Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation

Neurite growth requires two guanine nucleotide-binding protein polymers of tubulins and septins. However, whether and how those cytoskeletal systems are coordinated was unknown. Here we show that the acute knockdown or knockout of the pivotal septin subunit SEPT7 from cerebrocortical neurons impairs their interhemispheric and cerebrospinal axon projections and dendritogenesis in perinatal mice, when the microtubules are severely hyperacetylated. The resulting hyperstabilization and growth retardation of microtubules are demonstrated in vitro. The phenotypic similarity between SEPT7 depletion and the pharmacological inhibition of α-tubulin deacetylase HDAC6 reveals that HDAC6 requires SEPT7 not for its enzymatic activity, but to associate with acetylated α-tubulin. These and other findings indicate that septins provide a physical scaffold for HDAC6 to achieve efficient microtubule deacetylation, thereby negatively regulating microtubule stability to an optimal level for neuritogenesis. Our findings shed light on the mechanisms underlying the HDAC6-mediated coupling of the two ubiquitous cytoskeletal systems during neural development

Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection

BACKGROUND: Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection. METHODS AND FINDINGS: Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling. CONCLUSIONS: These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.Oncogene advance online publication, 8 October 2012; doi:10.1038/onc.2012.446.In Press → 発行後6か月より全文を公開

Improved detectability of small-bowel lesions via capsule endoscopy with computed virtual chromoendoscopy: A pilot study

Objective. Real-time video capsule endoscopy (CE) with flexible spectral imaging color enhancement (FICE) improves visibility of small-bowel lesions. This article aims to clarify whether CE-FICE also improves detectability of small-bowel lesions. Patients and methods. A total of 55 patients who underwent CE at Hiroshima University Hospital during the period November 2009 through March 2010 were enrolled in the study. Five patients were excluded from the study because residues and transit delays prevented sufficient evaluation. Thus, 50 patients participated. Two experienced endoscopists (each having interpreted more than 50 capsule videos) analyzed the images. One interpreted conventional capsule videos; the other, blinded to interpretation of the conventional images, interpreted CE-FICE images obtained at settings 1-3 (setting 1: red 595 nm, green 540 nm, blue 535 nm; setting 2: red 420 nm, green 520 nm, blue 530 nm; setting 3: red 595 nm, green 570 nm, blue 415 nm). Lesions were classified as angioectasia, erosion, ulceration, or tumor. Detectability was compared between the two modalities. Time taken to interpret the capsule videos was also determined. Results. Seventeen angioectasias were identified by conventional CE; 48 were detected by CE-FICE at setting 1, 45 at setting 2, and 24 at setting 3, with significant differences at settings 1 and 2 (p = 0.0003, p < 0.0001, respectively). Detection of erosion, ulceration, and tumor did not differ statistically between conventional CE and CE-FICE, nor did interpretation time (conventional CE 36 ± 6.9 min; CE-FICE setting 1, 36 ± 6.4 min; setting 2, 38 ± 5.8 min; setting 3, 35 ± 6.7 min). Conclusions. CE-FICE is superior in the lesion detection in comparison with conventional CE and improves detection of angioectasia

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Reactivation of hepatitis in a bladder cancer patient receiving chemotherapy

Reactivation of hepatitis is a serious complication of chemotherapy in hepatitis B virus (HBV) carriers. There are many reports of this in lymphoma patients but few in urological cancer patients. A 59-year-old woman with bladder cancer who was an HBV carrier developed severe liver dysfunction after 2 cycles of chemotherapy. The diagnosis was reactivation of hepatitis. She improved with administration of lamivudine with a steroid and is currently well without disease. Care should be taken about the risk of reactivation when performing chemotherapy in HBV carriers and prophylaxis by lamivudine should be considered

Enhancing mechanism of intestinal absorption of highly lipophilic compounds using microemulsion – Quantitative analysis of the partitioning to the mesenteric lymph in intestinal cells

The purpose of this study was to quantify the effect of the fatty acid alkyl-chain length of a polyethylene glycol (PEG) glyceryl ester, which was used as a microemulsion oil component, on the partitioning of highly lipophilic compounds to the mesenteric lymph after oral administration. Oil blue N, a highly lipophilic anthraquinone derivative, was orally administered to lymph duct-cannulated and untreated rats in two kinds of different microemulsions. Gelucire® 50/13 and Gelucire® 44/14 were used as the oil component with long chain and medium chain fatty acid portions, respectively, of PEG glyceryl esters in microemulsions. The cumulative amount of oil blue N in lymph fluid was almost the same between the two microemulsions, although the transferred amount of oil component (triglyceride) in the lymph after administration of the Gelucire® 50/13 microemulsion was significantly higher than that of the Gelucire® 44/14 microemulsion. On the other hand, the solubility of oil blue N in Gelucire® 44/14 was much higher than that in Gelucire® 50/13. No significant differences were observed between microemulsions in the bioavailability of oil blue N. From these data, the partitioning of oil blue N to the lymph was calculated using a mathematical model, showing that the partitioning ratios of oil blue N to the lymph fluid were almost the same for both microemulsions. The solubility of oil blue N to the oil component of the microemulsions and the transfer of triglycerides to the lymph after administration of the microemulsions counteract each other, leading to similar partitioning ratios of oil blue N to the lymph

A comprehensive policy for reducing sugar beverages for healthy life extension

Abstract The excessive consumption of sugar-sweetened beverages is a public health concern worldwide. Several clinical trials examining the effects of consuming sucrose or high-fructose corn syrup demonstrated the link between this consumption and increased risk factors for cardiometabolic diseases. In this issue of Environmental Health and Preventive Medicine, Li et al. examined the sugar-sweetened beverage consumption among undergraduate students and evaluated the relationship between this consumption and the “late” chronotype, sleep duration, and weight increase. They concluded that the sugar-sweetened beverage intake might mediate the associations among sleep duration, late chronotype, and weight gain and that the intake of sugar-sweetened beverages in the evening may be a risk factor for the development of overweight/obesity. A systematic review and meta-analysis of prospective cohort studies and randomized controlled trials provided evidence that the consumption of sugar-sweetened beverages promotes weight gain in both children and adults. The World Health Organization guideline highly recommends reducing the intake of sugars to less than 10% of one’s total energy intake. The Dietary Approaches to Stop Hypertension diet and the Mediterranean diet were shown to help individuals refrain from sweets and sugar-containing beverages. A global evaluation revealed how much disability during accumulated lifetime hours is due to sugar-sweetened beverages. Interventions are necessary, but many individuals find it quite difficult to reduce or eliminate their high intake of sugar-sweetened beverages. The taxation of sugar-sweetened beverages was demonstrated to have a significant positive influence on individuals’ planned purchases and the probability of the purchase of healthy beverages. Western countries are working on the social regulation of sugar-sweetened beverages, but Japan has not implemented any similar regulations. The social regulation of sugar-sweetened beverages is necessary to stop the increase of diabetes morbidity and the increase in dementia that often accompanies this morbidity