Photobiomodulation Recovers the Submandibular Gland in Vismodegib-Treated Rats.

Objective: The submandibular gland (SMG) produces the most saliva, and factors such as aging and chemotherapy can affect its structure and function. However, there are only temporary treatments available for salivary hypofunction. This study aimed to evaluate the effects of photobiomodulation (PBM) on the function of SMG by using a rat animal model and vismodegib, an antagonist of the sonic hedgehog (SHH) pathway. Methods: Vismodegib (10 mg/kg) drug was gavaged orally for 14 days in rats to significantly decrease the SHH signaling proteins [SHH, protein patched homolog 1 (PTCH1), smoothened protein (SMO), glioma-associated oncogene homolog 1 (GLI1)], induce damage in SMG tissue, and affect salivary functional markers AQP5 and Keratin5. After that, in conjunction with vismodegib administration, PBM was performed using an 850 nm high-power light-emitting diode (LED) device treated daily for 6 days at varying total energy densities of 60, 120, and 180 J/cm2 in at least 3 rats per group. The test results were confirmed by Western blot, immunofluorescence staining, and hematoxylin and eosin staining, and the statistics were t-test or one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests. Results: Significant decreases in the expression of SHH-related proteins (PTCH1, SMO, GLI1, p < 0.05) with damage of SMG ductal cells were observed with vismodegib administration. However, a significant increase in the expression levels of SHH-related proteins (SHH, SMO, GLI1, p < 0.05) and recovery of SMG ductal cells damaged after vismodegib administration were observed for PBM-treated groups. Salivary functional marker AQP5 also showed the same increase or decrease. Conclusions: This study found that vismodegib damages SMG ductal cells and decreases SHH-related proteins and associated salivary functional markers. Also, 850 nm high-power LED recovered the damaged structure of SMG and increased SHH-related proteins and salivary functional markers. The study results suggest that PBM can restore SMG structure and function through SHH signaling.

Mucosal Immunity Related to CD8+ T Lymphocytes in Children with Helicobacter pylori Gastritis.

Purpose: We investigated the role of CD8+T cells as host immune factors in pediatric patients with Helicobacter pylori gastritis. Methods: Gastric mucosal tissue and blood samples were collected from 39 children, including 11 children with H. pylori infection and 28 children as controls. Anti-CD8 and anti-T-bet antibodies were used for immunohistochemistry of the gastric mucosa. For the cell surface and intracellular staining, peripheral blood mononuclear cells were stained with anti-IL7Rα, anti-CX3CR1, anti-CD8, anti-T-bet, and anti-IFN-γ antibodies. Cytokines of sera such as tumor necrosis factor alpha (TNF-α) and CX3CL1 were analyzed using enzyme- linked immunosorbent assay (ELISA). Results: In the immunohistochemistry of gastric mucosa, the frequency of CD8+ and T-bet+ T cells cells was higher in the H. pylori-positive group than in the control group (26.9± 7.8% vs. 16.9±3.3%, p<0.001; 5.0±2.5% vs. 2.2±0.7%, p=0.001). Between the control and H. pylori-positive groups, the frequency of IL-7RαlowCX3CR1+ CD8+ and T-bet+ INF-γ+ CD8+ T cells were not significantly different between surface and intracellular staining, respectively (40.4±24.0% vs. 38.2±17.8%, p=0.914; 40.4±24.0% vs. 38.2±17.8%, p=0.914). In the ELISA, no significant differences in TNF-α and CX3CL1 concentrations were observed between the control and H. pylori-positive groups (34.3±12.1 pg/mL vs. 47.0±22.6 pg/mL, p=0.114/0.5± 0.1 pg/mL vs. 0.5±0.1 pg/mL, p=0.188). Conclusion: CD8+ T and Th1 cells, which secrete IFN-γ, might play important roles in the mucosal immunity of the stomach in children with H. pylori infection.

Spine Metastasis Is Associated with the Development of Brain Metastasis in Non-Small-Cell Lung Cancer Patients.

Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74-3.37, p < 0.001; 1.94 and 1.19-3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.

