Decompression Illness in Divers With or Without Patent Foramen Ovale : A Cohort Study.

BACKGROUND: In previous studies, the prevalence of patent foramen ovale (PFO) has been reported to be higher in scuba divers who experienced decompression illness (DCI) than in those who did not. OBJECTIVE: To assess the association between PFO and DCI in scuba divers. DESIGN: Prospective cohort study. SETTING: Tertiary cardiac center in South Korea. PARTICIPANTS: One hundred experienced divers from 13 diving organizations who did more than 50 dives per year. MEASUREMENTS: Participants had transesophageal echocardiography with a saline bubble test to determine the presence of a PFO and were subsequently divided into high- and low-risk groups. They were followed using a self-reported questionnaire while blinded to their PFO status. All of the reported symptoms were adjudicated in a blinded manner. The primary end point of this study was PFO-related DCI. Logistic regression analysis was done to determine the odds ratio of PFO-related DCI. RESULTS: Patent foramen ovale was seen in 68 divers (37 at high risk and 31 at low risk). Patent foramen ovale-related DCI occurred in 12 divers in the PFO group (non-PFO vs. high-risk PFO vs. low-risk PFO: 0 vs. 8.4 vs. 2.0 incidences per 10 000 person-dives; P = 0.001) during a mean follow-up of 28.7 months. Multivariable analysis showed that high-risk PFO was independently associated with an increased risk for PFO-related DCI (odds ratio, 9.34 [95% CI, 1.95 to 44.88]). LIMITATION: The sample size was insufficient to assess the association between low-risk PFO and DCI. CONCLUSION: High-risk PFO was associated with an increased risk for DCI in scuba divers. This finding indicates that divers with high-risk PFO are more susceptible to DCI than what has been previously reported and should consider either refraining from diving or adhering to a conservative diving protocol. PRIMARY FUNDING SOURCE: Sejong Medical Research Institute.

29-Plex tandem mass tag mass spectrometry enabling accurate quantification by interference correction.

Tandem mass tag (TMT) mass spectrometry is a mainstream isobaric chemical labeling strategy for profiling proteomes. Here we present a 29-plex TMT method to combine the 11-plex and 18-plex labeling strategies. The 29-plex method was examined with a pooled sample composed of 1×, 3×, and 10× Escherichia coli peptides with 100× human background peptides, which generated two E. coli datasets (TMT11 and TMT18), displaying the distorted ratios of 1.0:1.7:4.2 and 1.0:1.8:4.9, respectively. This ratio compression from the expected 1:3:10 ratios was caused by co-isolated TMT-labeled ions (i.e., noise). Interestingly, the mixture of two TMT sets produced MS/MS spectra with unique features for the noise detection: (i) in TMT11-labeled spectra, TMT18-specific reporter ions (e.g., 135N) were shown as the noise; (ii) in TMT18-labeled spectra, the TMT11/TMT18-shared reporter ions (e.g., 131C) typically exhibited higher intensities than TMT18-specific reporter ions, due to contaminated TMT11-labeled ions in these shared channels. We further estimated the noise levels contributed by both TMT11- and TMT18-labeled peptides, and corrected reporter ion intensities in every spectrum. Finally, the anticipated 1:3:10 ratios were largely restored. This strategy was also validated using another 29-plex sample with 1:5 ratios. Thus the 29-plex method expands the TMT throughput and enhances the quantitative accuracy.

Evaluation of the efficacy and safety of conventional and biportal endoscopic decompressive laminectomy in patients with lumbar spinal stenosis (ENDO-B trial): a protocol for a prospective, randomized, assessor-blind, multicenter trial.

