•PAHs were detected in the cooking exhaust from the fat-rich food samples.•The major PAHs generated by grilling were phenanthrene, fluoranthene, and pyrene.•The percentage of 5- to 7-rings PAHs ...increased as the particle diameter decreased.•Most of PAHs generated were concentrated in particles with diameters of <0.43μm.•More than 90% of the PAHs emitted by grilling would reach the alveolar region.
The concentration and particle size distribution of 19 major polycyclic aromatic hydrocarbons (PAHs) emitted by thermal cooking were investigated. Corn, trout, beef, prawns, and pork were selected for grilling. The PAHs in the oil mist emitted when the food was grilled were collected according to particle size range and analysed by GC/MS. Much higher concentrations of PAHs were detected in the oil mist emitted by grilled pork, trout, and beef samples, which were rich in fat. The main components of the cooking exhaust were 3- and 4-ring PAHs, regardless of food type. The particle size distribution showed that almost all the PAHs were concentrated in particles with diameters of <0.43μm. For pork, the toxic equivalent of benzoapyrene accounted for 50% of the PAHs in particles with diameters of <0.43μm. From these results, we estimated that >90% of the PAHs would reach the alveolar region of the lungs.
Background
A survival benefit of extensive intraoperative peritoneal lavage (EIPL) has been reported in patients with gastric cancer with positive peritoneal cytology. The hypothesis of this study ...was that EIPL may reduce peritoneal recurrence in patients with advanced gastric cancer who undergo surgery with curative intent.
Methods
This was an open‐label, multi‐institutional, randomized, phase 3 trial to assess the effects of EIPL versus standard treatment after curative gastrectomy for resectable gastric cancer of T3 status or above. The primary endpoint was disease‐free survival (DFS); secondary endpoints were overall survival, peritoneal recurrence‐free survival and incidence of adverse events.
Results
Between July 2011 and January 2014, 314 patients were enrolled from 15 institutions and 295 patients were analysed (145 and 150 in the EIPL and no‐EIPL groups respectively). The 3‐year DFS rate was 63·9 (95 per cent c.i. 55·5 to 71·2) per cent in the EIPL group and 59·7 (51·3 to 67·1) per cent in the control group (hazard ratio (HR) 0·81, 95 per cent c.i. 0·57 to 1·16; P = 0·249). The 3‐year overall survival rate was 75·0 (67·1 to 81·3) per cent in the EIPL group and 73·7 (65·9 to 80·1) per cent in the control group (HR 0·91, 0·60 to 1·37; P = 0·634). Peritoneal recurrence‐free survival was not significantly different between the two groups (HR 0·92, 0·62 to 1·36; P = 0·676). No intraoperative complications related to EIPL were observed.
Conclusion
EIPL did not improve survival or peritoneal recurrence in patients who underwent gastrectomy for advanced gastric cancer. Registration number: 000005907 (http://www.umin.ac.jp/ctr/index.htm).
Antecedentes
Se ha descrito que un lavado peritoneal extenso intraoperatorio (extensive intraoperative peritoneal lavage, EIPL) proporciona un beneficio en la supervivencia en pacientes con cáncer gástrico con citología peritoneal positiva. La hipótesis de este estudio era que el EIPL podría disminuir la recidiva peritoneal en pacientes con cáncer gástrico avanzado sometidos a cirugía con intención curativa.
Métodos
Ensayo clínico fase 3, abierto, multicéntrico y aleatorizado para evaluar los efectos de un lavado peritoneal extenso intraoperatorio (EIPL) frente a tratamiento estándar tras gastrectomía curativa por cáncer gástrico ≥T3 resecable. La variable de resultado primaria fue la supervivencia libre de enfermedad (disease‐free survival, DFS), y las variables de resultado secundarias fueron la supervivencia global (overall survival, OS), la supervivencia libre de recidiva peritoneal y la incidencia de efectos adversos.
Resultados
Entre julio de 2011 y enero de 2014, se reclutaron 314 pacientes de 15 instituciones y se analizaron los datos de 295 pacientes (145 en el grupo con EIPL y 150 en el grupo sin EIPL). La DFS a los 3 años fue 63,9% (i.c. del 95% 55,5‐71,2) en el grupo con EIPL y 59,7% (i.c. del 95% 51,3‐67,1) en el grupo control (cociente de riesgos instantáneos, hazard ratio, HR 0,81 (i.c. del 95% 0,57‐1,16), P = 0,249). La OS a los 3 años fue 75,0% (i.c. del 95% 67,1‐81,3) en el grupo con EIPL y 73,7% (i.c. del 95% 65,9‐80,1) en el grupo control (HR 0,91 i.c. del 95% 0,60‐1,37), P = 0,634). No se observaron diferencias estadísticamente significativas entre los dos grupos en la supervivencia libre de recidiva peritoneal (P = 0,676, HR 0,92 (i.c. del 95% 0,62‐1,36). No se observaron complicaciones intraoperatorias relacionadas con EIPL.
