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Immunotherapy has become a standard treatment option for non-small cell lung cancer (NSCLC), with the tumor microenvironment attracting significant attention. CD8 + and forkhead box protein P3 + (FoxP3 +) tumor-infiltrating lymphocytes (TILs) influence the tumor microenvironment, but the clinical significance of CD8 + and FoxP3 + TILs in stage IA lung adenocarcinoma (LAD) is poorly understood. We analyzed 203 patients with stage IA primary LAD who had undergone surgery at Kyushu University from January 2003 to December 2012. We evaluated CD8 + and FoxP3 + TILs by immunohistochemistry. We set the cutoff values at 50 cells/0.04 mm2 for CD8 + TILs and 20 cells/0.04 mm2 for FoxP3 + TILs, respectively. We divided the patients into four groups: CD8-Low/FoxP3-Low; CD8-High/FoxP3-Low; CD8-Low/FoxP3-High; and CD8-High/FoxP3-High. We compared clinical outcomes among them. Programmed cell death ligand-1 (PD-L1) expression by tumor cells was also evaluated as previously reported. Respectively, 104 (51.2%), 46 (22.7%), 22 (10.8%), and 31 (15.3%) patients were classified as CD8-Low/FoxP3-Low, CD8-High/FoxP3-Low, CD8-Low/FoxP3-High, and CD8-High/FoxP3-High. Both disease-free survival (DFS) and overall survival (OS) were significantly worse in the CD8-Low/FoxP3-High group than the other groups (5-year DFS: 66.3% vs. 90.5%; P = 0.0007, 5-year OS: 90.9% vs. 97.0%; P = 0.0077). In the multivariate analysis, CD8-Low/FoxP3-High and PD-L1 expression were independent prognostic factors of DFS, and lymphatic invasion, surgical procedure, and PD-L1 expression were independent prognostic factors of OS. CD8-Low/FoxP3-High was an independent prognostic factor of DFS (hazard ratio: 3.22; 95% confidence interval: 1.321–7.179; P = 0.0121) in stage IA LAD. Immunosuppressive conditions were associated with poor prognosis in stage IA LAD.

Background There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naive cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. Conclusions This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Background and purpose: To compare chemoradiotherapy (CRT) with low-dose continuous 5-fluorouracil (5FU) to CRT with 5FU+cisplatin (CDDP) for esophageal squamous cell carcinoma (ESCC) in a retrospective cohort study. Methods and materials: We reviewed the cases of Stage I–IV ESCC patients who underwent definitive CRT in 2000–2014. Concomitant chemotherapy was one of the three regimens: (1) high-dose intermittent 5FU and CDDP (standard-dose FP: SDFP), (2) low-dose continuous 5FU and CDDP (LDFP), or (3) low-dose continuous 5FU (LD5FU). The general selection criteria for chemotherapy were: SDFP for patients aged

Polyarteritis nodosa (PAN) is a rare form of vasculitis that occurs in childhood and affects small- and medium-sized arteries. Large aneurysms due to PAN can induce fatal complications like rupturing or occlusion of the affected arteries. Here, we report a case of a 4-month-old girl with PAN complicated by a large superior mesenteric artery aneurysm and ileal obstruction. We controlled her blood pressure to prevent the artery from rupturing. A combination of prednisolone, intravenous cyclophosphamide, and plasma exchange reduced the inflammation. She developed mechanical ileus due to ileum stricture and underwent bowel resection. Histopathological examinations revealed reparative arteritis around the healed ulcer. Her postoperative course was uneventful without further dilatation of the aneurysm. This case highlights the importance of intensive immunosuppressive therapy and appropriate blood pressure control in pediatric patients with PAN complicated by large aneurysms. Mechanical ileus can develop and may require surgical management even after remission of vasculitis.

