[Intraoperative slide rail CT assistance in percutaneous sacroiliac joint screws for the treatment of pelvic posterior ring injury].

OBJECTIVE: To compare the clinical efficacy of intraoperative slide rail CT combined with C-arm X-ray assistance and just C-arm for percutaneous screw in the treatment of pelvic posterior ring injury. METHODS: A retrospective analysis was performed on the patient data of 76 patients with posterior pelvic ring injury admitted to the Department of Orthopedic Trauma from December 2018 to February 2022. Among them, 39 patients in the CT group were treated with C-arm combined with slide rail CT-assisted inline fixation including 23 males and 16 females with an average age of (44.98±7.33) years old;and the other 37 patients in the C-arm group were treated with intraline fixation treatment under only C-arm fluoroscopy including 24 males and 13 females with an average age of (44.37±10.82) years old. Among them, 42 patients with anterior ring fractures were treated with percutaneous inferior iliac spines with internal fixation (INFIX) or suprapubic support screws to fix the anterior pelvic ring. Postoperative follow-up time, operation time, complications of the two groups were compared. Results of Matta reduction criteria, Majed efficacy evaluation, the CT grading and the rate of secondary surgical revision were compared. RESULTS: The nailing time of (32.63±7.33) min in CT group was shorter than that of (52.95±10.64) min in C-arm group (t=-9.739, P<0.05). The follow-up time between CT group (11.97±1.86) months and C-arm group (12.03±1.71) months were not statistically significant(P>0.05). The postoperative complication rates between two groups were not statistically significant (χ2=0.159, P>0.05). Results of Matta reduction criteria (Z=2.79, P<0.05), Majeed efficacy evaluation(Z=2.79, P<0.05), CT grading (Z=2.83, P<0.05) in CT group were better than those in C-arm group(P<0.05); the secondary surgical revision rate in the CT group was significantly lower than that in the C-arm group (χ2=5.641, P<0.05). CONCLUSION: Compared with traditional C-arm fluoroscopy, intraoperative slide rail CT combined with C-arm assisted percutaneous sacroiliac joint screw placement surgery has the characteristics of short operation time, high accuracy and safety, and significant decrease in postoperative secondary revision rate, and is one of the effective methods for re-establishing the stability of the posterior ring of pelvic fracture.

The clinical practice and dosimetric outcome of the manual adaptive planning during definitive radiotherapy for cervical cancer.

PROPOSE: To evaluate the advantage of the manual adaptive plans comparing to the scheduled plans, and explored clinical factors predicting patients suitable for adaptive strategy. METHODS AND MATERIALS: Eighty two patients with weekly online cone-beam computed tomography (CBCT) were enrolled. The re-CT simulation was performed after 15 fractions and a manual adaptive plan was developed if a significant deviation of the planning target volume (PTV) was found. To evaluate the dosimetric benefit, D98, homogeneity index (HI) and conformity index (CI) for the planning target volume (PTV), as well as D2cc of the bowel, bladder, sigmoid and rectum were compared between manual adaptive plans and scheduled ones. The clinical factors influencing target motion during radiotherapy were analyzed by chi-square test and logistic regression analysis. RESULTS: The CI and HI of the manual adaptive plans were significantly superior to the scheduled ones (P = 0.0002, 0.003, respectively), demonstrating a better dose coverage of the target volume. Compared to the scheduled plans, D98 of the manual adaptive plans increased by 3.3% (P = 0.0002), the average of D2cc to the rectum, bladder decreased 0.358 Gy (P = 0.000034) and 0.240 Gy (P = 0.03), respectively. In addition, the chi-square test demonstrated that age, primary tumor volume, and parametrial infiltration were the clinical factors influencing target motion during radiotherapy. Multivariate analysis further identified the large tumor volume (≥ 50cm3, OR = 3.254, P = 0.039) and parametrial infiltration (OR = 3.376, P = 0.018) as the independent risk factors. CONCLUSION: We found the most significant organ motion happened after 15 fractions during treatment. The manual adaptive plans improved the dose coverage and decreased the OAR doses. Patients with bulky mass or with parametrial infiltration were highly suggested to adaptive strategy during definitive radiotherapy due to the significant organ motion.

