Prevention of dementia using mobile phone applications (PRODEMOS): a multinational, randomised, controlled effectiveness-implementation trial.

BACKGROUND: The expected increase of dementia prevalence in the coming decades will mainly be in low-income and middle-income countries and in people with low socioeconomic status in high-income countries. This study aims to reduce dementia risk factors in underserved populations at high-risk using a coach-supported mobile health (mHealth) intervention. METHODS: This open-label, blinded endpoint, hybrid effectiveness-implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in people aged 55-75 years of low socioeconomic status in the UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in cardiovascular risk factors, ageing, and incidence of dementia (CAIDE) risk score from baseline to after 12-18 months of intervention. Implementation outcomes were coverage, adoption, sustainability, appropriateness, acceptability, fidelity, feasibility, and costs assessed using a mixed-methods approach. All participants with complete data on the primary outcome, without imputation of missing outcomes were included in the analysis (intention-to-treat principle). This trial is registered with ISRCTN, ISRCTN15986016, and is completed. FINDINGS: Between Jan 15, 2021, and April 18, 2023, 1488 people (601 male and 887 female) were randomly assigned (734 to intervention and 754 to control), with 1229 (83%) of 1488 available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months (SD 2·5), the mean CAIDE score improved 0·16 points in the intervention group versus 0·01 in the control group (mean difference -0·16, 95% CI -0·29 to -0·03). 1533 (10%) invited individuals responded; of the intervention participants, 593 (81%) of 734 adopted the intervention and 367 (50%) of 734 continued active participation throughout the study. Perceived appropriateness (85%), acceptability (81%), and fidelity (79%) were good, with fair overall feasibility (53% of intervention participants and 58% of coaches), at low cost. No differences in adverse events between study arms were found. INTERPRETATION: A coach-supported mHealth intervention is modestly effective in reducing dementia risk factors in those with low socioeconomic status in the UK and any socioeconomic status in China. Implementation is challenging in these populations, but those reached actively participated. Whether this intervention will result in less cognitive decline and dementia requires a larger RCT with long follow-up. FUNDING: EU Horizon 2020 Research and Innovation Programme and the National Key R&D Programmes of China. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Evaluation of Different Fixation Methods Combinations After L-Shaped Osteotomy Reduction Malarplasty: An In Vitro Biomechanical Study.

BACKGROUND: This in vitro study compared the stability of different fixation method combinations for the zygomatic complex after simulated L-shaped osteotomy reduction malarplasty, a common facial contouring surgery in East Asia with high postoperative complications due to poor fixation methods. MATERIALS AND METHODS: The study used 108 zygoma replicas with various fixation methods combinations in the zygomatic body (L-shaped plate with short wing on zygoma and on the maxilla, two bicortical screws, one bicortical screw with L-shaped plate, square plate, and rectangular plate) and zygomatic arch (Mortise-Tenon structure, 3-hole plate, and Mortise-Tenon structure plus short screw). The failure force under incremental load was applied through the Instron tensile machine to a well-stabilized model using a rubber band simulating the masseter muscle and recorded the increasing force digitally. ANOVA test was used for comparison between recorded values (P < 0.05). RESULTS: The results showed that the most stable combination was a six-hole rectangular plate and a Mortise-Tenon structure plus one short screw (358.55 ± 51.64 N/mm2). The results also indicated that the placement vector of the fixation methods around the L-shaped osteotomy and the use of the two-bridge fixation method were important factors in enhancing the stability of the zygomatic complex. CONCLUSION: The study suggested that surgeons should choose appropriate fixation methods based on these factors to reduce postoperative complications and improve surgical outcomes. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Morphological Changes of the Mandibular Angle After Orthognathic Surgery with Class III Deformity in East Asia.

