Nuclear GRP75 Binds Retinoic Acid Receptors to Promote Neuronal Differentiation of Neuroblastoma

Retinoic acid (RA) has been approved for the differentiation therapy of neuroblastoma (NB). Previous work revealed a correlation between glucose-regulated protein 75 (GRP75) and the RA-elicited neuronal differentiation of NB cells. The present study further demonstrated that GRP75 translocates into the nucleus and physically interacts with retinoid receptors (RARα and RXRα) to augment RA-elicited neuronal differentiation. GRP75 was required for RARα/RXRα-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARα/RXRαin a RA-dependent manner. More intriguingly, the level of GRP75/RARα/RXRα tripartite complexes was tightly associated with the RA-induced suppression of tumor growth in animals and the histological grade of differentiation in human NB tumors. The formation of GRP75/RARα/RXRα complexes was intimately correlated with a normal MYCN copy number of NB tumors, possibly implicating a favorable prognosis of NB tumors. The present findings reveal a novel function of nucleus-localized GRP75 in actively promoting neuronal differentiation, delineating the mode of action for the differentiation therapy of NB by RA

Dynamic Effects of Axial Loading on the Lumbar Spine During Magnetic Resonance Imaging in Patients with Suspected Spinal Stenosis

BackgroundPrevious studies have shown that axial compression in extension (ACE) of the spine during magnetic resonance imaging (MRI) has revealed unexpected pathological features compared with the conventional psoas-relaxed position (PRP) used in imaging. The purpose of this study was to evaluate the dynamic effect of axial loading on lumbar spinal stenosis using MRI in patients with spinal stenosis.MethodsA total of 14 women and 11 men with lumbar spinal stenosis were examined in both PRP and ACE positions. We calculated the dural-sac cross-sectional area (DCSA) to evaluate severity of spinal canal stenosis. DCSA, as well as the dural-sac anteroposterior diameter (DAPD) and dural-sac transverse diameter (DTD) in both positions were measured using a digital image view station. A paired t test determined the differences in DCSA, DAPD and DTD between the two positions at each intervertebral disc level.ResultsAxial loading increased severity of lumbar spinal stenosis during MRI, as demonstrated by a decrease in DCSA from 20.5% to 6.3% (mean, 11.40 ± 3.66%) between the PRP and ACE positions (p < 0.01). Significant differences were also noted in DAPD and DTD between the PRP and ACE positions (p < 0.01). A significant correlation was found between the decrease in mean DCSA and that in DAPD and DTD. The decrease in mean DCSA, DAPD and DTD following axial compression was greatest at the L4/5 and L5/S1 levels.ConclusionAxial loading increases severity of lumbar canal stenosis and the effect of axial loading on MRI examination is greatest at the L4/5 and L5/S1 levels

Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study

<p>Abstract</p> <p>Background</p> <p>Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect uterus; however, their biological behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate 3 different scoring mechanisms of p16^INK4aimmunohistochemical (IHC) staining in distinguishing between primary ECAs and EMAs.</p> <p>Methods</p> <p>A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue array sections were immunostained with a commercially available antibody of p16^INK4a. Avidin-biotin complex (ABC) method was used for antigens visualization. The staining intensity and area extent of the IHC reactions was evaluated using the semi-quantitative scoring system. The 3 scoring methods were defined on the bases of the following: (1) independent cytoplasmic staining alone (Method C), (2) independent nucleic staining alone (Method N), and (3) mean of the sum of cytoplasmic score plus nucleic score (Method Mean of C plus N).</p> <p>Results</p> <p>Of the 3 scoring mechanisms for p16^INK4aexpression, Method N and Method Mean of C plus N showed significant (<it>p-values </it>< 0.05), but Method C showed non-significant (p = 0.245) frequency differences between ECAs and EMAs. In addition, Method Mean of C plus N had the highest overall accuracy rate (81.6%) for diagnostic distinction among these 3 scoring methods.</p> <p>Conclusion</p> <p>According to the data characteristics and test effectiveness in this study, Method N and Method Mean of C plus N can significantly signal to distinguish between ECAs and EMAs; while Method C cannot do. Method Mean of C plus N is the most promising and favorable means among the three scoring mechanisms.</p

Orderly arranged NLO materials on exfoliated layeredtemplates based on dendrons with alternating moietiesat the periphery†

