Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

BACKGROUND: Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. AIM: To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. METHODS: Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. RESULTS: The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. CONCLUSION: Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

LIPUS Promotes Endothelial Differentiation and Angiogenesis of Periodontal Ligament Stem Cells by Activating Piezo1.

Background and Objectives: Low-intensity pulsed ultrasound (LIPUS) promotes differentiation and regulates biological functions of various stem cells, but its effect on the endothelial differentiation of periodontal ligament stem cells (PDLSCs) is unclear. This study investigated the effect of LIPUS on endothelial differentiation and angiogenesis in PDLSCs and the role of the mechanically sensitive ion channel Piezo1 in this process. Methods and Results: PDLSCs obtained from healthy people were used for endothelial induction, and 10 µg/ml lipopolysaccharide (LPS) was used to simulate the inflammatory state. The induced cells were treated with LIPUS (50 mW/cm2, 1.5 MHz) to study its effect on the endothelial differentiation of PDLSCs and the tube formation of differentiated cells. PCR, flow cytometry, immunofluorescence, and Matrigel tube formation assays were used to detect the differentiation and tube formation of PDLSCs. GsMTx4 was used to inhibit the expression of Piezo1, and the role of the Piezo1 pathway in the endothelial differentiation and microvascular formation of PDLSCs after LIPUS treatment was studied. The data showed that LIPUS increased endothelial differentiation and angiogenesis in PDLSCs under inflammatory or noninflammatory conditions. The use of an inhibitor weakened the effect of LIPUS. Conclusions: This study demonstrated that LIPUS can activate the expression of Piezo1 and promote the endothelial differentiation and microvascular formation of PDLSCs.

Destrin Contributes to Lung Adenocarcinoma Progression by Activating Wnt/ß-Catenin Signaling Pathway.

Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of ß-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating ß-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma. IMPLICATIONS: This finding indicates that DSTN facilitates ß-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.

The Effects of a Toothpaste Containing the Active Ingredients of Galla chinensis and Sodium Fluoride on Dentin Hypersensitivity and Sealing of Dentinal Tubules: An In Vitro Study and an Eight-Week Clinical Study in 98 Patients.

BACKGROUND This study aimed to evaluate the desensitizing effect of toothpaste containing the active ingredients of an extract of Galla chinensis, both in vitro and in patients with dentin hypersensitivity. MATERIAL AND METHODS Ninety-eight patients with dentin hypersensitivity were divided into two study groups and given toothpaste containing either the active ingredients of Galla chinensis extract and sodium fluoride, or a control toothpaste containing only sodium fluoride. Assessments included the tactile stimulation test and the Schiff cold air sensitivity scale, which were conducted at the baseline examination and after 4 and 8 weeks of dental brushing. Twenty-five intact human premolars from 24 patients with dentin hypersensitivity were prepared and randomly divided into four groups, the untreated baseline group, the study group, the positive control group, and the control group. After brushing with different toothpaste for 7 days, the effects on dentinal tubule sealing in each group was determined by scanning electron microscopy (SEM), and the degree of dentinal tubule plugging and diameter of the open dentinal tubules were calculated. RESULTS Toothpaste containing the active ingredients of Galla chinensis and sodium fluoride significantly reduced the degree of dentin hypersensitivity when compared with toothpaste containing sodium fluoride alone after 4 weeks and 8 weeks of use. Toothpaste containing the active ingredients of Galla chinensis significantly reduced the number and diameter of the open dentinal tubules. CONCLUSIONS Toothpaste that contained the active ingredients of Galla chinensis and sodium fluoride reduced the symptoms of dentin hypersensitivity by sealing the dentinal tubules.

[Investigation of oral health knowledge, attitude, behavior of 12-15 years old children in Chongqing].