We sought to identify peripheral blood markers associated with two immune-related factors-programmed cell death-ligand-2 (PD-L2) and indoleamine 2,3-dioxygenase-1 (IDO1)-that are expressed on tumor cells in primary lung adenocarcinoma (AD) specimens. We randomly selected 448 patients (70%) from 640 consecutive patients with resected stage I-III primary lung AD, who had been treated at that point with surgery alone. Expression of PD-L2 and IDO1 in these patients was assessed by immunohistochemistry, and evaluated with respect to peripheral blood markers measured before surgery, including white blood cells, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count (AMC), absolute eosinophil count (AEC), serum C-reactive protein, and serum lactate dehydrogenase levels. Membrane PD-L2 expression and cytoplasmic IDO1 expression were defined by tumor proportion score (TPS); samples with TPS < 1% were considered negative. Logistic regression models were used to identify variables associated with the immune-related factors. Advanced stage (P = 0.0090), higher AMC (P = 0.0195), and higher AEC (P = 0.0015) were independent predictors of IDO1 expression. PD-L2 expression was not associated with any tested peripheral blood markers. Peripheral blood markers, especially AMC and AEC, could potential predict IDO1 expression in lung AD. This study should be replicated in another cohort; further efforts to explore other biomarkers that predict PD-L2 or IDO1 expression are also warranted.

Cluster of differentiation 69 (CD69), known as an early activation marker of lymphocytes, has been demonstrated to regulate inflammatory events in various disease models. Although the increased number of CD69-expressed T lymphocytes in the lungs of patients with chronic obstructive pulmonary disease (COPD) has been reported, a functional role of CD69 in the pathogenesis of COPD remains unknown. To address to this question, CD69-deficient (CD69KO) mice and wild-type (WT) mice were subjected to a mouse model of porcine pancreatic elastase (PPE)-induced pulmonary inflammation and emphysema. In the two genotypes, PPE increased counts of macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) and induced emphysematous changes in the lung, whereas those two pathological signs were significantly enhanced in CD69KO mice compared to WT mice. Moreover, the PPE-induced levels of IL-17 and IL-6 in BALF were significantly higher in CD69KO mice than in WT mice at the acute inflammatory phase. Immunofluorescent studies showed that IL-17 and IL-6 were predominantly expressed in CD4+ and γδ T cells and macrophages, respectively. Concomitant administration of IL-17- and IL-6-neutralizing antibodies significantly attenuated the PPE-induced emphysematous changes in the two genotypes. These findings suggest that CD69 negatively regulates the development of PPE-induced emphysema in part at least through modulating function of IL-17-producing T cells., Highlights • CD69 negatively modulated elastase-induced pulmonary inflammation and emphysema. • Disruption of the CD69 gene enhanced the elastase-induced IL-6 and IL-17 expression. • Th17 and γδ T cells affected the elastase-induced emphysema via producing IL-17. • Neutralization of IL-6&17 signals attenuated the elastase-induced emphysema.

We investigated the outcomes of treatment for patients with localized prostate cancer (PCa) treated with 3D conformal radiation therapy (3D-CRT) followed by two-fraction high-dose-rate brachytherapy within a single day (2-fr.-HDR-BT/day) at a single institution. A total of 156 consecutive Asian males (median age, 67 years) were enrolled. To compare our findings with those of other studies, we analyzed our results using the D'Amico classification, assigning the patients to low- ( n = 5; 3.2%), intermediate- ( n = 36; 23.1%) and high-risk ( n = 115; 73.7%) groups (Stage T3 PCa patients were classified as high-risk). One patient in the D'Amico low-risk group (20%), 13 intermediate-risk patients (36.1%) and 99 high-risk patients (86.1%) underwent androgen deprivation therapy. We administered a prescription dose of 39 Gy in 13 fractions of 3D-CRT combined with 18 Gy of HDR-BT in two 9-Gy fractions delivered within a single day. We did not distinguish between risk groups in determining the prescription dose. The median follow-up period was 38 months. Of the 156 patients, one died from primary disease and five died from other diseases. The 3-year overall survival (OS) rates were 100%, 100% and 93.7%, and the 3-year ‘biochemical no evidence of disease (bNED)’ rates were 100%, 100% and 96.9% for the D'Amico low-, intermediate- and high-risk groups, respectively. No patient developed ≥ Grade 3 early toxicity. The Grade 3 late genitourinary toxicity rate was 2.6%, and no ≥ Grade 3 late gastrointestinal toxicity occurred. The efficacy and safety of this study were satisfactory, and longer-term follow-up is necessary.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS.

