Balanced opioid-free anesthesia with lidocaine and esketamine versus balanced anesthesia with sufentanil for gynecological endoscopic surgery: a randomized controlled trial.

In this randomized controlled trial, 74 patients scheduled for gynecological laparoscopic surgery (American Society of Anesthesiologists grade I/II) were enrolled and randomly divided into two study groups: (i) Group C (control), received sufentanil (0.3 µg/kg) and saline, followed by sufentanil (0.1 µg/kg∙h) and saline; and (ii) Group F (OFA), received esketamine (0.15 mg/kg) and lidocaine (2 mg/kg), followed by esketamine (0.1 mg/kg∙h) and lidocaine (1.5 mg/kg∙h). The primary outcome was the 48-h time-weighted average (TWA) of postoperative pain scores. Secondary outcomes included time to extubation, adverse effects, and postoperative sedation score, pain scores at different time points, analgesic consumption at 48 h, and gastrointestinal functional recovery. The 48-h TWAs of pain scores were 1.32 (0.78) (95% CI 1.06-1.58) and 1.09 (0.70) (95% CI 0.87-1.33) for Groups F and C, respectively. The estimated difference between Groups F and C was - 0.23 (95% CI - 0.58 - 0.12; P = 0.195). No differences were found in any of the secondary outcomes and no severe adverse effects were observed in either group. Balanced OFA with lidocaine and esketamine achieved similar effects to balanced anesthesia with sufentanil in patients undergoing elective gynecological laparoscopic surgery, without severe adverse effects.Clinical Trial Registration: ChiCTR2300067951, www.chictr.org.cn 01 February, 2023.

Regulating Benzene Ring Number as Connector in Covalent Organic Framework for Boosting Photosynthesis of H2O2 from Seawater.

Photosynthesis of H2O2 from seawater represents a promising pathway to acquire H2O2, but it is still restricted by the lack of a highly active photocatalyst. In this work, we propose a convenient strategy of regulating the number of benzene rings to boost the catalytic activity of materials. This is demonstrated by ECUT-COF-31 with adding two benzene rings as the connector, which can result in 1.7-fold enhancement in the H2O2 production rate relative to ECUT-COF-30 with just one benzene ring as the connector. The reason for enhancement is mainly due to the release of *OOH from the surface of catalyst and the final formation of H2O2 being easier in ECUT-COF-31 than in ECUT-COF-30. Moreover, ECUT-COF-31 provides a stable photogeneration of H2O2 for 70 h, and a theoretically remarkable H2O2 production of 58.7 mmol per day from seawater using one gram of photocatalyst, while the cost of the used raw material is as low as 0.24 $/g.

Ultra-selective uranium separation by in-situ formation of π-f conjugated 2D uranium-organic framework.

With the rapid development of nuclear energy, problems with uranium supply chain and nuclear waste accumulation have motivated researchers to improve uranium separation methods. Here we show a paradigm for such goal based on the in-situ formation of π-f conjugated two-dimensional uranium-organic framework. After screening five π-conjugated organic ligands, we find that 1,3,5-triformylphloroglucinol would be the best one to construct uranium-organic framework, thus resulting in 100% uranium removal from both high and low concentration with the residual concentration far below the WHO drinking water standard (15 ppb), and 97% uranium capture from natural seawater (3.3 ppb) with a record uptake efficiency of 0.64 mg·g-1·d-1. We also find that 1,3,5-triformylphloroglucinol can overcome the ion-interference issue such as the presence of massive interference ions or a 21-ions mixed solution. Our finds confirm the superiority of our separation approach over established ones, and will provide a fundamental molecule design for separation upon metal-organic framework chemistry.

Strong Electron Transfer in Covalently Integrating Cu(I)-Organic Frameworks Enabling Effective Radionuclide Capture.

Rational construction of strong electron-transfer materials remains a challenging task. Herein, we show a design rule for the construction of strong electron-transfer materials through covalently integrating electron-donoring Cu(I) clusters and electron-withdrawing triazine monomers together. As expected, Cu-CTF-1 (Cu(I)-triazine framework) was found to enable strong electron transfer up to 0.46|e| from each Cu(I) metal center to each adjacent triazine fragment. This finally leads to good spatial separation in both photogenerated electron-hole pairs and function units for photocatalytic uranium reduction under ambience and no sacrificial agent and to good charge separation of [I+][I5-] for I2 immobilization under extremely rigorous conditions. The results have not only opened up a structural design principle to access electron-transfer materials but also solved several challenging tasks in the field of radionuclide capture and CTFs.

