Search

Background: Tumor-associated macrophages (TAMs), particularly M2-polarized TAMs, are significant contributors to tumor progression, immune evasion, and therapy resistance in gastric cancer (GC). Despite efforts to target TAM recruitment or depletion, clinical efficacy remains limited. Consequently, the identification of targets that specifically inhibit or reprogram M2-polarized TAMs presents a promising therapeutic strategy., Objective: This study aims to identify a dual-function target in GC cells that drives both malignant phenotypes and M2 macrophage polarization, revealing its molecular mechanisms to provide novel therapeutic targets for selectivly targeting M2-polarized TAMs in GC., Methods: Transcriptomic and clinical data from GC and adjacent tissues were utilized to identify mRNAs associated with high M2 macrophage infiltration and poor prognosis. Single-cell sequencing elucidated cell types expressing the target gene. Transwell co-culture and exosome intervention experiments demonstrated its role in M2 polarization. Small RNA sequencing of exosomes, western blotting, and CoIP assays revealed the molecular mechanisms underlying exosome-mediated M2 polarization. Protein array, ChIP and dual-luciferase reporter assays clarified the molecular mechanisms by which the target gene regulated exosomal miRNA. In vivo validation was performed using xenograft tumor models., Results: SERPINE1 was identified as a highly expressed mRNA in GC tissues and cells, significantly associated with advanced clinical stages, worse prognosis, and higher M2 macrophage infiltration in patients with GC. SERPINE1 overexpression in GC cells promoted tumor growth and M2 macrophage polarization. SERPINE1 facilitated the transfer of let-7 g-5p to macrophages via cancer-derived exosomes, inducing M2 polarization. Exosomal let-7 g-5p internalized by macrophages downregulated SOCS7 protein levels, disrupting its interaction with STAT3 and relieving the inhibition of STAT3 phosphorylation, thereby leading to STAT3 hyperactivation, which consequently drove M2 polarization. Additionally, in GC cells, elevated SERPINE1 expression activated JAK2, enhancing STAT3 binding to the let-7 g-5p promoter and promoting its transcription, thereby increasing let-7 g-5p levels in exosomes., Conclusion: GC cell-derived SERPINE1, functioning as a primary driver of GC growth and TAM M2 polarization, promotes M2 polarization through the regulation of exosomal let-7 g-5p transfer via autocrine activation of the JAK2/STAT3 signaling pathway. These findings elucidate a novel mechanism of SERPINE1-induced M2 polarization and highlight SERPINE1 as a promising target for advancing immunotherapy and targeted treatments in GC., Competing Interests: Declarations. Ethics approval and consent to participate: The Ethics Committee of The Second Hospital of Lanzhou University approved the study (No. 2024 A-662), with informed consent from all participants. Animal experiment was approved by Animal Ethics Committee of Gansu University of Chinese Medicine followed the guidelines for the Care and Use of Laboratory Animals (No. 2021-063). Consent for publication: All authors contributed significantly to the conception, design, execution, and interpretation of the research. They reviewed and approved the manuscript and agreed to be listed as co-authors. Competing interests: All authors declare no confict of interest., (© 2024. The Author(s).)

Primary cilia detect and transmit environmental signals into cells. Primary cilia are absent in a subset of ductal carcinomas characterized by distinctive biological activities, and recovery of cilia with normal functionality has been shown to have therapeutic potential in some cancer types. Therefore, elucidation of the underlying mechanism and clinical significance of ciliary loss in ductal carcinomas could help develop effective treatment strategies. Here, we identified a link between Shc1-binding protein (SHCBP1) and cilia in ductal carcinomas. Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Single-cell transcriptome analysis revealed a functional connection between SHCBP1 deficiency and increased tumor ciliogenesis. SHCBP1 ablation restored ciliogenesis in unciliated ductal carcinoma by promoting the proximity between the midbody remnant (MBR) and centrosome through enhanced Rab8 GTPase activity and Rab8GTP positioning within the MBR. Inhibition of tumor progression by SHCBP1 loss relied on the recovery of ciliogenesis. Analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis. Restoring ciliogenesis via SHCBP1 ablation elicited therapeutic effects in patient-derived xenograft models. Together, this study delineates that induction of MBR-centrosome proximity through SHCBP1-deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas. Significance: SHCBP1 depletion rescues tumor ciliogenesis by enhancing Rab8 GTPase activity to restore the proximity of the  midbody remnant to the centrosome, which impedes progression of ductal carcinomas and suggests potential therapeutic strategies., (©2024 American Association for Cancer Research.)