BACKGROUND: Recent studies on biportal endoscopic spine surgery in patients with lumbar spinal stenosis have reported good clinical results. However, these studies have been limited by the small sample sizes and use of a retrospective study design. Therefore, we aim to compare the efficacy and safety of biportal endoscopic decompressive laminectomy with those of conventional decompressive laminectomy in a multicenter, prospective, randomized controlled trial. METHODS: This study will include 120 patients (60 per group, aged 20-80 years) with 1- or 2-level lumbar spinal stenosis, who will be recruited from six hospitals. The study will be conducted from July 2021 to December 2024. The primary outcome (Oswestry Disability Index at 12 months after surgery) will be evaluated through a modified intention-to-treat method. The secondary outcomes will include the following: visual analog scale score for low back and lower extremity radiating pain, EuroQol 5-dimensions score, surgery satisfaction, walking time, postoperative return to daily life period, postoperative surgical scars, and some surgery-related variables. Radiographic outcomes will be analyzed using magnetic resonance imaging or computed tomography. All outcomes will be evaluated before the surgery and at 2 weeks, 3 months, 6 months, and 12 months postoperatively. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines for reporting of clinical trial protocols. DISCUSSION: It is hypothesized that the efficacy and safety of biportal endoscopic and conventional decompressive laminectomy will be comparable in patients with lumbar spinal stenosis. The results of this trial will provide a high level of evidence for the efficacy and safety of the biportal endoscopic technique in patients with lumbar spinal stenosis and facilitate the development of clinical practice guidelines. Furthermore, the results of this study may indicate the feasibility of the biportal endoscopic technique for other types of spinal surgery. TRIAL REGISTRATION: The ENDO-B trial is registered at Clinical Research Information Service (CRIS, cris.nih.go.kr ) (KCT0006057; April 52,021).

Replacement of the Common Chromium Source CrCl3(thf)3 with Well-Defined [CrCl2(µ-Cl)(thf)2]2.

CrCl3(thf)3 is a common starting material in the synthesis of organometallic and coordination compounds of Cr. Deposited as an irregular solid with no possibility of recrystallization, it is not a purity guaranteed chemical, causing problems in some cases. In this work, we disclose a well-defined form of the THF adduct of CrCl3 ([CrCl2(µ-Cl)(thf)2]2), a crystalline solid, that enables structure determination by X-ray crystallography. The EA data and XRD pattern of the bulk agreed with the revealed structure. Moreover, its preparation procedure is facile: evacuation of CrCl3·6H2O at 100 °C, treatment with 6 equivalents of Me3SiCl in a minimal amount of THF, and crystallization from CH2Cl2. The ethylene tetramerization catalyst [iPrN{P(C6H4-p-Si(nBu)3)2}2CrCl2]+[B(C6F5)4]- prepared using well-defined [CrCl2(µ-Cl)(thf)2]2 as a starting material exhibited a reliably high activity (6600 kg/g-Cr/h; 1-octene selectivity at 40 °C, 75%), while that of the one prepared using the impure CrCl3(thf)3 was inconsistent and relatively low (~3000 kg/g-Cr/h). By using well-defined [CrCl2(µ-Cl)(thf)2]2 as a Cr source, single crystals of [(CH3CN)4CrCl2]+[B(C6F5)4]- and [{Et(Cl)Al(N(iPr)2)2}Cr(µ-Cl)]2 were obtained, allowing structure determination by X-ray crystallography, which had been unsuccessful when the previously known CrCl3(thf)3 was used as the Cr source.

Lithocholic acid increases intestinal phosphate and calcium absorption in a vitamin D receptor dependent but transcellular pathway independent manner.

Phosphate/calcium homeostasis is crucial for health maintenance. Lithocholic acid, a bile acid produced by intestinal bacteria, is an agonist of vitamin D receptor. However, its effects on phosphate/calcium homeostasis remain unclear. Here, we demonstrated that lithocholic acid increases intestinal phosphate/calcium absorption in an enterocyte vitamin D receptor-dependent manner. Lithocholic acid was found to increase serum phosphate/calcium levels and thus to exacerbate vascular calcification in animals with chronic kidney disease. Lithocholic acid did not affect levels of intestinal sodium-dependent phosphate transport protein 2b, Pi transporter-1, -2, or transient receptor potential vanilloid subfamily member 6. Everted gut sac analyses demonstrated that lithocholic acid increased phosphate/calcium absorption in a transcellular pathway-independent manner. Lithocholic acid suppressed intestinal mucosal claudin 3 and occludin in wild-type mice, but not in vitamin D receptor knockout mice. Everted gut sacs of claudin 3 knockout mice showed an increased permeability for phosphate, but not calcium. In patients with chronic kidney disease, serum 1,25(OH)2 vitamin D levels are decreased, probably as an intrinsic adjustment to reduce phosphate/calcium burden. In contrast, serum and fecal lithocholic acid levels and fecal levels of bile acid 7α-dehydratase, a rate-limiting enzyme involved in lithocholic acid production, were not downregulated. The effects of lithocholic acid were eliminated by bile acid adsorptive resin in mice. Thus, lithocholic acid and claudin 3 may represent novel therapeutic targets for reducing phosphate burden.