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer.

OBJECTIVE: Although the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC. SUBJECTS AND METHODS: This was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC). RESULTS: The median follow-up was 5.2 years. Compared with instillation for 1-2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3-6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27-12.41;0.26-9.28;0.07-0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC. CONCLUSIONS: In our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

ED95 of remimazolam in nasal administration for attenuating preoperative anxiety in children.

Background: Preoperative anxiety often prevails in children at higher levels than adults, which is a common impediment for surgeons and anesthesiologists. It is of great necessity to explore an appropriate medication to improve this situation. Remimazolam, a type of benzodiazepine drug, has been indicated for the induction and maintenance of procedural sedation in adults since 2020. To date, rare studies were reported to investigate the effect of remimazolam on children. In this study, we investigated the safety and efficacy of intranasal drops of remimazolam and tried to determine the 95% effective dose (ED95) of remimazolam in single intranasal administration in attenuating preoperative anxiety in children. Methods: In this study, 114 children were enrolled who underwent laparoscopic high-level inguinal hernia ligation between January 2021 and December 2022 and were divided into an early childhood children group and a pre-school children group. The biased coin design (BCD) was used to determine the target doses. A positive response was defined as the effective relief of preoperative anxiety (modified Yale Preoperative Anxiety Scale, mYPAS < 30). The initial nasal dose of remimazolam was 0.5 mg·kg-1 in the two groups. An increment or decrement of 0.1 mg·kg-1 was applied depending on the sedative responses. Isotonic regression and bootstrapping methods were used to calculate the ED95 and 95% confidence intervals (CIs), respectively. Results: A total of 80 children completed the study, including 40 in the early childhood group and 40 in the pre-school children group. As statistical analysis indicated, the ED95 of a single intranasal infusion of remimazolam for the relief of preoperative anxiety is 1.57 mg·kg-1 (95% CI: 1.45-1.59 mg·kg-1) in early childhood children and 1.09 mg·kg-1 (95% CI: 0.99-1.11 mg·kg-1) in pre-school children, and the CIs did not overlap each other. Conclusion: Remimazolam is an effective medication to relieve preoperative anxiety in children. Moreover, the ED95 of single nasal administration of remimazolam for effective relief of preoperative anxiety was 1.57 and 1.09 mg·kg-1 in early childhood children and pre-school children, respectively.

Total Glucosides of Paeony Regulate Immune Imbalance Mediated by Dermal Mesenchymal Stem Cells in Psoriasis Mice.

OBJECTIVE: To investigate the therapeutic effects of total glucosides of paeony (TGP) on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells (DMSCs). METHODS: A total of 30 male BALB/c mice were divided into 6 groups (n=5 in each) by a random number table method, including control, psoriasis model (model, 5% imiquimod cream 42 mg/d), low-, medium- and high-dose TGP (50, 100, and 200 mg/kg, L, M-, and H-TGP, respectively), and positive control group (2.5 mg/kg acitretin). After 14 days of continuous administration, the skin's histopathological changes, apoptosis, secretion of inflammatory cytokines, and proportion of regulatory T cells (Treg) and T helper cell 17 (Th17) were evaluated using hematoxylin-eosin (HE) staining, TdT-mediated dUTP nick end labeling staining, enzyme-linked immunosorbent assay, and flow cytometry, respectively. DMSCs were further isolated from the skin tissues of normal and psoriatic mice, and the cell morphology, phenotype, and cycle were observed. Furthermore, TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation. RESULTS: TGP alleviated skin pathological injury, reduced epidermis layer thickness, inhibited apoptosis, and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice (P<0.05 or P<0.01). There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs (P>0.05), however, more psoriatic DMSCs remained in G0/G1 phase compared with the normal DMSCs (P<0.01). TGP treatment of psoriatic DMSCs significantly increased cell viability, decreased apoptosis, relieved inflammatory response, and inhibited the expression of toll-like receptor 4 and P65 (P<0.05 or P<0.01). CONCLUSION: TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs.

Attention bias modification for depression: A systematic review and meta-analysis.