Effect of whole-brain radiotherapy with platinum-based chemotherapy in non-small cell lung cancer patients with multiple metastases including brain metastases.

Current guidelines recommend that cytotoxic chemotherapy be considered first in non-small cell lung cancer (NSCLC) patients with multiple metastases, and whole-brain radiotherapy (WBRT) is not initially recommended even if brain metastases are present. However, cytotoxic chemotherapeutic agents are less effective in brain metastases due to poor blood-brain barrier permeability. We investigated the effect of WBRT in combination with cytotoxic chemotherapy on survival in NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases. From January 2005 to December 2018, histologically confirmed NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases were included in this study. Patients were classified into two groups based on receiving WBRT prior to or concurrently with administration of first-line chemotherapeutic agents or receiving chemotherapy only. We compared intracranial progression-free survival (iPFS) and overall survival (OS). Of the 240 NSCLC patients with brain metastases at diagnosis and an ECOG PS of 2, 67 patients were EGFR, ALK, and PD-L1 negative with multiple metastases including brain metastases. Among those patients, 43 (64.2%) received WBRT prior to or concurrently with platinum-based chemotherapy. Patients who received WBRT prior to or concurrently with chemotherapy had better iPFS (7.7 months [4.8-10.6] vs. 3.5 months [2.1-4.9], p = 0.009) and OS (10.8 months [5.9-15.7] vs. 6.1 months [1.9-10.3], p = 0.038) than those who did not receive WBRT. In multivariate analyses, WBRT was significantly associated with iPFS (HR: 1.94 and 95% CI 1.11-3.40, p = 0.020) and OS (HR: 1.92 and 95% CI 1.08-3.42, p = 0.027). In NSCLC patients who are EGFR, ALK, and PD-L1 negative, have an ECOG PS of 2, and have multiple metastases including brain metastases, WBRT prior to or concurrently with chemotherapy could improve iPFS and OS. Therefore, the combination of WBRT with cytotoxic chemotherapy should be considered in these patients.

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients.

Massive cerebral air embolism following percutaneous transhepatic biliary drainage: A case report.

RATIONALE: Cerebral air embolism from portal venous gas rarely occurs due to invasive procedures (e.g., endoscopic procedures, liver biopsy, or percutaneous transhepatic biliary drainage) that disrupt the gastrointestinal or hepatobiliary structures. Here, we report a rare case of fatal cerebral air embolism following a series of percutaneous transhepatic biliary drainage tube insertions. PATIENT CONCERNS: A 50-year-old woman with a history of cholecystectomy, liver wedge resection, and hepaticojejunostomy for gallbladder cancer presented with altered mental status 1 week after percutaneous transhepatic biliary drainage tube placement. DIAGNOSES: Extensive cerebral air embolism and acute cerebral infarction. INTERVENTIONS: Brain computed tomography and magnetic resonance imaging, hyperbaric oxygen therapy, medical therapy. OUTCOMES: Despite the use of hyperbaric oxygen therapy and medical treatment including vasopressors, the patient eventually died due to massive systemic air embolism. LESSONS: To date, there have been no reports of cerebral air embolism due to percutaneous transhepatic biliary drainage with pronounced radiologic images. We reviewed previously reported fatal cases associated with endoscopic hepatobiliary procedures and assessed the possible mechanisms and potential causes of air embolism.

Application of Immunoprofiling Using Multiplexed Immunofluorescence Staining Identifies the Prognosis of Patients with High-Grade Serous Ovarian Cancer.

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420-0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.

Isovaleric acid ameliorates ovariectomy-induced osteoporosis by inhibiting osteoclast differentiation.