Primary biliary cholangitis with features of autoimmune hepatitis in a 19-year-old adolescent with 14q24.1q24.2 deletion: a case report.

Introduction: Primary biliary cholangitis (PBC) is a rare and chronic autoimmune liver disease characterized by the progressive destruction of small intrahepatic bile ducts that may eventually lead to cirrhosis. PBC with features of autoimmune hepatitis (AIH) has rarely been reported in pediatric patients with genetic defects. We present the case of an adolescent with chromosome 14q24.1q24.2 deletion who was given the diagnosis of stage IV PBC with features of AIH. Case presentation: A 19-year-old male adolescent with multiple congenital abnormalities and an intellectual disability presented with abnormal liver enzymes levels and pruritus for more than 5 years. Laboratory examinations revealed elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase. After the exclusion of viral hepatitis, alpha-1 antitrypsin deficiency, Wilson's disease, and other genetic cholestatic liver diseases by laboratory tests and whole exome sequencing, a liver biopsy was performed and stage IV PBC was diagnosed. Notably, features of AIH were also noted in the histopathological report, indicating the presence of PBC with AIH features. The patient responded well to a combination therapy of ursodeoxycholic acid and steroids. Array comparative genomic hybridization analysis performed to study the congenital abnormalities revealed a 3.89 Mb 14q24.1q24.2 deletion. Conclusion: PBC with AIH features has rarely been reported in an adolescent with a chromosomal abnormality. The present case can increase awareness for early-onset PBC and its possible correlation with chromosomal defects.

Sichen Formula Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Blocking the TLR4 Signaling Pathways.

Purpose: Sichen (SC) formula is a classic prescription of Tibetan medicine. Due to its potential anti-inflammatory effect, the SC formula has been clinically used to treat respiratory diseases for many years in the Chinese Tibet region. The present study aimed to investigate the anti-inflammatory effect of SC and explore the underlying mechanisms. Methods: SC formula was characterized by HPLC analysis. The acute lung injury (ALI) mouse model was induced by direct intratracheal lipopolysaccharide (LPS) instillation, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. Meanwhile, RAW264.7 macrophages were stimulated by LPS. The contents of inflammatory mediators in the culture medium were determined by ELISA. Protein levels were determined by immunohistochemical staining or Western blotting. Nuclear localization of NF-κB, AP-1, and IRF3 was performed using immunofluorescence and Western blotting. Results: In the LPS-induced ALI mouse model, SC treatment suppressed the secretion of inflammatory mediators (TNF-α, IL-6, IL-1ß, MCP-1, MIP-1α, and RANTES) in BALF. SC treatment hindered the recruitment of macrophages. SC treatment also inhibited the expression of CD68, p-p65, and TLR4 in the lung tissue. In the LPS-exposed RAW264.7 cells, the cell viability was not changed up to 400 µg/mL of SC. SC concentration-dependently suppressed the production of nitric oxide, prostaglandin E2, TNF-α, IL-6, MCP-1, MIP-1α, and RANTES in LPS-challenged RAW264.7 cells. The expression levels of iNOS, COX-2, p-p38, p-JNK, p-ERK, p-TBK1, p-IKKα/ß, p-IκB, p-p65, p-c-Jun, and p-IRF3 were decreased after SC treatment. Moreover, the nuclear translocation of p65, c-Jun, and IRF3 was also blocked by SC treatment. Conclusion: SC treatment inhibited the inflammatory responses in LPS-induced ALI mouse model/RAW264.7 macrophages. The underlying mechanism of this action may be closely associated with the suppression of TLR4 signaling pathways. These research findings provide further pharmacological justifications for the medicinal use of SC in the management of respiratory diseases.

[A new approach for optimizing empirical prescriptions of famous physicians based on network target: taking Qingluo Decoction as an example].