Background: Depression is a mental health disorder characterized by affective, somatic, and cognitive symptoms. Attention bias modification (ABM) has been widely used to treat depression. However, the results seem inconsistent. We conducted a systematic review and meta-analysis to investigate the efficacy of ABM for depression and to explore the optimal protocol of ABM. Methods: Seven databases were systematically searched from their inceptions to 5 October 2022 to include randomized controlled trials (RCTs) of ABM for depression. Two independent reviewers selected the eligible articles, extracted data, and evaluated the risk of bias using version 2 of the Cochrane risk-of-bias tool (ROB 2.0) for randomized trials. The primary outcome was the evaluation of depressive symptoms using widely accepted and validated scales. The secondary outcomes included rumination and attentional control. Meta-analysis was conducted by using RevMan (version 5.4) and Stata (version 12.0). Subgroup analyses and meta-regressions were performed to identify the source of heterogeneity. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: A total of 19 trials involving 20 datasets (1,262 participants) were included. The overall risk of bias in one study was rated as low risk of bias, three studies were considered as high, and the remaining studies were some concerns. Compared with attention control training (ACT), ABM had a greater effect in the improvement of depression (SMD = -0.48, 95% CI -0.80 to -0.17, I2 = 82%) and rumination (MD = -3.46, 95% CI -6.06 to -0.87, I2 = 0%). No significant differences were observed in the attentional control outcome between ABM and ACT (MD = 3.07, 95% CI -0.52 to 6.65, I 2 = 0%). Subgroup analysis demonstrated that adults exhibited a greater decrease in depression scores than adolescents. ABM using the dot-probe task, training target stimulus presented by face, and training directions by left-right were associated with better antidepressant effects. ABM training delivered in the laboratory tended to yield a better effect than those conducted at home. Sensitivity analysis indicated that the results were robust. The certainty of the evidence for all outcomes was low or very low, and publication bias may exist. Conclusion: Due to high heterogeneity and limited studies, not enough current evidence supported that ABM could be an effective intervention to relieve depressive symptoms. More rigorous RCTs are required to verify the benefits and to explore the optimal protocol of ABM training for depression.Systematic Review Registration: [PROSPERO], identifier [No. CRD42021279163].

Creating High-Number Defect Sites through a Bimetal Approach in Metal-Organic Frameworks for Boosting Trace SO2 Removal.

Herein, we represent a bimetallic approach to enhance the defect number, leading to eight defect sites per node in a metal-organic framework, showing both a higher SO2 adsorption capacity and higher SO2/CO2 selectivity. The results can be further strongly supported by density functional theory calculations.

Intravenous lidocaine on postoperative pain and opioid consumption during gynecological surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: This study aimed to evaluate the role of intravenous lidocaine as a adjuvant anesthetics in patients undergoing gynecological surgery. EVIDENCE ACQUISITION: We conducted a meta-analysis of randomized controlled trials (RCTs) from PUMED/MELINE, EMBASE and clinic trails.gov involving the use of intravenous lidocaine in gynecological surgery. We used a more comprehensive search strategy to adequately screen for randomized controlled trials involving intravenous lidocaine infusion in gynecological surgery. First outcomes were postoperative pain scores. And secondary outcomes included 24 h postoperative opioids consumption, time to first flatus, and incidence of postoperative nausea and vomiting. EVIDENCE SYNTHESIS: A total of 6 RCTs comprising 375 patients were included in the meta-analysis. There were statistically significant between postoperative pain scores. The consumption of opioids and anesthetics during surgery and 24 hours after surgery was statistically significant when compared with the control group. Postoperative pain scores were similar at 2,4,6,8,10,12,24,48 hour between groups. No statistical differences were found in postoperative complications including nausea, vomiting and restoration of the intestinal function. CONCLUSIONS: Our results indicated that the current literature supports the perioperative use of intravenous lidocaine as part of multimodal analgesia and beneficial to patients in early postoperative analgesia, reduced opioid consumption.

Coexistence of cervical extramedullary plasmacytoma and squamous cell carcinoma: A case report.

BACKGROUND: Extramedullary plasmacytoma (EMP), a variant form of myeloma, is a rare solid plasma cell tumor that originates from the bone marrow hematopoietic tissue and accounts for about 3% of all plasma cell tumors. EMP can affect various tissues and organs, about 90% of which is found in the head and neck. However, EMP in the reproductive organs is rare, and is difficult to be distinguished from other primary or metastatic genital tumors according to clinical symptoms and imaging findings. CASE SUMMARY: Herein, we report a case with coexistence of EMP and squamous cell carcinoma in the cervix. The first histopathological report of neoplasms on the surface of the cervix and vagina showed an EMP. Both ultrasound and pelvic enhanced magnetic resonance imaging (MRI) indicated that there was a tumor in the cervix. Thus, another cervical biopsy and pathological examination were performed, which indicated EMP combined with squamous cell carcinoma. Then, the patient underwent extensive total hysterectomy (type C1) + systemic lymph node dissection and received 25 external pelvic irradiations with a dose of 50 Gy following surgery. During 2-year follow-up, no recurrence was reported. CONCLUSION: In conclusion, EMP involving the reproductive system is relatively rare. In this case, MRI, B-ultrasound, and cervical canal scraping were used to further determine the diagnosis of EMP combined with squamous cell carcinoma. The patient had improved prognosis after appropriate treatments.

