Comparable effectiveness of transforaminal endoscopic spine system technique combined with selective nerve root block between far lateral lumbar disc herniation and central or paracentral herniation.

OBJECTIVES: This study aims to compare the clinical effectiveness of transforaminal endoscopic spine system (TESSYS) technique combined with selective nerve root block (SNRB) in treating patients with far lateral lumbar disc herniation (FLDH) and patients with central or paracentral herniation (C/PDH). PATIENTS AND METHODS: Between June 2015 and June 2019, a total of 204 patients (80 males, 124 females; mean age: 62.3±5.4 years; range, 51 to 66 years) with a herniated disc were included. Of these, 22 consecutive adult patients with FLDH formed the FLDH group, while 182 patients with C/PDH formed the C/PDH group. Considering that FLDH was a rare type of LDH and occurred outside the spinal canal, the patients with LDH in the spinal canal (C/PDH) were selected as the controls in our study. All cases received ultrasound-guided SNRB to identify the diseased disc and treated by the TESSYS technique. Data including demographics, duration of operation, duration of hospital stay, surgical cost, complications, Visual Analog Scale (VAS) scores for the back and leg, and Oswestry Disability Index (ODI) scores and the modified MacNab criteria were analyzed. RESULTS: The FLDH group presented the similar clinical outcomes and costs with the C/PDH group. No significant differences in the VAS score, ODI score, and Macnab score were observed between the groups (p>0.05 for all). Both groups showed the significantly improved postoperative VAS scores on Day 3, at 1, 3, 6, and 12 months compared to baseline. The postoperative ODI scores at 6 and 12 months were also significantly improved (p<0.05). At the final follow-up at 12 months, the FLDH group showed the MacNab criteria rating excellent and good of 81.8% and C/PDH group showed 84.62%. CONCLUSION: The FLDH patients presented the comparable clinical effectiveness with C/PDH patients. Based on these findings, the TESSYS technique combined with ultrasound-guided SNRB for FLDH is safe and feasible with caution, although the risk of nerve root injury may be worried.

Clinical value of next-generation sequencing in guiding decisions regarding endocrine therapy for advanced HR-positive/HER-2-negative breast cancer.

Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor (HR)-positive advanced breast cancer. Circulating tumor DNA (ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2 (HER-2)-negative metastatic breast cancer patients. Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy; 2) estrogen receptor 1 (ESR1) mutation preferred fulvestrant; 3) HER-2 mutations preferred pyrotinib; and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival (PFS), and the secondary outcome measure was overall survival (OS). Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio (HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group (P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group (P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation. Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing (NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.

Volcanically driven lacustrine ecosystem changes during the Carnian Pluvial Episode (Late Triassic).

The Late Triassic Carnian Pluvial Episode (CPE) saw a dramatic increase in global humidity and temperature that has been linked to the large-scale volcanism of the Wrangellia large igneous province. The climatic changes coincide with a major biological turnover on land that included the ascent of the dinosaurs and the origin of modern conifers. However, linking the disparate cause and effects of the CPE has yet to be achieved because of the lack of a detailed terrestrial record of these events. Here, we present a multidisciplinary record of volcanism and environmental change from an expanded Carnian lake succession of the Jiyuan Basin, North China. New U-Pb zircon dating, high-resolution chemostratigraphy, and palynological and sedimentological data reveal that terrestrial conditions in the region were in remarkable lockstep with the large-scale volcanism. Using the sedimentary mercury record as a proxy for eruptions reveals four discrete episodes during the CPE interval (ca. 234.0 to 232.4 Ma). Each eruptive phase correlated with large, negative C isotope excursions and major climatic changes to more humid conditions (marked by increased importance of hygrophytic plants), lake expansion, and eutrophication. Our results show that large igneous province eruptions can occur in multiple, discrete pulses, rather than showing a simple acme-and-decline history, and demonstrate their powerful ability to alter the global C cycle, cause climate change, and drive macroevolution, at least in the Triassic.

Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis.

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at days 7-28 with a peak at day 21 tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Enhanced expression of microtubule-associated protein 7 functioned as a contributor to cervical cancer cell migration and is predictive of adverse prognosis.

