A single institutional clinical outcome for stages III and IV ovarian cancer patients treated with dose-dense TC therapy in the frontline or first platinum-sensitive relapse setting.

AIM: Dose-dense paclitaxel /carboplatin (ddTC) therapy was shown to be more effective against ovarian cancer than conventional tri-weekly TC in the JGOG3016 study. However, two phase III studies performed after JGOG3016 did not show the same positive results. Because we have been using ddTC in the frontline or first platinum-sensitive relapse of ovarian cancer, we investigated the clinical outcome of the patients treated with ddTC. METHODS: We retrospectively examined the response rate (RR), progression free survival (PFS) and adverse events of the patients who were treated with ddTC for stage III and IV epithelial ovarian, tubal and peritoneal cancer from January 2012 to December 2018. RESULTS: We analyzed 50 patients for frontline treatment and 11 patients for first platinum-sensitive relapse treatment, excluding those receiving maintenance therapy. Among the patients that received frontline ddTC treatment, RR was 82.9% for those in a neo-adjuvant chemotherapy (NACT) setting and 85.0% for those in an adjuvant setting. The median progression-free survival (PFS) was 20 months after initial therapy. Among 31 cases that achieved remission by frontline surgery and the following ddTC, 22 had a platinum-sensitive relapse. RR of 11 patients treated with ddTC therapy alone for the first platinum-sensitive relapse was 81.8%, and the median PFS of these patients was 22 months after the first recurrence. CONCLUSIONS: ddTC therapy for advanced ovarian cancer achieved high response rates in all settings (NACT, adjuvant or platinum-sensitive relapse). ddTC therapy was effective for improving the prognosis of patients with stages III and IV of ovarian cancer.

Identification of long noncoding RNAs downregulated specifically in ovarian high-grade serous carcinoma.

Purpose: To investigate whether long noncoding RNAs (lncRNAs) are involved in the development or malignant behavior of ovarian high-grade serous carcinoma (HGSC), we attempted to identify lncRNAs specific to HGSC. Methods: Total RNAs were isolated from HGSC, normal ovarian, and fallopian tube tissue samples and were subjected to a PCR array that can analyze 84 cancer-associated lncRNAs. The lncRNAs that were upregulated and downregulated in HGSC in comparison to multiple samples of normal ovary and fallopian tube were validated by real-time RT-PCR. To infer the function, ovarian cancer cell lines that overexpress the identified lncRNAs were established, and the activation of cell proliferation, migration, and invasion was analyzed. Results: Eleven lncRNAs (ACTA2-AS1, ADAMTS9-AS2, CBR3-AS1, HAND2-AS1, IPW, LINC00312, LINC00887, MEG3, NBR2, TSIX, and XIST) were downregulated in HGSC samples. We established the cell lines that overexpress ADAMTS9-AS2, CBR3-AS1, or NBR2. In cell lines overexpressing ADAMTS9-AS2, cell proliferation was suppressed, but migration and invasion were promoted. In cell lines overexpressing CBR3-AS1 or NBR2, cell migration tended to be promoted, although cell proliferation and invasion were unchanged. Conclusion: We identified eleven lncRNAs that were specifically downregulated in HGSC. Of these, CBR3-AS1, NBR2, and ADAMTS9-AS2 had unique functions in the malignant behaviors of HGSC.

Live attenuated VZV vaccination induces antitumor immunity in ATLL patients.

Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C-C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.

Association between complete revascularization of the coronary artery and clinical outcomes in peripheral artery disease: a sub-analysis of the I-PAD Nagano registry.

Peripheral artery disease (PAD) is commonly caused by atherosclerosis and has an unfavorable prognosis. Complete revascularization (CR) of the coronary artery reduces the risk of major adverse cardiovascular event (MACE) in patients with coronary artery disease (CAD). However, the impact of CR in patients with PAD has not been established to date. Therefore, we evaluated the impact of CR of CAD on the five-year clinical outcomes in patients with PAD. This study was based on a prospective, multicenter, observational registry in Japan. We enrolled 366 patients with PAD undergoing endovascular treatment. The primary endpoint was MACE, defined as a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. After excluding ineligible patients, 96 and 68 patients received complete revascularization of the coronary artery (CR group) and incomplete revascularization of the coronary artery (ICR group), respectively. Freedom from MACE in the CR group was significantly higher than in the ICR group at 5 years (66.7% vs 46.0%, p < 0.01). Multivariate analysis revealed that CR emerged as an independent predictor of MACE (Hazard ratio: 0.56, 95% confidential interval: 0.34-0.94, p = 0.03). CR of CAD was significantly associated with improved clinical outcomes in patients with PAD undergoing endovascular treatment.