Case Report: Acute Renal Infarction in a Child With Coarctation of Aorta.

Renal arterial infarction can present with hematuria, proteinuria, and hypertension, features often linked to glomerular disease. An aortic aneurysm is an extraordinarily rare complication of coarctation of the aorta. Acute renal infarction caused by emboli from the aortic aneurysm is a possible complication that has not been reported. We herein report a 10-year-old boy who presented with hematuria, proteinuria, hypertension, and skin rashes on both lower extremities mimicking acute glomerulonephritis but actually resulting from acute renal infarction caused by a coarcted aneurysm-associated thrombus. He was successfully treated with surgical excision of the coarcted aorta and aneurysm followed by subcutaneous low molecular weight heparin without recurrence.

[Research Advance on In Vitro Generation of Human Hematopoietic Stem Cells for Transplantation--Review].

Abstract　　Currently, hematopoietic stem cell (HSC) transplantation is widely used in the therapy of hematological malignancies, non-malignant refractory anemia, genetic diseases and certain tumors with satisfactory therapeutic efficacy. HSC sources used for transplantation include bone marrow, mobilized peripheral blood and neonate umbilical cord blood. However, for many patients, sufficient number of human leukocyte antigen (HLA) -matched HSC cannot be found for transplantation, because the number of HSC in these tissues is small and HLA-identical donors are rare. Thus, in vitro generation of HSC has recently been focused. At present, the origin of HSC is hPSC, including hESC and hiPSC, which is worth to be the new origin of HSC transplantation. However, to generate functional hematopoietic stem cells which have efficient multi-lineage differentiation and in vivo engraftment potentials still is a big challenge to be confronted. In this review, the recent technical progress in HSC generation is summarizd, and the problems to be solved and new challenges to be confronted were discussed.

MicroRNA-132-3p inhibits tumor malignant progression by regulating lysosomal-associated protein transmembrane 4 beta in breast cancer.

Lysosomal-associated protein transmembrane 4 beta (LAPTM4B), a proto-oncogene, has been shown to be a positive modulator in cancer progression. However, the mechanism of LAPTM4B regulation is not fully elucidated. Aberrant microRNAs (miRNAs) can regulate gene expression by interfering with target transcripts and/or translation to exert tumor-suppressive or oncogenic effects in breast cancer. In the present study, miR-132-3p, which was predicted by relevant software, was confirmed to directly bind to the 3' untranslated region (3'UTR) of LAPTM4B and negatively regulate its expression in luciferase reporter and western blot assays. Subsequently, we validated that miR-132-3p was downregulated in breast cancer tissues. Receiver-operating characteristic curve analysis indicated that miR-132-3p had accurate diagnostic value, and a Kaplan-Meier and Cox regression model showed that miR-132-3p was a potential prognostic marker for recurrence, showing low levels in breast cancer patients. In addition, we showed that miR-132-3p was inversely correlated with LAPTM4B expression in the above samples. Functionally, miR-132-3p suppressed the migration and invasion of breast carcinoma cells through LAPTM4B by mediating epithelial-mesenchymal transition signals, and partially reversed the carcinogenic effects of LAPTM4B by inhibiting the PI3K-AKT-mTOR signaling pathway. Taken together, these findings provide the first comprehensive analysis of miR-132-3p as a direct LAPTM4B-targeted miRNA, and shed light on miR-132-3p/LAPTM4B as a significant functional axis involved in the oncogenesis and metastasis of breast cancer.

LAPTM4B is a novel diagnostic and prognostic marker for lung adenocarcinoma and associated with mutant EGFR.