Based on the network target approach and technology, this study proposed for the first time a novel optimization method for Chinese medicine formulae. Moreover, with Qingluo Decoction as an example, a method for the research and development of Chinese medicine, which combines scientific methodology and experience of famous doctors, was developed. Specifically, based on the composition of Qingluo Decoction, this study used the using network target for intelligent and quantitative analysis on drug actions(UNIQ) to predict the medicinals that targeted the key pathways of rheumatoid arthritis(RA) such as angiogenesis. Then, combining the experience of the first national Chinese medical master LI Ji-ren and Aihui famous Chinese medicine doctor LI Yan and Chinese medicine theory, this study developed a novel angiogenesis-targeted prescription modified Qingluo Decoction(MQLD). Afterward, the clinical efficacy and mechanism of MQLD were verified. The results showed that 27 medicinals with significant regulatory effect on angiogenesis-related key signaling pathways were identified by UNIQ, among which 6 were selected by the Chinese medicine physicians to develop the MQLD. Clinical trials demonstrated that the clinical efficacy of MQLD, in terms of either American College of Rheumatology 20% improvement and 50% improvement criteria(ACR20, ACR50) or TCM syndrome evaluation, was better than that of Qingluo Decoction. Experimental study revealed that MQLD can inhibit RA angiogenesis by acting on the vascular endothelial growth factor(VEGF) pathway, nuclear factor κB(NF-κB) pathway, inflammatory cytokine release, and immune cell regulation. Taken together, this study developed a new formula MQLD with improved clinical efficacy, precise applicable clinical settings, and authorized patent through the network target technology, thus providing a new way for the precise development of Chinese medicine and preservation of the experience of famous physicians.

Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts.

BACKGROUND: The odontogenic jaw cyst is a cavity containing liquid, semifluid or gaseous components, with the development of the disease. In recent years, with the rapid development of oral materials and the transformation of treatment of jaw cysts, more options are available for treatment of postoperative bone defect of jaw cysts. Guided bone regeneration (GBR) places biomaterials in the bone defect, and then uses biofilm to separate the proliferative soft tissue and the slow-growing bone tissue to maintain the space for bone regeneration, which is widely used in the field of implantology. AIM: To observe the clinical effect of GBR in repairing bone defect after enucleation of small and medium-sized odontogenic jaw cysts. METHODS: From June 2018 to September 2020, 13 patients (7 male, 6 female) with odontogenic jaw cysts were treated in the Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Adults without hypertension, heart disease, diabetes or other systemic diseases were selected. The diagnosis was based on the final pathological results: 11 cases were diagnosed as apical cysts, one as primordial cyst, and one as dentigerous cyst. The lesions were located in the maxilla in seven cases, and in the mandible in six cases. All cases were treated with the same method of enucleation combined with GBR. RESULTS: Three to four months after the operation, the boundary between the implant site and the surrounding normal stroma was not obvious in patients with small-sized odontogenic jaw cysts. The patients with tooth defects were treated with implant after 6 mo. For the patients with medium-sized odontogenic jaw cysts, the density of the center of the implant area was close to the normal mass at 6 mo after surgery, and there was a clear boundary between the periphery of the implant area and the normal mass. The boundary between the periphery of the implant area and the normal mass was blurred at 8-9 mo after surgery. Patients with tooth defects were treated with implants at > 6 mo after the operation. CONCLUSION: Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts can shorten the time of osteogenesis, increase the amount of new bone formation, reduce complications, and improve quality of life.

A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis.

BACKGROUND: Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial-mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. METHODS: The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. RESULTS: The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients' survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. CONCLUSIONS: Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.

Effects of prolonged cold ischemia on the DCD kidney function and Inflammasome expression in rat kidney transplants.

BACKGROUND: Acute kidney injury (AKI) is the main reason for the bad outcome of the donation of circulatory death (DCD) kidney after transplantation. Prolonged cold storage (CS) is a risk factor for the occurrence of the delayed graft function in DCD kidney. The protein NLR-domain containing receptor 3 (NLRP3) plays a crucial role in renal ischemia reperfusion injury by triggering inflammasome formation. Herein, we investigated whether the NLRP3 signal participate in the CS-induced damage of DCD kidney in rat kidney transplantation models. MATERIALS AND METHODS: DCD kidney and living donor (LD) kidney of SD rats were preserved in UW solution at 4 °C for 2 h or 18 h, and then transplanted into syngeneic recipient. Thus, the animals were randomly divided into 4 groups: 2-h LD group, 2-h DCD group, 18-h LD group and 18-h DCD group. The renal function and pathological changes were determined. The expressions of NLRP3 and inflammatory factor IL-1ß were assessed. The concentration of ferrous iron (Fe2+) was analyzed both in kidneys and in the preservation solution. The renal morphological changes were examined by hematoxylin eosin staining. RESULTS: Our results showed that the levels of Cr and BUN were higher in 18-h LD group as compared to the 2-h LD group, which were remarkably increased in 18-h DCD group. The expression levels of NLRP3 and IL-1ß were increased by 18-h CS compared to 2-h CS in both LD kidney and DCD kidney. In addition, the Fe2+ concentration has significantly increased in 18-h LD group than that in 2-h LD group, and the elevation of Fe2+ was more remarkable in DCD kidneys. CONCLUSION: In conclusion, our study demonstrated that prolonged hypothermic storage of DCD kidney deteriorated the graft function via the increased Fe2+ concentration, which was associated with the upregulation of NLRP3 expression.