Osteoclasts (OCs) play important roles in bone remodelling and contribute to bone loss by increasing bone resorption activity. Excessively activated OCs cause diverse bone disorders including osteoporosis. Isovaleric acid (IVA), also known as 3-methylbutanoic acid is a 5-carbon branched-chain fatty acid (BCFA), which can be generated by bacterial fermentation of a leucine-rich diet. Here, we find that IVA suppresses differentiation of bone marrow-derived macrophages into OCs by RANKL. IVA inhibited the expression of OC-related genes. IVA-induced inhibitory effects on OC generation were attenuated by pertussis toxin but not by H89, suggesting a Gi -coupled receptor-dependent but protein kinase A-independent response. Moreover, IVA stimulates AMPK phosphorylation, and treatment with an AMPK inhibitor blocks IVA-induced inhibition of OC generation. In an ovariectomized mouse model, addition of IVA to the drinking water resulted in significant decrease of body weight gain and inhibited the expression of not only OC-related genes but also fusogenic genes in the bone tissue. IVA exposure also blocked bone destruction and OC generation in the bone tissue of ovariectomized mice. Collectively, the results demonstrate that IVA is a novel bioactive BCFA that inhibits OC differentiation, suggesting that IVA can be considered a useful material to control osteoclast-associated bone disorders, including osteoporosis.

HKR3 regulates cell cycle through the inhibition of hTERT in hepatocellular carcinoma cell lines.

Hepatocellular carcinoma is a malignant disease with improved hepatic regeneration and survival, and is activated by human telomere transferase (hTERT). hTERT is expressed during early fetal development and switched off in most adult tissues, but it becomes reactivated in HCC. The exact mechanism regulating these expression changes remains unknown during HCC progress. We evaluated the relationship between hTERT expression and human kruppel-related 3 (HKR3) and cell cycle-related factors in HCC cell lines. Following transfection for hTERT knockdown and HKR3 overexpression, proteomic and transcriptomic analyses related to hTERT were performed using liquid chromatography/mass spectrometry (LC/MS) and RNA sequencing (RNAseq) in HCC cell lines. The expression levels of hTERT, HKR3, and cell cycle-related factors were measured using western blotting, and tumor growth were evaluated via cell proliferation and cell cycle assays. Transcriptomic and proteomic analyses showed that HKR3, hTERT and cyclin-dependent kinase inhibitor 2A (CDKN2A) were correlated. Up-regulation of HKR3 expression decreased hTERT and cyclin activation and suppressed the G1/S phase of the cell cycle through CDKN2A activation. Our results suggest that HKR3 induced regulation of cell cycle through hTERT inhibition and CDKN2A activation. Our results will facilitate further exploration of the pathways regulating human telomerase activity in HCC cell lines.

An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy.

This study was designed to analyze urinary proteins associated with ovarian cancer (OC) and investigate the potential urinary biomarker panel to predict malignancy in women with pelvic masses. We analyzed 23 biomarkers in urine samples obtained from 295 patients with pelvic masses scheduled for surgery. The concentration of urinary biomarkers was quantitatively assessed by the xMAP bead-based multiplexed immunoassay. To identify the performance of each biomarker in predicting cancer over benign tumors, we used a repeated leave-group-out cross-validation strategy. The prediction models using multimarkers were evaluated to develop a urinary ovarian cancer panel. After the exclusion of 12 borderline tumors, the urinary concentration of 17 biomarkers exhibited significant differences between 158 OCs and 125 benign tumors. Human epididymis protein 4 (HE4), vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were the top three biomarkers representing a higher concentration in OC. HE4 demonstrated the highest performance in all samples withOC(mean area under the receiver operating characteristic curve (AUC) 0.822, 95% CI: 0.772-0.869), whereas TTR showed the highest efficacy in early-stage OC (AUC 0.789, 95% CI: 0.714-0.856). Overall, HE4 was the most informative biomarker, followed by creatinine, carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), and TTR using the least absolute shrinkage and selection operator (LASSO) regression models. A multimarker panel consisting of HE4, creatinine, CEA, and TTR presented the best performance with 93.7% sensitivity (SN) at 70.6% specificity (SP) to predict OC over the benign tumor. This panel performed well regardless of disease status and demonstrated an improved performance by including menopausal status. In conclusion, the urinary biomarker panel with HE4, creatinine, CEA, and TTR provided promising efficacy in predicting OC over benign tumors in women with pelvic masses. It was also a non-invasive and easily available diagnostic tool.

Characteristics, trend, and methodological quality of systematic reviews and meta-analyses in nuclear medicine: A bibliometric analysis of studies published between 2005 and 2016.