Ingestion of difructose anhydride III partially suppresses the deconjugation and 7α-dehydroxylation of bile acids in rats fed with a cholic acid-supplemented diet.

Difructose anhydride III (DFAIII) is a prebiotic involved in the reduction of secondary bile acids (BAs). We investigated whether DFAIII modulates BA metabolism, including enterohepatic circulation, in the rats fed with a diet supplemented with cholic acid (CA), one of the 12α-hydroxylated BAs. After acclimation, the rats were fed with a control diet or a diet supplemented with DFAIII. After 2 weeks, each group was further divided into two groups and was fed diet with or without CA supplementation at 0.5 g/kg diet. BA levels were analyzed in aortic and portal plasma, liver, intestinal content, and feces. As a result, DFAIII ingestion reduced the fecal deoxycholic acid level via the partial suppression of deconjugation and 7α-dehydroxylation of BAs following CA supplementation. These results suggest that DFAIII suppresses production of deoxycholic acid in conditions of high concentrations of 12α-hydroxylated BAs in enterohepatic circulation, such as obesity or excess energy intake. Abbreviation: BA: bile acid; BSH: bile salt hydrolase; CA: cholic acid; DCA: deoxycholic acid; DFAIII: difructose anhydride III; MCA: muricholic acid; MS: mass spectrometry; NCDs: non-communicable diseases; LC: liquid chromatography; SCFA: short-chain fatty acid; TCA: taurocholic acid; TCDCA: taurochenodeoxycholic acid; TDCA: taurodeoxycholic acid; TUDCA: tauroursodeoxychlic acid; TαMCA: tauro-α-muricholic acid; TßMCA: tauro-ß-muricholic acid; TωMCA: tauro-ω-muricholic acid.

Effect of Al Addition on Corrosion Protection of Ti-39Nb-6Zr Alloy for Biological Applications.

For metals to be used as biomaterials, there must not be harmful reaction between the corrosion product of metal or eluted ion, and bio-tissue. Titanium is one of the excellent bio-compatible materials and generally it has tendency to have a small amount elution of Ti ions inside the body. Titanium alloy need to have low elastic modulus for reducing the stress shield effect. Ti-39Nb-6Zr alloy which is consist of biocompatible element such as Nb and Zr, has low elastic modulus with below 60 GPa, but it shows lower yield stress and tensile stress compared with Ti-6Al-4V alloy. In order to increase the strength of Ti-39Nb-6Zr alloy, aluminum was added in this alloy. Since aluminum elements are reported to lead to Alzheimer disease in human, high corrosion resistance is required to use Ti-39Nb-6Zr-0.45Al alloy containing a small amount of Al. In this study, corrosion behaviors were investigated under the solution of three conditions of 0.9% NaCl (pH 7), 0.1% NaF (pH 3) and 0.1% NaF (pH 5). The behaviors were stable under all the conditions. But Ti-39Nb- 6Zr-0.45Al alloy had better corrosion resistance than Ti-39Nb-6Zr alloy in all the conditions. This is because oxide mixtures such as Al3Ti5O2, Al2TiO5 are formed inside the surface layer, which results in forming more stable oxide film than TiO2 surface film. Ti-39Nb-6Zr-0.45Al alloy has high corrosion resistance and can reduce the concern about aluminum ion elution inside the body.

Microstructural Control for Characteristics of Biomedical Ti-39Nb-6Zr-0.45Al Alloy.

Ti-39Nb-6Zr-0.45Al alloy was developed for biological applications as exchangeable hard tissue. This alloy has very low elastic modulus, but lower strength than Ti-6Al-4V alloy. This study was performed for improving the strength by various heat treatments and microstructural characteristics and mechanical properties of Ti-39Nb-6Zr-0.45Al alloy were investigated. Heat treatments were conducted at 350 °C, 400 °C, 450 °C, 500 °C, 550 °C and 600 °C, followed by water quenching. Microstructures of Ti-39Nb-6Zr-0.45Al alloy showed two types of different features. One of the features was not visible for grains at low temperature heat conditions (350 °C, 400 °C and 450 °C), because of the effect of cold swaging. On the contrast, at high temperature conditions (500 °C, 550 °C and 600 °C), the grains were visible. Tensile properties had similar tendency to hardness properties under all low temperature conditions. The samples showed high strength and low elongation under low temperatures, but showed the opposite results under high temperature conditions. These results were due to thermal ω phases and secondary α phases inside the matrix of this alloy. ω phases, which were precipitated under low temperature heat treatments, induce high strength and low elongation. In case of high temperature conditions, ω phases disappeared into the matrix and secondary α phases with fine size appeared. γoung's moduli of the samples under all the conditions were lower (about 60 GPa) than those of the as-swaged (about 70 GPa). Consequently, the heattreated Ti-39Nb-6Zr-0.45Al alloy had high strength and very low elastic modulus for biomedical applications.