Growing teratoma syndrome (GTS) of the lung is extremely rare, and there are very few reports on this condition. This is a case report of GTS of the lung that was successfully treated by resection. A 19-year-old man, who had been diagnosed with a testicular tumor, lung metastases and left hilar lymph node metastasis, underwent surgical resection for left testicular cancer. After orchiectomy and chemotherapy, the patient was successfully treated with wedge resection of the right upper lobe and left upper lobectomy. In conclusion, the current case suggests that some patients with GTS might be successfully treated by surgical resection.

Objectives: Even with advanced image guidance, biopsies occasionally fail to diagnose small lung lesions, which are highly suggestive of primary lung cancer by radiological examination. The aim of this study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) to treat small lung lesions clinically diagnosed as primary lung cancer., Materials and methods: This is a prospective, multi-institutional observation study. Strict inclusion and exclusion criteria were determined in a nation-wide consensus meeting and used to include patients who were clinically diagnosed with primary lung cancer using precise imaging modalities, for whom further surgical intervention was not feasible, who refused watchful waiting, and who were highly tolerable of SBRT with informed consent. SBRT was performed with 48 Gy in 4 fractions at the tumor isocenter., Results: From August 2009 to August 2014, 62 patients from 11 institutions were enrolled. Their median age was 80 years. The tumors ranged in size from 9 to 30 mm in diameter (median, 18 mm). The median follow-up interval was 55 months. The 3-year overall survival rate was 83.3% (95% confidence interval (CI) 71.1–90.7%) for all the patients and 94.7% (95% CI 68.1–99.2%) for the patients younger than 75 years. Local failure, regional lymph node metastases and distant metastases occurred in 4 (6.4%), 3 (4.8%) and 11 (17.7%) patients, respectively. Grades 3 and 4 toxicities were observed in 8 (12.9%) patients and 1 (1.6%) patient, respectively. No grade 5 toxicities were observed., Conclusions: SBRT is safe and effective for patients with small lung lesions clinically diagnosed as primary lung cancer that satisfied the proposed strict indication criteria as previously reported. A prospective interventional study is required to ascertain if SBRT is an alternative strategy for these patients.

To determine the current practice of stereotactic irradiation (STI) for brain metastases in Japan by a questionnaire survey. A questionnaire was distributed to 313 institutions performing STI with one of the following machines: Gamma Knife (GK), CyberKnife (CK), Novalis (Nov), or other linear accelerator (LINAC)-based systems (OLS). The participation was voluntary. There were 163 responding institutions. The total number of STI treatments between April 2013 and March 2014 was 10,684. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) were performed in 8624 (80.7%) and 2060 (19.3%) cases, respectively. Whole-brain radiation therapy (WBRT) was performed for a total of 3515 cases. For a case model of a 1.5-cm solitary brain metastasis in a non-eloquent area, the most common GTV-PTV margin was 2 mm (22 of 114 institutions), and an institutional standard fraction was 1 (75 of 114 institutions). The doses for the model case also varied from 13.0 to 26.0 Gy (Median 20 Gy) when converted to SRS (α/β = 10). A prescription point was at the PTV margin the most. The median dose constraints which were converted to SRS (α/β = 3) to organs at risk were 12.2, 12.7, and 13.7 Gy for optic nerves, cavernous sinus, and brainstem, respectively. STI for brain metastases in current practice varied significantly among institutions. These different strategies relied mostly on the type of treatment machine used. It is thus necessary to establish a common guideline to express dose prescriptions and plan qualities for different STI machines.

Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.