Malignant solitary fibrous tumor in the central nervous system treated with surgery, radiotherapy and anlotinib: A case report.

BACKGROUND: Solitary fibrous tumor (SFT) of the central nervous system is rare. It is predominantly benign and rarely malignant. There is no established standardized treatment regimen for malignant intracranial SFTs. CASE SUMMARY: We present a rare case of SFT in a 9-year-old girl with a space-occupying effect in the frontal-parietal lobes. She underwent craniotomy, and the mass was resected. Immunohistochemistry examination of the specimen showed that Ki-67 proliferation index staining was highly positive in 80% of tumor cells. Whole exome sequencing of the surgical tissue showed 38 somatic gene mutations and 1 gene amplification such as fibroblast growth factor receptor 4 or TP53. At 1.5 mo after surgery, head magnetic resonance imaging revealed that the tumor had recurred. The patient received 60 Gy and 30 fractions of intensity modulated radiotherapy. The patient then received anlotinib 8 mg po qd for 1-14 d of a 21 d cycle. Following this regimen, the patient achieved stable disease for > 17 mo. Magnetic resonance imaging at 1.5 year after surgery showed that the tumor had not progressed. CONCLUSION: This is the first reported case of SFT of the central nervous system treated with surgery, radiotherapy and anlotinib. This regimen may be an effective treatment option for malignant intracranial SFT patients.

Abdominopelvic leiomyoma with large ascites: A case report and review of the literature.

BACKGROUND: Leiomyoma of the uterus is relatively common, but uterine leiomyoma of the greater omentum is rare. CASE SUMMARY: Here, we report the case of a 22-year-old woman who presented with a 3 mo history of progressive abdominal distension and a hypervascular abdominopelvic mass. Due to a high serum concentration of CA125, the preoperative diagnosis was unclear. During surgery, 5 L of ascites was removed. An 18.8 cm solid mass, which was pedunculated from the uterine fundus and exhibited complex adhesion to the greater omentum, was removed. The CA125 level was reduced postoperatively, and a pathologic study confirmed that the mass was a leiomyoma that originated in the uterus. CONCLUSION: Uterine leiomyoma can share vessels with the greater omentum. This case highlights the difficulty of diagnosing pseudo-Meigs syndrome and the importance of imaging and laboratory examinations.

HPV-16/18 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1.

Oncogenic high-risk human papillomavirus (HR-HPV) infection causes a majority of cases of cervical cancer and pre-cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV-16/18-infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA-seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV-16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV-16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA-mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl-capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV-16 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.

Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats.

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.

CapsCarcino: A novel sparse data deep learning tool for predicting carcinogens.

Determining chemical carcinogenicity in the early stages of drug discovery is fundamentally important to prevent the adverse effect of carcinogens on human health. There has been a recent surge of interest in developing computational approaches to predict chemical carcinogenicity. However, the predictive power of many existing approaches is limited, and there is plenty of room for improvement. Here, we develop a new deep learning architecture, termed CapsCarcino, to distinguish between carcinogens and noncarcinogens. CapsCarcino is constructed based on a dynamic routing algorithm that requires less data, extracts more comprehensive information, and does not require feature selection. We find that CapsCarcino provides a significantly improved predictive and generalization ability over, and outperforms five other machine learning models. Specifically, the best model of CapsCarcino achieves an accuracy of 85.0% on an external validation dataset. In addition, we discover that the enhanced predictive capability of CapsCarcino over that of the other methods is robust and can be achieved using sparse datasets. Training on merely 20% of the dataset, CapsCarcino performs comparably to the other methods based on the full training dataset. Further mechanism analysis indicates that CapsCarcino could efficiently learn the characteristics of carcinogens even if structural alerts are insufficiently represented. The results indicate that CapsCarcino should be helpful for carcinogen risk assessment.