Clinical and radiological results of posterior cervical foraminotomy at two or three levels: a 3-year follow-up.

BACKGROUND: Single-level unilateral posterior cervical foraminotomy is regarded as a safe method. However, the outcomes of posterior cervical foraminotomy performed on two or three levels are uncertain and debated. We aimed to analyze the long-term clinical and radiological outcomes of posterior cervical foraminotomy at two or three levels. METHODS: From September 2008 to December 2011, a total of 42 patients who underwent a posterior cervical foraminotomy at two or three levels and were followed for at least 3 years were analyzed with retrospective cohort study. Clinical assessments were performed using the visual analog scale (VAS), neck disability index (NDI) and modified MacNab criteria. Radiological evaluation included the assessment of static and dynamic lateral radiographs to identify instability, postlaminectomy kyphotic deformity, adjacent segmental degeneration (ASD), and focal degeneration. RESULTS: The mean VAS improved from preoperative score 8.5 ± 0.3 to postoperative score 1.8 ± 0.5 significantly. The mean presenting NDI score was 32.9 ± 2.0 and the mean postoperative NDI score was 14.2 ± 1.3. Improvement of radiculopathy was displayed in 39 patients (92.9%). During radiological evaluation, no significant change in disc height related to ASD and focal degeneration was noted. However, we confirmed one patient with radiological instability and one patient with radiological postlaminectomy kyphotic deformity. CONCLUSIONS: Posterior cervical foraminotomy at two or three levels is fairly effective for treating patients with cervical radiculopathy, and results in long-lasting pain relief and improved quality of life in nearly all patients. However, further studies of three levels that include more patients are needed.

Impact of Intracranial Atherosclerotic Stenosis on the Prognosis in Acute Ischemic Stroke Patients with Cardioembolic Source.

BACKGROUND AND AIM: In recent days, intracranial atherosclerotic stenosis (IAS) has been reportedly related to recurrent stroke and mortality in the total patient population with ischemic stroke. However, its impact on the prognosis of the patients with cardioembolic source is not yet established. This study attempted to investigate whether IAS was associated with poor outcome in stroke patients with cardioembolic source. METHODS: Overall, 223 patients with acute ischemic stroke and cardioembolic source were included in this study. IAS was defined as ≥ 50% stenosis on enhanced MRA, and cardioembolic sources were detected by ECG and echocardiography. Follow-up data were obtained from outpatient medical records and/or telephone interviews. RESULTS: Overall, 60 major clinical events causing poor outcome occurred in 58 patients (26.0%). Patients with IAS had significantly higher rates of death and stroke recurrence than those without IAS (p = 0.015 and 0.046 each by log rank test). The multivariate Cox proportional hazards regression analysis showed that IAS was significantly related to the poor outcome (hazard ratio 1.725, 95% confidence interval 1.020-2.920, p = 0.042). CONCLUSIONS: In acute ischemic stroke patients with cardioembolic source, IAS may be considered a marker of a high risk of stroke recurrence or death.

