regarding management of cholecystoenteric fistula (CEF) and identify the most effective diagnostic methods and surgical treatment. Methods In total, 10,588 patients underwent laparoscopic cholecystectomy for cholecystolithiasis from January 2000 to December 2014 at the Research Institute of General Surgery, Jinling Hospital (Nanjing, China). Twenty-nine patients were diagnosed with CEF preoperatively or intraoperatively. Data were retrospectively collected on demographics, preoperative diagnostics, intraoperative findings, laparoscopic procedures, complications, and follow-up. Results Twenty-nine patients (female/male ratio, 2.2; mean age, 68.7 years) with CEF were evaluated. Twenty-three (79.3%) patients had a cholecystoduodenal fistula (CDF), four (13.8%) had a cholecystocolonic fistula (CCF), one (3.4%) had a cholecystogastric fistula, and one (3.4%) had a CDF combined with a CCF. Only nine (31.0%) patients obtained a preoperative diagnosis. All patients initially underwent laparoscopic treatment, but five (17.2%) underwent conversion to open surgery; three of these five developed postoperative morbidity or mortality, and the other two had an uneventful postoperative course. Among patients managed successfully by laparoscopy, the hospital stay ranged from 3 to 6 days (mean, 4 days). All patients were asymptomatic at a mean follow-up of 13 months (range, 3-21 months). Conclusion Ultrasound and computed tomography can provide valuable diagnostic clues for CEF. Laparoscopic management of CEF in experienced hands is safe, feasible, and associated with rapid postoperative recovery.

Combination therapy with thymosin alpha1 and dexamethasone helps mice survive sepsis.

Immune dysfunction is a major cause of mortality in septic patients. Current evidence indicates an important role for dendritic cells (DCs) in the pathophysiology of immune dysfunction, and these cells are potential targets of immunomodulation therapies. In the present study, our aim was to enhance the resistance of endotoxemic mice to bacterial translocation and secondary infection and to improve the outcome of these infections using a combination therapy consisting of thymosin alpha1 and dexamethasone in a timely manner according to the changes of DCs' number. The effect of treatment with dexamethasone (DXM) and thymosin alpha1 (Tα1) on DCs was investigated by examining their number, MHCII and CD86 expression and their capacity to induce T cell activation. Endotoxemic mice were randomly divided into five treatment groups. The survival rates, the levels of TNF-α and IL-10, the occurrence of bacterial translocation, and the ability to clear secondary infections were determined. Additionally, the behavior of DCs over time was also evaluated. Tα1 induced significant increases in DC numbers in vivo, whereas DXM reduced cell numbers both in vitro and in vivo. However, neither drug induced significant changes in the capacity of DCs to induce T cell activation or their expression of MHCII or CD86. Among the five treatment groups, the mice treated with a combination of DXM and Tα1 had the highest survival rate; this increased survival was associated with a decrease in bacterial translocation to extra-intestinal organs and an enhanced ability to eradicate secondary infections by reversing the change in DC numbers during endotoxemia. Immunomodulatory therapy that combines Tα1 and DXM in a timely manner and was based on changes in DCs enhanced the resistance of endotoxemic mice to bacterial translocation and secondary infections, improving the outcome of the infection.

Accumulation of DC in lamina propria induced by FMS-like tyrosine kinase 3 ligand aggravates the intestinal inflammatory response during endotoxemia.

It is known that the loss of DC plays an important role for immune suppression during endotoxemia or sepsis. To verify our hypothesis that pre-enrichment of the lamina propria (LP) DC pool may improve protective immunity to bacterial translocation and outcome in endotoxemic mice, we pre-treated mice with Flt3L or normal saline, and then challenged them with or without LPS. Twelve hours later the population size and maturity of DC in the LP and circulation were analyzed by flow cytometry. Bacterial translocation to distant organs, inflammatory responses in the intestine and the survival rate of mice were evaluated. We observed that pretreatment of Flt3L significantly expanded DC in the LP and blood, but did not alter their maturation. However, exacerbation of DC growth induced by Flt3L-pretreatment aggravated intestinal inflammation and increased the mortality of endotoxemic mice rather than enhancing their resistance to bacterial translocation.