BACKGROUND: Lysosomal-associated protein transmembrane-4 beta (LAPTM4B), a novel oncogene, promotes tumorigenesis and may be a potential prognostic biomarker in several cancers. This study was to determine the clinical significance and biological roles of LAPTM4B in lung adenocarcinoma (LAC). METHODS: LAPTM4B expression was analyzed by immunohistochemistry (IHC) of 63 LAC tumors. Serum levels of LAPTM4B were measured by enzyme-linked immuosorbent assays (ELISA). The study included untreated group (n = 216), chemotherapy group (n = 29), chemotherapy efficacy group (n = 179), EGFR-TKIs group (n = 57) and 68 healthy controls. Statistical analysis was performed to explore the correlation between LAPTM4B expression and clinicopathological parameters in LAC. Kaplan-Meier analysis was performed to assess the prognostic significance of LAPTM4B in LAC. In vitro assays were performed to assess the biological roles of LAPTM4B in LAC cells. Western blotting assays were examined to identify the underlying pathways involved in the tumor-promoting role of LAPTM4B. RESULTS: We found LAPTM4B was upregulated in LAC tissues and high LAPTM4B expression was significantly correlated with poor prognosis. Serum LAPTM4B levels were significantly decreased after chemotherapy. Patients in invalid response group showed higher LAPTM4B levels than the valid response group. Overexpression of LAPTM4B promoted, while silencing of LAPTM4B inhibited proliferation, invasion and migration of LAC cells via PI3K/AKT and EMT signals. LAPTM4B expression level was associated with epidermal growth factor receptor (EGFR) gene mutations. In addition, LAPTM4B plays important roles in EGFR-promoted cell proliferation, migration and invasion and gefitinib-induced apoptosis. CONCLUSIONS: Collectively, our data propose that LAPTM4B may be a cancer biomarker for LAC and a potential therapeutic target which facilitates the development of a novel therapeutic strategy against LAC.

Discover the leading compound of 4ß-S-(5-fluorobenzoxazole)-4-deoxy-4'-demethylepipodophyllotoxin with millimolar-potency toxicity by modifying the molecule structure of 4'-demethylepipodophyllotoxin.

4'-Demethylepipodophyllotoxin (DMEP) derivatives are broad-spectrum and potent antitumor leading compound. Because of their unacceptable toxicity, DMEP derivatives often failed in the development of new drug. Until now, there was no report on the millimolar-potency toxicity of DMEP derivatives by modifying the molecule structure of DMEP. For the first time, this work discovered leading compounds with millimolar-potency toxicity by modifying the molecule structure of DMEP. The IC50 value of 4ß-S-(5-fluorobenzoxazole-2-)-4-deoxy-4'-demethylepipodophyllotoxin (Compound 2) was around 323.4-2000.9 µM on human healthy cells (i.e., HL-7702, H8, MRC-5 and HMEC), which was significantly reduced by 171-1999 times than podophyllotoxin (1.0-2.6 µM) and 9-80 times than etoposide (21.5-75.4 µM). Compared with the treatment of etoposide, DNA repair proteins HMGB1 and PARK7 were specifically activated and the expression of anti-apoptotic proteins were up-regulated in HL-7702 cells after the treatment of Compound 2. These indicated the toxicity of Compound 2 was synergistically reduced by DNA repair and anti-apoptosis pathway.

Experience with thoracic endovascular aortic repair applied in treating Stanford type B aortic dissection: An analysis of 98 cases.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has been frequently applied in Stanford type B aortic dissection since thoracic aortic diseases were first treated with artificial vessels. OBJECTIVES: The aim of this study was to analyze the clinical value of TEVAR applied in treating Stanford type B aortic dissection. MATERIAL AND METHODS: Between January 2007 and April 2014, 167 consecutive Stanford type B aortic dissection patients were treated with TEVAR and retrospectively analyzed. RESULTS: All patients had a successful operation. A total of 98 patients were followed-up and the duration of the follow-up ranged from 3 to 63 months with a mean of 25.6 ±8.4 months. Proximal type I endoleak occurred in 18 patients with an incidence rate of 18.37% and a cuff was deployed in 7 patients, in whom the endoleak disappeared after 3 months. Two patients died in the perioperative period: one died from aortic dissection rupture, while the other died from infectious shock. One patient died from acute myocardial infarction during the follow-up period. Tears occurred in the end piece of stent grafts in 12 patients, and additional TEVAR was performed. One patient had a proximal retrograde type A dissection; the patient was in an acceptable state of health apart from persistent chest and back pain, and is still in follow-up. Spinal cord ischemia, stent displacement and collapse did not occur. CONCLUSIONS: TEVAR is reliable and safe, and it can be widely applied in treating Stanford type B aortic dissection.

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression.

