Educating adolescents on preventing substance use: The role of 24-h movement behaviors ─ data from 2021 Youth Risk Behavior Surveillance.

BACKGROUND: Little is known about how adhering to the health guidelines for physical activity (PA), screen time (ST), and sleep duration (SD) relates to substance use in adolescents. Thus, this study aims to explore the potential association between adherence to the 24-h movement behavior (24-h MB) guidelines and substance use among adolescents. METHODS: Data from the 2019 Youth Risk Behavior Surveillance was analyzed. Participants reported their weekly PA, ST, SD, and substance use (alcohol and smoking) over the past 30 days. The mean age in the total participants was 15.56, and 48.03 % of the participants were females. Logistic regression was used in this study to explore the potential association between 24-h MB and substance use. Odds ratios (ORs) were reported alongside a 95 % confidence interval to enhance understanding of the observed association. RESULTS: Only 2.22 % participants adhered to all three 24-h MB guidelines, while 47.99 % did not follow any guidelines. Notably, there was no significant difference in the odds of cigarette smoking between participants who followed none of the guidelines and those who followed some or all of them. Nevertheless, adherence to one or more guidelines was found to be associated with higher odds of abstaining from alcohol consumption compared to non-adherence (one guidelines: OR = 1.17 [1.08, 1.28], two guidelines: OR = 1.28 [1.13, 1.44]). CONCLUSIONS: Adhering to 24-h MB guidelines may reduce adolescents' alcohol consumption, but the adherence was not significantly associated with smoking. Longitudinal studies are needed to confirm these findings. These results can inform adolescent health policies and interventions aimed at reducing substance use from the perspective of healthy time-use behaviors, which can be used for researchers and educator.

Proteomic profiling and biomarker discovery for predicting the response to PD-1 inhibitor immunotherapy in gastric cancer patients.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, a significant proportion of gastric cancer (GC) patients do not respond to this therapy. Consequently, there is an urgent need to elucidate the mechanisms underlying resistance to ICIs and identify robust biomarkers capable of predicting the response to ICIs at treatment initiation. Methods: In this study, we collected GC tissues from 28 patients prior to the administration of anti-programmed death 1 (PD-1) immunotherapy and conducted protein quantification using high-resolution mass spectrometry (MS). Subsequently, we analyzed differences in protein expression, pathways, and the tumor microenvironment (TME) between responders and non-responders. Furthermore, we explored the potential of these differences as predictive indicators. Finally, using machine learning algorithms, we screened for biomarkers and constructed a predictive model. Results: Our proteomics-based analysis revealed that low activity in the complement and coagulation cascades pathway (CCCP) and a high abundance of activated CD8 T cells are positive signals corresponding to ICIs. By using machine learning, we successfully identified a set of 10 protein biomarkers, and the constructed model demonstrated excellent performance in predicting the response in an independent validation set (N = 14; area under the curve [AUC] = 0.959). Conclusion: In summary, our proteomic analyses unveiled unique potential biomarkers for predicting the response to PD-1 inhibitor immunotherapy in GC patients, which may provide the impetus for precision immunotherapy.

Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer.

Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC50 = 0.108 µM. By applying EP16 to gastric cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation.

Exploring the synthetic approaches and clinical prowess of established macrocyclic pharmaceuticals.

Macrocyclic compounds, characterized by cyclic structures, often originate from either modified forms of unicyclic canonical molecules or natural products. Within the field of medicinal chemistry, there has been a growing fascination with drug-like macrocycles in recent years, primarily due to compelling evidence indicating that macrocyclization can significantly influence both the biological and physiochemical properties, as well as the selectivity, when compared to their acyclic counterparts. The approval of contemporary pharmaceutical agents like Lorlatinib underscore the notable clinical relevance of drug-like macrocycles. Nonetheless, the synthesis of these drug-like macrocycles poses substantial challenges, primarily stemming from the complexity of ring-closing reactions, which are inherently dependent on the size and geometry of the bridging linker, impacting overall yields. Nevertheless, macrocycles offer a promising avenue for expanding the synthetic toolkit in medicinal chemistry, enabling the creation of bioactive compounds. To shed light on the subject, we delve into the clinical prowess of established macrocyclic drugs, spanning various therapeutic areas, including oncology, and infectious diseases. Case studies of clinically approved macrocyclic agents illustrate their profound impact on patient care and disease management. As we embark on this journey through the world of macrocyclic pharmaceuticals, we aim to provide a comprehensive overview of their synthesis and clinical applications, shedding light on the pivotal role they play in modern medicine.

