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The article presents a study which develops a Fortran90 input/output library called gtool5 for use with numerical simulation models in the fields of earth and planetary sciences. In this study, the use of this library will simplify implementation of input/output operations into program code in a consolidated form independent of the size and complexity of the software and data. Moreover, this library enables simple specification of the metadata needed for postprocessing and visualization.

The article presents a study on the Fortran90 input/output library, gtool5, which is made for application with numerical simulation models in Earth fields and planetary sciences. It mentions that its utilization will simplify the enforcement of input/output operations into program code in a fused form making it independent of the software and data's size and complexity. It also notes its ability specify necessary metadata for post-processing and visualization.

Background: Distant metastases of ovarian cancer are rarely detected alone. The effectiveness of surgical intervention for pulmonary metastases from ovarian cancer remains uncertain. This study aimed to investigate the clinicopathologic characteristics and outcomes of patients undergoing resection for pulmonary metastasis from ovarian cancer., Case Presentation: The clinicopathologic characteristics and outcomes of radical surgery for pulmonary metastasis from ovarian cancer were investigated. Out of 537 patients who underwent pulmonary metastasis resection at two affiliated hospitals between 2010 and 2021, four (0.74%) patients who underwent radical surgery for pulmonary metastasis from ovarian cancer were included. The patients were aged 67, 47, 21, and 59 years; the intervals from primary surgery to detection of pulmonary metastasis from ovarian cancer were 94, 21, 36, and 50 months; and the overall survival times after pulmonary metastasectomy were 53, 50, 94, and 34 months, respectively. Three of the four patients experienced recurrence after pulmonary metastasectomy. Further, preoperative carbohydrate antigen (CA) 125 levels were normal in two surviving patients and elevated in the two deceased patients., Conclusion: In this study, three of the four patients experienced recurrence after pulmonary metastasectomy, but all patients survived for > 30 months after surgery. Patients with ovarian cancer and elevated CA125 levels may not be optimal candidates for pulmonary metastasectomy. To establish appropriate criteria for pulmonary metastasectomy in patients with ovarian cancer, further research on a larger patient cohort is warranted., (© 2024. The Author(s).)

