ALKBH8 contributes to neurological function through oxidative stress regulation.

Transfer RNA (tRNA) modification is essential for proper protein translation, as these modifications play important roles in several biological functions and disease pathophysiologies. AlkB homolog 8 (ALKBH8) is one of the nine mammalian ALKBH family molecules known to regulate selenoprotein translation through the modification of the wobble uridine (U34) in tRNA; however, its specific biological roles remain unclear. In this study, we investigated the role of ALKBH8 using Alkbh8-knockout (Albkh8-/-) mice, which were observed to have reduced 5-methoxycarbonylmethyluridine (mcm5U) and (S)-5-methoxycarbonylhydroxymethyluridine levels; notably, the mcm5U level was partially compensated only in the brain. The results of the novel object recognition test showed reduction in time to explore a novel object in Albkh8-/- mice; increased latency to fall in the rotarod performance test and latency to the immobility period in the forced swim test were also observed. These abnormal behaviors indicate dysfunction of the central nervous system. Furthermore, we observed reduced brain weight and ischemic pathological changes in the cerebral cortex and hippocampus in the form of weak eosin staining in the fiber tracts adjacent to the hippocampal cornu ammonis 1 region and an increase in pyramidal cells in the temporal lobe. Concordantly, we identified the differential expression of oxidative stress-related proteins and metabolites in the cerebral cortex and hippocampus using omics analyses. Finally, neurons and glial cells derived from Albkh8-/- mice show reduced mitochondrial membrane potential. Collectively, these findings indicate that ALKBH8 maintains neural function through an oxidative stress-regulatory mechanism.

Identification of key yeast species and microbe-microbe interactions impacting larval growth of Drosophila in the wild.

Microbiota consisting of various fungi and bacteria have a significant impact on the physiological functions of the host. However, it is unclear which species are essential to this impact and how they affect the host. This study analyzed and isolated microbes from natural food sources of Drosophila larvae, and investigated their functions. Hanseniaspora uvarum is the predominant yeast responsible for larval growth in the earlier stage of fermentation. As fermentation progresses, Acetobacter orientalis emerges as the key bacterium responsible for larval growth, although yeasts and lactic acid bacteria must coexist along with the bacterium to stabilize this host-bacterial association. By providing nutrients to the larvae in an accessible form, the microbiota contributes to the upregulation of various genes that function in larval cell growth and metabolism. Thus, this study elucidates the key microbial species that support animal growth under microbial transition.

Head and neck small-cell carcinoma: A multicenter study of 39 cases from 10 institutions.

Objective: Basal information of head and neck small-cell carcinoma (HNSmCC) including epidemiology, primary site, treatment, and prognosis remains sparse due to its rarity. We report here a multicenter retrospective study on the diagnosis, treatment, and outcomes of patients with HNSmCC. Materials and methods: This study involved 47 patients with HNSmCC from 10 participating institutions. Eight patients were excluded for whom no pathological specimens were available (n = 2) and for discrepant central pathological judgements (n = 6). The remaining 39 patients were processed for data analysis. Results: As pretreatment examinations, computed tomography (CT) was performed for the brain (n = 8), neck (n = 39), and chest (n = 32), magnetic resonance imaging (MRI) for the brain (n = 4) and neck (n = 23), positron emission tomography-CT (PET-CT) in 23 patients, bone scintigraphy in 4, neck ultrasonography in 9, and tumor markers in 25. Primary sites were oral cavity (n = 1), nasal cavity/paranasal sinuses (n = 16), nasopharynx (n = 2), oropharynx (n = 4), hypopharynx (n = 2), larynx (n = 6), salivary gland (n = 3), thyroid (n = 2), and others (n = 3). Stages were II/III/IV-A/IV-B/IV-C/Not determined = 3/5/16/6/5/4; stage IV comprised 69%. No patient had brain metastases. First-line treatments were divided into 3 groups: the chemoradiotherapy (CRT) group (n = 27), non-CRT group (n = 8), and best supportive care group (n = 4). The CRT group included concurrent CRT (CCRT) (n = 17), chemotherapy (Chemo) followed by radiotherapy (RT) (n = 5), and surgery (Surg) followed by CCRT (n = 5). The non-CRT group included Surg followed by RT (n = 2), Surg followed by Chemo (n = 1), RT alone (n = 2), and Chemo alone (n = 3). The 1-year/2-year overall survival (OS) of all 39 patients was 65.3/53.3%. The 1-year OS of the CRT group (77.6%) was significantly better compared with the non-CRT group (31.3%). There were no significant differences in adverse events between the CCRT group (n = 22) and the Chemo without concurrent RT group (n = 9). Conclusion: Neck and chest CT, neck MRI, and PET-CT would be necessary and sufficient examinations in the diagnostic set up for HNSmCC. CCRT may be recommended as the first-line treatment. The 1-year/2-year OS was 65.3%/53.3%. This study would provide basal data for a proposing the diagnostic and treatment algorithms for HNSmCC.