One of the mitogen-activated protein kinases, p38α plays a crucial role in various inflammatory diseases and apoptosis of various types of cells. In this study, we investigated the pathophysiological roles of p38α in spinal cord injury (SCI), using a mouse model. Lateral hemisection at T9 of the SC was performed in wild type (WT) and p38α+/- mice (p38α-/- showed embryonic lethality). p38α+/- mice showed a better functional recovery from SCI-associated paralyzed hindlimbs compared to WT mice at 7 days post-injury (dpi), which remained until 28 dpi (an end time point of monitoring the behavior). In histopathological analysis at 28 dpi, there was more axonal regeneration with remyelination on the caudal side of the lesion epicenter in p38α+/- mice than in WT mice. At 7 dpi, infiltration of inflammatory cells into the lesion and expression of cytokines in the lesion were reduced in p38α+/- mice compared with WT mice. At the same time point, the number of apoptotic oligodendrocytes in the white matter at the caudal boarder of the lesion of p38α+/- mice was lower than that of WT mice. At 14 dpi, more neural and oligodendrocyte precursor cells in the gray matter and white matter, respectively, were observed around the lesion epicenter of p38α+/- mice compared with the case of WT mice. At the same time point, astrocytic scar formation was less apparent in p38α+/- than in WT mice, while compaction of inflammatory immune cells associated with the wound contraction was more apparent in p38α+/- than in WT mice. Furthermore, we verified the effectiveness of oral administration of SB239063, a p38α inhibitor on the hindlimb locomotor recovery after SCI. These results suggest that p38α deeply contributes to the pathogenesis of SCI and that inhibition of p38α is a beneficial strategy to recovery from SCI.

Objectives: We evaluated the efficacy of balloon dilatation after bilateral pulmonary artery banding for the treatment of severe congenital heart disease that depends on patent ductus arteriosus for systemic circulation. Background: Neonatal cardiopulmonary bypass can cause brain injury, which may result in a severely impaired neurodevelopmental outcome. Hence, we perform bilateral pulmonary artery banding combined with postoperative percutaneous trans catheter angioplasty with balloon dilatation as first-stage palliation. Methods: From October 2007 to December 2013, 27 consecutive patients underwent bilateral pulmonary artery banding at our institution. We retrospectively obtained their diagnostic, clinical, and catheter examination data from the medical records. Results: Bilateral pulmonary artery banding was performed at a median of 7 days. Among the 27 patients, 16 underwent expansive angioplasty using a balloon catheter at each banding site to increase pulmonary blood flow. The mean age at dilatation was 53.4 ± 25.9 days, and the mean pulmonary artery index significantly increased from 130.6 mm2/m2 ± 51.1 mm2/m2 before dilatation to 243.6 mm2/ m2 ± 93.5 mm2/m2 after dilatation (p

Aims We evaluated whether pathophysiological events in the brain in sepsis are mediated by ET-1/ETB receptor axis. Main methods We prepared raw fecal fluid from soft stool of mice. Mice were randomly divided into three groups: pre-PBS + raw fecal fluid group (Sepsis, easy stool method (ESM) group); pre-BQ788 + raw fecal fluid group (BQ group); and pre-BQ788 + PBS group (PBS group). According to each experimental condition, PBS or BQ788 was intravenously injected into mice prior to intraperitoneal administration of fecal fluid or PBS. All groups of mice were sacrificed at 8 h after administration, and then brain samples were prepared. Key findings In the ESM group, an increase of apoptotic neuroblasts was demonstrated in the subgranular zone of the hippocampal dentate gyrus, enhanced expression of c-FOS was observed in arginine-vasopressin-containing neurons in the hypothalamic paraventricular nucleus, and various cytokines involving TNF-α were upregulated in the brain, compared with those in the PBS group. In the region corresponding to their findings, the number of reactive microglia and vascular leakage was markedly increased. BQ788 inhibited the induction of c-FOS expression, neuroblast apoptosis, cytokine upregulation and reactive microglia without affecting vascular leakage. Significance We demonstrated that BQ788 could protect the brain from the following sepsis-associated pathophysiological output: neural cell death, inflammatory response and the Hans Selye's environmental stress reaction.