Unlocking the synthetic approaches and clinical application of approved small-molecule drugs for gastrointestinal cancer treatment: A comprehensive exploration.

Gastrointestinal (GI) cancers encompass a group of malignancies affecting the digestive system, including the stomach, esophagus, liver, colon, rectum and pancreas. These cancers represent a significant global health burden, necessitating effective treatment strategies. Small-molecule drugs have emerged as crucial therapeutic options in the fight against GI cancers due to their oral bioavailability, targeted mechanisms of action, and well-established safety profiles. The review then elucidates the clinical applications and synthetic methods of clinically approved small-molecule drugs for the treatment of GI cancer, shedding light on their mechanisms of action and their potential in mitigating GI cancer progression. The review also discusses future prospects and the evolving landscape of small-molecule drug development in GI oncology, highlighting the potential for personalized medicine. In summary, this review provides valuable insights into cutting-edge strategies for harnessing clinically approved small-molecule drugs to combat GI cancer effectively.

Discovery of neddylation E2s inhibitors with therapeutic activity.

Neddylation is the writing of monomers or polymers of neural precursor cells expressed developmentally down-regulated 8 (NEDD8) to substrate. For neddylation to occur, three enzymes are required: activators (E1), conjugators (E2), and ligators (E3). However, the central role is played by the ubiquitin-conjugating enzymes E2M (UBE2M) and E2F (UBE2F), which are part of the E2 enzyme family. Recent understanding of the structure and mechanism of these two proteins provides insight into their physiological effects on apoptosis, cell cycle arrest and genome stability. To treat cancer, it is therefore appealing to develop novel inhibitors against UBE2M or UBE2F interactions with either E1 or E3. In this evaluation, we summarized the existing understanding of E2 interaction with E1 and E3 and reviewed the prospective of using neddylation E2 as a pharmacological target for evolving new anti-cancer remedies.

Safety and effectiveness of the combination of remimazolam tosilate and propofol in gastroscopy: a multicenter, randomized controlled, single-blind clinical trial.

Remimazolam tosilate (RT) is a new short-acting γ-aminobutyric acid A (GABAA) receptors agonist. However, its optimal use mode and dosage still remain unclear. This study aimed to examine the safety and effectiveness of the combination of RT and propofol in gastroscopy. This was a prospective, single-blind, randomized, multicenter, parallel-group study. All eligible 256 patients were randomized into the following 3 groups. Patients were anesthetized with propofol (Group P), RT (Group R) or the combination of RT and propofol (Group RP). The primary efficacy endpoints were: body movement score; satisfaction of gastroscopy doctors; success rate of sedation and effects on sleep status. Sedation induction time, time to be fully alert and adverse events were also recorded. The probability of complete immobility was lower in group R (33.73%) than in group P (86.67%) and RP (83.13%). The rate of doctors' satisfaction was much lower in group R (28.92%) than in group P (77.78%) and RP (72.29%). The success rate of sedation and sleep outcome score has no difference in the three groups. The time to adequate sedation was longer in group RP (77.27 ± 18.63 s) than in group P (64.47 ± 24.36 s), but much shorter than that in group R (102.84 ± 46.43s). The time to be fully alert was shorter in group R (6.30 ± 1.52 min) and RP (6.54 ± 1.13 min) than in group P (7.87 ± 1.08 min). The proportion of sedative hypotension was significantly higher in group P (41.11%) than in group R (1.20%) and group RP (3.61%) (p < 0.001). The incidence of respiratory depression was much higher in group P (17.78%) than in group R (no patient) and group RP (1.2%). The incidence of adverse events was lower in groups R (4.82%) and RP (9.64%) than in group P (31.11%). The combination of RT and propofol takes effect quickly, makes patients alert quickly, provides a sufficient depth of sedation, reduces body movement, does not inhibit circulation and respiratory function, does not affect sleep, and is the preferred mode for gastroscopy doctors and anesthesiologists.

Combinations of physical activity, screen time and sleep, and their association with subjective wellbeing in children.