An autopsy case of COVID-19 with a sudden death: Clinico-pathological comparison.

Autopsy was performed on a COVID-19 patient, who suddenly died despite the extensive anti-viral and anti-inflammatory therapies. Although moderate subpleural fibrosis was seen, pathology of DAD, a well-known cause for pulmonary failure, was minimum. Instead, severe hemorrhage was observed. Therapeutic effects were indicated; however, why severe hemorrhage occurred was unclear.

Treatment Outcome of External Auditory Canal Carcinoma: The Utility of Lateral Temporal Bone Resection.

We examined the role of lateral temporal bone resection (LTBR) in the treatment of external ear canal (EAC) carcinoma between 2007 and 2018. The estimated 3-year disease-free survival (DFS) and disease-specific survival (DSS) according to the tumor stage and treatments were investigated in 36 patients with EAC squamous cell carcinoma. T stage classification according to the University of Pittsburgh staging system was as follows: 14 patients in T1, four patients in T2, nine patients in T3, and nine patients in T4. The 3-year DFS rate was 77.4% for T1 tumors, 100% for T2, 44.4% for T3 tumors, and 11.1% for T4 tumors (p < 001). The 3-year DSS rate was 100% for T1/T2 tumors, 87.5% for T3 tumors, and 11.1% for T4 tumors (p < 0.01). T1/T2 patients received mostly LTBR. Among nine T3 tumors, five patients (56%) received LTBR combined with preoperative chemotherapy and/or postoperative radiation (RT). Four of them had negative surgical margin and survived with no evidence of disease. The DFS of T3 patients who underwent concurrent chemoradiotherapy and LTBR was 0 and 80%, respectively (p = 0.048). For T1/T2 tumors, surgery achieved an excellent outcome. For T3 tumors, LTBR achieved negative surgical margin and showed good survival when combined with preoperative chemotherapy and/or postoperative RT. In contrast, the prognosis of T3 patients who could not undergo surgery was as poor as that of T4 patients. Therefore, in addition to subtotal temporal bone resection, LTBR-based treatment strategy may be a treatment option for limited cases of T3 patients.

Tumor-like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin-induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat.

AIMS/INTRODUCTION: Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non-large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin-induced insulin secretion (IIIS) in these islets. MATERIALS AND METHODS: Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks-of-age were isolated. The islets of fa/fa rats at 12 weeks-of-age were separated into non-large islets (≤200 µm in diameter) and enlarged islets (>300 µm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets. RESULTS: The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for ß-cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets. CONCLUSIONS: The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell-like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age-dependent increase in such islets could contribute to the pathophysiology of obese diabetes.

Programmed folding into spiro-multicyclic polymer topologies from linear and star-shaped chains.

The development of precise folding techniques for synthetic polymer chains that replicate the unique structures and functions of biopolymers has long been a key challenge. In particular, spiro-type (i.e., 8-, trefoil-, and quatrefoil-shaped) polymer topologies remain challenging due to their inherent structural complexity. Herein, we establish a folding strategy to produce spiro-type multicyclic polymers via intramolecular ring-opening metathesis oligomerization of the norbornenyl groups attached at predetermined positions along a synthetic polymer precursor. This strategy provides easy access to the desired spiro-type topological polymers with a controllable number of ring units and molecular weight while retaining narrow dispersity (Ɖ < 1.1). This effective strategy marks an advancement in the development of functionalized materials composed of specific three-dimensional nanostructures.

A rare case of pulmonary typical carcinoid with prominent acinic cell differentiation, resembling acinic cell carcinoma.

We herein describe a rare case of low-grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha-1-antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen-type granules (600-800 nm in diameter) in the acinic cell component, whereas neuroendocrine-type granules (200-300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen-type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.

Sentinel Lymph Node Biopsy Using Preoperative Computed Tomographic Lymphography and Intraoperative Indocyanine Green Fluorescence Imaging in Patients With Localized Tongue Cancer.