The aims of this study were to analyze the morphological changes of the mandibular angle after orthognathic surgery for mandibular setback and investigate related factors. This retrospective study included patients from January 2017 to December 2021 diagnosed with skeletal class III deformity who underwent BSSRO (Group I) or bimaxillary surgery (Group II). Preoperative (T0), within 1 month postoperatively (T1), and 6 months postoperatively (T2) CT scans were collected from 61 patients to three-dimensionally analyze the proximal segment displacement, the linear and angular changes of the mandibular angle. The gonion points moved posteriorly and laterally (P < 0.001), while the inferior movement was not significant (P = 1.000, P = 0.274). The intergonial width increased by 3.32 ± 1.87 mm and 2.34 ± 1.77 mm as revealed by T2 CTs, respectively, in Group I and Group II. Mandibular angle decreased in both groups and by 1.41 ± 2.95° in Group I and 1.37 ± 3.41° in Group II. The increase in intergonial width between T1 and T0 was negatively correlated with the preoperative mandibular angle (P = 0.003) and positively correlated with the transverse outward movement of the proximal segment (P < 0.001). After surgery, the intergonial width increased and the inferior and posterior border of the proximal segment flared outward. The changes in intergonial width and mandibular angle were mainly related to the rotation of the proximal segment, which has a certain impact on the aesthetics of the lower face. Therefore, controlling the position of the proximal segment is of vital importance to lessen the changes in the mandibular angle area.Level of Evidence III. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Stability of different fixation methods after reduction malarplasty under average and maximum masticatory forces: a finite element analysis.

BACKGROUND: Although titanium plates/screws are effective fixation methods (FM) after L-shaped osteotomy reduction malarplasty (LORM), the ideal FM remains controversial. This first finite element analysis (FEA) aimed to study the effect of various zygomatic body/zygomatic arch FM combinations and their placement vectors on the zygoma complex stability after virtual LORM under the effect of both average (150 N/mm2) and maximum (750 N/mm2) forces and three-dimensional (3D) mapping of stress and strain parameters distribution over the zygomatic bone, fixation methods, and total model. RESULTS: The fixation methods about the short-arm of the L-shaped osteotomy showed lower stress, strain, and displacement values than those across the long-arm osteotomy site. Combined with any zygomatic arch fixation methods (ZAFm), the two bicortical screws group (2LS) on the zygomatic body osteotomy site resulted in smaller displacements and the lowest zygoma bone stress and displacement when combined with Mortice-Tenon structure (MT) as zygomatic arch fixation method. Applied forces caused statistically significant differences in zygomatic bone stress (P < 0.001 and P = 0.001) and displacement (P = 0.001 and P = 0.002). CONCLUSION: All FMs both on the zygomatic body and zygomatic arch provide adequate zygomatic complex stability after LORM. The 2LS group showed better resistance than rectangular plate (RP) and square plate (SP) with lower stress concentrations. The L-shaped plate with short-wing on the maxilla (LPwM) is more stable than having the short-wing on the zygoma bone (LPwZ). Future prospective clinical studies are required to validate the current findings.

Qingyihuaji Formula promotes apoptosis and autophagy through inhibition of MAPK/ERK and PI3K/Akt/mTOR signaling pathway on pancreatic cancer in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingyihuaji Formula (QYHJ), a widely used traditional Chinese medicine (TCM), has been used to treat patients with cancer in China. However, the effect and mechanism of QYHJ on pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIM OF THE STUDY: This study aimed to explore the roles and evaluate the possible underlying molecular mechanisms of QYHJ and its core component in PDAC using label-free quantitative proteomics in conjunction with network pharmacology-based analysis. MATERIALS AND METHODS: By screening differentially expressed proteins (DEPs) in proteomics and QYHJ-predicted gene sets, we identified QYHJ-related PDAC targets annotated with bioinformatic analysis. A subcutaneous tumor model was established to assess the role of QYHJ in vivo. The effects of quercetin (Que), a core component of QYHJ, on cell proliferation, migration, invasion, apoptosis, and autophagy in SW1990 and PANC-1 cells were investigated in vitro. Immunohistochemistry, western blotting, mRFP-GFP-LC3 adenovirus, and kinase analysis were used to determine the underlying mechanisms. RESULTS: Bioinformatics analysis revealed that 41 QYHJ-related PDAC targets were closely related to the cellular response to nitrogen compounds, positive regulation of cell death, regulation of epithelial cell apoptotic processes, and chemokine signaling pathways. CASP3, SRC, STAT1, PTPN11, PKM, and PAK1 with high expression were identified as hub DEPs in the PPI network, and these DEPs were associated with poor overall survival and STAT 1, MAPK/ERK, and PI3K/Akt/mTOR signaling pathways in PDAC patients. QYHJ significantly promoted tumor death in nude mice. Moreover, quercetin inhibited the proliferation, migration, and invasion of PDAC cells. Additionally, Que induced apoptosis and autophagy in PDAC cells. Mechanistically, QYHJ and Que significantly activated STAT 1 and remarkably inhibited the MAPK/ERK and PI3K/Akt/mTOR signaling pathways in vivo and in vitro, respectively. Importantly, ERK1/2 inactivation contributes to que-induced apoptosis in SW1990 and PANC-1 cells. CONCLUSIONS: These results suggest that QYHJ and Que are promising anti-PDAC avenues that benefit from their multiform mechanisms.