Radiation disasters pose distinctive medical challenges, requiring diverse care approaches. Beyond radiation exposure assessment, addressing health impacts due to lifestyle changes, especially among vulnerable populations, is vital. Evacuation orders issued in radiation-affected areas introduce unique healthcare dynamics, with their duration significantly influencing the recovery process. Understanding evolving patient demographics and medical needs after lifting evacuation orders is crucial for post-disaster care planning. Minamisoma Municipal Odaka Hospital, located 13 to 20 km from Fukushima Daiichi Nuclear power plant in a post-evacuation zone, was greatly affected by the Great East Japan Earthquake and subsequent radiation disaster. Data were retrospectively collected from patient records, including age, gender, visit date, diagnoses, and addresses. Patient records from April 2014 to March 2020 were analyzed, comparing data before and after the July 2016 evacuation order lift. Data was categorized into pre and post-evacuation order lifting periods, using International Classification of Diseases, Tenth Edition codes, to identify the top diseases. Statistical analyses, including χ-square tests, assessed changes in disease distributions. Population data for Odaka Ward and Minamisoma City fluctuated after lifting evacuation orders. As of March 11, 2011, Odaka Ward had 12,842 residents (27.8% aged 65+ years), dropping to 8406 registered residents and 2732 actual residents by April 30, 2018 (49.7%). Minamisoma City also saw declines, with registered residents decreasing from 71,561 (25.9%) to 61,049 (34.1%). The study analyzed 11,100 patients, mostly older patients (75.1%), between 2014 and 2020. Post-lifting, monthly patient numbers surged from an average of 55.2 to 213.5, with female patients increasing from 33.8% to 51.7%. Disease patterns shifted, with musculoskeletal cases declining from 23.8% to 13.0%, psychiatric disorders increasing from 9.3% to 15.4%, and trauma-related cases decreasing from 14.3% to 3.9%. Hypertension (57.1%) and dyslipidemia (29.2%) prevailed post-lifting. Urgent cases decreased from 1.3% to 0.1%. This study emphasizes the importance of primary care in post-evacuation zones, addressing diverse medical needs, including trauma, noncommunicable diseases, and psychiatric disorders. Changing patient demographics require adaptable healthcare strategies and resource allocation to meet growing demands. Establishing a comprehensive health maintenance system tailored to these areas' unique challenges is crucial for future disaster recovery efforts., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study evaluated the feasibility of performing non-intubated video-assisted thoracoscopic surgery (VATS) with local anesthesia for parapneumonic effusion and empyema resistant to conservative treatment., Methods: We retrospectively reviewed 80 patients who underwent surgery for parapneumonic effusions and empyema between 2015 and 2021. Patients were divided into those who received non-intubated local anesthesia and general anesthesia during surgery. Patient demographics, characteristics, laboratory findings, treatment progress, and treatment outcomes were compared. The primary outcomes were duration of postoperative drainage, postoperative complication rate, and postoperative mortality rate within 30 days., Results: Among patients who received local (n = 21) and general anesthesia (n = 59), there was a significant difference in age (median 79.0 years [interquartile range (IQR) 77.0-80.0] vs. 68.0 years [IQR 54.5-77.5]; p < 0.001), preoperative performance status (3.0 [IQR 2.0-4.0] vs. 2.0 [IQR 1.0-3.0]; p < 0.001), and operative time (69 min [IQR 50-128] vs. 150 min [IQR 107-198]; p < 0.001) but not in preoperative white blood cell count (12,100/μL [IQR 8,400-18000] vs. 12,220/μL [IQR 8,950-16,724]; p = 0.840), C-reactive protein (15.2 mg/dL [8.8-21.3] vs. 17.9 mg/dL [IQR 9.5-23.6]; p = 0.623), postoperative drainage period (11 days [IQR 7-14] vs. 9 days [7-13]; p = 0.216), postoperative hospital stay (22 days [IQR 16-53] vs. 18 days [IQR 12-26]; p = 0.094), reoperation rate (9.5% vs. 15.3%; p = 0.775), postoperative complication rate (19.0% vs. 18.6%; p = 0.132), or postoperative 30-day mortality rate (4.8% vs. 0%; p = 0.587)., Conclusions: VATS using local anesthesia is feasible for patients with treatment-resistant parapneumonic effusion and empyema with poor general condition., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

The impact of repeated administration of cinntamtannin A2 (A2, 25 μg/kg) on skeletal muscle disuse atrophy model mice induced by hindlimb suspension for 14 days was examined. In soleus, weight loss and a reduction in the average myofibre size with shifting to the smaller side of the peak were observed in the suspension-vehicle group, but A2 reduced these changes. Average myofibre size significantly increased in ground-A2 compared to ground-vehicle. A marked increase in the dephosphorylation of forkhead box O (FoxO) 3a by the suspension was reduced by A2. The phosphorylation of protein kinase B (Akt) and eukaryotic translation initiation factor 4E-binding protein (4EBP)-1 were significantly increased by the treatment of A2. In addition, a single dose of A2 increased dramatically in the 24-h excretion of catecholamines in urine. These results suggest that A2 administration results in sympathetic nerve activation and promotes hypertrophy while inhibiting the progress of disuse muscle atrophy., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2023 JCBN.)

Introduction: Intercellular adhesion molecule 1 (ICAM-1) is a critical molecule responsible for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1, that SARS-CoV-2 shares several features with these viruses via interactions between cells, and that SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. From these previous arguments, it is assumed that ICAM-1 can be related to SARS-CoV-2 cell-to-cell transmission in COVID-19 patients. Indeed, the time-dependent change of the ICAM-1 expression level has been detected in COVID-19 patients. However, signaling pathways that consist of ICAM-1 and other molecules interacting with ICAM-1 are not identified in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM1 -associated pathways will be indispensable for clarifying the mechanism of COVID-19. Materials and methods: This study builds ICAM1 -associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, single-cell omics data analysis extracts coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate the models. Finally, mapping the models onto existing pathways identifies new ICAM1 -associated pathways. Results: Comparison of the obtained pathways between different cell types and time points reproduces the known pathways and indicates the following two unknown pathways: (1) upstream pathway that includes proteins in the non-canonical NF- κ B pathway and (2) downstream pathway that contains integrins and cytoskeleton or motor proteins for cell transformation. Discussion: In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1 -associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanism of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Odaka, Magnin and Inoue.)