Analysis of Risk Factors Causing New Symptomatic Vertebral Compression Fractures After Percutaneous Vertebroplasty for Painful Osteoporotic Vertebral Compression Fractures: A 4-year Follow-up.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: New vertebral compression fracture (NVCF) is a highly potential risk after percutaneous vertebroplasty (PVP). The study aimed at analyzing the incidence and risk factors of NVCF and preventing its development. SUMMARY OF BACKGROUND DATA: PVP is widely used and highly effective technique for reducing pain caused by an osteoporotic vertebral compression fracture. However, there is a great deal of debate about whether PVP is associated with NVCF, and many risk factors of NVCF have been hypothesized. METHODS: From January to December 2008, a total of 198 patients (176 women, 22 men; mean age, 76.6±0.5 y) who underwent PVP at 270 levels for painful osteoporotic VCF were retrospectively analyzed during a 4-year follow-up. The following parameters were evaluated: NVCF incidence and average time, body mass index (BMI), smoking history, the existence of trauma, and bone mineral density (BMD) before and after PVP. Cement location, intradiscal leakage, distribution pattern, kyphotic angle, sagittal index, compression ratio, injected cement volume, and numbers of fractures and thoracolumbar junction fractures were analyzed. RESULTS: During follow-up, 34 patients (17.2%) sustained symptomatic NVCF for 4-year follow-up. All 34 patients with NVCF had lower BMD than that before initial PVP. For adjacent VCF, multivariable analysis showed that a higher risk of NVCF after vertebroplasty was associated with a larger number of VCF (P=0.025) and lower BMI (P=0.045), whereas for remote VCF, the risk of NVCF was higher in patients who had not experienced trauma and lower BMD (P=0.045). None of the radiographic evaluation values were related to the occurrence of NVCF. CONCLUSIONS: The most important elements related to reducing NVCF were treating osteoporosis and improving BMD and BMI. More aggressive BMD and BMI correction is more important than the vertebroplasty technique.

Cytotoxic sesterterpenoids isolated from the marine sponge Scalarispongia sp.

Eight scalarane sesterterpenoids, including four new compounds, were isolated from the marine sponge Scalarispongia sp. The structures of the new compounds were elucidated by 2D-NMR and HRMS analyses. All of the isolated compounds, with the exception of 16-O-deacetyl-12,16-epi-scalarolbutanolide, showed significant in vitro cytotoxicity (GI50 values down to 5.2 µM) against six human cancer cell lines.

Relationship between diabetes mellitus with dural arteriovenous fistula.

INTRODUCTION: The aetiology of dural arteriovenous fistula (DAVF) is not well known, but it has been suggested that abnormality in angiogenesis plays a pathological role. Abnormality in angiogenesis is also involved in diabetes mellitus (DM). The purpose of this study was to quantify the relation between DAVF and DM in a Korean population. METHODS: Medical records of 192 patients with DAVF between 2002 and 2011 were reviewed. Age, sex and the presence of DM, hypertension, hyperlipidaemia, stroke, coronary artery disease and cancers were compared between DAVF and control subjects. Data for control were obtained from the Korean National Health and Nutrition Examination Survey. The relationship of DM and DAVF location, presenting symptoms (benign vs. aggressive) and classification (Borden and Geibprasert) were assessed using the Pearson's chi-square test. RESULTS: Prevalence of DM was higher in DAVF patients (19.8 %) than in controls (9.5 %; p = 0.004). Univariate analysis showed that DM (odds ratio (OR), 2.356; 95 % confidence interval (CI), 1.634-3.399; p < 0.001) and age (OR, 1.022; 95 % CI, 1.012-1.032; p < 0.001) increased the odds of DAVF. This was supported by multivariate analysis (DM: OR, 2.092; 95 % CI, 1.391-3.145; p = 0.0004 and Age: OR, 1.021; 95 % CI, 1.009-1.033; p = 0.001). When these analyses were repeated after stratification by sex, there was no relation between age and DAVF in men. Borden II and III (p = 0.038) and aggressive symptoms (p = 0.023) were related to DM. CONCLUSION: There was a positive relation between DM and DAVF in a Korean population. DAVFs with aggressive symptoms and behaviour were more commonly related to DM.

Comparison of surgical outcomes after cervical laminoplasty: open-door technique versus French-door technique.