IMPORTANCE: The indocyanine green method alone is unsuitable for sentinel lymph node biopsy in patients with oral cancer because of poor transcutaneous identification of the fluorescent signal through the platysma and sternocleidomastoid muscles. OBJECTIVE: To assess the utility of a novel sentinel lymph node biopsy technique using preoperative computed tomographic (CT) lymphography followed by the intraoperative indocyanine green fluorescence method. DESIGN, SETTING, AND PARTICIPANTS: In this prospective study performed at Akita University Hospital, Akita, Japan, participants comprised 18 patients with previously untreated cN0 tongue cancer (squamous cell carcinoma) were enrolled from November 2012 to November 2016. Median observer period was 38 (range, 14-62) months. Analysis was completed between January 10 and March 10, 2018. INTERVENTIONS: For preoperative sentinel lymph node mapping, CT lymphography was performed the day before sentinel lymph node biopsy. For sentinel lymph node biopsy, a minimum skin incision was made according to the predetermined location of sentinel lymph nodes. Sentinel lymph nodes were excised under indocyanine green fluorescence guidance. MAIN OUTCOMES AND MEASURES: Identification rate of preoperative sentinel lymph node mapping by CT lymphography and the number of sentinel lymph node successfully identified by the intraoperative indocyanine green fluorescence method. RESULTS: Among 18 patients (8 men, 10 women; median age, 65.5 [range, 40-83] years), sentinel lymph nodes could be mapped by preoperative CT lymphography in 16 patients (89%). At least 1 sentinel lymph node was successfully identified and excised in each of these 16 patients using intraoperative indocyanine green fluorescence. Among the 16 patients in whom sentinel lymph nodes were excised, metastases to sentinel lymph nodes were found in 5 patients (31%). CONCLUSIONS AND RELEVANCE: The novel sentinel lymph node biopsy technique of preoperative CT lymphography mapping with intraoperative indocyanine green fluorescence has a high potential for identifying sentinel lymph nodes in patients with cN0 tongue cancer. Because the intraoperative indocyanine green method alone cannot identify sentinel lymph nodes in the neck region, this combined method has clinical potential as a sentinel lymph node biopsy technique that does not require radioisotopes.

A versatile synthetic strategy for macromolecular cages: intramolecular consecutive cyclization of star-shaped polymers.

Cage-shaped polymers, or "macromolecular cages", are of great interest as the macromolecular analogues of molecular cages because of their various potential applications in supramolecular chemistry and materials science. However, the systematic synthesis of macromolecular cages remains a great challenge. Herein, we describe a robust and versatile synthetic strategy for macromolecular cages with defined arm numbers and sizes based on the intramolecular consecutive cyclization of highly reactive norbornene groups attached to each end of the arms of a star-shaped polymer precursor. The cyclizations of three-, four-, six-, and eight-armed star-shaped poly(ε-caprolactone)s (PCLs) bearing a norbornenyl group at each arm terminus were effected with Grubbs' third generation catalyst at high dilution. 1H NMR, SEC, and MALDI-TOF MS analyses revealed that the reaction proceeded to produce the desired macromolecular cages with sufficient purity. The molecular sizes of the macromolecular cages were controlled by simply changing the molecular weight of the star-shaped polymer precursors. Systematic investigation of the structure-property relationships confirmed that the macromolecular cages adopt a much more compact conformation, in both the solution and bulk states, as compared to their linear and star-shaped counterparts. This synthetic approach marks a significant advance in the synthesis of complex macromolecular architectures and provides a platform for novel applications using cage-shaped molecules with polymer frameworks.

Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death.

Protein crystallization in human tissue rarely occurs. Charcot-Leyden crystals (CLCs) were described in various eosinophilic diseases >150 years ago, but our understanding of CLC formation still remains limited. In this study, we demonstrate that CLCs observed in varied inflamed human tissues are closely associated with eosinophil cell-free granules and nuclear envelope/plasma membrane disintegration with release of filamentous chromatin (extracellular traps), typical morphologies of a regulated pathway of extracellular trap cell death (ETosis). During the process of eosinophil ETosis, eccentrically localized cytoplasmic and perinuclear CLC protein (galectin-10) is homogeneously redistributed in the cytoplasm. Rapid (1-2 minutes) formation of intracytoplasmic CLCs was observed using time-lapse imaging. Plasma membrane rupture enabled the release of both intracellularly formed CLCs and soluble galectin-10 that further contributed to formation of CLCs extracellularly, in parallel with the expulsion of free intact granules and extracellular traps. CLC formation and galectin-10 release were dependent on nicotinamide adenine dinucleotide phosphate oxidase activation. To our knowledge, this is the first demonstration of natural formation of CLCs in association with an active physiological process (ie, ETosis). These results indicate that dynamic changes in intracellular localization and release of galectin-10 contribute to CLC formation in vivo and suggest that CLC/galectin-10 might serve as an indicator of ETosis.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

Acquired amegakaryocytic thrombocytopenia previously diagnosed as idiopathic thrombocytopenic purpura in a patient with hepatitis C virus infection.