We report a rare case of intratumoral hemorrhage during postoperative radiotherapy for pituitary adenoma. A 57-year-old Asian male, complaining of long-standing eye strain, underwent a medical checkup of the brain. Magnetic resonance imaging showed a multicystic giant pituitary adenoma. The patient underwent an endoscopic endonasal transsphenoidal partial removal of the adenoma to provide optic pathway decompression and got relief from the visual symptoms. Just before completion of the postoperative radiotherapy for residual adenoma, the patient developed right hemiparesis, mild motor aphasia, and right oculomotor palsy. A cranial CT scan showed intratumoral hemorrhage into the intratumoral cyst. The patient therefore had to undergo three additional craniotomies for evacuation of cyst contents over the next 8 months. The follow-up MRI at 11 months after the initial hemorrhage showed that the new oozing of blood in the intratumoral cyst was still appearing. Intratumoral hemorrhage is a rare, albeit life-threatening, complication of pituitary adenoma. We reviewed relevant literature and suggested that the cystic component in pituitary adenoma could be a key pathogenesis of this rare complication. In conclusion, we suggest that it may be necessary to realize that cases which have cystic giant pituitary adenoma may cause hemorrhage by chance with the foreseeability.

Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive function (NCF) after WBRT in different dose fractionation schedules. We administered the HVLT-R (Japanese version) before (baseline) and at four and eight months after WBRT in 45 patients who received either therapeutic (35Gy-in-14, n = 16; 30Gy-in-10, n = 18) or prophylactic (25Gy-in-10, n = 11) WBRT. Sixteen patients dropped out before the eight-month examination, due mostly to death from cancer. The Karnofsky Performance Status (KPS) 80–100 group had significantly higher baseline total recall (TR) scores (p = 0.0053), delayed recall (DR) scores (p = 0.012), and delayed recognition (DRecog) scores (p = 0.0078). The patients aged ≤65 years also had significantly higher TR scores (p = 0.030) and DRecog scores (p = 0.031). The patients who underwent two examinations (worse-prognosis group) had significantly decreased DR scores four months after WBRT compared to the baseline (p = 0.0073), and they were significantly more likely to have declined individual TR scores (p = 0.0017) and DR scores (p = 0.035) at four months. The eight-month HVLT-R scores did not significantly decline regardless of the WBRT dose fractionation. The baseline NCF was determined by age and KPS, and the early decline in NCF is characteristic of the worse-prognosis group.

To investigate the effects of a respiratory gating and multifield technique on the dose-volume histogram (DVH) in radiotherapy for esophageal cancer. Twenty patients who underwent four-dimensional computed tomography for esophageal cancer were included. We retrospectively created the four treatment plans for each patient, with or without the respiratory gating and multifield technique: No gating-2-field, No gating-4-field, Gating-2-field, and Gating-4-field plans. We compared the DVH parameters of the lung and heart in the No gating-2-field plan with the other three plans. In the comparison of the parameters in the No gating-2-field plan, there are significant differences in the Lung V5Gy, V20Gy, mean dose with all three plans and the Heart V25Gy–V40Gy with Gating-2-field plan, V35Gy, V40Gy, mean dose with No Gating-4-field plan and V30Gy–V40Gy, and mean dose with Gating-4-field plan. The lung parameters were smaller in the Gating-2-field plan and larger in the No gating-4-field and Gating-4-field plans. The heart parameters were all larger in the No gating-2-field plan. The lung parameters were reduced by the respiratory gating technique and increased by the multifield technique. The heart parameters were reduced by both techniques. It is important to select the optimal technique according to the risk of complications.

A case of a 62-year-old woman with breast cancer who developed an atypical femoral fracture during denosumab therapy for bone metastasis is reported. About 8.5 years before the fracture, she was diagnosed with breast cancer with liver and bone metastases and started receiving chemotherapy. Three and a half years later, zoledronic acid (40 mg every 4 weeks) was added, which was continued for 2 years and 4 months. At around 1.5 years after discontinuation of zoledronic acid, bone metastasis recurred and she began treatment with denosumab at 120 mg every 4 weeks. Fifteen months after starting denosumab, she sustained a left subtrochanteric fracture. Faint hot spots in the bilateral subtrochanteric regions were found on bone scintigraphy 2 months after the start of denosumab, and the tracer accumulation was slightly increased on bone scintigraphy 1 year later. Prior to the fracture, she had been experiencing a dull ache in her left thigh for a few months. Our case suggests that denosumab treatment for bone metastasis is a risk factor for atypical femoral fractures, and that thigh pain and subtrochanteric hot spots on bone scintigraphy could be signs of an impending fracture.