Background: Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2 , a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression., Methods: Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021. Cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2 -associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC., Results: NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro . NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models., Conclusions: Collectively, NUF2 -mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Sulforaphane (SFN) exerts anticancer effect on various cancers including gastric cancer. However, the regulatory effect of SFN on programmed death-ligand 1 (PD-L1) and checkpoint blockade therapy in gastric cancer have not been elucidated. Here we demonstrated that SFN suppressed gastric cancer cell growth both in vitro and in vivo study. SFN upregulated PD-L1 expression through activating ΔNP63α in gastric cancer cells. Further, we found that SFN impaired the anticancer effect of anti-PD-L1 monoclonal antibody (α-PD-L1 mab) on gastric cancer cells. These results uncover a novel PD-L1 regulatory mechanism and the double-edged role of SFN in gastric cancer intervention., (© 2024 Wiley Periodicals LLC.)

The crucial role of cancer-associated fibroblasts (CAFs) in promoting T-cell exclusion has a significant impact on tumor immune evasion and resistance to immunotherapy. Therefore, enhancing T-cell infiltration into solid tumors has emerged as a pivotal area of research. We achieved a conventional knockout of Shcbp1 (Shcbp1 -/- ) through CRISPR/Cas9 gene editing and crossed these mice with spontaneous breast cancer MMTV-PyMT mice, resulting in PyMT Shcbp1 -/- mice. The different CAF subtypes were detected by flow cytometry analysis (FCA). We evaluated collagen and CAFs levels using Sirius red staining, immunohistochemistry (IHC), and immunofluorescence (IF). Primary tumor cells and CAFs were isolated from both PyMT Shcbp1 +/+ and PyMT Shcbp1 -/- mice. We analyzed CAFs' proliferation, invasion, migration, apoptosis, and cell cycle. Transwell coculture experiments were performed with primary tumor cells and CAFs to evaluate the role of CAFs in increasing the sensitivity of tumor cells to Erdafitinib. Tumors from PyMT Shcbp1 +/+ and PyMT Shcbp1 -/- mice were orthotopically transplanted to assess the therapeutic effect of the Erdafitinib and PD-1 combination. CAFs and T-cell infiltration in these tumors were assessed using FCA and IF. Knockout of Shcbp1 leads to a significant reduction in tumor burden, promotes longer survival, and decreases CAFs in MMTV-PyMT. Moreover, knockout of Shcbp1 enhances the sensitivity of Erdafitinib, leading to effective inhibition of CAFs' proliferation and invasion, as well as the induction of apoptosis. Additionally, it results in cell cycle arrest at the G2/M phase in vitro. Meanwhile, Shcbp1 -/- CAFs change the sensitivity of Shcbp1 -/- tumor cells to Erdafitinib compared to Shcbp1 +/+ CAFs. Importantly, knockout of Shcbp1 boosts the effectiveness of Erdafitinib in combination with immune checkpoint blockade therapy by augmenting T-cell infiltration through CAFs regulation in vivo. Our findings demonstrate that knockout of Shcbp1 holds significant potential in enhancing the therapeutic response of Erdafitinib combined with PD-1 antibody treatment, offering promising prospects for future breast cancer therapies., (© 2024 Wiley Periodicals LLC.)

Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing effective strategies for PC treatment is of utmost importance. Here, we revealed that SHCBP1 is significantly overexpressed in PC and negatively correlated with patient prognosis. Knockout of SHCBP1 inhibits the proliferation and migration of PC cells in vitro, and suppresses the tumor growth in vivo. In addition, we identified AZD5582 as a novel inhibitor of SHCBP1, which efficiently restrains the growth of PC in cell lines, organoids, and patient-derived xenografts. Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Polymer-derived ceramics (PDCs) have many advantages in ceramic molding and ceramic properties, but because of the obvious volume shrinkage in the process of precursor transformation into ceramics, it is easy for defects to appear in the forming process of bulk PDCs. Herein, theoretical analyses and experimental studies were carried out to improve the quality of sintered samples and realize the parametric design of raw materials. Firstly, based on the HPSO/D 4 Vi cross-linking system, the mathematical model of the free cross-linking ratio was established, and the theoretical value was calculated. After that, the samples with different free cross-linking rates were heated at 450 °C and 650 °C for different holding times. It was found that the free cross-linking ratio (α) had a significant impact on the weight loss of the samples. When the difference of the α value was 10%, the difference of the samples' weight loss ratio could reach 30%. Finally, the morphology of sintered products with different α values was analyzed, and it was found that obvious defects will occur when the free cross-linking ratio is too high or low; when this value is 40.8%, dense and crack-free bulk ceramics can be obtained. According to analysis of the chemical reaction and cross-linking network density during sintering, the appropriate value of the free cross-linking ratio and reasonable control of the cross-linking network are beneficial for reducing the loss of the main chain element and C element, alleviating the sintering stress, and thus obtaining qualified pressureless sintered bulk ceramic samples.

The present study was conducted to investigate the underlying mechanisms and effective components of Polygonum hydropiper in ethanol-induced acute gastric mucosal lesions. The ethanol extract was purified on an AB-8 macroporous resin column and eluted with 60% ethanol and was then injected into the HPLC system for quantitative analysis. Sprague-Dawley rats were orally pretreated with P. hydropiper extract (PHLE; 50, 100, and 200 mg/kg) for 5 days and then absolute ethanol was administered to induce gastric mucosal damage. One hour after ethanol ingestion, the rats were euthanized and stomach samples were collected for biochemical analysis. Antioxidant enzymes and anti-inflammatory cytokines were quantified. Western blotting was used to detect the expression levels of proteins. Cell proliferation was assayed by CCK-8 assays. The proportion of total flavonoids in the final extract of P. hydropiper was 50.05%, which contained three major bioactive flavonoid constituents, including rutin, quercitrin, and quercetin. PHLE significantly increased cell viability and effectively protected human gastric epithelial cells-1 against alcohol-induced damage in vitro. PHLE pretreatment attenuated gastric mucosal injuries in a dose-dependent manner in rats, and increased the activity of superoxide dismutase, glutathione peroxidase, and glutathione, and decreased the levels of malondialdehyde in gastric tissue. Pretreatment with PHLE also reduced the generation of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β in gastric tissue by downregulating the expression of nuclear factor-kappa B. PHLE exerted protective effects against gastric injury through antioxidant and anti-inflammatory pathways. Flavonoids might be the main effective components of P. hydropiper against gastric mucosal injury.

Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3'-digallate (TFBG) is identified as an inhibitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.

In order to explore the changes of intestinal flora and serum levels of relevant substances in patients with gastric cancer before and after surgery with carbon nanoparticle laparoscopy, a total of 180 patients with early distal gastric cancer who adopted laparoscopic radical gastrectomy for distal gastric cancer in the general surgery department of TCM Hospital of Shi Jia Zhuang City from January 2018 to January 2020 were selected and randomly divided into two groups: traditional laparoscopic operation (control group) and carbon nanoparticle laparoscopic operation (experimental group) were adopted for treatment for the two groups, respectively. Postoperative evaluation included the difference between the two groups in the operative time, the efficiency of intraoperative lymph node dissection, and the number of lymph node detection. The adverse reactions, changes of intestinal flora before and after surgery in the two groups, and the serum levels of epidermal growth factor receptor (EGFR), interleukin-32 (IL-32), and gastrin 17 were evaluated. In the experimental group, the success rate of carbon nanoparticle tracer black staining reached 100%, and the operation time of the experimental group was significantly shorter than that of the control group ( P < 0.05). The lymph node detection rate of the experimental group was higher than that of the control group ( P < 0.05), but there was no significant difference in the lymph node metastasis rate between the two groups ( P > 0.05). The sentinel lymph node sensitivity of the experimental group reached 92.3%, and the specificity, accuracy, and positive and negative prediction rates reached 100%; the experimental group patients were with an obviously higher incidence of level I-II gastrointestinal reaction ( P < 0.05). Postoperative increases in Bifidobacteria and Lactobacillus were observed in both groups, while decreases in Enterococcus and Escherichia coli were observed in both groups ( P < 0.05). Moreover, the degree of increase and decrease in the experimental group was greater than that in the control group ( P < 0.05). The serum levels of EGFR, IL-32, and gastrin 17 in the two groups were significantly lower than those in the control group on 3 d, 7 d, and 15 d after surgery ( P < 0.05). In the radical gastrectomy for distal gastric cancer, carbon nanoparticle laparoscopy was not only helpful for the localization of small tumors but also for the thorough dissection of lymph nodes after the surgery, and the postoperative adverse reactions of carbon nanoparticle laparoscopy were also less, which was of great significance for the improvement of intestinal flora and the reduction of serum levels of EGFR, IL-32, and gastrin 17 in gastric cancer patients., Competing Interests: The author declare that they have no conflicts of interest., (Copyright © 2021 Liping Bai et al.)