BACKGROUND: Subjective wellbeing is an important indicator of health outcomes in children. 24-hour movement behaviours (i.e., physical activity, sedentary behaviour, sleep and their combination), a set of modifiable lifestyle behaviours, have been demonstrated to be associated with subjective wellbeing. Thus, the aim of this study was to investigate the relationship between the compliance of the 24-h movement guidelines and subjective wellbeing in a sample of Chinese children. METHODS: Cross-sectional data from primary and secondary school students in Anhui Province, China were used for the analysis. A total of 1098 study participants (mean age: 11.6 years, body mass index: 19.7 ± 2.9) were included, of which 51.5% were boys. Physical activity, screen time, sleep, and subjective wellbeing were measured using validated self-reported questionnaires. Multivariable logistic regression analysis was used to assess the relationships between the compliance of different combinations of 24-h movement guidelines and subjective wellbeing in participants. RESULTS: The compliance of (i.e., physical activity recommendations, screen time recommendations and sleep recommendations) 24-h movement guidelines was associated with better subjective wellbeing (OR: 2.09; 95CI%: 1.01-5.90) compared to the compliance of none of the guidelines. Furthermore, there was a dose-response relationship between the number of guidelines met (3 > 2 > 1 > 0) and improved subjective wellbeing (p < 0.05). Despite some exceptions, there was a significant relationship between the compliance of different combinations of the guidelines and better subjective wellbeing. CONCLUSION: This study found that the compliance of 24-h movement guidelines was associated with greater subjective wellbeing in Chinese children.

Combination of physical activity and screen time on life satisfaction in adults: A cross-sectional survey.

Background: Sufficient physical activity (PA) and limited screen time (ST) have been shown to be positively associated with a variety of mental health outcomes. It has been known that PA and ST are independently associated with life satisfaction. Whereas, little is known about the association between combinations of PA and ST with life satisfaction in adults. This study aimed to explore the associations between PA and ST (in insolation or combination) and life satisfaction in adults. Methods: Data from the 2014 European Social Survey (ESS) round 7 consisting of 22 countries were analyzed in this study. In total, self-reported data from 40,185 adults were included in the final analysis. The self-administered method was used to collect demographic information, PA, ST, and life satisfaction. The prevalence of meeting PA guidelines (at least 150 min per week) and ST guidelines (no more than 3 h per day) was calculated according to Canadian 24-h Movement Guidelines for Adults. Results: Adults who were engaged in sufficient PA and limited ST were more likely to report a higher level of life satisfaction. Meeting PA or ST guidelines was more likely to report higher life satisfaction scores [odds ratio (OR) = 1.31, 95% CI: 1.16-1.47]. Compared with not meeting any guidelines, those who met both PA and ST guidelines had a higher OR (OR = 1.55, 95% CI: 1.37-1.76). Conclusion: This study found that participating PA while limiting ST concurrently was linked with better life satisfaction. Creating an active lifestyle is important to population's well-being.

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer.

Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.

Identification of a Novel Ferroptosis Inducer for Gastric Cancer Treatment Using Drug Repurposing Strategy.

Gastric cancer remains one of the major contributors to global cancer mortality, although there is no promising target drug in clinics. Hence, the identification of novel targeted drugs for gastric cancer is urgent. As a promising strategy for inducing ferroptosis for gastric cancer treatment, the ferroptosis inducer is a potential drug. Nevertheless, no ferroptosis inducer has entered clinics. So, our purpose was to identify a novel ferroptosis inducer for gastric cancer treatment using a drug repurposing strategy. Firstly, using a drug repurposing strategy with the aid of a commercialized compound library, HC-056456, a small molecule bioactive CatSper channel blocker, was characterized to inhibit the growth of gastric cancer line MGC-803. At the same time, this anti-proliferation effect can be blocked by ferrostatin-1, a ferroptosis inhibitor, indicating that HC-056456 is a ferroptosis inducer. Then, HC-056456 was identified to decrease GSH content via p53/SLC7A11 signaling pathway. Then Fe2+ and lipid peroxide were accumulated when cells were exposed to HC-056456. Finally, HC-056456 was found to suppress the growth of gastric cancer cells by increasing p53 and repressing SLC7A11 in vivo but not in the presence of ferrostatin-1. In sum, we systematically elucidate that HC-056456 exerts anti-gastric cancer effect by provoking ferroptosis in vitro and in vivo, suggesting its potential role in gastric cancer treatment.

