Surgical outcomes in patients with small cell lung cancer: comparative analysis of computed tomograpy-detected patients with others

Background: It is shown that low-dose computed tomography (CT) screening is useful for a reduction in lung-cancer- specific mortality in heavy smokers. However, the information about effectiveness according to the histological types of lung cancer has not been adequately investigated especially small cell lung cancer (SCLC). The present study was performed to see the clinical benefit of CT screening in patients with SCLC following thoracotomy. Methods: We retrospectively reviewed the outcome in patients with early stage SCLC who initially underwent thoracotomy. The clinical stages and actuarial survival were estimated according to the three means of detection of SCLC: chest CT, radiographic screen, and symptomatically prompted cases. Results: Sixty-nine patients (men/women, 63/6; mean age, 70 years) with SCLC underwent thoracotomy between 1991 and 2010 including chest CT (n = 13), radiographic screening (n = 39), and symptomatically prompted cases (n = 17). Pathological staging information included stage IA (n = 25), IB (n = 8), IIA (n = 13), IIB (n = 5), IIIA (n = 11), and IIIB (n = 7). Median survival time was 30.0 (95% confidence interval (CI): 22.0 to 57.0) months, with overall survival at 5 years of 34.3% (95% CI, 23.47 to 47.3). Nine patients (69%) with stage I were detected by CT which was significantly higher than those in other detection arms. However, there were no significant differences in the survival between CT and other detection arms. Conclusions: CT examination may be useful for detection in early stage SCLC potentially suitable for surgery, but the contribution to better clinical outcome in patients with SCLC remains unclear.ArticleWORLD JOURNAL OF SURGICAL ONCOLOGY. 11:61 (2013)journal articl

成長期における食餌性リンによるα-klotho発現制御

Inorganic phosphate (Pi) is an essential nutrient for maintaining various biological functions, particularly during growth periods. Excess intake of dietary Pi increases the secretion of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) to maintain plasma Pi levels. FGF23 is a potent phosphaturic factor that binds to the α-klotho/FGFR complex in the kidney to promote excretion of Pi into the urine. In addition, excess intake of dietary Pi decreases renal α-klotho expression. Down-regulation or lack of α-klotho induces a premature aging-like phenotype, resulting from hyperphosphatemia, and leading to conditions such as ectopic calcification and osteoporosis. However, it remains unclear what effects dietary Pi has on α-klotho expression at different life stages, especially during growth periods. To investigate this, we used C57BL/6J mice in two life stages during growing period. Weaned (3 weeks old) and periadolescent (7 weeks old) were randomly divided into seven experimental groups and fed with 0.02, 0.3, 0.6, 0.9, 1.2, 1.5, or 1.8% Pi diets for 7 days. As a result, elevated plasma Pi and FGF23 levels and decreased renal α-klotho expression were observed in weaned mice fed with a high Pi diet. In addition, a high Pi diet clearly induced renal calcification in the weaned mice. However, in the periadolescent group, renal calcification was not observed, even in the 1.8% Pi diet group. The present study indicates that a high Pi diet in weaned mice has much greater adverse effects on renal α-klotho expression and pathogenesis of renal calcification compared with periadolescent mice

年齢に応じた血中活性型ビタミンD濃度, 腎Cyp27b1およびCyp24a1発現に対する食餌性リン反応性の変化には腎α-Klotho遺伝子発現が関連する

In this study, we investigated the relationship between age-related changes in renal α-Klotho gene expression, vitamin D metabolism and the responsiveness of dietary phosphate in 1, 2 and 13 month-old mice fed a high phosphate (phosphate 1.2%) diet or low phosphate (phosphate 0.02%) diet for 5 days. We found that 1,25-dihydroxyvitamin D levels in plasma were significantly lower in the high phosphate group than the low phosphate group for 1 and 2 month-old mice, but not 13 month-old mice. In addition, in the high phosphate group plasma 1,25-dihydroxyvitamin D levels were decreased in 2 month-old mice relative to 1 month-old mice, but 13 month-old mice had higher levels than 2 month-old mice. In fact, plasma 1,25-dihydroxyvitamin D levels showed a significant correlation with vitamin D metabolism gene Cyp27b1 and Cyp24a1 mRNA expression in the high phosphate group. Interestingly, renal α-Klotho mRNA and protein levels were significant change with age. Furthermore, α-Klotho mRNA expression showed a significant negative correlation with plasma 1,25-dihydroxyvitamin D levels in the high phosphate group. Our results suggest that age-related alterations in renal α-Klotho expression could affect the responsiveness of dietary phosphate to vitamin D metabolism