Ti/Ti-Al and SiC f -reinforced Ti/Ti-Al laminated composites were fabricated through vacuum hot-pressure using pure Ti foils, pure Al foils and SiC fibers as raw materials. The effects of SiC fiber and a laminated structure on the properties of Ti-Al laminated composites were studied. A novel method of fiber weaving was implemented to arrange the SiC fibers, which can guarantee the equal spacing of the fibers without introducing other elements. Results showed that with a higher exerted pressure, a more compact structure with fewer Kirkendall holes can be obtained in SiC f -reinforced Ti/Ti-Al laminated composites. The tensile strength along the longitudinal direction of fibers was about 400 ± 10 MPa, which was 60% higher compared with the fabricated Ti/Ti-Al laminated composites with the same volume fraction (60%) of the Ti layer. An in situ tensile test was adopted to observe the deformation behavior and fracture mechanisms of the SiC f -reinforced Ti/Ti-Al laminated composites. Results showed that microcracks first occurred in the Ti-Al intermetallic layer.

Background: The development of new treatment strategies to improve peripheral nerve repair after injury, especially those that accelerate axonal nerve regeneration, is very important. The aim of this study is to elucidate the molecular mechanisms of how bone marrow stromal cell (BMSC)-derived exosomes (EXOs) participate in peripheral nerve regeneration and whether the regenerative effect of EXOs is correlated with dose., Method: BMSCs were transfected with or without an siRNA targeting Ago2 (SiAgo2). EXOs extracted from the BMSCs were administered to dorsal root ganglion (DRG) neurons in vitro. After 48 h of culture, the neurite length was measured. Moreover, EXOs at four different doses were injected into the gastrocnemius muscles of rats with sciatic nerve crush injury. The sciatic nerve functional index (SFI) and latency of thermal pain (LTP) of the hind leg sciatic nerve were measured before the operation and at 7, 14, 21, and 28 days after the operation. Then, the number and diameter of the regenerated fibers in the injured distal sciatic nerve were quantified. Seven genes associated with nerve regeneration were investigated by qRT-PCR in DRG neurons extracted from rats 7 days after the sciatic nerve crush., Results: We showed that after 48 h of culture, the mean number of neurites and the length of cultured DRG neurons in the SiAgo2-BMSC-EXO and SiAgo2-BMSC groups were smaller than that in the untreated and siRNA control groups. The average number and diameter of regenerated axons, LTP, and SFI in the group with 0.9 × 10 10 particles/ml EXOs were better than those in other groups, while the group that received a minimum EXO dose (0.4 × 10 10 particles/ml) was not significantly different from the PBS group. The expression of PMP22, VEGFA, NGFr, and S100b in DRGs from the EXO-treated group was significantly higher than that in the PBS control group. No significant difference was observed in the expression of HGF and Akt1 among the groups., Conclusions: These results showed that BMSC-derived EXOs can promote the regeneration of peripheral nerves and that the mechanism may involve miRNA-mediated regulation of regeneration-related genes, such as VEGFA. Finally, a dose-effect relationship between EXO treatment and nerve regeneration was shown.

