Late-onset pulmonary and cardiac toxicities in a patient treated with immune checkpoint inhibitor monotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) can cause immune-related adverse events (irAEs) in organs throughout the body. Of the irAEs, ICPI-induced interstitial lung disease (ILD) is the most notable one that can be life-threatening. No less than that, ICPI-induced cardiac irAEs are serious ones and are recently attracting attention. IrAEs usually develop within a few months after the initiation of ICPI treatment, but some of them occur after a long period of time from the start of treatment. CASE: A 60-year-old male patient with squamous cell carcinoma developed ICPI-induced ILD more than 2 years after the initiation of ICPI therapy. A few months after the ICPI-induced ILD improved, he developed heart failure, which was presumed to be caused by impaired cardiac ejection. Both irAEs improved without administration of corticosteroids. CONCLUSION: Although rare, these irAEs may appear even after a long period of time from the start of administration, and chest physicians should be careful of late-onset irAEs.

Analysis of effects and indications of cryosurgery for oral mucoceles.

Cryosurgery is a recognized method for the treatment of mucoceles in the oral cavity. In this study, cryosurgery was used for mucoceles at the lip or buccal mucosa, and the effect and the indication were evaluated clinically. The subjects were patients with a clinical diagnosis of mucocele on the lip or buccal mucosa and who chose cryosurgery after procedures for both surgical excision and cryosurgery for the lesion were explained. Cryosurgery was performed with a freezing device using liquid nitrogen without local anesthesia. Twenty-four patients chose cryosurgery, including seven preschool children. There were no serious adverse events during and after cryosurgery. Healing progress after cryosurgery was not affected by patient age, lesion size, or how long the patients had the lesion. Two cases later underwent surgical excision because cryosurgery was not successful. Twenty-three patients chose surgical excision, one case had a recurrence. The number of younger patients who chose cryosurgery was significantly higher than that who chose surgical excision. This study suggests that cryosurgery is effective for mucoceles of the lip or buccal mucosa and is a simple and safe treatment method, especially for preschool children.

Renal arteriolar hyalinosis, not intimal thickening in large arteries, is associated with cardiovascular events in people with biopsy-proven diabetic nephropathy.

AIMS: Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. METHODS: This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. RESULTS: Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. CONCLUSIONS: Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

Minimally invasive spinal decompression for degenerative lumbar spondylolisthesis and stenosis maintains stability and may avoid the need for fusion.

Aims: The aim of this study was to investigate the clinical and radiographic outcomes of microendoscopic laminotomy in patients with lumbar stenosis and concurrent degenerative spondylolisthesis (DS), and to determine the effect of this procedure on spinal stability. Patients and Methods: A total of 304 consecutive patients with single-level lumbar DS with concomitant stenosis underwent microendoscopic laminotomy without fusion between January 2004 and December 2010. Patients were divided into two groups, those with and without advanced DS based on the degree of spondylolisthesis and dynamic instability. A total of 242 patients met the inclusion criteria. There were 101 men and 141 women. Their mean age was 68.1 years (46 to 85). Outcome was assessed using the Japanese Orthopaedic Association and Roland Morris Disability Questionnaire scores, a visual analogue score for pain and the Short Form Health-36 score. The radiographic outcome was assessed by measuring the slip and the disc height. The clinical and radiographic parameters were evaluated at a mean follow-up of 4.6 years (3 to 7.5). Results: There were no significant differences in the preoperative measurements between the group and no significant differences between the clinical parameters at the final follow-up. The mean percentage slip was 17.1% preoperatively and 17.7% at the final follow-up (p = 0.35). Progressive instability was noted in 13 patients (8.2%) with DS and 6 patients (7.0%) with advanced DS, respectively (p = 0.81). There was radiological evidence of restabilization of the spine in 30 patients (35%) with preoperative instability. The success rate of microendoscopic laminotomy was good/excellent in 166 (69%), fair in 49 (20%) and poor in 27 patients (11%) in both groups. Conclusion: Microendoscopic laminotomy is an effective form of surgical treatment for patients with DS and stenosis. Preservation of the stabilizing structures using this technique prevents postoperative instability. Cite this article: Bone Joint J 2018;100-B:499-506.

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung.

Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment. Previously Shugoshin-1 (Sgo1(-/+)) mice, a transgenic mouse model of CIN, showed mild proneness to spontaneous lung and liver cancers. In this study, adoptive (T/B-cell based) immunity-deficient RAG1(-/-) Sgo1(-/+) double mutant mice developed lung adenocarcinomas more aggressively than did Sgo1(-/+) or RAG1(-/-) mice, suggesting immune system involvement in CIN-mediated lung carcinogenesis. To identify molecular causes of the lung adenocarcinoma, we used systems biology approach, comparative RNAseq, to RAG1(-/-) and RAG1(-/-) Sgo1(-/+). The comparative RNAseq data and follow-up analyses in the lungs of naive Sgo1(-/+) mice demonstrate that, (i) glutathione is depleted, making the tissue vulnerable to oxidative stress, (ii) spontaneous DNA damage is increased, (iii) oncogenic Wnt signaling is activated, (iv) both major branches of the immune system are weakened through misregulations in signal mediators such as CD80 and calreticulin and (v) the actin cytoskeleton is misregulated. Overall, the results show multi-faceted roles of CIN in lung carcinoma development in Sgo1(-/+) mice. Our model presents various effects of CIN and will help to identify potential targets to prevent CIN-driven carcinogenesis in the lung.

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

UNLABELLED: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. INTRODUCTION: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. METHODS: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. RESULTS: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. CONCLUSION: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Ectopic expression of c-myc fails to overcome downregulation of telomerase activity induced by herbimycin A, but ectopic hTERT expression overcomes it.

Correction to: Leukemia (2000); 14: 1260­1265; doi: 10.1038/sj.leu.2401828. Since the publication of the above article the authors have identified an error in Figure 1. Figure 1 shows the modulation of telomerase activity by herbimycin A in K562 cells: (a) cell cycle and (b) telomerase activity, mRNA expressions of hTERT, hTERC, TEP-1, c-myc, cyclin D1 and b-actin, and c-Myc protein. The authors however wish to inform the readers that Figure 1b incorrectly shows hTERT mRNA, which is the result of herbimycin A treatment of cyclin-D1-transfected K562 cells (Figure 3b, hTERT mRNA). While preparing Figure 1, the authors mistakenly submitted a figure that used the incorrect photo data following confusion regarding file names. The correct figure can be found below: The authors wish to apologise for any inconvenience caused and confirm that the conclusions drawn from this research are not affected by this error.

Endoplasmic reticulum stress response and bone loss in experimental periodontitis in mice.

BACKGROUND AND OBJECTIVE: Endoplasmic reticulum (ER) stress is the cell response that activates the unfolded protein response (UPR) pathway in a variety of conditions, such as inflammation and bone metabolism. The UPR may be associated with the pathogenesis of periodontal disease because the disease is inflammatory in nature, and alveolar bone resorption is a characteristic feature of the disease. However, the relationship between ER stress and alveolar bone resorption observed in periodontal disease remains elusive. MATERIAL AND METHODS: C57BL/6 mice were orally administered Porphyromonas gingivalis, a representative periodontopathic bacterium, in the presence or absence of a chemical chaperone, 4-phenylbutyrate (4-PBA). The gene expression of UPR-related molecules and cytokines in gingival tissues were analyzed using real-time polymerase chain reaction, and alveolar bone resorption and osteoclast numbers were evaluated histologically. The in vitro effect of 4-PBA on the differentiation of mouse bone marrow cells induced by receptor activator of nuclear factor-κB ligand in the presence of macrophage colony-stimulating factor was analyzed. RESULTS: The gene expression levels of UPR-related molecules and proinflammatory cytokines and alveolar bone resorption were significantly increased in P. gingivalis-administered mice. UPR-related gene expression and alveolar bone resorption were significantly suppressed by the administration of 4-PBA. However, no effect of 4-PBA was observed for proinflammatory cytokine expression in gingival tissues. Osteoclastic differentiation of bone marrow cells was also suppressed by 4-PBA with a concomitant reduction in the gene expression of cathepsin K and tartrate-resistant alkaline phosphatase genes. CONCLUSION: ER stress induced by oral administration of P. gingivalis is involved in alveolar bone resorption independent of inflammatory cytokines in mice.

Epithelial TRPV1 signaling accelerates gingival epithelial cell proliferation.

Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca(2+) levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

BACKGROUND: It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. OBJECTIVE: To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. METHODS: We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. RESULTS: In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. CONCLUSIONS: Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

Leiomyosarcoma of the broad ligament: a case report with CT and MRI images.