Background: IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN., Methods: We used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0-8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2-44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed., Results: More than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-β inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings., Conclusions: The present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria., (© 2023. The Author(s).)

Background: Metastatic lung tumors rarely present with cystic formations. This is the first report of multiple cystic formations in pulmonary metastases from mucinous borderline ovarian tumors written in English., Case Presentation: A 41-year-old woman underwent left adnexectomy + partial omentectomy + para-aortic lymphadenectomy for a left ovarian tumor 4 years ago. The pathological finding was mucinous borderline ovarian tumor with a microinvasion. A chest computed tomography performed 3 years after surgery revealed multiple cystic lesions in both lungs. After 1-year follow-up, the cysts increased in size and wall thickness. Subsequently, she was referred to our department with multiple cystic lesions in both lungs. No laboratory findings indicated infectious diseases or autoimmune disorders that could cause cystic lesions in both lungs. Positron emission tomography showed slight accumulation in the cyst wall. Partial resection of the left lower lobe was performed to confirm the pathological diagnosis. The diagnosis was consistent with pulmonary metastases from a previous mucinous borderline ovarian tumor., Conclusions: This is a rare case of lung metastases from a mucinous borderline ovarian tumor presenting with multiple lesions with cystic formation. Pulmonary cystic formations in patients with a borderline ovarian tumor should be considered as possible pulmonary metastases., (© 2023. The Author(s).)

[Purpose] To examine whether fear of falling and mobility skills improved after judo ukemi practice in healthy older adults, and whether a relationship exists between improvements in fear of falling and changes in mobility skills. [Participants and Methods] Ten healthy older adults who participated in exercise classes for middle-aged and elderly people to promote health performed ukemi practice three times in total, increasing the degree of difficulty every week. [Results] No significant differences in fear of falling or 10-m walking times were noted in Steps 1, 2, and 3. A significant reduction in timed up and go test results was observed in Steps 2 and 3. No correlation was found between change in fear of falling and change in mobility skills before and after ukemi practice for all combinations. [Conclusion] The results suggest that judo ukemi practice improves mobility skills in healthy older individuals with relatively high physical ability. These changes may not be due to a reduced fear of falling but rather to quicker physical reactivity and other psychological factors., Competing Interests: All authors have no conflicts of interest in conducting this study., (2023©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Background: Anti-phospholipase A2 receptor autoantibody (PLA2R Ab)-associated membranous nephropathy (MN) is the most common form of primary MN (pMN). On the other hand, bucillamine (BCL), an antirheumatic drug developed in Japan, was reported to cause a rare form of secondary MN (sMN). Between these MN forms, comparative proteomic analysis of glomerular proteins has not been performed., Methods: We used renal biopsy specimens from 6 patients with PLA2R Ab (+) pMN, 6 patients with PLA2R Ab (‒) pMN, 6 patients with BCL-induced sMN, and 5 control cases (time 0 transplant biopsies). Proteins were extracted from laser-microdissected glomeruli and analyzed using mass spectrometry. The quantification values of protein abundance in each MN group were compared with those in the control group., Results: More than 800 proteins with high confidence were identified. Principal component analysis revealed a different distribution between the pMN and sMN groups. For further analysis, 441 proteins matched with ≥ 3 peptides were selected. Among the pMN and sMN groups, we compared the profiles of several protein groups based on the structural and functional characteristics, such as immunoglobulins, complements, complement-regulating proteins, podocyte-associated proteins, glomerular basement membrane proteins, and several proteins that are known to be associated with kidney diseases, including MN. In all MN groups, increased levels of immunoglobulins (IgG, IgA, and IgM), complements (C3, C4, and C9), complement factor H-related protein 5, type XVIII collagen, calmodulin, polyubiquitin, and ubiquitin ligase were observed. For some proteins, such as type VII collagen and nestin, the fold-change values were significantly different between the pMN and sMN groups., Conclusions: Between the pMN and BCL-induced sMN groups, we observed common and different alterations in protein levels such as known disease-associated proteins and potential disease marker proteins., (© 2022. The Author(s).)