Impact of Frailty and Age on Clinical Outcomes in Patients Who Underwent Endovascular Therapy.

PURPOSE: Information on the relationship between frailty and the outcome of endovascular therapy (EVT) in elderly patients with lower extremity peripheral artery disease (PAD) is scarce. This study aimed to reveal the impact of frailty on the prognosis of super-elderly patients who underwent EVT. MATERIALS AND METHODS: From August 2015 to August 2016, 335 consecutive patients who underwent EVT were enrolled in the I-PAD registry from 7 institutes in Nagano prefecture. Among them, we categorized 323 patients into 4 groups according to age and the presence or absence of frailty as follows: elderly with frailty (age ≥ 75, Clinical Frailty Scale [CFS] ≥ 5), elderly without frailty (age ≥ 75, CFS ≤ 4), young with frailty (age < 75, CFS ≥ 5), and young without frailty (age < 75, CFS ≤ 4); we analyzed them accordingly. The primary endpoints were major adverse cardiovascular and limb events (MACLE), defined as a composite of cardiovascular death, myocardial infarction, stroke, admission for heart failure, major amputation, and revascularization. The secondary endpoint was cardiovascular death. RESULTS: The median follow-up period was 2.7 years. In the elderly with frailty, elderly without frailty, young with frailty, and young without frailty groups, the freedom rates from MACLE were 34.9%, 55.7%, 35.4%, and 63.0%, respectively (p<0.001) and from all-cause death were 43.5%, 73.4%, 50.7%, and 90.9%, respectively (p<0.001). The freedom rates from MACLE were significantly higher among elderly patients with frailty than among young patients without frailty (55.7% vs 35.4%, p=0.01). In multivariate analysis, frailty was independently associated with MACLE incidence. CONCLUSION: Frailty as defined by CFS might be a predictor of MACLE incidence in patients with PAD who underwent EVT. By considering treatment indications for patients with PAD by focusing on frailty rather than age, we may examine whether EVT policies are appropriate and manage patient and caregiver expectations for potential improvement in functional outcomes. Further studies are expected to investigate whether changes in frailty after EVT change prognosis.

Gender difference in heart failure with preserved ejection fraction: clinical profiles, examinations, and prognosis.

Heart failure with preserved ejection fraction (HFpEF) has currently become a major concern in the aging society owing to its substantial and growing prevalence. Recent investigations regarding sacubitril/valsartan have suggested that there is a gender difference in the efficacy of the medication in HFpEF cohort. However, information of gender difference in clinical profiles, examination, and prognosis have not been well investigated. The present study aimed to evaluate the differences in baseline characteristics and outcomes between women and men in a Japanese HFpEF cohort. We analyzed the data from our prospective, observational, and multicenter cohort study. Overall, 1036 consecutive patients hospitalized for acute decompensated heart failure were enrolled. We defined patients with an ejection fraction (EF) of ≥ 50% as HFpEF. Patients with severe valvular disease were excluded; the remaining 379 patients (women: n = 201, men: n = 178) were assessed. Women were older than men [median: 85 (79-89) years vs. 83 (75-87) years, p = 0.013]. Diabetes mellitus, hyperuricemia, and coronary artery disease were more prevalent in men than in women (34.8% vs. 23.9%, p = 0.019, 23.6% vs. 11.4%, p = 0.002, and 23.0% vs. 11.9%, p = 0.005, respectively). EF was not significantly different between women and men. The cumulative incidence of cardiovascular death or hospitalization for congestive heart failure (CHF) was significantly lower in women than in men (log-rank p = 0.040). Women with HFpEF were older and less often exhibited an ischemic etiology; further, they were associated with a lower risk for cardiovascular death or hospitalization for CHF compared with men in the Japanese population.

Comparison of prognostic impact of anticoagulants in heart failure patients with atrial fibrillation and renal dysfunction: direct oral anticoagulants versus vitamin K antagonists.