Primary leiomyosarcoma of the broad ligament is a very rare and highly malignant gynecological tumor. The authors report a 61-year-old postmenopausal woman with signs and symptoms of malignant ovarian tumor. Preoperative magnetic resonance imaging (MRI) was interpreted as being suspicious for malignant tumors, such as an ovarian cancer or a leiomyosarcoma of the broad ligament, so laparotomy was performed. Macroscopically, the tumor was revealed with a 18 x 13.7 x 9.5 cm degenerated, multiple cystic part and solid whitish part arising from broad ligament which on histopathology proved to be leiomyosarcoma. To the best of the authors' knowledge, primary leiomyosarcoma of the broad ligament has been documented in 21 reports or so, and no imaging findings are available. Here the authors present the MRI findings of primary leiomyosarcoma of the broad ligament.

Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle.

Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFRα as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeletal muscle. PDGFRα(+) cells represent a cell population distinct from CD56(+) myogenic cells, and adipogenic and fibrogenic potentials were highly enriched in the PDGFRα(+) population. Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. Our results revealed the pathological relevance of PDGFRα(+) mesenchymal progenitors to human muscle diseases and provide a basis for developing therapeutic strategy to treat muscle diseases.

Natural killer T cells mediate alveolar bone resorption and a systemic inflammatory response in response to oral infection of mice with Porphyromonas gingivalis.

BACKGROUND AND OBJECTIVE: T and B cells are known to be involved in the disease process of periodontitis. However, the role of natural killer T cells in the pathogenesis of periodontitis has not been clarified. MATERIALS AND METHODS: To examine the role of these cells, C57BL/6J (wild-type), CD1d(-/-) and α-galactosylceramide (αGC)-stimulated wild-type mice were orally infected with Porphyromonas gingivalis strain W83. RESULTS: Apart from CD1d(-/-) mice, the level of alveolar bone resorption was elevated by the infection and was further accelerated in αGC-stimulated mice. The infection induced elevated levels of serum amyloid A and P. gingivalis-specific IgG in the sera, although the degree of elevation was much smaller in the CD1d(-/-) mice. Infection-induced RANKL elevation was only observed in αGC-stimulated mice. Although the cytokines produced by splenocytes were mainly T-helper 1 type in wild-type mice, those in αGC-stimulated mice were predominantly T-helper 2 type. In the liver, the infection demonstrated no effect on the gene expression for interferon-γ, interleukin-4 and RANKL except αGC-stimulated mice in which the infection upregulated the gene expressions. CONCLUSION: This study is the first to show that natural killer T cells upregulated systemic and local inflammatory responses induced by oral infection with P. gingivalis, thereby contributing to the progression of alveolar bone resorption.

Increase in prominence of electrocardiographic J waves after a single dose of propofol in a patient with early ventricular repolarisation.

J waves appear on an electrocardiogram as an elevation of the J point in the terminal portion of the QRS complex. J waves are often benign, but may be associated with malignant ventricular arrhythmias. In some cases, such problems appear to have been precipitated by propofol infusions. We observed a sudden increase in J waves and profound hypotension following a single intravenous dose of propofol in an 84-year-old woman with early repolarisation in the inferior ventricular wall. When early repolarisation (as shown by electrocardiographic J waves) is observed in the inferior ventricular wall pre-operatively, patients should be carefully monitored. Myocardial ischaemia and the use of drugs that might worsen J waves should be avoided.

Safety and factors contributing to the difficulty of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: The safety of laparoscopic surgery for rectal cancer following chemoradiotherapy (CRT) has not been fully established. The aim of our retrospective study was to examine the outcomes and the factors contributing to the difficulty of laparoscopic surgery after CRT. METHODS: Eighty-seven consecutive rectal cancer patients treated with CRT were analyzed. Clinicopathological factors were compared between laparoscopic surgery (n = 57) and open surgery (n = 30) groups, and factors that correlated with operation time and blood loss were analyzed in low anterior resection (LAR) cases in the laparoscopic surgery group (n = 46). RESULTS: There was less blood loss in the laparoscopic surgery group than in the open surgery group (191 vs. 1,043 ml, p = 0.0001), and the operation time in the two groups was similar (329 vs. 322 min, p = 0.8). The rate of conversion from laparoscopic surgery to open surgery was 1.8 %. There was no significant difference in the morbidity rate (laparoscopic surgery 22.8 % vs. open surgery 33.3 %, p = 0.3). All circumferential resection margins were clear. Three-year cumulative rates of local recurrence were as follows: laparoscopic surgery: 1.9 % vs. open surgery: 8.4 % (p = 0.4), and distant recurrence was 28.5 % in laparoscopic surgery vs. 22.7 % in open surgery (p = 0.8) and these rates were not significantly different. In laparoscopic LAR cases, a shorter distance of the tumor from the anal verge was associated with a longer operation time. A high computed tomography Hounsfield units value of the mesorectum (CTV) was associated with increased blood loss in the first 23 cases, but not in the other 23 cases. CONCLUSIONS: Laparoscopic surgery following CRT was safe and feasible. A shorter anal verge was associated with a longer operation time. Blood loss increased in cases with high CTV, but this can likely be mitigated by experience.