To evaluate the characteristics, trend, and quality of systematic reviews and meta-analyses in nuclear medicine.We performed a PubMed search to identify systematic reviews and meta-analyses published between 2005 and 2016 in the field of nuclear medicine. The following data were extracted: journal name, impact factor, type of study, topics with cancer type, imaging modalities, authors (number, country, affiliation, presence of nuclear medicine specialists and statisticians, discordance between the first and corresponding authors), funding, methodological quality, methods used for quality assessment, and statistical methods.We included 185 nuclear medicine articles. Meta-analyses (n = 164; 88.6%) were published about 7 times more frequently than systematic reviews. Oncology was the most commonly studied topic (n = 125, 67.6%). The first authors were most frequently located in China (n = 73; 39.5%). PET was the most commonly used modality (n = 150; 81.1%). Both the number of authors and the ratio of discordance between the first and corresponding authors tended to progressively increase over time.The mean AMSTAR score increased over time (5.77 in 2005-2008, 6.71 in 2009-2012, and 7.44 in 2013-2016). The proportion of articles with quality assessment increased significantly (20/26 in 2005-2008, 54/65 in 2009-2012, and 79/94 in 2013-2016). The most commonly used assessment tool was quality assessment of diagnostic accuracy studies (n = 85; 54.9%).The number and quality of systematic reviews and meta-analyses in nuclear medicine have significantly increased over the review period; however, the quality of these articles varies. Efforts to overcome specific weaknesses of the methodologies can provide opportunities for quality improvement.

Prospective study of the efficacy and utility of TP53 mutations in circulating tumor DNA as a non-invasive biomarker of treatment response monitoring in patients with high-grade serous ovarian carcinoma.

OBJECTIVE: Somatic TP53 mutation (TP53mut) is a characteristic finding in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the clinical efficacy and utility of TP53mut circulating tumor DNA (ctDNA) monitoring as a biomarker for managing HGSOC. METHODS: TP53muts were evaluated in patients who received primary treatment for suspected ovarian cancer at Asan Medical Center. In patients diagnosed with HGSOC and with TP53mut, ctDNA, cancer antigen 125 (CA 125), and computed tomography were followed up according to the treatment course. RESULTS: Direct sequencing analysis of 103 tumor tissues from 61 HGSOC patients confirmed TP53muts in 41 patients (67.2%). All these patient-specific somatic mutations were detected in plasma cell-free DNA. The mean value of preoperative TP53 mutant allele count (TP53MAC) in stage III patients was 12.2 copies/µL and in stage IV patients was 45.3 copies/µL. TP53MAC was significantly reduced by treatment and there was no significant difference in the rate of decrease compared to CA 125 by the generalized linear mixed model. When patients were divided into a low TP53MAC group (<0.2 copies/µL) and a high TP53MAC group (≥0.2 copies/µL) based on the TP53MAC value at 3 months after the end of chemotherapy, there was a significant difference in time to progression between the two groups (p=0.038). CONCLUSION: TP53mut ctDNA shows potential as a tumor-specific biomarker for treatment response monitoring in HGSOC. TP53mut ctDNA levels at 3 months post treatment has a significant prognostic utility than that of CA 125.

Optimization to detect TP53 mutations in circulating cell-free tumor DNA from patients with serous epithelial ovarian cancer.