Research on the Structure Design and Mechanical Properties of Performance Optimized Multi-Axial Geogrid.

In order to solve the problem of low transverse tensile strength of triaxial geogrid, a kind of performance-optimized multi-axial geogrid (POMG) that can bear larger transverse loads was designed. Firstly, the forming equipment and process of POMG are designed. Secondly, through the test of formability and mechanical properties, the POMG with good formability and mechanical properties is obtained, and the average tensile strength of POMG with circular and semicircular holes is the highest, reaching more than 16 KN/m. Finally, the feasibility of the process is further verified by numerical simulation, and the shape distribution and stress-strain law of POMG during the forming process are obtained, which provides further guidance for the actual production.

Research on the Mechanical Properties and Stretch Forming Simulation of Triaxial Geogrid with Different Pre-Punched Hole Diameters.

In this paper, the tensile behavior of industrial polypropylene triaxial geogrid with different pre-punched hole diameters was studied by experiment and numerical analysis. The industrial polypropylene sheets with different diameters of circular holes were stretched at elevated temperature and then the tensile properties of triaxial geogrids at room temperature were evaluated. It was found that the pre-punched hole diameter of triaxial geogrid had a very close relationship with the mechanical properties. With the increase of the pre-punched hole diameter, the tensile strength of triaxial geogrid shows a trend of first increasing and then decreasing. Combined with numerical simulation, the optimal pre-punched hole diameter can be accurately obtained, and the distribution law of the width, thickness, stress, and strain of triaxial geogrid can be obtained. Under the condition of a stretching ratio of 3 and node spacing of 3 mm, it was found that the mechanical properties of industrial polypropylene triaxial geogrid was the best when the pre-punched hole diameter was 2.6 mm.

Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer.

Pancreatic cancer is a highly aggressive cancer with an exceedingly low rate of response to treatments, which calls for comprehensive molecular characterization of pancreatic cancer cell lines (PCCLs). We screened multi-layer molecular data of 36 PCCLs, including gene mutation, gene expression, microRNA (miRNA) expression, and protein profiles. Our comparative analysis of genomic mutations found that PCCLs recapitulated genomic alterations of the primary tumor and suggested potential therapeutic strategies for clinical interventions. The panel of 36 PCCLs was classified into 2 subgroups based on transcriptomic mRNA expression, wherein the C1 subgroup was characterized with differentiation, whereas C2 cell lines were featured with immunity, angiogenesis, epidermis, and proliferation. Transcriptomic classification was further recapitulated by miRNA and protein expression. Additionally, the differential proteins between C1 and C2 subgroups were prominently involved in epidermal growth factor receptor (EGFR) signaling, phosphatidylinositol 3-kinase (PI3K) signaling, and mitogen-activated protein kinase (MAPK) signaling pathways. Tumor samples from different subgroups exhibited distinct infiltration of CD4 naive cells and monocytes. Remarkably, patients in subgroups C1 showed longer survival, whereas those in C2 had worse clinical outcome. Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer.

Study on the Influence of Different Factors on Spontaneous Oil Recovery of Nanosurfactants in a Tight Reservoir.