We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ol (FL)s, a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FLs possibly activate sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FLs. In addition, we examined the impact of the repeated administration of 50 mg/kg FLs for 14 days on adipose tissues in mice. In BAT, FLs tended to increase the level of Ucp-1 along with significant increase of thermogenic transcriptome factors expressions, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR domain-containing (PRDM)1 . Expression of browning markers, CD137 and transmembrane protein (TMEM) 26 , in addition to PGC-1α were increased in epididymal adipose (eWAT) by FLs. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 by FLs. These results exert that FLs induce browning in adipose, and this change is possibly produced by the activation of the SNS.

Computational modeling and simulation of viral dynamics would explain the pathogenesis for any virus. Such computational attempts have been successfully made to predict and control HIV-1 or hepatitis B virus. However, the dynamics for SARS-CoV-2 has not been adequately investigated. The purpose of this research is to propose different SARS-CoV-2 dynamics models based on differential equations and numerical analysis towards distilling the models to explain the mechanism of SARS-CoV-2 pathogenesis. The proposed four models formalize the dynamical system of SARS-CoV-2 infection, which consists of host cells and viral particles. These models undergo numerical analysis, including sensitivity analysis and stability analysis. Based on the sensitivity indices of the four models' parameters, the four models are simplified into two models. In advance of the following calibration experiments, the eigenvalues of the Jacobian matrices of these two models are calculated, thereby guaranteeing that any solutions are stable. Then, the calibration experiments fit the simulated data sequences of the two models to two observed data sequences, SARS-CoV-2 viral load in mild cases and that in severe cases. Comparing the estimated parameters in mild cases and severe cases indicates that cell-to-cell transmission would significantly correlate to the COVID-19 severity. These experiments for modeling and simulation provide plausible computational models for the SARS-CoV-2 dynamics, leading to further investigation for identifying the essential factors in severe cases., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Background: Minimally invasive thoracoscopic lobectomy is the recommended surgery for clinical stage I non-small cell lung cancer (NSCLC). The purpose of this study was to identify the risk factors, including sarcopenia, for postoperative complications in patients undergoing a complete single-lobe thoracoscopic lobectomy for clinical stage I NSCLC, as well as the impact of complications on disease-free survival., Methods: We retrospectively investigated 173 patients with pathologically-diagnosed NSCLC who underwent curative thoracoscopic lobectomies between April 2013 and March 2018. Sarcopenia was assessed using the psoas muscle index calculated from preoperative computed tomography images at the third lumbar vertebral level., Results: Complications developed in 38 (22%) patients, including 21 with prolonged air leak. In univariate analysis, the significant risk factors for complications were advanced age, male sex, higher Charlson Comorbidity Index (CCI) score, lower cholinesterase, lower albumin, higher creatinine level, pleural adhesion, operative time ≥ five hours, nonadenocarcinoma cancer, and larger tumor size. Multivariate analysis showed that age ≥ 75 years (P = 0.002) and pleural adhesion (P = 0.026) were significant independent risk factors for complications. Compared with the patient group without complications, postoperative complications were independently associated with shorter disease-free survival (P = 0.01)., Conclusions: Advanced age and pleural adhesion were independent risk factors for complications after complete single-lobe thoracoscopic lobectomies for clinical stage I NSCLC, and postoperative complications were statistically associated with poor prognosis. Surgical teams should ensure an experienced surgeon leads the operation for patients at higher risk to avoid prolonged postoperative hospitalization and a possible poor prognosis., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