In an earlier study, we showed that mitochondria hyperpolarized after short periods of oxygen-glucose deprivation (OGD), and this response appeared to be associated with subsequent apoptosis or survival. Here, we demonstrated that hyperpolarization following short periods of OGD (30 min; 30OGD group) increased the cytosolic Ca(2+) ([Ca(2+)](c)) buffering capacity in mitochondria. After graded OGD (0 min (control), 30 min, 120 min), rat cultured hippocampal neurons were exposed to glutamate, evoking Ca(2+)influx. The [Ca(2+)](c) level increased sharply, followed by a rapid increase in mitochondrial Ca(2+) [Ca(2+)](m). The increase in the [Ca(2+)](m) level accompanied a reduction in the [Ca(2+)](c) level. After reaching a peak, the [Ca(2+)](c) level decreased more rapidly in the 30OGD group than in the control group. This buffering reaction was pronounced in the 30OGD group, but not in the 120OGD group. The enhanced buffering capacity of the mitochondria may be linked to preconditioning after short-term ischemic episodes.

Background Various signals are known to participate in the pathogenesis of lung fibrosis. Our aim was to determine which signal is predominantly mobilized in the early inflammatory phase and thereafter modulates the development of lung fibrosis. Methods Mice received a single dose of 3 mg/kg body weight of bleomycin (BLM) and were sacrificed at designated days post-instillation (dpi). Lung homogenates and sections from mice in the early inflammatory phase were subjected to phospho-protein array analysis and immunofluorescence studies, respectively. Bronchoalveolar lavage fluid (BALF) from mice was subjected to an enzyme-linked immunosorbent assay (EIA) for interleukin (IL)-6 and evaluation of infiltrated cell populations. The effects of endogenous and exogenous IL-6 on the BLM-induced apoptotic signal in A549 cells and type 2 pneumocytes were elucidated. In addition, the effect of IL-6-neutralizing antibody on BLM-induced lung injury was evaluated. Results Phospho-protein array revealed that BLM induced phosphorylation of molecules downstream of the IL-6 receptor such as Stat3 and Akt in the lung at 3 dpi. At 3 dpi, immunofluorescence studies showed that signals of phospho-Stat3 and -Akt were localized in type 2 pneumocytes, and that BLM-induced IL-6-like immunoreactivity was predominantly observed in type 2 pneumocytes. Activation of caspases in BLM-treated A549 cells and type 2 pneumocytes was augmented by application of IL-6-neutralizing antibody, a PI3K inhibitor or a Stat3 inhibitor. EIA revealed that BLM-induced IL-6 in BALF was biphasic, with the first increase from 0.5 to 3 dpi followed by the second increase from 8 to 10 dpi. Blockade of the first increase of IL-6 by IL-6-neutralizing antibody enhanced apoptosis of type 2 pneumocytes and neutrophilic infiltration and markedly accelerated fibrosis in the lung. In contrast, blockade of the second increase of IL-6 by IL-6-neutralizing antibody ameliorated lung fibrosis. Conclusions The present study demonstrated that IL-6 could play a bidirectional role in the pathogenesis of lung fibrosis. In particular, upregulation of IL-6 at the early inflammatory stage of BLM-injured lung has antifibrotic activity through regulating the cell fate of type 2 pneumocytes in an autocrine/paracrine manner. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0261-z) contains supplementary material, which is available to authorized users.