The surface of a tight reservoir appears to be oil-wet or mixed-type wet upon soaking in crude oil for a long time, and the yield decreases rapidly after fracturing under the influence of capillary force. The oil sweep efficiency affected by many factors such as formation water dilution, salinity, crude oil type, temperature, and pressure can be enhanced by adding nanosurfactants into the fracturing fluid, so it is necessary to study the influence of different factors on the spontaneous imbibition replacement efficiency of nanosurfactants. In this study, the basic properties of nanosurfactants such as particle size, oil-water interfacial tension (IFT), and the wetting modification effect were tested, and the influence of surfactant type, concentration, temperature, and pressure on imbibition replacement efficiency was studied. The main conclusions are as follows: (1) The particle size of the nanosurfactant that was synthesized by a microemulsion method is 12-21 nm, which indicated good injectability in tight cores. Moreover, the IFT values between the crude oil and five kinds of 0.30 wt % nanosurfactants were all lower than 0.15 mN/m, and nanosurfactant C had the best wetting modification effect with increasing the contact angle by 100.30°. (2) The type and concentration of surfactant have a certain influence on imbibition replacement efficiency, and appropriate concentration of anionic nanosurfactant is beneficial to enhancing the imbibition replacement efficiency. The imbibition replacement efficiency of 0.30 wt % anionic surfactant C solution is higher than that of nonionic and cationic surfactant solutions, and the imbibition replacement efficiency is as high as 33.386% under NTP. (3) The nanosurfactant in brine is prone to forming fine emulsified oil droplets with crude oil and activates the oil droplets in the small pores to enhance the imbibition replacement efficiency. The crude oil type, temperature, and pressure can influence imbibition replacement efficiency, and the influence of crude oil type and temperature is greater than that of pressure. This work further studies the influencing factors of imbibition replacement efficiency.

Design and Development of a Mobile Health (mHealth) Platform for Dementia Prevention in the Prevention of Dementia by Mobile Phone Applications (PRODEMOS) Project.

Background: Mobile health (mHealth) has the potential to bring preventive healthcare within reach of populations with limited access to preventive services, by delivering personalized support at low cost. Although numerous mHealth interventions are available, very few have been developed following an evidence-based rationale or have been tested for efficacy. This article describes the systematic development of a coach-supported mHealth application to improve healthy lifestyles for the prevention of dementia and cardiovascular disease in the United Kingdom (UK) and China. Methods: Development of the Prevention of Dementia by Mobile Phone applications (PRODEMOS) platform built upon the experiences with the Healthy Aging Through Internet Counseling in the Elderly (HATICE) eHealth platform. In the conceptualization phase, experiences from the HATICE trial and needs and wishes of the PRODEMOS target population were assessed through semi-structured interviews and focus group sessions. Initial technical development of the platform was based on these findings and took place in consecutive sprint sessions. Finally, during the evaluation and adaptation phase, functionality and usability of the platform were evaluated during pilot studies in UK and China. Results: The PRODEMOS mHealth platform facilitates self-management of a healthy lifestyle by goal setting, progress monitoring, and educational materials on healthy lifestyles. Participants receive remote coaching through a chat functionality. Based on lessons learned from the HATICE study and end-users, we made the intervention easy-to-use and included features to personalize the intervention. Following the pilot studies, in which in total 77 people used the mobile application for 6 weeks, the application was made more intuitive, and we improved its functionalities. Conclusion: Early involvement of end-users in the development process and during evaluation phases improved acceptability of the mHealth intervention. The actual use and usability of the PRODEMOS intervention will be assessed during the ongoing PRODEMOS randomized controlled trial, taking a dual focus on effectiveness and implementation outcomes.

BaBao Dan Suppresses Tumor Growth of Pancreatic Cancer Through Modulating Transcriptional Reprogramming of Cancer-Related Genes.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of refractory malignancies without efficient therapeutics. Babao Dan (BBD) was partially effective to suppress tumor growth of PDAC in clinical practice. However, the molecular mechanisms were unclear. METHODS: We established PDAC mice models and treated them with BBD through intragastric administration. Treatment and control groups were then subjected to high-throughput RNA sequencing. We presented the transcriptional changes upon BBD treatment by using computational analysis comparing BBD treatment and control groups. Functional enrichment analysis was employed to investigate the biological processes or pathways that BBD modulates. RESULTS: BBD treatment showed strong suppression on tumor growth of PDAC, even stronger than Gemcitabine. Through differential analysis comparing BBD treatment and control groups, we identified 638 up-regulated and 259 down-regulated genes in the BBD treatment group. BBD was found to activate tumor suppressor genes, such as MTUS1, PDGFB, SOD3, and UCHL1. Furthermore, we revealed that BBD treatment inhibited cancer-related pathways and elevated activities of metabolism-related processes. The BBD-modulated metabolic genes were further showed to be associated with patient survival in an independent cohort with pancreatic cancer. CONCLUSION: BBD repressed the tumor growth of PDAC. BBD treatment modulated expression of cancer-related genes in PDAC. BBD suppressed cancer-related pathways and activated metabolic processes in PDAC. Our study suggests BBD treatment as potential effective therapeutics for patients with pancreatic cancer.

HIFU is safe, effective, and feasible in pancreatic cancer patients: a monocentric retrospective study among 523 patients.