BACKGROUND: Cervical cancer (CC) is one of the most common female malignancies over the world. Microtubule-associated protein 7 (MAP7) belongs to the family of microtubule-associated proteins (MAPs) which involve in microtubule dynamics and are critical in several important cellular and intracellular activities. This study aimed to investigate the expression and potential role of MAP7 in CC. METHODS: The expression level of MAP7 in CC tissues and normal tissues were analyzed using the data obtained from The cancer genomes atlas (TCGA) and genotype-tissue expression (GTEx) databases. The prognostic value of MAP7 in patients with CC was analyzed by Kaplan-Meier analysis, Univariate and Multivariate analyses. Moreover, the influences of MAP7 expression alteration on the viability and motility of Caski, HeLa and C-33A cells was measured by CCK8 assay, colony formation assay, scratch assay, and transwell migration and invasion assays. Flow cytometry was conducted to determine cell apoptosis. Western blot was performed to evaluate the impact of MAP7 on the expression of apoptotic-related proteins as well as mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. In vivo tumorigenicity assay was performed to explore the influence of MAP7 on tumor growth. RESULTS: Up-regulation of MAP7 was observed in CC tissues and high MAP7 expression was positively correlated with worse prognosis. Multivariate analyses suggested that MAP7 expression can be served as an independent predictor for overall survival of patients with CC. Knockdown of MAP7 markedly suppressed Caski and HeLa cell viability, migration and invasion while notably induced cell apoptosis. Furthermore, depletion of MAP7 in Caski and HeLa cells elevated the expression levels of Active-caspase 3 and Bax, but declined the level of Bcl-2. Whilst, overexpression of MAP7 in C-33A cells presented the opposite outcomes. Additionally, knockdown of MAP7 significantly decreased the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) in Caski and HeLa cells, and overexpression of MAP7 increased their phosphorylation in C-33A cells, indicating that MAP7 may regulate the MAPK signaling pathway in CC cells. In vivo assays revealed that knockdown of MAP7 remarkably repressed the growth of CC tumors. CONCLUSION: The results of the present study suggest that MAP7 functions as a promoter during the occurrence and progression of CC, and that MAP7 may serve as a promising therapeutic target in CC.

Neonatal ketamine exposure-induced hippocampal neuroapoptosis in the developing brain impairs adult spatial learning ability.

Ketamine exposure can lead to selective neuroapoptosis in the developing brain. p66ShcA, the cellular adapter protein expressed selectively in immature neurons, is a known pro-apoptotic molecule that triggers neuroapoptosis when activated. Sprague-Dawley rats at postnatal day 7 were subcutaneously injected in the neck with ketamine 20 mg/kg, six times at 2-hour intervals. At 0, 1, 3, and 6 hours after final injection, western blot assay was used to detect the expression of cleaved caspase-3, p66ShcA, and phosphorylated p66ShcA. We found that the expression of activated p66ShcA and caspase-3 increased after ketamine exposure and peaked at 3 hours. The same procedure was performed on a different group of rats. At the age of 4 weeks, spatial learning and memory abilities were tested with the Morris water maze. Latency to find the hidden platform for these rats was longer than it was for control rats, although the residence time in the target quadrant was similar. These findings indicate that ketamine exposure resulted in p66ShcA being activated in the course of an apoptotic cascade during the neonatal period. This may have contributed to the deficit in spatial learning and memory that persisted into adulthood. The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas at Arlington, USA (approval No. A13.008) on January 22, 2013.

TGR5 agonist INT-777 mitigates inflammatory response in human endometriotic stromal cells: A therapeutic implication for endometriosis.

Endometriosis is a condition characterized by the presence of endometrial tissues outside the uterus. Endometriotic stromal cells (ESCs) are known to undergo regeneration and are linked to the causation of endometriosis. Activation of stromal cells by local inflammatory cytokines is proposed to be one of the mechanisms of endometriosis development. Takeda-G-protein-receptor-5 (TGR5) is a G protein-coupled bile acid receptor that plays multiple roles in various cells and tissues. In this study, we show that activation of TGR5 by its specific agonist, INT-777, protects ESCs from inflammation and oxidative stress induced by tumor necrosis factor-α (TNF-α). TGR5 is fairly expressed in cultured ESCs, and TNF-α treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces the production of pro-inflammatory cytokines and adhesion molecules by TNF-α, including interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Moreover, INT-777 suppresses TNF-α-induced NADPH oxidase 4 (NOX4) expression and ameliorates cellular oxidative stress. Mechanistically, our findings demonstrate that INT-777 suppresses TNF-α-induced c-Jun N-terminal kinase (JNK) activation via suppression of p-JNK. INT-777 inhibits TNF-α-induced activation of the activator protein-1 (AP-1) pathway owing to its suppression of c-Jun and c-fos as well as transfected AP-1 promoter. INT-777 also inhibits nuclear factor-κB (NF-κB) activation as revealed by its suppression of TNF-α-induced nuclear p65 accumulation and NF-κB promoter. Collectively, our data indicate that activation of TGR5 by its agonist has protective effects against inflammation and reactive oxygen species (ROS) in cytokine-induced activation of ESCs. Therefore, INT-777 may have an implication in the clinical treatment of endometriosis.

Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis.