STUDY DESIGN: A retrospective case series. OBJECTIVE: To compare the surgical outcomes of open-door and French-door cervical laminoplasty for decompressing multilevel cervical spinal cord compressions. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is an effective method for decompressing multilevel cervical spinal cord compressions. Laminoplasty is usually classified as an open-door or French-door technique, but it is still unclear whether laminoplasty affects cervical alignment and clinical outcomes. METHODS: Fifty-one patients underwent cervical laminoplasty over a 2-year period for cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, or for a mixed-type condition. The following criteria were evaluated and compared retrospectively for open-door laminoplasty (group A) and French-door laminoplasty (group B): Nurick grades, Japanese Orthopedic Association (JOA) scores, neck disability index, and visual analog scale scores for axial neck pain and radiating pain. During radiologic evaluations, changes in cervical lordotic angles and range of motion were measured at C2-C7. RESULTS: Postoperatively, radiating pain improved significantly in both groups (P<0.05), but axial neck pain was more severe in both groups at last follow-up than preoperatively (P>0.05). Mean neurological improvement was 12.5% according to Nurick grades and 28% according to JOA scores in all study subjects. In particular, the mean Nurick grades showed significant improvement in group A (P<0.05), and the recovery rate was higher in group A than in group B according to Nurick grades (23.5% vs. 6.3%; P<0.05) and JOA scores (44.4% vs. 13%; P<0.05). In contrast, radiologically, cervical lordotic angle and range of motion were more significantly decreased in group B (P<0.05). CONCLUSIONS: Although open-door and French-door laminoplasty techniques were found to be effective for treating cervical compressive myelopathy, the open-door technique seems to be superior with respect to clinical and radiologic outcomes.

Saving Stabilizing Structure Treatment With Bilateral-Contralateral Decompression for Spinal Stenosis in Degenerative Spondylolisthesis Using Unilateral Biportal Endoscopy.

OBJECTIVE: This study aimed to evaluate the treatment of spinal stenosis with spondylolisthesis using bilateral-contralateral unilateral biportal endoscopic (UBE) decompression to minimize facet joint damage. METHODS: We retrospectively evaluated 42 patients with grade 1 spondylolisthesis who underwent bilateral-contralateral UBE decompression between July 2018 and September 2019. To identify segmental instability, static and dynamic images from preoperative and postoperative procedures and final follow-up radiographs were reviewed. Lateral radiograph slippage ratio, sagittal motion, and facet joint preservation were evaluated. Clinical assessments were conducted using the visual analogue scale (VAS), Oswestry Disability Index (ODI), and modified MacNab criteria. RESULTS: The average final follow-up period was 26.5 ± 1.3 months. The average preoperative slip percentage was 15.70% ± 5.25%, which worsened to 18.80% ± 5.41% at the final follow-up (p < 0.005). The facet joint preservation rate was 95.6% ± 4.1% on the contralateral side. Improvements in the VAS scores (leg pain: from 7.9 ± 2.2 to 3.1 ± 0.7; p < 0.005; back pain: from 7.2 ± 3.0 to 2.8 ± 1.0; p < 0.005) were observed at the final follow-up. The mean preoperative ODI was 26.19 ± 3.42, which improved to 9.6 ± 1.0 (p < 0.005). Thirteen patients exhibited delayed focal segmental instability following decompression. Despite the absence of symptoms or improvement with conservative treatment in the majority of patients with delayed instability, two patients required fusion surgery to address the instability. Additionally, 2 patients developed facet synovial cysts, while 2 experienced spinous process fractures. CONCLUSION: Bilateral decompression with a contralateral UBE approach could be an effective and alternative treatment method to reduce instability in spinal stenosis with grade 1 spondylolisthesis.

Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts.

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress) and triggers the unfolded protein response (UPR). Recent studies suggest that ER stress is involved in idiopathic pulmonary fibrosis (IPF). The present study was undertaken to determine the role of ER stress on myofibroblastic differentiation of fibroblasts. Fibroblasts in fibroblastic foci of IPF showed immunoreactivity for GRP78. To determine the role of ER stress on α-smooth muscle actin (α-SMA) and collagen type I expression in fibroblasts, mouse and human lung fibroblasts were treated with TGF-ß1, and expression of ER stress-related proteins, α-SMA, and collagen type I was analyzed by Western blotting. TGF-ß1 significantly increased expression of GRP78, XBP-1, and ATF6α, which was accompanied by increases in α-SMA and collagen type I expression in mouse and human fibroblasts. A chemical chaperone, 4-PBA, suppressed TGF-ß1-induced UPR and α-SMA and collagen type I induction. We also showed that TGF-ß1-induced UPR was mediated through the reactive oxygen species generation. Our study provides the first evidence implicating the UPR in myofibroblastic differentiation during fibrosis. These findings of the role of ER stress and chemical chaperones in pulmonary fibrosis may improve our understanding of the pathogenesis of IPF.

Expression of ER stress and autophagy-related molecules in human non-small cell lung cancer and premalignant lesions.