OBJECTIVE: Circulating cell-free tumor DNA (cfDNA) is the DNA released by apoptotic and necrotic cells of the primary tumor into the blood during the period of tumor development. The cfDNA reflects the genetic and epigenetic alterations of the original tumor. TP53 mutations are a defining feature of high-grade serous ovarian carcinoma. We optimized the methods for detecting TP53 mutations in cfDNA from blood samples. We confirmed the correlation of TP53 mutation in primary ovarian cancer tissue and it in cfDNA using digital polymerase chain reaction (dPCR). METHODS: We found 12 frequent mutation sites in TP53 using The Cancer Genome Atlas and Catalogue of Somatic Mutations in Cancer data and manufactured 12 primers. The mutations in tissues were evaluated in fresh-frozen tissue (FFT) and formalin-fixed paraffin-embedded tissue (FFPET). We performed a prospective analysis of serial plasma samples collected from 4 patients before debulking surgery. We extracted cfDNA and calculated its concentration in blood. dPCR was used to analyze TP53 mutations in cfDNA, and we compared TP53 mutations in ovarian cancer tissue with those in cfDNA. RESULTS: Ten primers out of 12 detected the presence of TP53 mutations in FFT, FFPET, and cfDNA. In FFT and FFPET tissue, there were no significant differences. The average cfDNA concentration was 2.12±0.59 ng/mL. We also confirmed that mutations of cfDNA and those of FFT were all in R282W site. CONCLUSION: This study developed detection methods for TP53 mutations in cfDNA in ovarian cancer patients using dPCR. The results demonstrated that there are the same TP53 mutations in both ovarian cancer tissue and cfDNA.

Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05).

PURPOSE: Fibroblast growth factor (FGF) signals are important in carcinogenesis and progression of prostate cancer. Dovitinib is an oral, pan-class inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor (FGFR). We evaluated the efficacy and toxicity of dovitinib in men with metastatic castration resistant prostate cancer (mCRPC). MATERIALS AND METHODS: This study was a single-arm, phase II, open-label, multicenter trial of dovitinib 500 mg/day (5-days-on/2-days-off schedule). The primary endpointwas 16-week progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and prostate-specific antigen (PSA) response rate. Biomarker analyses for VEGFR2, FGF23, and FGFR2 using multiplex enzyme-linked immunosorbent assay was performed. RESULTS: Forty-four men were accrued from 11 hospitals. Eighty percent were post-docetaxel. Median PSA was 100 ng/dL, median age was 69, 82% had bone metastases, and 23% had liver metastases. Median cycles of dovitinibwas 2 (range, 0 to 33). Median PFSwas 3.67 months (95% confidence interval [CI], 1.36 to 5.98) and median OS was 13.70 months (95% CI, 0 to 27.41). Chemotherapy-naïve patients had longer PFS (17.90 months; 95% CI, 9.23 to 28.57) compared with docetaxel-treated patients (2.07 months; 95% CI, 1.73 to 2.41; p=0.001) and the patients with high serum VEGFR2 level over median level (7,800 pg/mL) showed longer PFS compared with others (6.03 months [95% CI, 4.26 to 7.80] vs. 1.97 months [95% CI, 1.79 to 2.15], p=0.023). Grade 3 related adverse events were seen in 40.9% of patients. Grade 1-2 nausea, diarrhea, fatigue, anorexia, and all grade thrombocytopenia are common. CONCLUSION: Dovitinib showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve benefitted from dovitinib.

Lysophosphatidic acid protects against acetaminophen-induced acute liver injury.

We investigated the effect of lysophosphatidic acid (LPA) in experimental acetaminophen (APAP)-induced acute liver injury. LPA administration significantly reduced APAP-challenged acute liver injury, showing attenuated liver damage, liver cell death and aspartate aminotransferase and alanine aminotransferase levels. APAP overdose-induced mortality was also significantly decreased by LPA administration. Regarding the mechanism involved in LPA-induced protection against acute liver injury, LPA administration significantly increased the glutathione level, which was markedly decreased in APAP challenge-induced acute liver injury. LPA administration also strongly blocked the APAP challenge-elicited phosphorylation of JNK, ERK and GSK3ß, which are involved in the pathogenesis of acute liver injury. Furthermore, LPA administration decreased the production of TNF-α and IL-1ß in an experimental drug-induced liver injury animal model. Mouse primary hepatocytes express LPA1,3-6, and injection of the LPA receptor antagonist KI16425 (an LPA1,3-selective inhibitor) or H2L 5765834 (an LPA1,3,5-selective inhibitor) did not reverse the LPA-induced protective effects against acute liver injury. The therapeutic administration of LPA also blocked APAP-induced liver damage, leading to an increased survival rate. Collectively, these results indicate that the well-known bioactive lipid LPA can block the pathogenesis of APAP-induced acute liver injury by increasing the glutathione level but decreasing inflammatory cytokines in an LPA1,3,5-independent manner. Our results suggest that LPA might be an important therapeutic agent for drug-induced liver injury.