Pro-inflammatory role of high-mobility group box-1 on brain mast cells via the RAGE/NF-κB pathway.

High-mobility group box-1 (HMGB-1) acts as a pro-inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro-inflammatory effects of HMGB-1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB-1 and explored whether this process is involved in the pro-inflammatory effects of HMGB-1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB-1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague-Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB-1. Increased levels of tumor necrosis factor and IL-1ß were observed in the P815 cells, as well as in the rats' brains, after HMGB-1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)-siRNA inhibited the HMGB-1-induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor-κB (NF-κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB-1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood-brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB-1-induced pro-inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro-inflammatory effect of HMGB-1 on the CNS, probably via activating the RAGE/NF-κB pathway.

Minor allele of rs1057317 polymorphism in TLR4 is associated with increased risk of Helicobacter pylori -induced gastric cancer.

BACKGROUND: Helicobacter pylori (HP) plays a significant role in the carcinogenesis of gastric cancer (GC), the second leading cause of cancer-related death worldwide. The aim of this study was to investigate the effect of rs1057317 polymorphism on the interaction between microRNA-034a (miR-034a) and toll-like receptor 4 (TLR4), and their involvement in the HP-associated GC. METHODS: Computation analyses, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and luciferase assays were performed to identify potential miRNAs involved in the carcinogenesis of HP-induced GC. Subsequently, the effect of miR-34a and recombinant TNFα-interacting protein α (rTip-α) on the expression of TLR4, interleukin (IL)-6, and tumor necrosis factor α (TNF-α) was measured. RESULTS: Three hundred and twelve HP-positive GC patients (HP+ GC) and 380 HP-negative GC patients (HP- GC) were enrolled into this study. It was found that, in HP-positive patient, the AA genotype of the rs1057317 polymorphism was closely associated with the risk of GC (95% confidence interval, 1.12 to 2.70; odds ratio, 1.74; P = 0.0129). Furthermore, between the HP+ GC and HP- GC groups, miR-34a was the only miRNA showing a significantly different expression. Subsequently, TLR4 was identified as a target gene of miR-34a. Interestingly, miR-34a evidently reduced the expression of TLR4 3'-untranslated region (3'-UTR) containing the C allele of the rs1057317 polymorphism, but the TLR4 3'-UTR containing the A allele in the rs1057317 was not affected by miR-34a. In addition, the expression of IL-6 and TNF-α was significantly downregulated by miR-34a, but increased by rTip-α. Both miR-34a and rTip-α could enhance the viability of cells, although the effect of rTip-α was stronger. CONCLUSION: The data of this study suggested that the rs1057317 polymorphism in the miR-34a binding site of TLR4 may predict the risk of HP-induced GC.

Erinacine Facilitates the Opening of the Mitochondrial Permeability Transition Pore Through the Inhibition of the PI3K/ Akt/GSK-3ß Signaling Pathway in Human Hepatocellular Carcinoma.