We report the first case of a patient with hepatitis C virus (HCV) infection and idiopathic thrombocytopenic purpura (ITP), who later developed acquired amegakaryocytic thrombocytopenia (AAMT), with autoantibodies to the thrombopoietin (TPO) receptor (c-Mpl). A 64-year-old woman, with chronic hepatitis C, developed severe thrombocytopenia and was diagnosed with ITP. She died of liver failure. Autopsy revealed cirrhosis and liver carcinoma. In the bone marrow, a marked reduction in the number of megakaryocytes was observed, while other cell lineages were preserved. Therefore, she was diagnosed with AAMT. Additionally, autoantibodies to c-Mpl were detected in her serum. Autoantibodies to c-Mpl are one of the causes of AAMT, acting through inhibition of TPO function, megakaryocytic maturation, and platelet formation. HCV infection induces several autoantibodies. HCV infection might also induce autoantibodies to c-Mpl, resulting in the development of AAMT. This mechanism may be one of the causes of thrombocytopenia in patients with HCV infection.

CD147 expression correlates with lymph node metastasis in T1-T2 squamous cell carcinoma of the tongue.

Cervical lymph node metastasis causes a poor prognosis in cases of stage T1-T2 squamous cell carcinoma (SCC) of the tongue. Recent studies have reported that cluster of differentiation (CD)147, also known as extracellular matrix metalloproteinase inducer, contributes to tumor progression. The present study evaluated the role of CD147 in the tumorigenesis of SCC of the tongue in vitro, as well as the association between CD147 expression and cervical lymph node metastasis in clinical samples of SCC of the tongue. Tongue SCC cell lines were used to evaluate in vitro tumorigenesis. In addition, 41 patients with clinical stage T1-T2 tongue SCC were assessed with a histopathological analysis. Univariate and multivariate analysis were performed to investigate the risk of cervical lymph node metastasis associated with histopathological findings. In the in vitro study, cell invasiveness was upregulated by S100 calcium-binding protein A9 (S100A9) stimulation and downregulated following CD147-blocking antibody treatment. The univariate and multivariate analyses identified CD147 expression in the invasive tumor front as an independent risk factor for metastasis. It was concluded that CD147 induces tongue carcinoma cell invasion through its interaction with S100A9. Thus, an evaluation of the extent of CD147 expression in cancer cell nests at the invasive tumor front may help in predicting cervical lymph node metastasis in patients with clinical N0 T1-T2 tongue SCC.

Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in ß-cell glutamate signaling for incretin-induced insulin secretion.

Incretins (GLP-1 and GIP) potentiate insulin secretion through cAMP signaling in pancreatic ß-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS) that requires two critical processes: 1) generation of cytosolic glutamate through the malate-aspartate (MA) shuttle in glucose metabolism and 2) glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse ß-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1), a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7, Slc17a6, and Slc17a8, respectively), which participate in glutamate transport into secretory vesicles. Got1 knockout (KO) ß-cell lines were defective in cytosolic glutamate production from glucose and showed impaired IIIS. Unexpectedly, different from the previous finding that global Slc17a7 KO mice exhibited impaired IIIS from pancreatic islets, ß-cell specific Slc17a7 KO mice showed no significant impairment in IIIS, as assessed by pancreas perfusion experiment. Single Slc17a7 KO ß-cell lines also retained IIIS, probably due to compensatory upregulation of Slc17a6. Interestingly, triple KO of Slc17a7, Slc17a6, and Slc17a8 diminished IIIS, which was rescued by exogenously introduced wild-type Slc17a7 or Slc17a6 genes. The present study provides direct evidence for the essential roles of AST1 and VGLUTs in ß-cell glutamate signaling for IIIS and also shows the usefulness of the CRISPR/Cas9 system for studying ß-cells by simultaneous disruption of multiple genes.

The Anti-tumor Effect of Cabozantinib on Ovarian Clear Cell Carcinoma In Vitro and In Vivo.