Although high thromboembolic risk was assumed in elderly patients with heart failure (HF) and atrial fibrillation (AF), inadequate control of prothrombin time/international normalized ratio was often observed in patients using vitamin K antagonists (VKAs). We hypothesized that patients treated with direct oral anticoagulants (DOAC) would have a better outcome than those treated with VKAs. The aim of this study was to compare the efficacies of DOACs and VKAs in elderly patients with HF and AF. We retrospectively analyzed data from a multicenter, prospective observational cohort study. A total of 1036 patients who were hospitalized for acute decompensated HF were enrolled. We assessed 329 patients aged > 65 years who had non-valvular AF and divided them into 2 groups according to the anticoagulant therapy they received. A subgroup analysis was performed using renal dysfunction based on estimated glomerular filtration rate (eGFR; mL/min/1.73 m2). The primary outcome was all-cause mortality, and the secondary outcomes were non-cardiovascular death or stroke. The median follow-up period was 730 days (range 334-1194 days). The primary outcome was observed in 84 patients; non-cardiovascular death, in 25 patients; and stroke, in 14 patients. The Kaplan-Meier analysis revealed that all-cause mortality was significantly lower in the DOAC group than in the VKA group (log-rank p = 0.033), whereas the incidence rates of non-cardiovascular death (log-rank p = 0.171) and stroke (log-rank p = 0.703) were not significantly different in the crude population. DOAC therapy was not associated with lower mortality in the crude population (log-rank p = 0.146) and in the eGFR ≥ 45 mL/min/1.73 m2 subgroup (log-rank p = 0.580). However, DOAC therapy was independently associated with lower mortality after adjustments for age, diabetes mellitus, and albumin level (hazard ratio, 0.55; 95% confidence interval, 0.30-0.99; p = 0.045) in the eGFR < 45 mL/min/1.73 m2 subgroup. Compared with VKA therapy, DOAC therapy was associated with lower risk of all-cause mortality in the elderly HF patients with AF and renal dysfunction.

Effects of cardiac surgical support on long-term outcomes of emergent or complex percutaneous coronary intervention cases: a sub-analysis of the SHINANO 5-year registry.

Significant improvements in percutaneous coronary intervention (PCI) technology have enabled cardiovascular procedures to be performed without onsite cardiac surgery facilities. However, little is known about the association between onsite cardiac surgical support and long-term outcomes of PCI, particularly among emergent and complex cases. We investigated whether the presence or absence of cardiovascular surgery affects the long-term prognosis after PCI, emergent and complex elective cases. The SHINANO 5-year registry, a prospective, observational, and multicenter cohort study registry in Nagano, Japan, consecutively included 1665 patients who underwent PCI between August 2012 and July 2013. The procedures were performed at 11 hospitals with onsite cardiac surgery facilities [onsite surgery (+) group; n = 1257] and 8 hospitals without onsite cardiac surgery facilities [onsite surgery (-) group; n = 408]. The primary endpoint was all-cause mortality and the secondary endpoint was major adverse cardiac and cerebrovascular events [MACCE: all-cause death, Q-wave myocardial infarction, non-fatal stroke, and target lesion revascularization]. The onsite surgery group (+) had a lower rate of emergent PCI and ST-segment elevation myocardial infarction (40.8% vs. 51.7%, p < 0.01 and 24.9% vs. 39.2%, p < 0.01, respectively), and a higher prevalence of hemodialysis and history of peripheral artery disease (7.6% vs. 2.45%, p < 0.01 and 12.1% vs. 6.9%, p < 0.01, respectively). However, the Kaplan-Meier analysis showed no difference in the 5-year mortality rate (16.4% vs. 15.2%, p = 0.421) and MACCE incidence (31.6% vs. 28.9%, p = 0.354) between the groups. Also, there were no differences in the mortality rate and incidence of MACCE among emergent cases of ST-segment elevation myocardial infarction and complex elective cases who underwent PCI. Long-term outcomes of PCI appear to be comparable between institutions with and without onsite cardiac surgical facilities.

Intensive exercise therapy for restenosis after superficial femoral artery stenting: the REASON randomized clinical trial.

Endovascular treatment (EVT) is the main treatment for peripheral artery disease (PAD). Despite advances in device development, the restenosis rate remains high in patients with femoropopliteal lesions (FP). This study aimed to evaluate the effectiveness of exercise training in reducing the 1-year in-stent restenosis rate of bare metal nitinol stents for FPs. This prospective, randomized, open-label, multicenter study was conducted from January 2017 to March 2019. We randomized 44 patients who had claudication with de novo stenosis or occlusion of the FP into an intensive exercise group (n = 22) and non-intensive exercise group (n = 22). Non-intensive exercise was defined as walking for less than 30 min per session, fewer than three times a week. We assessed exercise tolerance using an activity meter at 1, 3, 6, and 12 months, and physiotherapists ensured maintenance of exercise quality every month. The primary endpoint was instant restenosis defined as a peak systolic velocity ratio > 2.5 on duplex ultrasound imaging. Kaplan-Meier analysis was used to evaluate the data. There were no significant differences in background characteristics between the groups. Six patients dropped out of the study within 1 year. In terms of the primary endpoint, intensive exercise significantly improved the patency rate of bare nitinol stents at 12 months. The 1-year freedom from in-stent restenosis rates were 81.3% in the intensive exercise group and 47.6% in the non-intensive exercise group (p = 0.043). No cases of stent fracture were observed in the intensive exercise group. Intensive exercise is safe and reduces in-stent restenosis in FP lesions after endovascular therapy for PAD. Clinical trial registration: University Hospital Medical Information Network Clinical Trials Registry (No. UMIN 000025259).