Background: In this study, we aimed to investigate the preoperative serum carcinoembryonic antigen (CEA) in the diagnosis of positive lymph node metastasis (LNM), and to evaluated the relationship between CEA and survival in patients with locally advanced gastric cancer (LAGC)., Methods: The significance of the preoperative serum CEA level for the diagnose of LAGC and prediction of LNM was determined using the receiver operating characteristic (ROC) curve. The areas under the ROC of CEA were compared with those of other tumor markers or imaging examination including CT and MRI. Logistic regression was utilized to identify the risk factors predicting positive LNM. Independent prognosis factors were evaluated using univariate and multivariate COX regression analyses., Results: The ROC curves showed that the AUCs of CEA, CA199, and CA125 for diagnosing LAGC were 0.727, 0.594, and 0.566. When used to predict LNM, the AUC of CEA, CA199 and CA125 were 0.696, 0.531, and 0.588. Logistic regression analysis demonstrated that preoperative serum CEA were significantly associated with positive LNM. On combining imaging examination with CEA, the sensitivity and specificity were 85.3 and 79.4%, respectively, with the AUC equal to 0.853. The combination of CEA and imaging examination preformed the highest levels of AUC and sensitivity for diagnosing LNM, which is significantly higher than using either of them alone. Although patients with abnormal CEA have a poor prognosis, two models of multivariate analysis showed that CEA was not the independent prognosis factor for survival., Conclusions: CEA can be used to diagnose gastric cancer and determine whether it has LNM. Moreover, combined with CEA could improve the diagnostic sensitivity of imaging examination for lymph node involvement.

Background and Aim: Superior mesenteric artery (SMA) first approach was a new improvement for pancreaticoduodenectomy (PD), but there is no evidence whether this approach is advantageous to PD. This meta-analysis aimed to determine the effects of the superior mesenteric artery (SMA) first approach on outcomes of pancreaticoduodenectomy (PD)., Methods: Literature searches were conducted on PubMed, The Cochrane Library, EMBASE, Web of Science, Clinical Trials Registry and China Biology Medicine disc. We completed a meta-analysis of the SMA first approach in PD, assessing overall survival, R0 resection, blood loss, postoperative complications, operation time and postoperative stay. The odds ratios and weighted mean differences with 95% confidence intervals (CIs) were pooled., Results: Eighteen studies comprising 1483 participants were included. Patients who received SMA-PD had significantly lower overall complication rate (OR 0.62, 95% CI 0.47 to 0.81, P = 0.001) and less blood loss (WMD -264.84, 95% CI -336.1 to -193.58, P < 0.001). The obviously increased R0 resection rate (OR 2.92, 95% CI 1.72 to 4.96, P < 0.001) and 3-year OS (OR 2.15, 95% CI 1.34 to 3.43, P = 0.001) were found in the SMA-PD group., Conclusion: The SMA-PD group had better clinical outcomes, particularly in long-term survival of pancreatic cancer patients; furthermore, the patients acquired superior clinical efficacy via the posterior approach in SMA-PD., (Copyright © 2019 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Slit1 is one of the known signaling factors of the slit family and can promote neurite growth by binding to its receptor, Robo2. Upregulation of Slit1 expression in dorsal root ganglia (DRG) after peripheral nerve injury plays an important role in nerve regeneration. Each sensory neuronal soma in the DRG is encapsulated by several surrounding satellite glial cells (SGCs) to form a neural structural unit. However, the temporal and spatial patterns of Slit1 upregulation in SGCs in DRG and its molecular mechanisms are not well understood. This study examined the spatial and temporal patterns of Slit1 expression in DRG after sciatic nerve crush by immunohistochemistry and western blotting. The effect of neuronal damage signaling on the expression of Slit1 in SGCs was studied in vivo by fluorescent gold retrograde tracing and double immunofluorescence staining. The relationship between the expression of Slit1 in SGCs and neuronal somas was also observed by culturing DRG cells and double immunofluorescence labeling. The molecular mechanism of Slit1 was further explored by immunohistochemistry and western blotting after intraperitoneal injection of Bright Blue G (BBG, P2X7R inhibitor). The results showed that after peripheral nerve injury, the expression of Slit1 in the neurons and SGCs of DRG increased. The expression of Slit1 was presented with a time lag in SGCs than in neurons. The expression of Slit1 in SGCs was induced by contact with surrounding neuronal somas. Through injured cell localization, it was found that the expression of Slit1 was stronger in SGCs surrounding injured neurons than in SGCs surrounding non-injured neurons. The expression of vesicular nucleotide transporter (VNUT) in DRG neurons was increased by injury signaling. After the inhibition of P2X7R, the expression of Slit1 in SGCs was downregulated, and the expression of VNUT in DRG neurons was upregulated. These results indicate that the ATP-P2X7R pathway is involved in signal transduction from peripheral nerve injury to SGCs, leading to the upregulation of Slit1 expression., (Copyright © 2019 Zhang, Zhao, Shen, Zhang, Ren, Ma, He, Kang, Wang, Dong, Sun, Liu and Yi.)