Conclusión
El EIPL no mejoró la supervivencia o la recidiva peritoneal en pacientes sometidos a gastrectomía por cáncer gástrico avanzado.
This trial was conducted to clarify the effects of extensive intraoperative peritoneal lavage (EIPL) therapy after curative gastrectomy for resectable cT3 gastric cancer. The 3‐year DFS rate was slightly better in the EIPL group (63·9 per cent) than in the no‐EIPL group (59·7 per cent), but the difference was not statistically significant (hazard ratio 0·81, 95 per cent c.i. 0·57 to 1·16; P = 0·249). Superiority of EIPL therapy was not demonstrated.
No benefit
Abstract
Genebanks provide access to diverse materials for crop improvement. To utilize and evaluate them effectively, core collections, such as the World Rice Core Collection (WRC) in the Genebank ...at the National Agriculture and Food Research Organization, have been developed. Because the WRC consists of 69 accessions with a high degree of genetic diversity, it has been used for >300 projects. To allow deeper investigation of existing WRC data and to further promote research using Genebank rice accessions, we performed whole-genome resequencing of these 69 accessions, examining their sequence variation by mapping against the Oryza sativa ssp. japonica Nipponbare genome. We obtained a total of 2,805,329 single nucleotide polymorphisms (SNPs) and 357,639 insertion–deletions. Based on the principal component analysis and population structure analysis of these data, the WRC can be classified into three major groups. We applied TASUKE, a multiple genome browser to visualize the different WRC genome sequences, and classified haplotype groups of genes affecting seed characteristics and heading date. TASUKE thus provides access to WRC genotypes as a tool for reverse genetics. We examined the suitability of the compact WRC population for genome-wide association studies (GWASs). Heading date, affected by a large number of quantitative trait loci (QTLs), was not associated with known genes, but several seed-related phenotypes were associated with known genes. Thus, for QTLs of strong effect, the compact WRC performed well in GWAS. This information enables us to understand genetic diversity in 37,000 rice accessions maintained in the Genebank and to find genes associated with different phenotypes.
The sequence data have been deposited in DNA Data Bank of Japan Sequence Read Archive (DRA) (Supplementary Table S1).
Current R&D on the thermochemical water splitting iodine-sulfur (IS) process in Japan Atomic Energy Agency (JAEA) is summarized. Reactors were fabricated with industrial materials and verified by ...test operations: a Bunsen reactor, a H2SO4 decomposer, and a HI decomposer. Component materials of the reactors were stable in the operation environment. Small amount of H2SO4 in the anolyte solution in an electro-electrodialysis (EED) cell had no negative impact on cell performance parameters. Relationship between cell solution composition and temperature and cell parameters was formulated by experimental data. Demonstration of the test facility with process design of 100 L/h hydrogen production is performed to verify integrity of process components and stability of hydrogen production. Tests of sections were first conducted individually to show material processing rates were controllable. Based on the result, an 8-h continuous operation of the total IS process was performed in February 2016 with H2 production rate of 10 L/h. Demonstrations are planned for longer operation period and higher H2 production rate after improvement of components to prevent troubles.
•Current R&D on the iodine-sulfur (IS) process in JAEA is summarized.•Reactors of industrial materials showed corrosion stability.•Effect of compositions and temperature on the EED cell performance was evaluated.•Controllability of material processing rate in process components was verified.•H2 of 10 L/h was produced for 8 h in an industrial-material facility.
To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB).
Participants included 18 patients with PD, 21 patients with PDD/DLB, ...and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-11C-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis.
Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced.
Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.
Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of ...cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.
Display omitted
•Loss of function of DNMT3A or TET2 in human macrophages induces type I interferons•The type I interferon response is due to mitochondrial DNA release that activates cGAS•DNMT3A and TET2 maintain mitochondrial DNA integrity by regulating TFAM expression•DNMT3A and TET2 regulate TFAM expression by interacting with RBPJ and ZNF143
Clonal hematopoiesis due to mutations in DNMT3A or TET2 increases risk of cardiovascular disease, but mechanisms are presently unclear. Cobo et al. reveal that loss of function of DNMT3A and TET2 results in a type 1 interferon response in macrophages due to impaired mitochondrial DNA integrity.