Design of Sports Event Evaluation and Classification Method Based on Deep Neural Network.

Large-scale sports events with high-level competition as the main content will have a great impact on the host city whether from the economic level or from the social level. With the improvement of human civilization, people realize that the holding of large-scale sports events not only has a positive impact on the economy and society but also brings some negative effects, such as waste of resources and environmental pollution, which have attracted the attention of the government and investors. Therefore, how to scientifically, comprehensively, and reasonably evaluate large-scale sports events, especially the accurate evaluation of their economic and social effects, has become the focus of attention. The evaluation of large-scale sports events mainly includes two levels: economic and social. Through the specific analysis of the evaluation content and the weight calculation of the evaluation index, the overall optimization of the evaluation of large-scale sports events is realized, and the reference experience is provided for the holding and evaluation of large-scale sports events in the future. Based on this, this article proposes a sports event evaluation and classification method based on the deep neural network. Firstly, on the basis of literature review and field investigation, the evaluation index system of sports events is established. Deep learning models have strong fitting power and robustness and have been applied to many real-world tasks. Then the deep neural network is used to evaluate the holding effect of sports events. The experimental results show that the model has high evaluation accuracy and is of great significance to the supervision and guidance of sports events.

From DNMT1 degrader to ferroptosis promoter: Drug repositioning of 6-Thioguanine as a ferroptosis inducer in gastric cancer.

Though various therapeutic strategies have been developed to overcome gastric cancer, the overall prognosis and therapeutic effect are still not optimistic. As a novel identified type of cell death, ferroptosis has been considered as a promising tumor suppression mechanism with therapeutic potential against gastric cancer. In this work, we screened a collection of 4890 bioactivity compounds and committed to find novel agents that can induce apoptosis in gastric cancer. Among these compounds, 6-TG was identified as a potential ferroptosis inducer in gastric cancer cells for the first time. It could inactivate system xc-, block the generation of GSH, down-regulate the expression of GPX4, increase the level of lipid ROS, and finally trigger the Fe2+-mediated ferroptosis in MGC-803 and AGS cell lines. The date in vivo also suggested that compound 6-TG performed anti-tumor activity via inducing ferroptosis. These findings gave a support for 6-TG may play as a novel leading compound for gastric cancer treatment as a ferroptosis inducer.

The effect of QiangGuYin on osteoporosis through the AKT/mTOR/autophagy signaling pathway mediated by CKIP-1.

Osteoporosis is a systemic bone disease characterized by decreased bone mass and deterioration of bone microstructure, which leads to increased bone fragility and increased risk of fractures. Casein kinase 2 interacting protein 1 (CKIP-1, also known as PLEKHO1) is involved in the biological process of bone formation, differentiation and apoptosis, and is a negative regulator of bone formation. QiangGuYin (QGY) is a famous TCM formula that has been widely used in China for the clinical treatment of postmenopausal osteoporosis for decades, but the effect in regulating CKIP-1 on osteoporosis is not fully understood. This study aimed to explore the potential mechanism of CKIP-1 participating in autophagy in bone cells through the AKT/mTOR signaling pathway and the regulatory effect of QGY. The results in vivo showed that QGY treatment can significantly improve the bone quality of osteoporotic rats, down-regulate the expression of CKIP-1, LC3II/I and RANKL, and up-regulated the expression of p62, p-AKT/AKT, p-mTOR/mTOR, RUNX2 and OPG. It is worth noting that the results in vitro confirmed that CKIP-1 interacts with AKT. By up-regulating the expression of Atg5 and down-regulating the p62, the level of LC3 (autophagosome) is increased, and the cells osteogenesis and differentiation are inhibited. QGY inhibits the combination of CKIP-1 and AKT in osteoblasts, activates the AKT/mTOR signaling pathway, inhibits autophagy, and promotes cell differentiation, thereby exerting an anti-osteoporosis effect. Therefore, QGY targeting CKIP-1 to regulate the AKT/mTOR-autophagy signaling pathway may represent a promising drug candidate for the treatment of osteoporosis.

Psychometric Properties of the Generalized Anxiety Disorder Scale-7 Item (GAD-7) in a Large Sample of Chinese Adolescents.