Nonlinear optical dendrons with alternating terminal groups of the stearyl group (C18) and chromophorewere prepared through a convergent approach. These chromophore-containing dendrons were used asthe intercalating agents for montmorillonite via an ion-exchange process. An orderly exfoliatedmorphology is obtained by mixing the dendritic structure intercalated layered silicates with a polyimide.As a result, optical nonlinearity, i.e. the Pockels effect was observed for these nanocomposites withoutresorting to the poling process. EO coefficients of 9–22 pm V 1 were achieved despite that relativelylow NLO densities were present in the nanocomposites, particularly for the samples comprising thedendrons with alternating moieties. In addition, the hedging effects of the stearyl group on the selfalignmentbehavior, electro-optical (EO) coefficient and temporal stability of the dendron-intercalatedmontmorillonite/polyimide nanocomposites were also investigated

Clinical Study of Uric Acid Urolithiasis

Uric acid urolithiasis develops from various causes. To investigate the clinical and biochemical presentation of patients with uric acid urolithiasis, a retrospective study was designed. A total of 46 cases were enrolled between January 2004 and December 2005. The compositions of the stones were analyzed by infrared spectrophotometry. There were 39 males (84.8%) and seven females (15.2%), with a mean age of 61.5 ± 10.6 years and mean body mass index (BMI) of 26.7 ± 3.1 kg/m2. The stone location was kidney in 10 (21.7%), ureter in 22 (41.8%), and bladder in 14 (30.5%). Multiple stones were diagnosed in 36 patients (78.3%). Pre-existing comorbidities included diabetes mellitus in 11 patients (23.9%), hypertension in 23 (50%), gout in 13 (28.2%), and benign prostatic hyperplasia in 14 (30.4%). Mean serum creatinine and uric acid was 1.6 ± 0.6 mg/dL and 7.6 ± 1.8 mg/dL, respectively. There were 27 patients (58%) with creatinine > 1.4 mg/dL. The mean urinary pH was 5.42 ± 0.46. Patients with uric acid urolithiasis were predominantly male, older, with higher BMI, multiple stone presentation, with lower urinary pH, and hyperuricemia. Exacerbation of the renal function should also be of concern because of the high proportion of patients with renal insufficiency diagnosed in this study

Static Magnetic Field Attenuates Lipopolysaccharide-Induced Inflammation in Pulp Cells by Affecting Cell Membrane Stability

One of the causes of dental pulpitis is lipopolysaccharide- (LPS-) induced inflammatory response. Following pulp tissue inflammation, odontoblasts, dental pulp cells (DPCs), and dental pulp stem cells (DPSCs) will activate and repair damaged tissue to maintain homeostasis. However, when LPS infection is too serious, dental repair is impossible and disease may progress to irreversible pulpitis. Therefore, the aim of this study was to examine whether static magnetic field (SMF) can attenuate inflammatory response of dental pulp cells challenged with LPS. In methodology, dental pulp cells were isolated from extracted teeth. The population of DPSCs in the cultured DPCs was identified by phenotypes and multilineage differentiation. The effects of 0.4 T SMF on DPCs were observed through MTT assay and fluorescent anisotropy assay. Our results showed that the SMF exposure had no effect on surface markers or multilineage differentiation capability. However, SMF exposure increases cell viability by 15%. In addition, SMF increased cell membrane rigidity which is directly related to higher fluorescent anisotropy. In the LPS-challenged condition, DPCs treated with SMF demonstrated a higher tolerance to LPS-induced inflammatory response when compared to untreated controls. According to these results, we suggest that 0.4 T SMF attenuates LPS-induced inflammatory response to DPCs by changing cell membrane stability

Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma

Background: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. Objectives: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). Methods: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. Results: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8+LAG3+ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. Conclusions: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC

Management of Hepatic Angiomyolipoma

Preoperative diagnosis of hepatic angiomyolipoma is difficult, and the treatment for it remains controversial. The aim of this study is to review our experience in the treatment of hepatic angiomyolipoma and to propose a treatment strategy for this disease. We retrospectively collected the clinical, imaging, and pathological features of patients with hepatic angiomyolipoma. Immunohistochemical studies with antibodies for HMB-45, actin, S-100, cytokeratin, vimentin, and c-kit were performed. Treatment experience and long-term follow-up results are summarized. During a period of 9 years, 10 patients with hepatic angiomyolipoma were treated at our hospital. There was marked female predominance (nine patients). Nine patients received surgical resection without complications. One patient received nonoperative management with biopsy and follow-up. One patient died 11 months after surgery because of recurrent disease. We propose all symptomatic patients should receive surgical resection for hepatic angiomyolipoma. Conservative management with close follow-up is suggested in patients with asymptomatic tumors and meet the following criteria: (1) tumor size smaller than 5 cm, (2) angiomyolipoma proved through fine needle aspiration biopsy, (3) patients with good compliance, and (4) not a hepatitis virus carrier