BACKGROUND: Ovarian cancer is a prominent public health problem which affects people all around the world. Platinum-based chemotherapy is a common treatment for ovarian cancer, however, the effectiveness of chemotherapy varies from patient to patient. The excision repair cross complementation group 1 (ERCC1) protein may mediate chemotherapy resistance. A meta-analysis was conducted to explore whether platinum-based chemotherapy effectiveness could be attributed to the ERCC1 C19007T polymorphisms. METHODS: Seven major databases (EMBASE, Web of Science, Pubmed, Springer Link, Chinese National Knowledge Infrastructure (CNKI), EBSCO and Science Direct databases) were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the results. RESULTS: In this meta-analysis, 1169 subjects (425 non-responders and 744 responders) from 8 studies were included. The overall OR (C vs. T alleles) using random model was 1.07 (95% CI 0.75-1.52, P = 0.7), which was not statistically significant. Moreover, there was no significant difference in the analysis by race. CONCLUSION: There is no association between the ERCC1 C19007T polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer. The polymorphism did not have a significant impact on platinum-based chemotherapy in non-responders and responders.

[Preparation and characterization of mouse polyclonal antibody against conserved region of human FOXO3].

Objective To purify the recombinant protein specific to conserved region of forkhead box O3 (FOXO3) and prepare mouse anti-human FOXO3 polyclonal antibody. Methods The DNA fragment (aa290-472) encoding conserved domain of FOXO3 was amplified by PCR, and subsequently cloned into pET28a vector. Following transformation into E.coli BL21, the soluble fusion protein His-FOXO3 was induced by IPTG and purified by Ni-NTA affinity chromatography. The purified protein was used to immunize BALB/c mice to generate polyclonal antibody. The characteristics of the polyclonal antibody were assessed by ELISA, Western blotting and immunoprecipitation assays. Results We successfully prepared the expression vector pET28a-FOXO3 (aa290-472) and expressed the purified fusion protein in a soluble form. By immunizing mice with the fusion protein, we obtained anti-human FOXO3 polyclonal antibody. ELISA and Western blotting showed that the mouse antibody could recognize specifically the endogenous FOXO3 protein. Conclusion The polyclonal antibody against conserved domain of FOXO3 can identify the endogenous FOXO3 protein. It can be used to analyze the endogenous FOXO3 expression level.

Association Between the IL-6 rs1800795 Polymorphism and the Risk of Cervical Cancer: A Meta-Analysis of 1210 Cases and 1525 Controls.

Cervical cancer is the second most common cancer and the third leading cause of cancer-related death among females in less developed countries. Studies have shown that the single-nucleotide polymorphisms of interleukin 6 might be associated with cervical cancer risk. A total of 710 articles from EMBASE, EBSCO, Web of science, PubMed, Springer link, and Chinese National Knowledge Infrastructure databases were reviewed in our study. A meta-analysis on the associations between interleukin 6 rs1800795 polymorphism and cervical cancer risk was carried out by comparison using 5 genetic models. In this systematic review, 5 studies were analyzed. The pooled population included 2735 participants (1210 cases and 1525 controls). The overall odds ratio (G vs C alleles) using fixed-effects model was 0.85 (95% confidence interval 0.75-0.97), P = .02. Our results show that the C genotype of interleukin 6 rs1800795 is associated with higher cervical cancer risk. Our results indicate that interleukin 6 rs1800795 polymorphism might be associated with susceptibility to cervical cancer.

Different Effects of p52SHC1 and p52SHC3 on the Cell Cycle of Neurons and Neural Stem Cells.

SHC3 is exclusively expressed in postmitotic neurons, while SHC1 is found in neural stem cells and neural precursor cells but absent in mature neurons. In this study, we discovered that suppression of p52SHC1 expression by RNA interference resulted in proliferation defects in neural stem cells, along with significantly reduced protein levels of cyclin E and cyclin A. At the same time, p52SHC3 RNAi caused cell cycle re-entry (9.54% in S phase and 5.70% in G2-M phase) in primary neurons with significantly up-regulated expression of cyclin D1, cyclin E, cyclin A, CDK2, and phosphorylated CDK2. When p52SHC3 was overexpressed, the cell cycle of neural stem cells was arrested with reduced protein levels of cyclin D1, cyclin E, and cyclin A, while overexpression of p52SHC1 did not result in significant changes in postmitotic neurons. Our results indicate that p52SHC3 plays an important role in maintaining the mitotic quiescence of neurons, while p52SHC1 regulates the proliferation of neural stem cells.

Fabrication of aluminum terephthalate metal-organic framework incorporated polymer monolith for the microextraction of non-steroidal anti-inflammatory drugs in water and urine samples.