OBJECTIVE: To investigate the status of oral health knowledge, attitude, behavior of 12-15 years old children and provide a theoretical basis of prevention. METHODS: Multi-stage stratified sampling method was used to extract four middle school students from Chongqing districts and counties (2 in the main urban area and 2 suburbs), and their oral health knowledge, attitudes and behaviors were investigated through questionnaires. All data were entered using Epidata and statistical analysis was performed using SPSS 21.0 software. RESULTS: A total of 3 902 valid questionnaires were collected. The proportion of people who had good brushing habits was 39.7% (1 548), the average oral health knowledge accuracy rate was 58.9%, and the average oral health positive attitude was 88.6%. The number of middle school students who attended the dental experience was 54.5% (2 127), and that of the school who received oral health education was 17.5% (681). There were gender and regional differences in brushing habits. CONCLUSIONS: The knowledge and behavior of oral health among 12-15-year-old middle school students in Chongqing need to be improved. Oral health education for middle school students should be strengthened, especially in rural and suburban areas.

[Effect of the local application of stem cells on repairing facial nerve defects: a systematic review].

OBJECTIVE: To systematically evaluate the repairing effect of stem cells on facial nerve defects. METHODS: Articles regarding the regenerating effect of stem cells on facial nerves in animals were collected from the databases of Pubmed, Cochrane Library, Web of Science, Embase, Scopus, and CBM. Two professionals independently completed the article screening, data extraction, and bias risk assessment. RevMan 5.3 and random-effects models were used for the statistical analysis, and the results were presented in the form of mean differences (MD) with a 95%CI. The results of functional evaluation (vibrissae movement, facial paralysis) and histological evaluation (density of myelinated fibers, diameter of fibers, thickness of myelin sheath, G ratio) of facial nerve were Meta-analyzed. RESULTS: A total of 4 614 articles were retrieved from the 6 databases, and 15 of these articles were included in the Meta-analysis. For vibrissae movement and facial paralysis, the stem cell group scored significantly higher than the non-stem cell group (P<0.05). The density of myelinated fibers and thickness of the myelin sheath in the stem cell group were higher than those in the non-stem cell group (P<0.05). The G ratio in the stem cell group was smaller than that in the non-stem cell group (P=0.001). There was no significant difference in fiber diameter (P=0.08). CONCLUSIONS: Stem cells have potential in promoting facial nerve regeneration.

Association of molar incisor hypomineralization with premature birth or low birth weight: systematic review and meta-analysis.

Objective: Molar incisor hypomineralization (MIH) is a kind of enamel hypomineralization. MIH has a serious negative impact on patient's oral health. Whether neonates with premature birth or low birth weight are susceptible to MIH has not been rigorously evaluated. The purpose of this systematic review and meta-analysis was to determine whether premature birth and low birth weight increased the possibility of developing MIH in neonates.Method: We searched relevant studies published from 2001 to June 2018 on PubMed and Embase. The methodological quality of the studies included in the meta-analysis was assessed using the Agency for Health Care Research and Quality (AHRQ) inventory tool.Results: Premature birth promoted the prevalence of MIH (OR = 1.57, 95%CI: 1.07-2.31). Low-birth-weight neonates were approximately three times likely to suffer from MIH (OR = 3.25, 95%CI: 2.28-4.62).Conclusions: Our finding suggests that premature birth and low birth weight increase the prevalence of MIH.

[An investigation on the need, the utilization, and the influencing factors of dental services for pre-school children in selected areas in Chongqing province].

OBJECTIVE: The aim of this study is to survey the need, the utilization, and the influencing factors of dental services for children in selected areas in Chongqing province by investigating their oral health status. The survey will provide references for preventive oral health care in targeted Chongqing areas, which may improve the level of oral health among pre-school children. METHODS: Random cluster sampling was utilized according to standards of the Fourth National Oral Health Epidemiological sampling survey, and 1 300 children between the ages of three and four years old from 24 kindergartens in 12 subdistricts of three areas in Chongqing were interviewed for free dental checkups and to participate in the survey. The questionnaires were designed according to the Anderson model and were answered by the children's parents. The results were analyzed utilizing Chi-square test logistic regression. RESULTS: The prevalence rate of caries among the pre-school children in selected areas of Chongqing was 55.4%, the decay, missing, filled surface (dmfs) was 6 696, the mean dmfs was 5.2, and the caries filling constituent ratio was 2.3%. A total of 1 173 questionnaires were analyzed. The ratio for seeing a dentist for therapeutic reasons was 6.31% (74/1 173) and for prevalence was 22.93% (269/1 173). CONCLUSIONS: The oral health service needs of pre-school children in selected areas of Chongqing are large and the oral health service utilization rate is low. Oral health care processes are arduous; thus, targeted oral prevention policies should be created.