Anxiety symptoms are common among adolescents. A well-validated and easy-to-use tool is indispensable to measure and detect anxiety for timely interventions. The Generalized Anxiety Disorder Scale-7 item (GAD-7) is a self-report scale used to measure the severity of anxiety and has been validated in adult populations, but psychometric properties of the GAD-7 remained rarely tested in adolescents. The study aimed to investigate the reliability and validity of the GAD-7 in Chinese adolescents. Sex- and age-specific analyses were conducted in a large sample of adolescents (n = 67,281, aged 10-17 years). Our results showed that the GAD-7 scores were higher in female and older adolescents. The GAD-7 presented good internal consistency and a unidimensional structure across sex- and age-specific groups. The GAD-7 scores were significantly correlated with the scores of the Patient Health Questionnaire-9 item (PHQ-9, a self-reported scale to measure depression symptoms) in all subgroups, indicating acceptable criterion validity. In conclusion, the GAD-7 is a scale with good psychometrics and can serve as a tool for anxiety screening in Chinese adolescents at the populational level.

Data Mining Algorithm for Physical Health Monitoring of Young Students Based on Big Data.

With the continuous improvement of living standards, the level of physical development of adolescents has improved significantly. The physical functions and healthy development of adolescents are relatively slow and even appear to decline. This paper proposes a novel data mining algorithm based on big data for monitoring of adolescent student's physical health to overcome this problem and enhance young people's physical fitness and mental health. Since big data technology has positive practical significance in promoting young people's healthy development and promoting individual health rights, this article will implement commonly used data mining algorithms and Hadoop/Spark big data processing. The algorithm on different platforms verified that the big data platform has good computing performance for the data mining algorithm by comparing the running time. The current work will prove to be a complete physical health data management system and effectively save, process, and analyze adolescents' physical test data.

USP8 Inhibitor Suppresses HER-2 Positive Gastric Cancer Cell Proliferation and Metastasis via the PI3K/AKT Signaling Pathway.

PURPOSE: Referring to global cancer statistics, the incidence of gastric cancer (GC) was ranked sixth; however, detailed mechanisms underlying its development were not thoroughly investigated. Previous studies have reported that inhibition of ubiquitin-specific peptidase 8 (USP8) induced degradation of several receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), embryonic stem cells (ESCs), etc. Nevertheless, the regulation of HER-2 by USP8 and the molecular mechanisms controlling their role in the pathogenesis of GC remain unknown. PATIENTS AND METHODS: A total of 69 patients with histologically confirmed GC were recruited to satisfy the purpose of this study. Initially, tumor samples and GC cell lines were used to detect USP8 and HER-2 levels. Next, MTT and colony formation assays were applied to analyze cell proliferation capability. Cell migration and invasion ability were examined by transwell assays. To examine related mRNA and protein expressions, Western blot assays and quantitative real-time PCR (qRT-PCR) were performed. Immunofluorescence was used to detect the effect of USP8 inhibitor on GC cells. Finally, in vivo experiments were used to examine the effect of USP8 inhibitor. RESULTS: Patients with USP8 high-expression tumors have shown worse overall survival while opposite results found in patients with low USP8 expressions. Regarding disease prognosis, patients with low expression of USP8 and HER-2 were performed better prognosis, whereas those with overexpression of USP8 and HER-2 shown poor prognosis. USP8 inhibitor significantly inhibited HER-2 positive cell NCI-N87 proliferation and metastasis. In addition, USP8 stabilizes HER-2, preventing it from ubiquitin proteasome-mediated degradation. In vivo studies confirmed that the USP8 inhibitor inhibited HER-2 positive cell NCI-N87 tumor growth. However, it did not affect the HER2-negative cell MGC-803. Careful investigation unraveled that the USP8 inhibitor significantly inhibited NCI-N87 cell proliferation and metastasis via phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/AKT) pathway. CONCLUSION: The USP8 inhibited HER-2 positive GC cell proliferation and migration in vivo and in vitro and probably served as a novel potential therapeutic biomarker for HER-2 positive GC.

Proximal gastrectomy with anti-reflux anastomosis for patients with adenocarcinoma of the esophagogastric junction: The simple and safe triangle-valve technique.

