Intracellular Amyloid β Oligomers Impair Organelle Transport and Induce Dendritic Spine Loss in Primary Neurons

Introduction Synaptic dysfunction and intracellular transport defects are early events in Alzheimer’s disease (AD). Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood. Results We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons. Conclusions Our findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau

Social experiment for security camera which protects privacy embedded in vending machine

AbstractWith the cooperation of Gunma Prefecture Police Department and Mikuni Coca-Cola Group, e-JIKEI Network started Experiment of Security Camera Embedded in Vending Machine on 19th June 2007. In this experiment, the system of e-JIKEI Network is embedded in a vending machine to develop a new experiment environment. In this new development, our watch over system will not be restricted to residential area, but can also be used widely even in suburb area. Up until now, the camera has been working perfectly and the experiment progressed as expected. The authors are hoping that this system work perfectly without problems for 1-year cycle

Transient severe hypotension with once-weekly subcutaneous injection of teriparatide in osteoporotic patient : a case report and insight for the drug interaction between hypotensive agents and teriparatide

Teriparatide, a recombinant form of parathyroid hormone, were well recognized as a useful option for the treatment of the osteoporosis. Although some side effects of teriparatide include headache, nausea, dizziness, and limb pain were reported. Here we present a 80-year-old woman of transient asymptomatic hypotension with once-weekly subcutaneous injection of teriparatide for the treatment of osteoporosis with hypertension disease as acute-phase reactions. Systolic blood pressure decreased in both 30 min and 60 min after injection compared with before injection. Heart rate increased with passage of time. Statistically significant were observed among before, 30min, 60min after injection of teriparatide. Slight nausea was seen as subjective symptoms with the first and second injection after 30 min. This case indicates careful attention, at least 1 hr, was recommended with weekly subcutaneous injections of teriparatide in the treatment for osoteoproteic patient with hypertension decreases. This is a first report, to the best of our knowledge, to demonstrate the transient asymptomatic hypotension after once-weekly injection of teriparatide with hypertension disease. Transient hypotension occurred after injection of teriparatide during the treatment period and was asymptomatic except for the first 2 injections

The Role of Radiotherapy for Thymic Carcinoma

Objective: The aim of this study is to evaluate retrospectively the role of radiotherapy for thymic carcinoma. Methods: Between 1973 and 1998, 14 patients with thymic carcinoma were treated at Gunma Prefectural Cancer Center. Two patients who had hematogenous metastasis were excluded from this study, therefore 12 patients were analyzed. The Masaoka staging system was used; four patients were diagnosed with stage III disease and eight patients with stage IV disease. The pathological subtype according to the World Health Organization histological criteria for thymic tumors was squamous cell carcinoma (low-grade histology) in six cases and undifferentiated carcinoma (high-grade histology) in six. Ten patients underwent thoracotomy, and two patients underwent excisional biopsy without thoracotomy. Ten patients (83%) received radiotherapy as a curative intent, and the median dose was 60 Gy. Systemic chemotherapy was administered to four patients (33%), and the majority (75%) of the regimens contained cisplatin. Results: The 3-year overall survival rate was 25%. Histological subtype (low-grade versus highgrade), surgical resection (complete versus incomplete), radiotherapy and chemotherapy were evaluated as prognostic factors in a univariate analysis. Low-grade histology and complete resection were good prognostic factors, although these were not statistically significant. Patients who received radiotherapy had a better outcome than those who did not. The major sites of recurrence were the pleura and pericardium. Recurrence within the radiation field was observed in one of seven patients in whom failure patterns could be evaluated. Conclusion: Complete resection is mandatory if possible. Radiotherapy plays an important role in treating thymic carcinoma in terms of reducing local recurrence and prolonging survival time. Establishment of an innovative treatment protocol that includes chemotherapy is necessary to control intrathoracic relapse and distant metastasis

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naive patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P = 0.0008) and progression-free survival (P = 0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm-3 (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (≥4500 mm-3, n = 204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (≥4500 mm-3, n = 184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis

A diagnostic marker for superficial urothelial bladder carcinoma : lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression

Background: Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma. Methods: Seven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation. Results: ATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n= 110) and ATBF1− (n=7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008). Conclusions: Cleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

新規の循環型iNKT細胞を発見 --抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待--. 京都大学プレスリリース. 2022-10-24.Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244⁻CXCR6⁻), C1 (CD244⁻CXCR6⁺), or C2 (CD244⁺CXCR6⁺) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244⁺CXCR6⁺ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells

Researching peers and disaster vulnerable communities: an insider perspective

Conducting research among peers and communities that a researcher also serves may be both daunting and rewarding. Researching peers may make the researcher feel uncomfortable raising certain questions that are sensitive or that could be construed to be testing their competencies. This paper is inclined more towards showing that it is advantageous to be an insider, whose position can facilitate collection of information that could not have been accessed, or revealed to an outsider. The paper reports on fieldwork conducted in a low-income country in Sub-Sahara Africa as part of a doctoral study with communities affected by disasters and those that work with such communities. The paper demonstrates the complexities of conducting such research and provides some insights that may be useful to insiders, outsiders or “in-betweeners” embarking on fieldwork in low-income countries and among vulnerable population struggling with manifold stresses and shocks

Pretreatment glasgow prognostic score predicts survival among patients administered first-line atezolizumab plus carboplatin and etoposide for small cell lung cancer

BackgroundThere are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC.MethodsWe reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively.ResultsThe response rate was 72.6% (95% confidence interval: 63.0–82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9–5.9) months and 15.4 (95% CI: 11.4–16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0–1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p<0.0001).ConclusionsThis is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients

Management of Lung Cancer-Associated Malignant Pericardial Effusion with Intrapericardial Administration of Carboplatin: A Retrospective Study

It has been reported that 5.1–7.0% of acute pericarditis are carcinomatous pericarditis. Malignant pericardial effusion (MPE) can progress to cardiac tamponade, which is a life-threatening condition. The effectiveness and feasibility of intrapericardial instillation of carboplatin (CBDCA; 150 mg/body) have never been evaluated in patients with lung cancer, which is the most common cause of MPE. Therefore, we evaluated the effectiveness and feasibility of intrapericardial administration of CBDCA following catheter drainage in patients with lung cancer-associated MPE. In this retrospective study, 21 patients with symptomatic lung cancer-associated MPE, who were administered intrapericardial CBDCA (150 mg/body) at Gunma Prefectural Cancer Center between January 2005 and March 2018, were included. The patients’ characteristics, response to treatment, and toxicity incidence were evaluated. Thirty days after the intrapericardial administration of CBDCA, MPE was controlled in 66.7% of the cases. The median survival period from the day of administration until death or last follow-up was 71 days (range: 10–2435 days). Grade 1–2 pain, nausea, fever, and neutropenia were noted after intrapericardial CBDCA administration. No treatment-related deaths were noted in the current study. Intrapericardial administration of CBDCA (150 mg/body) did not cause serious toxicity, and patients exhibited promising responses to lung cancer-associated MPE. Prospective studies using larger sample sizes are needed to explore the efficacy and safety of this treatment for managing lung cancer-associated MPE