Prognostic usefulness of residual SYNTAX score combined with clinical factors for patients with acute coronary syndrome who underwent percutaneous coronary intervention from the SHINANO Registry.

The optimal strategy for percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) with multi-vessel disease (MVD) is still controversial. Residual anatomical features alone are not sufficient to appropriately stratify patient risk. Our aim was to assess the effectiveness of the residual Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score (rSS) combined with clinical factors to predict long-term clinical outcomes in ACS patients. A total of 120 patients with ACS and MVD undergoing PCI were recruited from the SHINANO 5-year registry: a prospective, multi-center, cohort study. The rSS combined with clinical factors (Combined Score) were calculated based on the residual coronary angiogram and each clinical feature after primary PCI. The Combined Score was calculated by replacing SS with rSS using the SYNTAX score II (SSII) calculator. We grouped the Combined Score in two groups according to the cut-off value calculated by the ROC curve (the C-statistic was 0.82 [95% CI 0.74-0.91]) for all-cause mortality. The primary endpoint was all-cause mortality during the 5-year follow-up. The Combined Score was associated with long-term mortality in Cox-regression analysis (HR 1.08, 95% CI 1.05-1.11, P < 0.001). The mortality rate was significantly higher in the high-score group compared with the low-score group (5.7% vs 38.0%; P < 0.001). In ACS with MVD, the Combined Score might be considered an important tool to predict long-term mortality following PCI.

Impact of nutritional index on long-term outcomes of elderly patients with coronary artery disease: sub-analysis of the SHINANO 5 year registry.

Nutritional status is a novel approach to prognostic assessment in patients with cardiovascular disease. However, assessment of nutritional status in elderly patients is challenging due to the significant differences between young patients. The TCBI (Triglycerides × Total cholesterol × Body Weight Index) is a novel and simple nutritional index for predicting long-term outcomes in patients with coronary artery disease. This retrospective study evaluated the efficacy of TCBI in 597 elderly (≥ 75 years) patients enrolled in the SHINANO 5 year registry. The SHINANO 5 year registry, a prospective observational multicenter cohort study, had enrolled 1501 consecutive patients who underwent elective/urgent percutaneous coronary intervention (PCI). In this study, patients were categorized into TCBI quartile groups. The primary endpoints were the occurrence of major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, stroke, and myocardial infarction at 5 year. The mean duration of follow up was 4.3 ± 1.7 years. The average patient age was 80.9 ± 4.3 years. MACCE was observed in 61 (40.9%) patients in the lowest TCBI quartile group. Kaplan-Meier analysis demonstrated an inverse relationship between MACCE and TCBI (log-lank P < 0.001). Multivariate analysis demonstrated that low TCBI significantly predicted the incidence of MACCE (hazard ratio: 1.44, 95% confidence interval: 1.03-2.00; P = 0.031). The TCBI is useful in predicting long-term outcomes in elderly patients undergoing PCI.

Prognostic ability of mid-term worsening renal function after percutaneous coronary intervention: findings from the SHINANO registry.