Purpose: To promote the understanding of pelvic fracture mechanism and make more accurate evaluation of maximal deformity at the moment of fracture, kinematic response of pelvis to lateral impact and the difference between peak and final displacement were investigated., Methods: A total of three human cadaver pelves were seated uprightly on a sled test table, explored to horizontal lateral impact by a 22.1-kg impactor at a speed of 5.2, 4.0, and 4.8 m/s. Kinematic data of pelvic osseous interesting points (POIP) were measured by the motion capture system. Trajectories of POIP, duration of impact, and deflection of pelvis were calculated as well as rotational movement of pelvis was evaluated. After impact, autopsy and CT scan were made to validate the motion capture data., Results: The peak deflection of pelvis under lateral impact was 31.9, 30.1, and 18.5%, while final deflection was 19.6, 13.8, and 13.8%. The final deflection was only 61.5, 45.9, and 74.46% of the peak deflection., Conclusions: In clinical practice, pelvic fracture displacement tends to be underestimated. The peak compression can be 1.3-2.2 times of final compression appearing on images in hospital. Clinicians shall give adequate estimation of displacement and related injuries.

Most compound acetabular fractures involving both the anterior and posterior columns are caused by high-energy injuries. Patients with compound acetabular fractures are often in critical or poor condition and cannot tolerate major surgery. This study aims to investigate the effectiveness of an ilioischial plate in treating compound acetabular fractures. A consecutive series of 40 patients with complex acetabular fractures were surgically treated and retrospectively reviewed. A modified Stoppa approach in combination with an iliac fossa approach was used. In all of the cases, the anterior column was stabilized with reconstruction plates for the iliac wing and along the iliopectineal line to the pubis. The posterior column was fixed either with the newly developed ilioischial plate running from the ilium to the ischial ramus or with standard fixation techniques. These included either conventional posterior column screws or quadrilateral plate fixation. Patients were divided into an experimental group (ilioischial plate for posterior column fixation) and a control group (standard fixation techniques). In both groups, we found that 90% of all reductions were good to excellent. According to the modified Merle Aubigne and Postel scoring system, the percentage of good to excellent was 85% in the experimental group as compared to 80% in the control group. Compared with the control group, physical function (PF), role physical (RP) and social function (SF) were significantly better in the experimental group (P<0.05). Fracture healing was achieved in all patients. By using the modified Stoppa approach combined with the iliac fossa approach, the ilioischial plate can be directly fixed to the posterior column and the ilium to stabilize the posterior column in patients with complex acetabular fractures.

Introduction: Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) may improve overall survival (OS) in patients with locally advanced gastric cancer (LAGC); however, evidence for its use as a standard treatment has not been established in China. The aim of this study was to investigate the effectiveness, safety, and feasibility of the FLOT regimen as neoadjuvant chemotherapy in Chinese patients with resectable LAGC. Methods: We conducted an observational study to compare the effectiveness of FLOT regimen consisting of docetaxel (60 mg/m 2 ), oxaliplatin (85 mg/m 2 ), leucovorin (200 mg/m 2 ), and 5-fluorouracil (2,600 mg/m 2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks versus initial surgery followed by chemotherapy in patients with clinical T3-4 LAGC. OS was compared by using the Cox proportional hazards regression model and the Kaplan-Meier curve adjusted by inverse probability of treatment weighting (IPTW) and propensity score-matched (PSM) analysis. In addition, we performed subgroup analyses to determine the effectiveness of the FLOT regimen in clinically relevant patient subsets. Results: Overall, 47 patients who received initial FLOT chemotherapy and 269 patients who received initial surgery were enrolled in this study. In the PSM analysis, the FLOT-first group showed favorable OS compared with the surgery-first group (41 vs 41 [HR, 0.416; 95% CI, 0.218-0.794; P =0.008]), and 3-year survival rates were 58.7% and 30.9% in the FLOT-first group and surgery-first group, respectively. IPTW analysis showed similar results. However, the effect of FLOT was low (HR, 0.868; 95 CI%, 0.215-3.504) in patients without lymph node metastasis. Conclusion: Our study suggests that preoperative FLOT chemotherapy is safe and feasible. In terms of OS, FLOT may be superior to initial surgery followed by chemotherapy in reducing morbidity with resectable LAGC., Competing Interests: The authors report no conflicts of interest in this study.

