Exo70 Promotes the Invasion of Pancreatic Cancer Cells via the Regulation of Exosomes.

Pancreatic cancer (PC) is an aggressive and fatal malignant tumor, and exosomes have been reported to be closely related to PC invasion and metastasis. Here we found that Exo70, a key subunit of the exocyst complex, promoted PC metastasis by regulating the secretion of tumor exosomes. Clinical sample studies showed that Exo70 was highly expressed in PC and negatively correlated with patients' survival. Exo70 promoted PC cell lines' invasion and migration. Interestingly, knockdown of Exo70, or using an Exo70 inhibitor (ES2) inhibited the secretion of tumor exosomes and increased the accumulation of cellular vesicles. Furthermore, Exo70 was found to accumulate in the exosomes, which then fused with neighboring PC cells and promoted their invasion. Moreover, Exo70 increased the expression of exosomal PD-L1, leading to the immune escape of PC cells. In vivo, knockdown of Exo70 or treatment with ES2 both decreased the tumor metastasis of PC cells in mice. This study provides new insight into the mechanism of invasion and metastasis in PC and identifies Exo70 as a potential prognostic factor and therapeutic target for PC.

Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib's Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion.

Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition.

Clinical research on restorations using CAD/CAM-fabricated monolithic zirconia endocrowns and post and core crowns after up to 5 years.

OBJECTIVE: To assess the clinical status of monolithic zirconia CAD/CAM endocrowns and crowns on post and core buildups in endodontically treated molars after 5 years of clinical service. MATERIALS AND METHODS: A total of 670 patients who received restorations for excessive defects at Ansteel Group Hospital from 2012 to 2015 were selected and randomly divided into two groups: 334 patients in the endocrown group and 336 in the post and core crown group. All the treatments were performed using a digital CAD/CAM system. The prostheses restorations at 1, 3, and 5 years after treatment were evaluated using the USPHS (United States Public Health Service) criteria and satisfaction questionnaire. In addition, the time cost of tooth preparation was recorded by the clinicians. RESULTS: Most of the patients in both groups reported grade A at the after-treatment follow-ups. Gingival health, food impaction, marginal accuracy, and general satisfaction at 3 and 5 years after treatment in the endocrown group rated higher (P < 0.05) than in the post and core crown group. There was no statistical difference in other indicators between the two groups at all observational after-treatment timepoints (P > 0.05). The time cost of tooth preparation in the post and core crown group was significantly higher than that in the endocrown group. CONCLUSION: A CAD/CAM scanning system combined with a monolithic zirconia endocrown restoration was rated very positively by the participants. Endocrown restorations are a significantly superior choice compared with post and core crowns in clinical application. (Int J Comput Dent 2022;25(3):287-294; doi: 10.3290/j.ijcd.b2599661).

ULK1 phosphorylates Exo70 to suppress breast cancer metastasis.

Increased expression of protein kinase ULK1 was reported to negatively correlate with breast cancer metastasis. Here we report that ULK1 suppresses the migration and invasion of human breast cancer cells. The suppressive effect is mediated through direct phosphorylation of Exo70, a key component of the exocyst complex. ULK1 phosphorylation inhibits Exo70 homo-oligomerization as well as its assembly to the exocyst complex, which are needed for cell protrusion formation and matrix metalloproteinases secretion during cell invasion. Reversely, upon growth factor stimulation, Exo70 is phosphorylated by ERK1/2, which in turn suppresses its phosphorylation by ULK1. Together, our study identifies Exo70 as a substrate of ULK1 that inhibits cancer metastasis, and demonstrates that two counteractive regulatory mechanisms are well orchestrated during tumor cell invasion.

Clinical performance of CAD/CAM-fabricated monolithic zirconia endocrowns on molars with extensive coronal loss of substance.

OBJECTIVE: To clinically evaluate computer-aided design/computer-aided manufacturing (CAD/CAM)-fabricated molar endocrowns after 6 months and 1, 2, and 3 years of clinical service. MATERIALS AND METHODS: 289 patients with 321 molars (267 patients with one endocrown, two patients with two endocrowns, and ten patients with three endocrowns) exhibiting extensive coronal loss of substance participated in the study. Endocrown preparations were scanned, and endocrowns designed and machined with the Cerec CAD/CAM system. The endocrowns were adhesively seated using a composite luting agent, and assessed using clinical United States Public Health Service (USPHS) criteria at baseline, 6 months, and 1, 2, and 3 years after placement. Patient satisfaction was evaluated using a questionnaire. RESULTS: None of the 289 endocrowns failed during the observation period. The high clinical rating criteria (97.2%) and the high satisfaction percentage (98.0%) remained practically unchanged (P > 0.05) throughout the follow-up assessments at 6 months and after 1, 2, and 3 years. CONCLUSION: Monolithic zirconia endocrown restorations represent an effective method of restoring posterior teeth after root canal therapy. Based on the short-term observation period of the present study, monolithic zirconia endocrowns can be considered a reliable restoration for endodontically treated molars with extensive coronal loss of substance.

[Assessment of life quality of for patients after tongue reconstruction with radial forearm free flap, anterolateral thigh perforator flap or submental island flap].

PURPOSE: The aim of this study was to evaluate operation-related factors and quality of life (QOL) for patients after tongue reconstruction with radial forearm free flap (RFFF), anterolateral thigh perforator flap (ALT) or submental island flap (SIF). METHODS: Totally 59 patients, diagnosed as tongue carcinoma, received glossectomy and simultaneous reconstruction with free flaps including RFFF, ALT or SIF in the Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, China Medical University from October 2004 to October 2014. All patients were followed up for 6 months and completed the University of Washington Quality of Life scale Version 4 questionnaires. The postoperative QOL was compared among the three groups. The data were analyzed using SPSS 21.0 software package. RESULTS: The operation duration of SIF group was significantly shorter than those of RFFF group or ALT group (P<0.05). The ALT group had a longer hospitalization time. There were statistically differences among the 3 groups regarding to the size of reconstructed defects. Action QOL score of the ALT group was significantly lower than those of RFFF group and SIF group. There was no significant difference in the total QOL score including chewing, swallowing, speech and postoperative pain among the 3 groups. CONCLUSION: In summary, there may be functional disability for patients after glossectomy and simultaneous reconstruction. The quality of life would be acceptable after tongue reconstruction with RFFF, ALT and SIF.