Chronic kidney disease is a prognostic factor for cardiovascular disease. Worsening renal function (WRF), specifically, is an important predictor of mortality in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI). We evaluate the prognostic impact of mid-term WRF after PCI on future cardiovascular events. We examined the renal function data of 1086 patients in the first year after PCI using the SHINANO 5-year registry. Patients were divided into two groups, mid-term WRF and non-mid-term WRF, and primary outcomes were major adverse cardiovascular events (MACE) and death. Mid-term WRF was defined as an increase in creatinine (≥ 0.3 mg/dL) in the first year after PCI. Mid-term WRF was found in 101 patients (9.3%), and compared to non-mid-term WRF, it significantly increased the incidence of MACE (p < 0.001), and all-cause death (p < 0.001), myocardial infarction (p = 0.001). Furthermore, mid-term WRF patients had higher incidence of future heart failure (p < 0.001) and new-onset atrial fibrillation (p = 0.01). Patients with both mid-term WRF and chronic kidney disease had increased MACE compared to patients with either condition alone (p < 0.001). Similarly, patients with mid-term WRF and acute kidney injury had increased MACE compared to patients with either condition alone (p < 0.001). Multivariate Cox regression analysis revealed mid-term WRF as a strong predictor of MACE (hazard ratio: 2.50, 95% confidence interval 1.57-3.98, p < 0.001). Mid-term WRF after PCI negatively affects MACE, as well as future admission due to heart failure and new-onset atrial fibrillation, chronic kidney disease, and acute kidney injury.

Fast and accurate phase-unwrapping algorithm based on the transport of intensity equation: comment.

In [Appl. Opt.56, 7079 (2017)APOPAI0003-693510.1364/AO.56.007079], an attractive phase unwrapping algorithm based on the transport of intensity equation is proposed. Although the effectiveness is experimentally evaluated, the derivation of the angular spectrum based expression is ambiguous. In this paper, the ambiguity is clarified with the Helmholtz equation.

Impact of changes in body mass index after percutaneous coronary intervention on long-term outcomes in patients with coronary artery disease.

Little is known about the impact of changes in body mass index (BMI) after the percutaneous coronary intervention (PCI) on long-term outcomes in patients with coronary artery disease (CAD). Therefore, this study aimed to clarify this issue. We investigated data on CAD obtained from the SHINANO Registry, a prospective, observational, multicenter cohort study, from 2012 to 2013 in Nagano, Japan. One year after PCI, the enrolled patients were divided into the following three groups based on changes in BMI by tertiles: reduced, maintained, and elevated BMI. The associations among the groups and the 4-year outcomes [major adverse cardiac events (MACEs), all-cause death, Q-wave myocardial infarction, and stroke] were examined. Five hundred seventy-two patients were divided into the reduced, maintained, and elevated BMI groups. Over the 4-year follow-up period, the cumulative incidence of MACEs was 10.5% (60 cases). In the Kaplan-Meier analysis, the incidence rates of MACE were significantly higher in the reduced BMI group than in the maintained and elevated BMI groups [17.7% versus (vs.) 7.3% vs. 9.0%, p = 0.004]. Multivariable cox regression analysis showed that the reduced group showed increased risks of MACEs (hazard ratio 2.15; 95% confidence interval 1.29-3.57; p = 0.003). The long-term clinical outcomes of patients with CAD who underwent PCI were affected by the reduction in BMI after PCI. Furthermore, the elevation of BMI after PCI was not a poor prognostic factor.

An optical and non-invasive method to detect the accumulation of ubiquitin chains.

The accumulations of excess amounts of polyubiquitinated proteins are cytotoxic and frequently observed in pathologic tissue from patients of neurodegenerative diseases. Therefore, optical and non-invasive methods to detect the increase of the amounts of polyubiquitinated proteins in living cells is a promising strategy to find out symptoms and environmental cause of neurodegenerative diseases, also for identifying compounds that could inhibit gathering of polyubiquitinated proteins. Therefore, we generated a pair of fluorescent protein [Azamigreen (Azg) and Kusabiraorange (Kuo)] tagged ubiquitin on its N-terminus (Azg-Ub and Kuo-Ub) and developed an Azg/Kuo-based Fluorescence Resonance Energy Transfer (FRET) assay to estimate the amount of polyubiquitin chains in vitro and in vivo. The FRET intensity was attenuated in the presence of ubiquitin-activating enzyme inhibitor, PYR-41, indicating that both fluorescent ubiquitin is incorporated into ubiquitin chains likewise normal ubiquitin. The FRET intensity was enhanced by the addition of the proteasome inhibitor, MG-132, and was reduced in the presence of the autophagy activator Rapamycin, designating that ubiquitin chains with fluorescent ubiquitin act as the degradation signal equally with normal ubiquitin chains. In summary, the above optical methods provide powerful research tools to estimate the amounts of polyubiquitin chains in vitro and in vivo, especially non-invasively in living cells.

Aryne-based strategy in the total synthesis of naturally occurring polycyclic compounds.

The total syntheses of polycyclic natural products by exploiting an aryne as the key reactive species are reviewed. A short introduction summarizes the basic reactivities of aryne species as well as the methods for its generation. In the main part, early examples and the recent reports (mainly 2012-present) on the use of arynes in multistep syntheses are described.