BACKGROUND: Several reports have shown that the overexpression of the MET proto-oncogene, receptor tyrosine kinase (MET), was more frequently observed in clear cell carcinoma (CCC) than in non-CCC. We evaluated the antitumor activity of cabozantinib, that targets MET. MATERIALS AND METHODS: A gene expression analysis of tumors from human ovarian cancers was carried out by transcriptome sequencing. An in vitro 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay (MTT assay) and in vivo experiments were performed to determine the activity of cabozantinib. RESULTS: The MET levels were higher in tumors with CCC than high-grade serous carcinoma (2.2-fold). Cabozantinib inhibited cell viability and phosphorylation of AKT and MAPK under the treatment of hepatocyte growth factor in RMG-I CCC cells. The tumors removed from mice given cabozantinib of 10 mg/kg weighed 70% less than control on day 15, and the immunohistochemical reactivity of phosphorylated MET was reduced compared with control mice. CONCLUSION: Cabozantinib contributes to tumor reduction, and phosphorylated MET represents an attractive target of CCC.

In vitro and in vivo antitumor activities of T-3764518, a novel and orally available small molecule stearoyl-CoA desaturase 1 inhibitor.

Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1. T-3764518 inhibited stearoyl-CoA desaturase-catalyzed conversion of stearoyl-CoA to oleoyl-CoA in colorectal cancer HCT-116 cells and their growth. Further, it slowed tumor growth in an HCT-116 and a mesothelioma MSTO-211H mouse xenograft model. Comprehensive lipidomic analyses revealed that T-3764518 increases the membrane ratio of saturated: unsaturated fatty acids in various lipid species such as phosphatidylcholines and diacylglycerols in both cultured cells and HCT-116 xenografts. Treatment-associated lipidomic changes were followed by activated endoplasmic reticulum (ER) stress responses such as increased immunoglobulin heavy chain-binding protein expression in HCT-116 cells. These T-3764518-induced changes led to an increase in cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptosis. Additionally, bovine serum albumin conjugated with oleic acid, an SCD1 product, prevented cell growth inhibition and ER stress responses by T-3764518, indicating that these outcomes were not attributable to off-target effects. These results indicate that T-3764518 is a promising new anticancer drug candidate.

Intratumor Heterogeneity in Primary Kidney Cancer Revealed by Metabolic Profiling of Multiple Spatially Separated Samples within Tumors.

Metabolic alteration constitutes a hallmark of cancer. Glycolysis and antioxidant pathways in kidney cancer are elevated, with frequent mutation of the VHL gene. Intratumor genetic heterogeneity has been recently demonstrated in kidney cancer. However, intratumor metabolic heterogeneity has not been investigated. Here, we used global metabolomics analysis and tissue slice tracer studies to demonstrate that different portions of a human primary kidney tumor possess different metabolic characteristics and drug sensitivity. Pyruvate levels were elevated and pyruvate metabolism was altered in some tumor sections. These observations indicated that pyruvate metabolism may constitute a possible vulnerability of kidney cancer; indeed, pyruvate stimulated the growth of primary kidney cancer cells and pharmacological inhibition of pyruvate transporters slowed the growth of patient-derived kidney tumors in mice. These findings deepen our understanding of the intratumor metabolic heterogeneity of kidney cancer and may inform novel therapeutic approaches in human kidney cancer.

Complementary and alternative medicine for allergic rhinitis in Japan.

BACKGROUND: Complementary and alternative medicine (CAM) is extensively used in patients with allergic diseases worldwide. The purpose of this study was to investigate the actual situation of CAM practice in the treatment of allergic rhinitis. METHODS: We distributed questionnaires to otolaryngologists at 114 facilities in Japan. The subjects who participated in this study included children <16 years of age and adults ≥16 years of age diagnosed with allergic rhinitis by otolaryngologists. The survey was performed in the period from September 2007 to August 2009. Furthermore, we performed the same investigation out of the hospital setting, such as during general health examinations. All questionnaires were returned to Chiba University and analyzed. RESULTS: The proportions of patients who had ever experimented with CAM in the hospital survey were 7.1% (225/3170) and 19.2% (1416/7363) of children and adults, respectively. Approximately 36.2% of the adult patients thought that the treatments were effective. The main reasons for CAM use were safety, convenience and low price. However, the group who spent more than $1000 on CAM felt more dissatisfaction and anxiety related to treatment at the hospital. The situation of CAM practice was not consistent and was instead influenced by the backgrounds of the subjects. CONCLUSIONS: Many patients who receive CAM report feeling that the effects of treatment provided by hospitals are insufficient and have concerns about the side effects of such treatments. Information regarding standard treatments, as described in the guidelines, should become widely known and diffused, and strong communication with patients should be considered.