[Prevalence and influencing factors of deciduous caries in preschool children in Chongqing city].

OBJECTIVE: This study aimed to determine the prevalence and related factors of deciduous caries in 3-5-year-old preschool children in Chongqing city. Results will be used to provide a basis for the establishment and adjustment of prevention and intervention of caries in preschool children. METHODS: We referred to the Fourth National Oral Health Epidemiological Survey. Data included caries prevalence in preschool children, and the questionnaires were distributed to children' parents in Chongqing city. Results were inputted by Epidata 3.1 and statistically analyzed using SPSS 21.0. RESULTS: A total of 1 350 preschool children were included in the study. We found that maxillary deciduous central incisor and mandibular deciduous molars were susceptible to decay. The prevalence of primary teeth caries in preschool children in Chongqing city was 51.4% (694/1 350). The mean decayed-missing-filled-teeth (dmft) index was 2.34. The caries prevalence and mean dmft between age groups were statistically significant (P<0.01) and increased with age (P<0.05). However, except the 5-year-old group (P<0.05), no significant difference in caries prevalence rate and mean dmft was found between male and female children (P>0.05). Approximately 61.7% of caries cases were concentrated in a small number (36.1%) of individuals. Multivariate Logistic regression analysis showed that age, highest educational level of parents, intake frequency of sweetened beverages and carbonated drinks, toothache or similar discomfort experience over the past year, dentist visits, and parents' assessment of teeth and oral health status of children were the factors influencing the prevalence of deciduous caries (P<0.05). CONCLUSIONS: More than half of the preschool children had dental caries. Majority of caries were concentrated in a small number of individuals. The age of children, highest educational level of parents, intake frequency of sweetened beverages and carbonated drinks, toothache or discomfort experience over the past year, dentist visits, and parents' assessment of teeth and oral health status of children were associated with the prevalence of deciduous caries.

Association between vitamin D receptor BsmI gene polymorphism and periodontitis: a meta-analysis in a single ethnic group.

Although many researchers have studied on the association between vitamin D receptor (VDR) BsmI polymorphism and periodontitis, this association remains elusive. To further assess the effects of VDR BsmI polymorphism on the risk of periodontitis, a meta-analysis was performed in a single ethnic group. We searched PubMed and Chinese databases for relevant studies till April 2017. The strength of the associations were assessed used pooled odds ratios (ORs) and 95% confidence intervals (CIs). Six studies including 757 periodontitis cases and 670 controls were identified at last. In the total analyses, VDR BsmI polymorphism was not associated with the risk of periodontitis in all models. The subgroup analyses suggested a significantly reduced risk of periodontitis in South China. In conclusion, our meta-analysis showed that VDR BsmI polymorphism was associated with the decreased risk of periodontitis in Chinese individuals from South China, and further studies in other ethic groups are required for definite conclusions.

Arginine-containing desensitizing toothpaste for the treatment of dentin hypersensitivity: a meta-analysis.