PURPOSE: This study aimed to evaluate the clinical value of high-intensity focused ultrasound (HIFU) combined with gemcitabine (GEM) in treating unresectable pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: A total of 523 unresectable PDAC patients were recruited from December 30, 2007 to January 30, 2015 at Fudan University Shanghai Cancer Center. Among them, 347 received HIFU combined with GEM (with regional intra-arterial chemotherapy [RIAC] or with systemic chemotherapy) and the remaining patients received GEM only. Postoperative complications were observed, and overall survival was recorded. RESULTS: The median overall survival of patients who received HIFU combined with GEM vs GEM alone was 7.4 vs 6.0 months (P=0.002); the 6-month, 10-month, 1-year, and 2-year survival rates for patients in these two groups were 66.3% vs 47.5% (P<0.0001), 31.12% vs 15.9% (P<0.0001), 21.32% vs 13.64% (P=0.033), and 2.89% vs 2.27% (P=0.78), respectively. In the combined therapy group, the most obvious survival benefits were obtained among patients who received HIFU plus RIAC and systemic chemotherapy (used in the intervals between RIAC treatments). There were no severe complications in patients undergoing HIFU treatment. CONCLUSION: We demonstrated the survival benefit of HIFU among PDAC patients treated with GEM. The benefit was most obvious in PDAC patients treated with HIFU plus RIAC and systemic chemotherapy.

Depth-driven variable-frequency sinusoidal fringe pattern for accuracy improvement in fringe projection profilometry.

Sinusoidal fringe pattern is widely used in optical profilometry; however, the traditional constant-frequency sinusoidal fringe pattern reduces 3D measurement accuracy in the defocus region. To this end, this paper presents a variable-frequency sinusoidal fringe pattern method that is optimized by the measurement depth. The proposed method improves the pixel matching accuracy and thus increases measurement accuracy. This paper theoretically determines the optimal frequency by analyzing the pixel matching error caused by intense noise in a captured image; presents the online frequency optimization along abscissa and ordinate axes in the sinusoidal fringe patterns; and details the encoding and decoding to use variable-frequency fringe patterns for 3D profilometry. Simulations and experiments demonstrate that our proposed method can improve the 3D measurement accuracy and increase measurement robustness.

Effects of baicalein on pancreatic cancer stem cells via modulation of sonic Hedgehog pathway.

Recent studies have suggested that sonic Hedgehog (Shh) signaling pathway is aberrantly activated in cancer stem cells (CSCs). A seven-herb Chinese medicinal formula composed of Amorphophallus rivieri Durieu, Oldenlandia diffusa (Wild) Roxb, Scutellaria barbata D. Don, Gynostemma pentaphyllum (Thunb.) Mak and Amomum cardamomum L, i.e. Qingyihuaji (QYHJ) formula, has been shown to inhibit proliferation of pancreatic CSCs by inhibiting Shh signaling pathway and thereby prolong the overall survival of pancreatic cancer patients. Mass spectrometry analysis revealed that baicalein is one of the major compounds of QYHJ formula. The objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms of baicalein involved in pancreatic cancer treatment. We examined the effects of baicalein on pancreatic CSCs both in vivo and in vitro. The results indicated that baicalein attenuated the pluripotency of pancreatic CSCs. Then, we investigated the underlying mechanism and found that nuclear transcription factors, such as Sox-2 and Oct-4 as well as members in Shh signaling pathway, e.g. SHH, SMO, and Gli-2, were downregulated after baicalein treatment. Furthermore, silencing Gli-2 expression by small interfering RNA decreased Sox-2 expression and blocked the inhibitory effects of baicalein, suggesting that the effects of baicalein may be mediated through inhibition of Shh pathway. Our results suggested that baicalein, an active compound in QYHJ formula, could suppress the self-renewal of pancreatic CSCs through inhibition of Shh signaling pathway.

Babaodan Capsule () combined with Qingyi Huaji Formula () in advanced pancreatic cancer-a feasibility study.