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress-related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin-1 and LC3) in non-small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin-1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin-1 was correlated with low tumor stage (p < 0.001 and p = 0.019, respectively) and longer survival (p = 0.007 and p <0.001, respectively) by Kaplan-Meier analysis. However, CHOP was correlated with high tumor stage (p = 0.038) and shorter survival (p = 0.012). Expression of GRP78 and Beclin-1 was positively correlated (p = 0.006). Our study showed that the expression of GRP78, CHOP, Beclin-1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin-1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC.

In vivo tissue engineering chamber supports human induced pluripotent stem cell survival and rapid differentiation.

Pluripotent stem cells are a potential source of autologous cells for cell and tissue regenerative therapies. They have the ability to renew indefinitely while retaining the capacity to differentiate into all cell types in the body. With developments in cell therapy and tissue engineering these cells may provide an option for treating tissue loss in organs which do not repair themselves. Limitations to clinical translation of pluripotent stem cells include poor cell survival and low cell engraftment in vivo and the risk of teratoma formation when the cells do survive through implantation. In this study, implantation of human induced-pluripotent stem (hiPS) cells, suspended in Matrigel, into an in vivo vascularized tissue engineering chamber in nude rats resulted in substantial engraftment of the cells into the highly vascularized rat tissues formed within the chamber. Differentiation of cells in the chamber environment was shown by teratoma formation, with all three germ lineages evident within 4 weeks. The rate of teratoma formation was higher with partially differentiated hiPS cells (as embryoid bodies) compared to undifferentiated hiPS cells (100% versus 60%). In conclusion, the in vivo vascularized tissue engineering chamber supports the survival through implantation of human iPS cells and their differentiated progeny, as well as a novel platform for rapid teratoma assay screening for pluripotency.

Fine-needle aspiration cytology of hyalinizing trabecular adenoma of the thyroid in a patient with Hashimoto's thyroiditis: a case report.

BACKGROUND: Hyalinizing trabecular adenoma (HTA) is a rare benign epithelial tumor of the thyroid which shows a prominent trabecular growth pattern and stromal hyalinization. On fine-needle aspiration cytology, HTA is frequently misdiagnosed as either papillary thyroid carcinoma (PTC) or medullary carcinoma. We present both the cytologic and the histopathologic features of HTA in a patient with Hashimoto's thyroiditis. CASE: Cytologically, the tumor cells showed a low nucleocytoplasmic ratio and eccentrically located nuclei, nuclear grooves, and eosinophilic pseudoinclusions. Lymphocyte-dominant inflammatory cells were present in the background, raising the possibility of thyroiditis. Histologically, the tumor was a 0.5 × 0.4 cm-sized mass and showed a trabecular and nested pattern of tumor cells separated by scant hyaline material in the background of Hashimoto's thyroiditis. Tumor cells showed abundant eosinophilic granular cytoplasms, nuclear grooves, and pseudoinclusions, as well as immunoreactivity for MIB-1 on the cell membrane. We diagnosed this lesion as HTA in a patient with Hashimoto's thyroiditis. CONCLUSION: Although distinction of HTA from PTC in the cytologic specimen is difficult, especially in cases associated with Hashimoto's thyroiditis, cohesive cell aggregates with a low nucleocytoplasmic ratio and eccentrically located nuclei may be helpful to consider the possibility of HTA.

Combining selinexor with alisertib to target the p53 pathway in neuroblastoma.

Neuroblastoma accounts for 15% of cancer-related deaths in children, highlighting an unmet need for novel therapies. Selinexor is a small molecule inhibitor of XPO1. XPO1 shuffles cargo proteins with a nuclear export sequence from the nucleus to the cytosol, many of which are essential for cancer growth and cell maintenance. We systematically tested the effect of selinexor against neuroblastoma cells in vitro and in vivo and used an advanced proteomic and phosphoproteomic screening approach to interrogate unknown mechanisms of action. We found that selinexor induced its cytotoxic effects in neuroblastoma through the predominantly nuclear accumulation of p53 and global activation of apoptosis pathways. Selinexor also induced p53 phosphorylation at site S315, which is one initiating step for p53 degradation. Since this phosphorylation step is undertaken mostly by aurora kinase A (AURKA), we used the clinically available AURKA inhibitor, alisertib, and found p53-mediated lethality could be further augmented in three orthotopic xenograft mouse models. These findings suggest a potential therapeutic benefit using selinexor and alisertib to synergistically increase p53-mediated cytotoxicity of high-risk neuroblastoma.