BACKGROUND/AIMS: Erinacine, which is extracted from the medicinal mushroom Hericium erinaceus, is known to play anticancer roles in human cancers. The following study aims to investigate the role of erinacine in the opening of the mitochondrial permeability transition pore (MPTP) in hepatocellular carcinoma (HCC) through the PI3K/Akt/GSK-3ß signaling pathway and highlights the applicability of erinacine in HCC treatments. METHODS: HCC and paracancerous tissues were obtained from 85 HCC patients who've undergone surgical resection. Immunohistochemistry was adopted to detect positive expression of PI3K, Akt, and GSK-3ß. Treatment of HepG-2 with LY294002 (an inhibitor of the PI3K/Akt/GSK-3ß signaling pathway) and different concentration of erinacine was performed to determine the involvement of LY294002 in erinacine action. The expressions of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, Bcl-2, E-cadherin, Bax, and caspase-9 were determined by RT-qPCR and Western blot analysis. Cell viability, colony formation rate, migration, invasion, cycle, and apoptosis were detected by MTT, colony formation, wound healing assay, Transwell assay, and flow cytometry, respectively. The size and weight of xenograft tumors were observed in nude mice. Mitochondrial membrane potential in HepG-2 was determined using laser scanning confocal microscopy following JC-1 staining. Mitochondrial Ca2+ indicator Rhod-2, AM was used to detect the changes of mitochondrial Ca2+, while western blot analysis was employed to detect the presence levels of cytochrome C (cyt-C). RESULTS: The results revealed that PI3K, Akt, and GSK-3ß were up-regulated in HCC tissues. Erinacine or LY294002 led to a decrease in mitochondrial membrane potential, increase in intracellular mitochondrial Ca2+, and the release of cyt-C in mitochondria. In addition, Erinacine was found to decrease the mitochondrial membrane potential, expression of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, and Bcl-2, cell proliferation, colony formation ability, migration, invasion, and xenograft tumor size, while E-cadherin, Bax, and caspase-9 expression, and cell apoptosis were elevated in a dose-dependent manner. Erinacine also stimulated the effects of LY294002 on the HCC. Following the addition of 500 µM Erinacine and MPTP opening inhibitor CsA, we found that the mitochondrial membrane potential level increased, while mitochondrial Ca2+ and Cyt-C decreased from the mitochondria. CONCLUSION: The results from the study demonstrated that erinacine induced MPTP opening, facilitates the release of cyt-C, and inhibited cell proliferation, migration, and invasion, while it promotes apoptosis by inactivating the PI3K/Akt/GSK-3ß signaling pathway, preventing the progression of HCC.

Metformin: a review of its potential indications.

Metformin is the most commonly prescribed drug for type 2 diabetes mellitus. In recent years, in addition to glucose lowering, several studies have presented evidence suggesting some potential role for metformin, such as antitumor effect, antiaging effect, cardiovascular protective effect, neuroprotective effect or an optional treatment for polycystic ovary syndrome. This paper will critically review the role of metformin to provide reference for doctors and researchers.

A case report of targeted therapy with apatinib in a patient with advanced gastric cancer and high serum level of alpha-fetoprotein.

BACKGROUND: Alpha-fetoprotein (AFP) is an important marker for hepatocellular carcinoma, and the detection of serum AFP is currently the principle method for the diagnosis of hepatocellular carcinoma. The prevalence of gastric cancer (GC) with high level of serum AFP is extremely rare, but has unique clinical features. CASE SUMMARY: We herein present a rare case with GC and high level of serum AFP. A 64-year-old Chinese female underwent gastrectomy was diagnosed as gastric adenocarcinoma and the pathological stage was T1bN0M0, IA. With the progression of disease, the tumor widely metastasized and the serum AFP level increased progressively with the highest level of 3396 ng/mL. She successively entered into 3 lines palliative systematic chemotherapy and fourth-line targeted therapy of apatinib, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. Although previous studies suggested that the prognosis of this special type of GC was poor, this patient lived for 22 months after tumor transfer. Apatinib kept her progression-free survival for 5 months, and the overall survival was 4.5 years. CONCLUSION: So, we speculate that maybe we can focus apatinib on serum AFP elevated GC patients.

Discovery of 2-((3-cyanopyridin-2-yl)thio)acetamides as human lactate dehydrogenase A inhibitors to reduce the growth of MG-63 osteosarcoma cells: Virtual screening and biological validation.

Lactate dehydrogenase A (LDHA) has emerged as an attractive target in the oncology field. In this paper, we present the identification of 2-((3-cyanopyridin-2-yl)thio)acetamide-containing compounds as LDHA inhibitors. The in vitro enzymatic assay suggested that inhibitor 9 had good inhibitory potency against LDHA with IC50 value as 1.24µM. Cytotoxicity assay showed that inhibitor 9 strongly inhibited the proliferation of cancer cell MG-63 (EC50=0.98µM). These findings indicated that inhibitor 9 could be employed as a lead for developing more potent LDHA inhibitor with anti-proliferative potency.