A simple and safe triangle-valve technique (TVT) was applied in proximal gastrectomy (PG) in order to prevent postoperative gastric reflux among patients with adenocarcinoma of the esophagogastric junction (AEG). The clinical outcomes were evaluated in comparison to those of canonical total gastrectomy (TG). This retrospective study of 74 AEG patients compared two surgical procedures, PG-TVT (n=44) and TG (n=30), in terms of surgical outcomes, postoperative complications and nutritional status. The Reflux Disease Questionnaire (RDQ) was used to evaluate reflux esophagitis, and patients with an RDQ score of ≥12 points were diagnosed with gastroesophageal reflux disease (GERD). The mean operative time was significantly shorter in the PG-TVT group (242.6 min) compared with that in the TG group (288.1 min). The overall postoperative complication rate did not differ significantly between the PG-TVT and TG groups. All the patients were followed up for 6 months, and none developed cancer recurrence in distant organs, gastric remnant, or lymph nodes. The GERD incidence was similar between the PG-TVT and TG groups. The mean levels of total protein and albumin within 6 months were significantly higher in the PG-TVT group compared with those in the TG group after adjustingtthe time effect and the interaction of time and surgical methods. The level of total protein significantly increased within 6 months in the PG-TVT group, but decreased in the TG group. Therefore, PG-TVT has several advantages over TG for patients with AEG, including a shorter operative time and better postoperative nutritional status, whereas the incidence of GERD was found to be similar between the two techniques.

Research progress of PD-1/PD-L1 immunotherapy in gastrointestinal tumors.

Gastrointestinal tumor (GIT) is a common malignant tumor of the digestive system, which seriously threatens people's health and life. With the deepening of the study on the mechanism of tumor immune escape, programmed death receptor ligand 1 (PD-L1) has been proved to interact with the tumor microenvironment to mediate tumor immune escape. PD-L1 inhibitor is a hot spot in tumor immunotherapy in recent years, which can restore the activity of T cells, enhance the body's ability of immune response, and ultimately enable the immune system to effectively identify and kill gastric cancer cells, then achieve long-term tumor remission in patients with GITs. At present, variety of PD-L1 inhibitors such as pembrolizumab, nivolumab and avelumab have been approved for the market, and they have achieved good results in clinical studies on the GIT. This paper reviews the progress of PD-1/PD-L1 immunotherapy in GITs which include gastric cancer, colon cancer and rectal cancer.

Down-Regulation of USP8 Suppresses HER-3 Positive Gastric Cancer Cells Proliferation.

BACKGROUND: Ubiquitin specific peptidase 8 (USP8) has been reported to induce the degradation of several receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), among which human epidermal growth factor receptor-3 (HER-3) is one of them. However, the role and functional mechanisms of USP8 and HER-3 in gastric cancer (GC) remain unknown. OBJECTIVE: To explore the function and mechanism of USP8 and HER-3 in the progression of GC. MATERIALS AND METHODS: Eighty-eight patients with histologically confirmed GC were recruited for this study. Tumor samples and GC cell lines were used to detect USP8 and HER-3 levels. MGC803 (HER-3 negative GC cell) was selected as the control group and NCI-N87, MKN-45 and AGS (HER-3 positive GC cells) as the experimental group. USP8i and si-RNA were then used to down-regulate USP8 in each group. Apoptosis and cell-cycle experiments were performed to detect the effects of USP8 on GC cells. Cytotoxicity Assay Kit (MTT) and colony formation assays were used to analyze cell proliferation. Cell migration and invasion ability were examined by wound healing. The expression of related mRNA and protein was detected by Western blot and quantitative real-time PCR (qRT-PCR). In vivo experiments were used to examine the effect of USP8 and HER-3. RESULTS: Patients with high expression of USP8 or HER-3 tumors alone died earlier than those with low expression and the patients with both USP8 and HER-3 high expression had a shorter overall survival than those with the opposite pattern (both USP8 and HER-3 low expression). Down-regulation of USP8 inhibited cell proliferation and cell metastasis and also reduced the HER-3 expression. We also observed that down-regulation of USP8 inhibited the proliferation of GC cells which highly expressed HER-3. Moreover, down-regulation of USP8 could promote the apoptosis of HER3-positive GC cells and inhibit the proliferation of them by affecting the cell-cycle. In vivo studies demonstrated that down-regulation of USP8 inhibited HER-3 positive tumors growth. CONCLUSION: Down-regulation of USP8 inhibits HER-3 positive GC cells proliferation in vivo and in vitro, which indicate that USP8 represents a feasible choice as a therapeutic target for HER-3 positive GC cells.