Distinct Subcellular Compartments of Dendritic Cells Used for Cross-Presentation.

Dendritic cells (DCs) present exogenous protein-derived peptides on major histocompatibility complex class I molecules to prime naïve CD8+ T cells. This DC specific ability, called cross-presentation (CP), is important for the activation of cell-mediated immunity and the induction of self-tolerance. Recent research revealed that endoplasmic reticulum-associated degradation (ERAD), which was first identified as a part of the unfolded protein response-a quality control system in the ER-plays a pivotal role in the processing of exogenous proteins in CP. Moreover, DCs express a variety of immuno-modulatory molecules and cytokines to regulate T cell activation in response to the environment. Although both CP and immuno-modulation are indispensable, contrasting ER conditions are required for their correct activity. Since ERAD substrates are unfolded proteins, their accumulation may result in ER stress, impaired cell homeostasis, and eventually apoptosis. In contrast, activation of the unfolded protein response should be inhibited for DCs to express immuno-modulatory molecules and cytokines. Here, we review recent advances on antigen CP, focusing on intracellular transport routes for exogenous antigens and distinctive subcellular compartments involved in ERAD.

Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence.

Bacteria inhabiting the human gut metabolize microbiota-accessible carbohydrates (MAC) contained in plant fibers and subsequently release metabolic products. Gut bacteria produce hydrogen (H2), which scavenges the hydroxyl radical (•OH). Because H2 diffuses within the cell, it is hypothesized that H2 scavenges cytoplasmic •OH (cyto •OH) and suppresses cellular senescence. However, the mechanisms of cyto •OH-induced cellular senescence and the physiological role of gut bacteria-secreted H2 have not been elucidated. Based on the pyocyanin-stimulated cyto •OH-induced cellular senescence model, the mechanism by which cyto •OH causes cellular senescence was investigated by adding a supersaturated concentration of H2 into the cell culture medium. Cyto •OH-generated lipid peroxide caused glutathione (GSH) and heme shortage, increased hydrogen peroxide (H2O2), and induced cellular senescence via the phosphorylation of ataxia telangiectasia mutated kinase serine 1981 (p-ATMser1981)/p53 serine 15 (p-p53ser15)/p21 and phosphorylation of heme-regulated inhibitor (p-HRI)/phospho-eukaryotic translation initiation factor 2 subunit alpha serine 51 (p-eIF2α)/activating transcription factor 4 (ATF4)/p16 pathways. Further, H2 suppressed increased H2O2 by suppressing cyto •OH-mediated lipid peroxide formation and cellular senescence induction via two pathways. H2 produced by gut bacteria diffuses throughout the body to scavenge cyto •OH in cells. Therefore, it is highly likely that gut bacteria-produced H2 is involved in intracellular maintenance of the redox state, thereby suppressing cellular senescence and individual aging. Hence, H2 produced by intestinal bacteria may be involved in the suppression of aging.

The novel antioxidant TA293 reveals the role of cytoplasmic hydroxyl radicals in oxidative stress-induced senescence and inflammation.

The hydroxyl radical (OH) possesses the strongest oxidation potential among reactive oxygen species (ROS). Hydroxyl radicals react nonpreferentially with proteins, lipids, and nucleic acids. Additionally, mitochondrial localization of OH causes dysfunction in the mitochondria. The cytoplasmic targets of OH-induced oxidation are unknown. No cytoplasm-specific OH scavenger is available; thus, elucidating the cytoplasmic targets of OH-induced oxidation has proven difficult. Accordingly, we developed a cytoplasm-specific OH-targeted scavenger, TA293, and a mitochondrion-specific scavenger, mitoTA293. Both TA293 and mitoTA293 scavenged OH but not O2- or H2O2. We then examined the intracellular localization of both scavengers in vitro and in vivo. TA293 scavenged pyocyanin-induced cytoplasmic OH but not antimycin A-induced mitochondrial oxidation. mitoTA293 scavenged antimycin A-induced mitochondrial OH but not cytoplasmic OH. TA293 but not mitoTA293 suppressed pyocyanin-induced oxidative damage in the lungs and kidneys of mice. Additionally, TA293 suppressed the expression of inflammatory signaling pathway components and mediators and suppressed OH-induced cellular senescence and apoptosis. These data suggested that TA293 could be used as a novel tool for studying the effects of hydroxyl radical damage within the cytoplasm.

Interstitial lung disease induced by alectinib (CH5424802/RO5424802).

A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.