FAM19A5, a brain-specific chemokine, inhibits RANKL-induced osteoclast formation through formyl peptide receptor 2.

Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a formyl peptide receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target receptor FPR2 can act as novel endogenous ligand/receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.

Serum amyloid A inhibits dendritic cell differentiation by suppressing GM-CSF receptor expression and signaling.

In this study, we report that an acute phase reactant, serum amyloid A (SAA), strongly inhibits dendritic cell differentiation induced by GM-CSF plus IL-4. SAA markedly decreased the expression of MHCII and CD11c. Moreover, SAA decreased cell surface GM-CSF receptor expression. SAA also decreased the expression of PU.1 and C/EBPα, which play roles in the expression of GM-CSF receptor. This inhibitory response by SAA is partly mediated by the well-known SAA receptors, Toll-like receptor 2 and formyl peptide receptor 2. Taken together, we suggest a novel insight into the inhibitory role of SAA in dendritic cell differentiation.

Incidental Paratracheal Air Cysts on Thoracic CT and Their Association with Chronic Inflammatory Lung Disease.

Purpose. To determine the association between the progression of upper lung fibrosis and paratracheal air cysts (PACs) size. Materials and Methods. The thoracic CT images of 4573 patients were reviewed for the prevalence, size, and location of PACs and their communication with trachea. In addition, the presence of upper lung fibrosis, emphysema, and bronchiectasis was evaluated in patients with PACs and compared with a control group without PACs. Upper lung fibrosis was analyzed using a fibrosis score system. Results. The prevalence of PACs was 6.8%. Communication with tracheal lumen was demonstrated by 31.5% of patients with PACs. The prevalence of fibrosis, emphysema, and bronchiectasis in patients with PACs were 67.5%, 21.9%, and 28.3%, respectively. The prevalence of fibrosis was significantly different in the two groups by univariable and multivariable analysis (odds ratio = 2.077, P < 0.001). 140 patients with fibrosis among PAC group underwent a previous or follow-up CT; the prevalence with increase in PAC sizes was higher in patients with increase in fibrosis score than those without it (66.2% versus 17.3%, P < 0.001). Conclusions. PACs appear to be highly related to upper lung fibrosis and moderately related to bronchiectasis. In patients with fibrosis, PAC sizes tended to increase with the progression of upper lung fibrosis.

Incidental thyroid nodules on thoracic contrast-enhanced computed tomography in clinical practice during a 10-year period: Characteristics, clinical outcomes, and factors contributing to further evaluation.

The purposes of this study were to assess the prevalence, malignancy rate, and characteristics of incidental thyroid nodules (ITNs), and to identify factors that contribute the additional workup by ultrasound.The medical records and imaging features of ITNs reported via thoracic computed tomography (CT) were retrospectively reviewed to determine the size, multiplicity, attenuation, shape, and presence of calcification. To identify the factors associated with additional workup, we compared the workup and non-workup groups in terms of nodule characteristics, indications, and CT slices. We identified factors that could distinguish malignant ITNs from non-malignant nodules.A total of 60,921 thoracic CT scans met the inclusion criteria, and ITNs were reported using formal radiology in 2733 patients (4.5%). Among all patients with reported ITNs, 546 (20.0%) underwent further workup. Of these patients, 62 (2.3%, 62/2773) were diagnosed with malignant nodules. Multivariable analysis identified multiple factors associated with additional workup, including female sex, younger age, larger nodule size, calcification, anteroposterior to transverse dimension ratio >1, heterogeneous attenuation in the nodule, and scanning indications such as infection or screening. However, only calcification was associated with malignant nodules (odds ratio [OR] = 2.313; 95% confidence interval [CI], 1.301-4.113).We observed discordance between the numbers of reported ITNs and case with additional workup and identified multiple factors associated with additional workup. We have, therefore, demonstrated a need for reliable subsequent evaluation guidelines and note that the appearance of calcification in an ITN on imaging may be a factor indicating the need for additional workup.