OBJECTIVE: To estimate the effect of arginine-containing desensitizing toothpaste on dentin hypersensitivity (DH). METHODS: Databases including China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, China Biology Medicine disc, Wangfang Data, PubMed, Web of Science, and Cochrane Trials Register were searched, and Google was used as a supplementary tool to search for information through February 2014. Randomized controlled trials (RCTs) of the treatment of DH with arginine-containing toothpaste were included. Relevant information was extracted, and a quality evaluation was performed. Meta-analyses were performed using RevMan 5.2 software. RESULTS: Eighteen RCTs with 1,423 patients were included. The results of the meta-analyses demonstrated that at days 0 and 3; weeks 2, 4, and 8; and more than 12 weeks, arginine-containing toothpaste led to significantly improved results on the tactile sensitivity test (standardized mean difference [SMD] =1.95, 95% confidence interval [CI] [1.14, 2.76]) and the air-blast test (SMD =-1.60, 95% CI [-2.14, -1.05]) at 4 weeks and the tactile sensitivity test (SMD =2.01, 95% CI [1.41, 2.61]) and the air-blast test (SMD =-1.41, 95% CI [-1.83, -0.98]) at 8 weeks compared to toothpastes containing other desensitizing components, thus indicating a superior therapeutic effect of arginine-containing desensitizing toothpaste. However, no significant differences between arginine-containing toothpaste and toothpastes containing other desensitizing components were observed in the air-blast test at days 0 and 3 and week 2 and in the tactile sensitivity and air-blast tests at more than 12 weeks. CONCLUSION: The current evidence indicates that arginine-containing toothpaste is effective for DH. However, further high-quality, large-sample RCTs are needed.

[Detection of micrometastases and its clinical significance in sentinel and non-sentinel lymph nodes from early cervical carcinoma].

OBJECTIVE: To investigate the clinical significance of micrometastasis detection in sentinel lymph nodes (SLN) from patients with early cervical carcinoma. METHODS: Thirty patients with early cervical carcinoma were studied to identify SLN intraoperatively using methylene blue. One lymph node was removed randomly from palpable SLN and other pelvic lymph nodes (nSLN) in each patient, so 268 lymph nodes were collected and cut into two halves, one half of the lymph node was used to analyze the expression of cytokeratin 19 (CK19) mRNA by real-time fluorescence quantitative polymerase chain reaction to determine the presence of micrometastasis, the other half was examined by routine histology with HE staining. RESULTS: 67 SLNs were detected in 28 cases (93.3%). Pelvic lymph nodes of 6 cases were confirmed pathological metastasis. The sensitivity of SLN detection was 66.7%, the accuracy rate was 96.4%, and the false negative rate was 16.7%. Among 268 lymph nodes (including 9 lymph nodes with pathological metastasis) detected by real-time fluorescence quantitative polymerase chain reaction, 68 lymph nodes were pathological negative but had micrometastasis, accounting for 26.3% (68/259) in pathologically negative lymph nodes. Among 24 patients with pathological negative lymph nodes, 16 cases had micrometastasis, accounting for 66.7% in those patients. Among 16 patients with micrometastasis, SLN of 3 cases were negative, but nSLN were micrometastasis, so the SLN false-negative rate rose to 18.2%. There were no significant relationships between pelvic lymph nodes micrometastasis and perivascular space involvement, deep stromal invasion and tumor grade (all P > 0.05). The micrometastasis rate of nSLN in patients with SLN micrometastasis was 100%, significantly higher than that in the patients with SLN non-micrometastasis (27.3%, P < 0.01). CONCLUSIONS: Real-time fluorescence quantitative polymerase chain reaction is a sensitive method to detect SLN micrometastasis. SLN micrometastasis may be an effective complement to SLN pathology to predict nSLN metastasis. Pelvic lymph nodes micrometastases have no significant relationship with pathological risk factors in cervical cancer and prognosis of patients.

[Feasibility of unilateral or bilateral nerve-sparing radical hysterectomy in patients with cervical cancer and evaluation of the post-surgery recovery of the bladder and rectal function].