ステロール応答領域結合タンパク質1は腎近位尿細管細胞において25-水酸化ビタミンD3 24-水酸化酵素遺伝子の転写を活性化する

The physiological activity of the steroid derived hormone vitamin D is regulated by several enzymatic steps. Both 25-hydroxy vitamin D3 1a-hydroxylase (CYP27B1) and 25-hydroxyvitamin D3 24-hydroxylase (CYP24A1) modulate blood levels of 1,25-dihydroxyvitamin D3, an activated form of vitamin D. We previously demonstrated that CYP27B1 expression was trans-activated by sterol regulatory element binding protein 1 (SREBP1), although whether SREBP1 also regulates CYP24A1 transcription was unclear. Here we investigated the ability of SREBP1 to affect CYP24A1 transcription. In a luciferase reporter assay, mouse and human CYP24A1 promoter activity was strongly activated by SREBP1 in opossum kidney proximal tubular cells (OK-P). Three putative SREs (pSREs) were found in the mouse Cyp24a1 gene promoter and the SREBP1 protein showed specific binding to the pSRE1 element in EMSAs. Site-directed mutagenesis of the pSRE1 element strongly decreased SREBP1-mediated Cyp24a1 gene transcription. Moreover, siRNA-mediated SREBP1 knock-down repressed CYP24A1 expression in human renal proximal tubular epithelial cells (HKC-8). In animal studies, mice given various doses of thyroid hormone (T3) showed dose-dependent reductions in renal Srebp1c and Cyp24a1 mRNA levels. Taken together, our results suggest that SREBP1 trans-activates CYP24A1 expression through SREBP binding elements present in the promoter

EGFR mutation and ALK fusion-positive non-small cell lung cancer: a multicenter prospective cohort study in Nagano Prefecture, Japan

Introduction. We prospectively examined current clinical practices in patients with inoperable epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion-positive (EGFR+ and ALK+, respectively) non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan.  Material and methods. The study population consisted of newly diagnosed patients with inoperable EGFR+ and ALK+ NSCLC in 14 hospitals in Nagano between May 2016 and March 2019. Both initial and subsequent treatment decisions were made at the discretion of the attending physician.  Results. A total of 281 patients with EGFR+ NSCLC (mean age, 74 years, 59.1% female) and 26 patients with ALK+ NSCLC (mean age, 66 years, 53.8% female) were included in the study. The study population consisted of 148/107/29/20/3 cases with performance status 0/1/2/3/4 and 6/2/31/194/75 cases with clinical stage I/II/III/IV/recurrence, respectively. First-line therapy with tyrosine kinase inhibitors was performed in 259 (92.2%) and 22 (84.6%) patients with EGFR+ and ALK+ NSCLC, respectively. The median overall survival rate was 41.2 months (95% CI 36.8–45.6 months) with EGFR+. It was not reached with ALK+ .  Conclusions. This observational analysis represents a valuable resource for evaluating the outcomes of treatment in patients with NSCLC

Mobile DHHC palmitoylating enzyme mediates activity-sensitive synaptic targeting of PSD-95

Protein palmitoylation is the most common posttranslational lipid modification; its reversibility mediates protein shuttling between intracellular compartments. A large family of DHHC (Asp-His-His-Cys) proteins has emerged as protein palmitoyl acyltransferases (PATs). However, mechanisms that regulate these PATs in a physiological context remain unknown. In this study, we efficiently monitored the dynamic palmitate cycling on synaptic scaffold PSD-95. We found that blocking synaptic activity rapidly induces PSD-95 palmitoylation and mediates synaptic clustering of PSD-95 and associated AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors. A dendritically localized DHHC2 but not the Golgi-resident DHHC3 mediates this activity-sensitive palmitoylation. Upon activity blockade, DHHC2 translocates to the postsynaptic density to transduce this effect. These data demonstrate that individual DHHC members are differentially regulated and that dynamic recruitment of protein palmitoylation machinery enables compartmentalized regulation of protein trafficking in response to extracellular signals

Treatment Outcomes in Patients with Atypical EGFR-positive Non-small Cell Lung Cancer in Nagano Prefecture, Japan

Article信州医学雑誌 70(6) : 367-405(2022)departmental bulletin pape