Background
Accumulating evidence suggests that radiotherapy success has an immune‐associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed ...in patients with locally advanced rectal cancer in this study.
Methods
CD8+ tumour‐infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole‐exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near‐complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non‐responders.
Results
Immunohistochemical examinations (275 patients) showed that pre‐CRT CD8+ TIL density was associated with better response to CRT and improved recurrence‐free survival, whereas pre‐CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence‐free survival. Whole‐exome sequencing (74 patients) showed that the numbers of single‐nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non‐responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte‐activation gene 3 (LAG3) (rS = 0·507).
Conclusion
Pre‐CRT neoantigen‐specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.
Antecedentes
Las evidencias existentes sugieren que el éxito de la radioterapia tiene un componente asociado con el sistema inmunitario. En este estudio se evaluaron los perfiles inmunogenómicos asociados con la respuesta a la quimiorradioterapia (chemoradiotherapy, CRT) en pacientes con cáncer de recto localmente avanzado.
Métodos
Las densidades de los linfocitos infiltrantes de tumor CD8+ (tumour‐infiltrating lymphocyte, TIL) y de los linfocitos del estroma se evaluaron por inmunohistoquímicas en las biopsias antes del tratamiento de pacientes con cáncer de recto localmente avanzado que recibieron CRT preoperatoria. Se realizó secuenciación de todo el exoma, así como microarrays de expresión génica, para investigar las propiedades genómicas asociadas con la respuesta a la CRT y a la densidad de los TIL CD8+. La respuesta a la CRT se determinó según el grado de regresión del tumor de Dworak (tumour regression grade, TRG), agrupándose como buenos respondedores los casos de regresión tumoral completa (TRG4) o casi completa (TRG3) y como no respondedores, los casos de grado TRG1.
Resultados
Los exámenes inmunohistoquímicos (n = 275) mostraron que la densidad pre‐CRT de TIL CD8+ se asoció con una mejor respuesta a la CRT y una mejor supervivencia libre de recidiva, aunque la densidad de células CD8+ del estroma previa a la CRT no se asoció con la respuesta a la CRT ni con la supervivencia libre de recidiva. La secuenciación de todo el exoma (n = 74) mostró que el número de variaciones de nucleótidos únicos (single nucleotide variations, SNVs) y los neoantígenos predichos a partir de los SNVs fueron mayores en los que respondieron bien que en los que no respondieron, y éstos se correlacionaron positivamente con la densidad de los TIL CD8+ (Spearman r = 0,315 y r = 0,334 respectivamente). Los microarrays de expresión génica (n = 90) mostraron que la expresión CD8A se correlacionó positivamente con la expresión del ligando de muerte programada‐1 (r = 0,264) y con el antígeno linfocitario del gen 3 (r = 0,507).
Conclusión
La activación de células T CD8+ específicas para neoantígenos previa a la CRT puede ser un evento clave en la respuesta a la misma donde las moléculas del punto de control inmunitario podrían ser dianas útiles para intensificar la regresión del tumor.
The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer using immunohistochemistry, whole‐exome sequencing and gene expression microarray. Pre‐CRT neoantigen‐specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression. SNV, single nucleotide variant; indels, insertions and deletions; TRG, tumour regression grade; MSI‐H, high‐level microsatellite instability; MSS, microsatellite stable.
Lymphocytes are key
The present study aimed to evaluate the applicability of using a single slice cross-sectional area (CSA) of the skeletal muscle for estimating segmental skeletal muscle volume (SMV). By using MRI, ...the SMV of each of the upper arm, lower arm, upper leg, lower leg, and trunk was determined in 29 males. First, step-wise multiple regression analysis was applied to develop the equation for each segmental SMV in which the CSAs at intervals of 10% of segment length (SL) were used as independent variables. Second, simple linear regression analysis with every CSA selected in the first step was applied to predict SMV in each body segment. In each segment, the standard error of estimate (SEE) in the simple linear regression equation was greater than that in the multiple regression one. The most appropriate slice level for measuring a single CSA to estimate SMV was 30% of the upper arm SL (R2=0.800, SEE=7.4%), 60% of the lower arm SL (0.788, 10.3%), 50% of the upper leg SL (0.795, 7.0%), and 20% of the trunk SL (0.813, 6.1%). For the lower leg, muscle CSAs at multiple slice levels are required to estimate SMV without the systematic error.
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