Swimming is generally considered ineffective for increasing bone mass in humans, at least compared with weight-bearing sports. However, swimming exercise has sometimes been shown to have a strong positive effect on bone mass in small animals. This study investigated the effects of swimming on bone mass, strength, and microarchitecture in ovariectomized (OVX) rats. OVX or sham operations were performed on 18-wk-old female Fisher 344 rats. Rats were randomly divided into four groups: sham sedentary (Sham-CON), sham swimming exercised (Sham-SWI), OVX sedentary (OVX-CON), and OVX swimming exercised (OVX-SWI). Rats in exercise groups performed swimming in a water bath for 60 min/day, 5 days/wk, for 12 wk. Bone mineral density (BMD) in right femurs was analyzed using dual-energy X-ray absorptiometry. Three-dimensional trabecular architecture at the distal femoral metaphysis was analyzed using microcomputed tomography (μCT). Geometrical properties of diaphyseal cortical bone were evaluated in the midfemoral region using μCT. The biomechanical properties of femurs were analyzed using three-point bending. Femoral BMD was significantly decreased following ovariectomy. This change was suppressed by swimming. Trabecular bone thickness, number, and connectivity were decreased by ovariectomy, whereas structure model index (i.e., ratio of rod-like to plate-like trabeculae) increased. These changes were also suppressed by swimming exercise. Femurs displayed greater cortical width and maximum load in SWI groups than in CON groups. Together, these results demonstrate that swimming exercise drastically alleviated both OVX-induced decreases in bone mass and mechanical strength and the deterioration of trabecular microarchitecture in rat models of osteoporosis.

Background To evaluate the risks and benefits of endoscopic submucosal dissection (ESD) in addition to chemoradiotherapy (CRT) for the treatment of superficial esophageal squamous cell carcinoma (SESCC). Methods and materials We retrospectively reviewed the treatment outcomes of 47 patients with SESCC treated between October 2000 and December 2011. Sixteen patients with invasion into the submucosal layer (T1b) or the muscularis mucosa (m3) with positive vascular invasion were treated with CRT after ESD (ESD-CRT group). The lymph node area was irradiated to a total dose of 40–44 Gy and a boost radiation was administered if PET-positive lymph nodes or positive margins were observed. The remaining 31 patients received definitive CRT only (dCRT group). Results The radiation field was significantly larger in the ESD-CRT group; the “long T” was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total radiation dose was smaller in the ESD-CRT group; 40 Gy was used in 10 patients (62.5%) in the ESD-CRT group and all but one patient in the dCRT group received ≥60 Gy (p = 0.00001). The 3-year overall survival rates in the dCRT and ESD-CRT groups were 63.2% and 90.0% respectively (p = 0.118). Recurrence developed in nine patients (29.0%) in the dCRT group and one (6.3%) in the ESD-CRT group. Local recurrence was observed in six patients (19%) in the dCRT group and none in the ESD-CRT-group (p = 0.029). Pericardial effusion (≥Grade 3) occurred in three patients (9.7%) in the dCRT group and none in the ESD-CRT group. Conclusions ESD followed by CRT is an effective and safe approach for SESCC at m3 or T1b. This combination of ESD and CRT improves the local control rate, and it could decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.

Aims Although endothelin (ET) is known to play pleiotropic roles in various pathological conditions, its relation to autoimmune disease has not been elucidated. Here, we focused on interleukin (IL)-17, which is closely related to the pathogenesis of multiple sclerosis, and investigated the effect of ET receptor blockers on the production of IL-17 by T lymphocytes. Main methods Lymph node cells from mice at 8 days post-immunization with MOG 35–55 were stimulated in vitro with MOG 35–55 in the presence or absence of an ET receptor blocker (BQ123 for ET A or BQ788 for ET B ). Naive T cells from mice were subjected to an in vitro model of Th17 differentiation, and ET-mediated IL-17 production was investigated under the states of Th17 differentiation and activation. Key findings ELISA revealed that MOG 35–55 -induced IL-17 production was significantly inhibited by BQ123 but not BQ788. Consistent with the ELISA results for IL-17, the frequency of CD4 + T cells producing IL-17 but not IFN-γ was reduced by BQ123. Under the differentiating state from naive T cells to Th17 cells, the spontaneous release of IL-17 from CD4 + T cells was increased, which was insensitive to BQ123, indicating that ET/ET A signaling did not affect Th17 differentiation. After the time period of Th17 differentiation, however, the increase in IL-17 production by restimulation of the cells with anti-CD3 plus anti-CD28 antibodies was significantly inhibited by BQ123. Significance We demonstrated that ET/ET A signaling plays a crucial role in IL-17 production by Th17. BQ123 might be expected to be a future therapeutic drug for multiple sclerosis.