The primary cilium, a sensory organelle that emanates from the cell surface of most mammalian cell types during growth arrest, has attracted the attention of many researchers over the past decade. Recently, a large number of new findings have assigned novel functions and roles to the primary cilium in signal transduction and related diseases, which has greatly augmented the importance of the cilium in human health and development. Here, we review emerging evidence supporting the primary cilium as a sensory organelle in signal transduction in microgravity, electromagnetic field sensing, chemosensation and tumorigenesis. We also present an overview of signal transduction crosstalk associated with the primary cilium in bone disease and cancer, including primary cilium-related Ca 2+ signaling, parathyroid hormone signaling, cAMP signaling, BMP/Smad1/5/8 signaling and Wnt signaling. We anticipate that emerging discoveries about the function of the primary cilium will provide novel insight into the molecular mechanisms of stimulus sensation, signal transduction and pathogenesis., (© 2019 Wiley Periodicals, Inc.)

Gastric neuroendocrine tumors are rarely seen in the gastric tumors, because there are few case reports and the clinical diagnosis rate is low. There is no consensus treatment method in the world. However, with the benefit of esophagogastrodenoscopy and widespread use of proton pump inhibitors, the diagnostic rate of gastric neuroendocrine tumors is on the increase, which gives us an updated understanding for the pathogenesis and pathophysiology of the disease. By studying its pathogenesis, scholars have found that hypergastrinemia caused by various causes is closely related to its occurrence. Gastric neuroendocrine tumors are classified into different types or pathological grades depending on the state of progression of the disease and the unique clinical manifestations. Clinically used diagnostic methods include gastroscopy, medical imageology, nuclear medicine, gastrin, CgA, etc. There are also differences in treatments depending on the clinical classification. If the disease progresses rapidly and the grade is high, surgical resection of the lesion plus postoperative adjuvant chemotherapy should be actively performed. Other better treatments are still being explored.

Objective: To explore the relationships between the expression level of different galectins and its prognostic value for patients with gastric cancer., Methods: The PubMed, EMbase, the Cochrane Library and Web of Science databases were systematically searched. All the eligible studies were included according to the inclusion and exclusion criteria. All the relevant data was extracted by two independent researchers. The quality assessment was conducted according to the evaluation of the quality of prognosis study which published by Harden in 2006. The STATA 12.0 software was used to perform a meta-analysis., Results: All of 8 retrospective case-controlled studies involving 2093 patients with gastric cancer were included in this study. The results of meta-analysis presented that the elevated galectin-1 which is related to the poor overall survival (HR = 1.85, 95% CI: 1.33-2.58; P < 0.001) may predicted a larger tumor size (OR = 2.20, 95% CI: 1.35-3.35; P = 0.001) and was positively associated with the higher expression of VEGF (OR = 1.44, 95% CI: 1.14-1.82; P = 0.002). Moreover, the decreased galectin-3 (HR = 0.49, 95% CI: 0.36-0.67; P < 0.001), galectin-8 (HR = 0.49, 95% CI: 0.36-0.67; P < 0.001) and galectin-9 (HR = 0.78, 95% CI: 0.66-0.92; P = 0.003) were also significantly associated with poorer prognosis. Our meta-analysis also showed that lower expression of galectin-3 was also related to lymphatic vessel invasion (OR = 0.48, 95% CI: 0.26-0.89; P = 0.018), worse TNM stages (OR = 0.47, 95% CI: 0.32-0.40; P < 0.001), deeper invasive depth (OR = 0.33, 95% CI: 0.21-0.51; P < 0.001) and poorer differentiation grade (OR = 0.10, 95% CI: 0.04-0.25; P < 0.001)., Conclusions: High expression of galectin-1 or low expression of galectin-3, -8 and -9 were significantly related to a poorer prognosis for patients with gastric cancer. The expression level of galectins was associated with clinical characteristics and were potential independent prognostic predictor for GC patients., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Misplaced screw during the internal fixation of acetabular fractures may penetrate the hip joint which might cause chondrolysis and traumatic osteoarthritis in the future. This study aims to acquire the safe path for screw insertion along inferior border of the arcuate line fixation route at acetabular area., Methods: Computed tomography (CT) scans of 98 patients without pelvic trauma were rebuilt for three-dimensional models of pelvis. After depicting the fixation route curve, five cross-sections perpendicularly to the curve were established from the anterior of pelvis to the posterior along inferior border of the arcuate line. The safe screw lengths for section 1 and 5 were measured from the computer models. In section 2, 3 and 4, a line from the screw entry point tangent to the inferior edge of the acetabulum was depicted and the measurements of minimum safe direction of screw insertion were performed then marked with angle θ., Results: The safe screw lengths for section 1 and 5 were 22.29 ± 4.41 mm and 32.64 ± 4.70 mm (n = 98). The minimum safe angles of screw insertion for the middle three sections 2, 3, and 4 were 65.38 ± 10.23°, 74.20 ± 10.20°, and 57.88 ± 11.11°(n = 98), respectively. The results for the male group (n = 98) indicated smaller minimum safe angles in these three sections compared with the female (n = 98)., Conclusions: Compared to male, the minimum safe angles of screw placement at acetabular area for female should be more away from inferior edge of acetabulum and tilt to the bottom of pelvis along inferior border fixation route in surgical management of acetabular fractures.