Polymer monolith microextraction (PMME) based on capillary monolithic column is an effective and useful technique to preconcentrate trace analytes from environmental and biological samples. Here, we report the fabrication of a novel aluminum terephthalate metal-organic framework (MIL-53(Al)) incorporated capillary monolithic column via in situ polymerization for the PMME of non-steroidal anti-inflammatory drugs (NSAIDs) (ketoprofen, fenbufen and ibuprofen) in water and urine samples. The fabricated MIL-53(Al) incorporated monolith was characterized by X-ray powder diffractometry, scanning electron microscopy, Fourier transform infrared spectrometry, and nitrogen adsorption experiment. The MIL-53(Al) incorporated monolith gave larger surface area than the neat polymer monolith. A 2-cm long MIL-53(Al) incorporated capillary monolith was applied for PMME coupled with high-performance liquid chromatography for the determination of the NSAIDs. Potential factors affecting the PMME were studied in detail. Under the optimized conditions, the developed method gave the enhancement factors of 46-51, the linear range of 0.40-200µgL(-1), the detection limits (S/N=3) of 0.12-0.24µgL(-1), and the quantification limits (S/N=10) of 0.40-0.85µgL(-1). The recoveries for spiked NSAIDs (20µgL(-1)) in water and urine samples were in the range of 77.3-104%. Besides, the MIL-53(Al) incorporated monolith was stable enough for 120 extraction cycles without significant loss of extraction efficiency. The developed method was successfully applied to the determination of NSAIDs in water and urine samples.

[Combination of narrow band imaging (NBI) and autofluorescence bronchoscopy (AFB) in the assessment of central lung cancer].

OBJECTIVE: To assess the diagnostic value of narrow-band imaging(NBI) in the diagnosis of central lung cancer. METHODS: Patients (n = 153) suspected of having lung cancer underwent white light bronchoscopy(WLB), NBI and autofluorescence bronchoscopy(AFB) in turn. At least 3 biopsies in each case were taken from sites visualized as lesions. The sensitivity and specificity of NBI, AFB and combination of NBI and AFB were compared. RESULTS: There were 106 male (69.3%) and 47 female patients (30.7%). By NBI, 91 and 62 cases were positive and negative respectively. The sensitivity and specificity of NBI were 63.5% (87/137) and 75.0% (12/16) respectively. By AFB, 140 and 13 cases were positive and negative respectively. The sensitivity and specificity of AFB were 94.2% (129/137) and 87.5% (5/16) respectively. By NBI combined with AFB, 133 and 20 cases were positive and negative respectively, the sensitivity and specificity being 95.6% (131/137) and 87.5% (14/16) respectively. The difference of specificity between NBI plus AFB and AFB alone was significant (P < 0.01), but the difference of sensitivity between NBI plus AFB and AFB alone(P > 0.05) was not. The difference of specificity between NBI plus AFB and NBI alone was significant (P < 0.01), but the P value of specificity between NBI plus AFB and NBI was 0.03. CONCLUSION: Combination of NBI and AFB could increase the specificity of lung cancer diagnosis compared to AFB alone.

The mTOR signaling pathway regulates pain-related synaptic plasticity in rat entorhinal-hippocampal pathways.

BACKGROUND: Our previous work demonstrated that persistent peripheral nociception (PPN) leads to synaptic plasticity and functional changes in the rat hippocampus. The protein kinase mTOR is a critical regulator of protein synthesis-dependent synaptic plasticity in the hippocampus as well as synaptic plasticity associated with central and peripheral pain sensitization. We examined the role of mTOR signaling in pain-associated entorhinal cortex (EC) - hippocampal synaptic plasticity to reveal possible cellular mechanisms underlying the effects of chronic pain on cognition and emotion. RESULTS: Subcutaneous injection of bee venom (BV) into one hind paw to induce PPN resulted in sustained (> 8 h) mTOR phospho-activation and enhanced phosphorylation of the mTOR target p70 S6 kinase (S6K) in the hippocampus. The magnitude and duration of long-term potentiation (LTP) in both EC - dentate gyrus (DG) and EC - CA1 synaptic pathways were elevated in BV-treated rats as measured by microelectrode array recording. Moreover, the number of potentiated synapses in the hippocampus was markedly upregulated by BV-induced PPN. Both elevated mTOR-S6K signaling and enhanced LTP induced by BV injection were reversed by systemic injection of the mTOR inhibitor rapamycin (RAPA). Rats injected with BV exhibited markedly reduced ambulation and exploratory activity in the open field (signs of depression and anxiety) compared to controls, and these effects were also reversed by RAPA. CONCLUSION: We suggest that PPN-induced enhancement of synaptic plasticity in EC - hippocampal pathways and the behavioral effects of PPN are dependent on mTOR-S6K signaling.