Geometry of the proximal femur is one determinant of fracture risk, and can be analyzed by a simple method using dual-energy X-ray absorptiometry (DXA). The aim of the present study was to investigate the accuracy of hip structural analysis (HSA) using clinical data in postmenopausal Japanese women. A total of 184 postmenopausal women aged 51–88 years (mean, 70.5 ± 8.7 years) who underwent artificial joint replacement surgery for osteoarthrosis of the hip or knee joint were included. Computed tomography (CT) data from preoperative assessment were utilized for analysis of proximal femoral geometry (CT-HSA) using QCTPro Software (Mindways Software Inc., Austin, TX) and compared with HSA results based on DXA (DXA-HSA). The results of femoral geometry were further compared with a CT-based finite-element method (CT/FEM). There was moderate to high correlation between DXA-HSA and CT-HSA (r=0.60-0.90, p

Background Cluster of differentiation 69 (CD69), an early activation marker antigen on T and B cells, is also expressed on activated macrophages and neutrophils, suggesting that CD69 may play a role in inflammatory diseases. To determine the effect of CD69 deficiency on bleomycin(BLM)-induced lung injury, we evaluated the inflammatory response following intratracheal BLM administration and the subsequent fibrotic changes in wild type (WT) and CD69-deficient (CD69-/-) mice. Methods The mice received a single dose of 3 mg/kg body weight of BLM and were sacrificed at 7 or 14 days post-instillation (dpi). Lung inflammation in the acute phase (7 dpi) was investigated by differential cell counts and cytokine array analyses of bronchoalveolar lavage fluid. In addition, lung fibrotic changes were evaluated at 14 dpi by histopathology and collagen assays. We also used reverse transcription polymerase chain reaction to measure the mRNA expression level of transforming growth factor β1 (TGF-β1) in the lungs of BLM-treated mice. Results CD69-/- mice exhibited less lung damage than WT mice, as shown by reductions in the following indices: (1) loss of body weight, (2) wet/dry ratio of lung, (3) cytokine levels in BALF, (4) histological evidence of lung injury, (5) lung collagen deposition, and (6) TGF-β1 mRNA expression in the lung. Conclusion The present study clearly demonstrates that CD69 plays an important role in the progression of lung injury induced by BLM.

Substantial evidence from animal studies indicates that jumping increases bone mass and strength. However, most studies have focused on the take-off, rather than the landing phase of jumps. Thus, we compared the effects of landing and upward jump impact on trabecular bone mass and microarchitecture. Male Wistar rats aged 10 weeks were randomly assigned to the following groups: sedentary control (CON), 40-cm upward jumps (40UJ); 40-cm drop jumps (40DJ); and 60-cm drop jumps (60DJ) (n = 10 each). The upward jump protocol comprised 10 upward jumps/day, 5 days/week for 8 weeks to a height of 40 cm. The drop jump protocol comprised dropping rats from a height of 40 or 60 cm at the same frequency and time period as the 40UJ group. Trabecular bone mass, architecture, and mineralization at the distal femoral metaphysis were evaluated using microcomputed tomography. Ground reaction force (GRF) was measured using a force platform. Bone mass was significantly higher in the 40UJ group compared with the DJ groups (+49.1% and +28.3%, respectively), although peak GRF (-57.8% and -122.7%, respectively) and unit time force (-21.6% and -36.2%, respectively) were significantly lower in the 40UJ group. These results showed that trabecular bone mass in growing rats is increased more effectively by the take-off than by the landing phases of jumps and suggest that mechanical stress accompanied by muscle contraction would be more important than GRF as an osteogenic stimulus. However, the relevance of these findings to human bone physiology is unclear and requires further study.