Nasopharyngeal carcinoma (NPC) is a highly metastatic malignancy, which is highly prevalent in Southeast Asia and North Africa. Recent studies implicated the critical role of nemo‑like kinase (NLK) in tumor biology. However, the functional role of NLK in NPC has yet to be elucidated. In the present study, the significance of NLK positivity in NPC was examined. NLK expression was evaluated by immunohistochemistry in a relatively large sample of patients with NPC (n=352) from December 1, 2002 to December 1, 2009. The correlation between the NLK expression status and clinicopathological features and prognosis was investigated. Univariate and multivariate Cox regression models were developed to evaluate the association between the NLK status and the relative risks for relapse and mortality. In total, 54% (190/352) of NPC samples were identified as positive for NLK. By contrast, all 176 specimens of adjacent normal tissue were negative for NLK. NLK positivity was associated with tumor extent, regional lymph node status and distant metastases. A Kaplan‑Meier survival analysis demonstrated that patients with NLK‑positive NPC exhibited significantly shorter disease‑free survival (DFS) and overall survival (OS). Furthermore, Cox regression analysis revealed that NLK positivity was an unfavorable prognostic indicator of DFS and OS in NPC, independent of other features. Additionally, NLK‑positive patients with NPC without distant metastases were more likely to relapse compared with NLK‑negative patients with NPC without distant metastases. The present study indicates that NLK is a good prognostic marker for NPC.

Mitochondrial oxidative stress induced by reactive oxygen species (ROS) has been strongly associated with the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). We used mitochondrial transgenic neuronal cell cybrid models of sporadic AD (SAD), which overproduce ROS compared to control cybrids, to investigate the protective effects of puerarin, an isoflavone purified from Chinese herb radix of Pueraria lobata, on viability, endogenous ROS and intracellular signaling pathways. SAD cybrids had increased apoptosis and increased accumulation of ROS that was inhibited by puerarin. Western blotting demonstrated that SAD cybrids had increased basal activation of the caspase-3, p38 and c-Jun N-terminal kinase (JNK) that were inhibited by puerarin. Puerarin was also found to decrease Bax/Bcl-2 ratio. These results suggest that expression of SAD mitochondrial genes in cybrids activates oxidative-stress-related signaling pathways and reduces viability, and that the protective effects of puerarin inhibit oxidative-stress-induced apoptosis through down-regulation of Bax/Bcl-2 ratio, which blocks the activation of JNK, p38 and caspase-3. Therefore, puerarin may act as an intracellular ROS scavenger, and protect neurons against oxidative-stress-induced apoptosis., (Copyright © 2010 Elsevier Inc. All rights reserved.)