OBJECTIVE: To observe the clinical effects of Babaodan Capsule (, BBD) combined with Qingyi Huaji Formula (, QYHJ) in treating patients with advanced pancreatic cancer. METHODS: Eighty-one patients with advanced pancreatic cancer (from January 1, 2013 to December 31, 2014) were enrolled. Patients were assigned to two groups: QYHJ plus BBD group (40 cases) and QYHJ only group (41 cases), and there were no significant differences for other treatment between two groups. The survival and cancer-related symptoms were compared between two groups over two cycles of treatment. RESULTS: The cancer-related symptoms of patients such as ascites, jaundice, pain, abdominal distension, anorexia and Karnofsky performance status of QYHJ plus BBD group were significantly improved as compared with those of the QYHJ group (P<0.01). In addition, the 1-year survival rate of patients in QYHJ plus BBD group was longer than that in the QYHJ group (65% vs. 33%, respectively, P=0.0023). CONCLUSIONS: BBD with QYHJ is feasible treatment to prolong the survival of patients with advanced pancreatic cancer. However, it deserves to be further investigated in randomized clinical trials.

Nanog Predicts Poor Prognosis in Human Pancreatic Cancer and Is Downregulated by QingyihuaJi Formula in Pancreatic Cancer Stem Cells.

Qingyihuaji formula (QYHJ), confirmed efficacious in a series of clinical trials, has been applied to human pancreatic carcinoma treatment in Shanghai Cancer Center for years. Recent evidence highlighted that pluripotent stem cells transcription factor Nanog plays a pivotal role in carcinogenesis. However, there is little published information regarding the underlying clinical significance and mechanisms of transcription factor Nanog in pancreatic cancer. In this study, our results indicated that Nanog is overexpressed in human pancreatic cancer stem cells and downregulated by QYHJ, which may contribute to explain the clinical effectiveness of QYHJ and provide advanced pancreatic cancer patients with a new therapeutic option, supporting our hypothesis that the degradation pathway is another mechanism by which QYHJ affects Nanog expression.

Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway.

Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.

A retrospective analysis of survival factors of high intensity focused ultrasound (HIFU) treatment for unresectable pancreatic cancer.

OBJECTIVE: To retrospectively evaluate possible impact factors of HIFU treatment outcome for unresectable pancreatic cancer patients. PATIENTS AND METHODS: A total of 689 patients with unresectable pancreatic cancer were recruited in our center from December 30, 2007 to January 30, 2015. 436 patients with unresectable pancreatic cancers received HIFU treatment; the other 253 patients received non-HIFU treatment. Among these 436 patients, 345 patients received a one-time HIFU treatment, 91 patients received HIFU treatment from 2 to 5 times in the same pancreatic mass; 89 patients received HIFU treatment alone; 347 patients received HIFU-based combined therapies. Complications and overall survivals (OS) data in each group were collected. RESULTS: The median overall survivals (mOS) in HIFU group and non-HIFU group were 7.1 vs. 5 months (P=0.005): 9.3 vs. 7.3 months (P=0.202) for patients with stage II disease, 8.3 vs. 7.3 months (P=0.783) for patients with stage III disease, and 6.4 vs. 4.2 months (P<0.0001) for patients with stage IV disease, respectively. Furthermore, there was a significant difference between repeated HIFU and one-time HIFU (mOS: 8.6 vs. 6.8 months, P=0.011). Time of HIFU treatment (P=0.0027), chemotherapy (P<0.0001), radiotherapy (P=0.0006), regional intra-arterial chemotherapy (RIAC) (P<0.0001), and stage (P<0.0001) were independent prognostic factors for the patients who received HIFU treatment. Cox analysis on the relative risk of prognostic factors showed that repeated HIFU vs. one-time HIFU (HR=0.729: 95% CI=0.576-0.924), chemotherapy vs. non-chemotherapy (HR=0.664: 95% CI=0.576-0.766), radiotherapy vs. non-radiotherapy (HR=0.580: 95% CI=0.427-0.789), RIAC vs. non-RIAC (HR=0.737: 95% CI=0.648-0.837), and stage (HR=1.386, 95% CI=1.187-1.619) were associated with significantly inferior survival. Overall, adverse events occurred in 23.2% (101/436) in the HIFU group, which included increase of serum or urinary amylase levels, incomplete intestinal obstruction, mild fever, etc. There were no severe adverse events such as skin burns or GI perforation related to HIFU therapy in any of the patients treated. CONCLUSION: This retrospective analysis revealed that the use of a multimodal treatment approach (the combined therapy of HIFU, RIAC, and chemotherapy, with or without radiotherapy) could improve survival of patients with unresectable pancreatic cancer, and repeated HIFU presented a survival benefit and did not increase risk.