Objectives: Difficult thoracoscopic surgery sometimes requires a long operative time. It is unclear whether patients benefit from such thoracoscopic surgeries. We investigated whether thoracoscopic surgery for difficult cases contributed to improvements in perioperative outcomes., Methods: We retrospectively reviewed cases of anatomical lung resection with thoracoscopic surgery, including conversion to thoracotomy, between January 2006 and December 2016 and compared patient demographics and perioperative outcomes of the long (≥360 min) and the normal operative time groups (<360 min)., Results: One hundred and seventy-six patients were in the long operative time group and 655 patients were in the normal operative time group. The long operative time group had more male patients, more progressive clinical stages, bilobectomy or pneumonectomy, conversion to thoracotomy and more blood loss than the normal operative time group. The long operative time group had higher rates of postoperative complications and longer hospital stay (30% vs 16%, P < 0.001 and 9 ± 9 days vs 7 ± 8 days, P < 0.001; respectively). Multivariate analysis showed that in the first half of the operative period, chronic obstructive pulmonary disease and bilobectomy or pneumonectomy were independent predictive factors for postoperative complications. The long operative time as a factor was close to statistical significance (odds ratio 1.689, P = 0.079) unlike the elective conversion to thoracotomy (odds ratio 0.784, P = 0.667) and emergency conversion to thoracotomy (odds ratio 0.938, P = 0.924)., Conclusions: In conclusion, when difficult cases are encountered, conversion to thoracotomy should be considered by surgeons if continuation of thoracoscopic surgery increases the operative time., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/β-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.

We report a change of the imaging biomarker distribution of circulating tumor cell (CTC) clusters in blood over time using an on-chip multi-imaging flow cytometry system, which can obtain morphometric parameters of cells and those clusters, such as cell number, perimeter, total cross-sectional area, aspect ratio, number of nuclei, and size of nuclei, as "imaging biomarkers". Both bright-field (BF) and fluorescent (FL) images were acquired at 200 frames per second and analyzed within the intervals for real-time cell sorting. A green fluorescent protein-transfected prostate cancer cell line (MAT-LyLu-GFP) was implanted into Copenhagen rats, and the blood samples of these rats were collected 2 to 11 days later and measured using the system. The results showed that cells having BF area of 90 μm² or larger increased in number seven days after the cancer cell implantation, which was specifically detected as a shift of the cell size distribution for blood samples of implanted rats, in comparison with that for control blood. All cells with BF area of 150 μm² or larger were arranged in cell clusters composed of at least two cells, as confirmed by FL nucleus number and area measurements, and they constituted more than 1% of all white blood cells. These results indicate that the mapping of cell size distribution is useful for identifying an increase of irregular cells such as cell clusters in blood, and show that CTC clusters become more abundant in blood over time after malignant tumor formation. The results also reveal that a blood sample of only 50 μL is sufficient to acquire a stable size distribution map of all blood cells to predict the presence of CTC clusters.

We examined a simultaneous combined spatiotemporal field potential duration (FPD) and cell-to-cell conduction time (CT) in lined-up shaped human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using an on-chip multielectrode array (MEA) system to evaluate two origins of lethal arrhythmia, repolarization and depolarization. The repolarization index, FPD, was prolonged by E-4031 and astemizole, and shortened by verapamil, flecainide and terfenadine at 10 times higher than therapeutic plasma concentrations of each drug, but it did not change after lidocaine treatment up to 100 μM. CT was increased by astemizol, flecainide, terfenadine, and lidocaine at equivalent concentrations of Nav1.5 IC 50 , suggesting that CT may be an index of cardiac depolarization because the increase in CT (i.e., decrease in cell-to-cell conduction speed) was relevant to Nav1.5 inhibition. Fluctuations (short-term variability; STV) of FPD and CT, STV FPD and STV CT also discriminated between torsadogenic and non-torsadogenic compounds with significant increases in their fluctuation values, enabling precise prediction of arrhythmogenic risk as potential new indices.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non-small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869). Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined. Results: Patients with NSCLC ( n = 155) were randomly assigned to receive vitamin D ( n = 77) or placebo ( n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment. Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089-97. ©2018 AACR ., (©2018 American Association for Cancer Research.)