OBJECTIVE: To investigate the feasibility of unilateral or bilateral nerve-sparing radical hysterectomy and evaluate the recovery of bladder and bowel function postoperatively. METHODS: From August 2008 to October 2009, sixty-one patients with cervical cancer stage Ib1 to IIa underwent radical hysterectomy (33 cases) and nerve-sparing radical hysterectomy (28 cases). Unilateral nerve-sparing radical hysterectomy was performed in 10 patients, and bilateral nerve-sparing radical hysterectomy (BNS) was performed in 18 patients. The data of operation time, blood loss, postoperative hospital stay days, residual urine volume, and postoperative complications were collected. The postoperative recovery of bladder and bowel function was evaluated. RESULTS: There were no significant differences between nerve-sparing radical hysterectomy (NSRH) and radical hysterectomy (RH) groups in operation time [NSRH: (224.5 ± 40.0) min, RH: (176.4 ± 30.0 min)], blood loss [NSRH: (464.3 ± 144.0) ml, RH: (374.2 ± 138.7) ml], postoperative hospital stay days [NSRH: (8.4 ± 2.0) d, RH: (9.2 ± 1.8) d, and residual urine volume [NSRH: (64.8 ± 16.9) ml, RH: (70.6 ± 16.0) ml]. There were also no significant differences between UNSRH and BNSRH groups in operation time [UNSRH: (208.5 ± 28.5) min, BNSRH: (233.3 ± 43.1) min], blood loss [UNSRH: (440.0 ± 104.9) ml, BNSRH: (477.8 ± 162.90) ml], postoperative hospital stay days [UNSRH: 9.1 ± 1.8) d, BNSRH: (8.7 ± 2.1 d], and the residual urine volume [UNSRH: (68.3 ± 12.5) ml, BNSRH: (62.8 ± 20.0) ml]. There was a significant difference in the time of the Foley catheter removal between NSRH [(12.4 ± 5.2) d] and RH [(22.4 ± 9.7) d] groups. There was a significant difference in the time of the Foley catheter removal between UNSRH [(18.2 ± 3.6) d] and BNSRH [(9.1 ± 2.0) d] groups. During the postoperative 3 weeks follow-up, the patients in the NSRH group had a higher rate of satisfaction at urination and defecation (100%, 75%) than the RH group (54.5%, 24.2%). CONCLUSION: UNSRH and BNSRH are safe and feasible techniques for early stage cervical cancer, and may significantly improve the recovery of bladder and rectal function.

[Sentinel lymph node detection and intra-operational diagnosis in patients with early stage cervical cancer].

OBJECTIVE: To study the effective method for rapid detection of sentinel lymph nodes in patients with early stage cervical cancer and clinical value thereof. METHODS: Thirty female patients with early stage cervical cancer, 14 at FIGO stage IB1 and 16 at stage IIA, underwent injection of 99mTc-labelled sulfur colloid 0.4 mci/0.4 ml at the positions of 3, 6, 9, and 12 o'clock of the cervix 5 h or 18 h before operation, and injection of 1 ml of methylene blue at the same cervical positions as mentioned above after the abdomen was opened. The blue-stained lymph nodes or the lymph nodes directed by the blue-stained lymph vessels were identified as SLNs: gamma-detector was used to position the hot nodes. The SLNs were resected and then radical hysterectomy and pelvic lymphadenectomy were performed. SLN frozen section and imprint cytology were conducted during the operation, the results were compared with that of HE staining RESULTS: SLN were detected successfully in 29 of the 30 patients with a detection rate of 96.7%. Routine HE staining indicated pelvic lymph node metastasis in 9 patients. The SLN was positive in 8 of the 29 patients, negative in 20 patients, and false negative in 1 patient. The sensitivity, accuracy, and false-negative rates of SLN detection were 88.9%, 96.6%, and 11.1% respectively. The sensitivity, specificity, accuracy, and positive and negative predictive rates were 92.3%, 100%, 98.9%, 100%, and 98.8% for frozen section, and 92.3%, 97.6%, 96.8%, 85.7%, and 98.8% for imprint cytology respectively. CONCLUSION: Frozen section and imprint cytology may be effective rapid methods to diagnose SLN metastasis during operation. SLN detection can predict pelvic lymph node metastasis in cervical cancer.