Profiles of vitamin D insufficiency and deficiency in Japanese men and women: association with biological, environmental, and nutritional factors and coexisting disorders: the ROAD study.

UNLABELLED: Assessments of serum 25-hydroxyvitamin D levels in 1,683 Japanese from a population-based cohort revealed prevalences of vitamin D insufficiency and deficiency were 81.3 and 1.2%, respectively. Vitamin D deficiency was significantly associated with female sex, examined month, current smoking, lack of regular walking, higher intact parathyroid hormone (iPTH), and poor daily vitamin D intake. INTRODUCTION: To clarify the characteristics of subjects with vitamin D insufficiency and deficiency among men and women in the general Japanese population. METHODS: We initiated research on osteoarthritis/osteoporosis against disability (ROAD), a large-scale population-based cohort study, in 2005-2007. Blood examination was performed to measure serum 25-hydroxyvitamin D (25D) and iPTH levels and biochemical markers of bone turnover in 1,683 participants (595 men, 1,088 women). Participants completed an interviewer-administered questionnaire, measurements of bone mineral density, and x-ray examination. Vitamin D deficiency and insufficiency were defined by serum 25D levels <10 and ≥10 but <30 ng/mL, respectively. RESULTS: The prevalence of vitamin D insufficiency and deficiency was 81.3 and 1.2%, respectively. Multinominal logistic regression analyses using potentially confounding variables revealed vitamin D insufficiency was significantly associated with age (+1 year, relative risk ratio, 0.98; 95% confidence interval, 0.96-0.99), gender (women vs. men, 2.28; 1.59-3.30), residing areas (coastal area vs. mountainous area, 0.58; 0.41-0.81), examined month (October, November, December vs. January, 0.51; 0.34-0.76), and serum levels of iPTH (+1 pg/mL, 1.02; 1.01-1.03). Vitamin D deficiency was significantly characterised by female sex (20.5; 3.1-136.7), examined month (0.28; 0.09-0.95), current smoking habit (6.39; 1.78-23.0), lack of regular outside walking (3.96; 1.34-11.7), higher iPTH (1.02; 1.01-1.03) and poor daily vitamin D intake (+10 µg/day, 0.48; 0.24-0.93). CONCLUSIONS: A high prevalence of vitamin D insufficiency and a low prevalence of vitamin D deficiency were found in Japanese men and women, and the characteristics of vitamin D status were clarified.

CD30L/CD30 is critical for maintenance of IL-17A-producing γδ T cells bearing Vγ6 in mucosa-associated tissues in mice.

CD30 ligand (CD30L, CD153), a member of the tumor necrosis factor (TNF) superfamily, and its receptor CD30 are important for differentiation and activation of CD4(+) T helper type 17 (Th17) cells. In this report, we demonstrate that the interleukin 17A (IL-17A)-producing γδ T cells normally developed in the fetal thymus, whereas Vγ1(-)Vγ4(-) γδ T cells expressed Vγ6/Vδ1 gene transcript selectively decreased in mucosa-associated tissues in naive CD30KO or CD30LKO mice. Moreover, CD30 and CD30L were expressed preferentially by Vγ1(-)Vγ4(-) γδ T cells in naive mice. The bacteria clearance was attenuated by the impaired response of the IL-17A-producing γδ T cells and decreased infiltration of neutrophils in CD30KO or CD30LKO mice. In vivo administration of agonistic anti-CD30 monoclonal antibody restored the ability of protection against Listeria monocytogenes by enhancing Vγ1(-)Vγ4(-) γδ T cells producing IL-17A not only in wild-type but also CD30LKO mice. Taken together, it appears that CD30L/CD30 signaling plays an important role in the maintenance and activation of IL-17A-producing γδ T cells presumably bearing Vγ6 in the mucosa-associated tissues of mice.

Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma.

BACKGROUND: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. METHODS: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. RESULTS: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. CONCLUSION: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.