Lysosomal-associated protein transmembrane-4 beta (LAPTM4B) is a novel oncogene, whose overexpression is involved in cancer occurrence and progression. However, the mechanism of LAPTM4B transcriptional regulation remains unclear. In this study, the results of transcription factor (TF) profiling plate arrays indicated that AP4 was a potential transcription factor regulating LAPTM4B expression. LAPTM4B was positively correlated with AP4 and they were both associated with poor overall and disease-free survival. Luciferase and electrophoretic mobility shift assay assays confirmed that AP4 directly bound to the polymorphism region of LAPTM4B promoter and modulated its transcription. Functionally, AP4 promoted cell proliferation, migration, invasion, and assisted drug resistance in part through upregulation of LAPTM4B. Taken together, these findings identify LAPTM4B as a direct AP4 target gene and the interaction of AP4 and LAPTM4B plays an important role in breast cancer progression.Implications: This study demonstrates that AP4 promotes cell growth, migration, invasion, and cisplatin resistance through upregulation of LAPTM4B expression, thus representing an attractive therapeutic target for breast cancer. Mol Cancer Res; 16(5); 857-68. ©2018 AACR.

Bone marrow-derived mesenchymal stem cells induced by inflammatory cytokines produce angiogenetic factors and promote prostate cancer growth.

BACKGROUND: Prostate is susceptible to infection and pro-inflammatory agents in a man's whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. Mesenchymal stem cells (MSCs) are often recruited to the tumor microenvironment due to local inflammation. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. The current study investigated the possible involvement of MSCs stimulated by pro-inflammatory cytokines in promotion and angiogenesis of prostate cancer through relative pathway in vitro and in vivo. METHODS: A syngeneic mouse model of C57 was established. The murine prostate cancer cells (RM-1) mixing with MSCs treated with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) or vehicle were subcutaneously injected into C57 mice. Tumor volume of C57 mouse model was estimated and serum level of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) was test by Enzyme-linked Immunosorbent Assay (ELISA). A hen egg test-chorioallantoic membrane (HET-CAM) assay was applied to test the effect of conditioned media of stimulated MSCs in chorioallantoic membrane angiogenesis. Short interfering RNA (siRNA) knocked down either hypoxia-inducible factor-1alpha (HIF-1α) or nuclear factor-erythroid-2-related factor 2 (NRF2) were employed. mRNA of PDGF and VEGF in MSCs, as well as NRF2 and HIF-1α was test by Real time polymerase chain reaction (PCR) analyses. Protein expression levels of PDGF and VEGF from conditioned medium, NRF2, HIF-1α, as well as PDGF and VEGF in MSCs were detected by Western blot analysis. RESULTS: MSCs treated with TNF-α and IFN-γ promote tumor growth in C57 syngeneic mouse model, correlating with increased serum level of PDGF, VEGF. HET-CAM assay shows the angiogenic effect of conditioned medium of MSCs pre-treated with the pro-inflammatory cytokines. mRNA and protein levels of two pro-angiogenic factors (PDGF and VEGF) and key hypoxia regulators (HIF-1α and NRF2) in MSCs were induced after MSCs' pretreatment. siRNA knockdown either HIF-1α or NRF2 results reduction of PDGF and VEGF expression. CONCLUSIONS: MSCs stimulated by pro-inflammatory cytokines increase the expression of PDGF and VEGF via the NRF2-HIF-1α pathway and accelerate prostate cancer growth in mice.

cAMP responsive element binding protein-1 is a transcription factor of lysosomal-associated protein transmembrane-4 Beta in human breast cancer cells.

Lysosomal-associated protein transmembrane-4 beta (LAPTM4B) is a potential proto-oncogene, whose overexpression is involved in cancer occurrence and progression. Its transcript is up-regulated in various types of solid tumors including breast cancer. However, its transcriptional regulation mechanism is still unclear. To investigate the mechanism of transcriptional regulation of LAPTM4B in human breast cancer cells, a series of luciferase reporter constructs and construct with mutated binding site for cAMP responsive element binding protein-1 (CREB1) were generated by PCR amplification and transiently transfected into breast cancer cells to determine the transcriptional activities of different promoter regions. The +10+292 promoter region was possessed the highest transcriptional activity. The ability of CREB1 to bind the LAPMT4B promoter was confirmed by electrophoretic mobility shift assay, super-shift and RNA interference experiments. Our study identified the core promoter region responsible for constitutive expression of LAPTM4B and clarified that CREB1 played an important role in LAPTM4B transcriptional regulation in human breast cancer cells.