Genome-Wide Association Study of Breast Cancer in the Japanese Population

Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P−5) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10−12, OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10−11, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10−10, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.</p

人工呼吸管理症例における呼気一酸化窒素測定方法に関する検討

一酸化窒素(nitric oxide:NO)はガス状メディエータとして,生体内反応に関与すると考えられ,特に炎症反応の制御に重要な役割を呈していることが明らかにされてきた.気道内で産生されるNOは呼気中に検:出されるため,その濃度を測定することは気道内での炎症の指標になりうる.特に気管支喘息の重症度評価では,すでに臨床使用されている.また,急性肺障害の早期診断に有効であるとする報告がされ,周術期,集中治療領域で応用できる可能性が示唆されている.呼気NO測定方法の要点は呼気流速を一定に保っことにあるが,従来の人工呼吸管理下で,呼気流速を一定にすることは難しく,確立された測定方法は存在しない.本研究の目的は,人工呼吸管理下での呼気NOの産生部位が推定できる測定法を確立することとし,その方法として人工呼吸回路に気道抵抗を加え,breath-holdingを併用した換気モードで測定することにより炎症部位診断を可能とする波形が得られるとの仮説を立て,研究を行った.全身麻酔下に手術を予定された5症例を対象とした.それぞれの症例で通常の換気モードと気道抵抗を加えbreath-holdingを併用した換気モードで測定を行った.結果,人工呼吸回路に気管チューブによる気道抵抗を加えて呼気流速の変化を少なくし,breath-holdingを併用した換気モードで測定することにより,炎症部位診断を可能とする波形が得ることができた.本方法は,呼気NO濃度測定から産生部位診断を含めたNO産生量を推定可能にし,single breathでの測定として有用であると考えられた.今後,連続モニタに応用可能な方法の開発と病態による波形や産生量の変化に関しての研究が必要であると考える.Exhaled nitric oxide is a marker of airway inflammation and lung injury. Exhaled NO values vary considerably with exhalation flow rate. Therefore, standardization of exhalation flow is critical for obtaining reproducible measurements. In ventilated patients, it is difficult to standardize the exhalation flow rate, and a detailed method of exhaled NO measurements has not yet been found. In a previous study, in natural airway patients, characterized exhaled NO curves were obtained by a single breath maneuver with breath-holding and constant flow exhalation. The exhaled NO curves are divided into a dead space (phase 1), a mixture of airway and alveolar gas (phase 2), and the alveolar plateau (phase 3). The aim of this study was to develop a technique for obtaining characterized exhaled NO curves in ventilated patients. Five patients that underwent planned operations under general anesthesia were enrolled. During general anesthesia, exhaled NO was continuously measured under normal ventilation (VT = l0ml/kg, f =10bpm, I : E =1 : 2, Tpause/Ti = 10%) and breath-holding ventilation (VT =15ml/kg, f = 4bpm, I : E = 2 : 1, Tpause/Ti = 50%) with an expiratory resistance tube to produce the constant flow exhalation. During normal ventilation, expiratory flow rate decelerated and exhaled NO curves showed a small peak (5.8 ± 2.7ppb) in phase 1 and 2 (dead space and airway), and then increased slowly (6.0 ± 4.2ppb) in phase 3 (alveolar gas). In constant flow exhaled ventilation, exhaled NO curves showed a large peak (20.8 ± 9.9 ppb) in phase 2 and decreased gradually to a constant plateau (6.0 ± 2.7ppb) in phase 3. Airway gas was clearly distinguishable from alveolar gas (p = 0.023). We used an expiratory resistance to produce constant expiratory flow in the ventilated patients. Breath-holding ventilation with expiratory resistance showed exhaled NO curves comparable to those of previous studies. This method during mechanical ventilation can be useful in differentiating airway and alveolar inflammation

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations

Non-inflammatory or non-ischemic vascular gas on emergent multi-detector computed tomography: Eight years&apos; experience A careful search for clues on MDct images was

AbstrAct the study aimed to characterize the etiology and clinical significance of non-inflammatory or non-ischemic vascular gas on multi-detector computed tomography (MDct). We reviewed MDct images and clinical charts of patients with vascular gas excluding inflammatory or ischemic entities in our hospital between 2008 and 2015. the local cases and the case report papers, which were extracted from English literature in PubMed were summarized according to iatrogenic or non-iatrogenic causes to analyze etiology for the entry of air into the circulation. Our local series demonstrated single or multiple collection of vascular gas in 15 patients including one with systemic arterial gas; the most frequent was cerebral vascular gas (cVG, n = 11, 0.8-12 mL) followed by hepatic vascular gas (n = 10, 0.4-256 mL). the accumulative 144 cases including the 15 local cases included 62 (43.1%) with iatrogenic vascular gas; the most frequent was central venous catheter-related cVG (48 cases) with 39.5% mortality followed by hepatic portal venous gas (20 cases) with 15% mortality. useful in discussing the etiology of vascular gas entry points and increased awareness of the emergent clinical settings where the vascular gas occurred. A careful search for clues on MDct images wa

Usefulness of N-butyl cyanoacrylate embolization versus coil embolization for control of massive hemorrhage in patients with pelvic fracture

$1682.1 ± 914.3) . the success rate of hemostasis by tAE and the mortality rate at 2 days or 30 days for the NbcA group and the non-NbcA group were 86.7%, 11.1%, 15.6% and 56.5%, 41.3%, 47.8%, respectively. transarterial embolization without NbcA was a significant factor associated with 2-day and 30-day mortality. conclusion: transarterial embolization with NbcA could be used in resuscitative strategies for patients with pelvic fracture and massive hemorrhage because it is effective for improving early hemorrhage control and prognosis without increasing the cost of devices for tAE

Microbiome analysis in women with endometriosis: Does a microbiome exist in peritoneal fluid and ovarian cystic fluid?

Abstract Purpose To investigate the relationship between the microbiome of the female genital tract and endometriosis. Methods This prospective cohort study included 36 women who underwent laparoscopic surgery for ovarian tumor from July 2019 to April 2020. Of them, 18 had endometriosis, and 18 did not have endometriosis. Vaginal secretions, endometrial fluid, peritoneal fluid, and ovarian cystic fluid were collected during surgery. Next‐generation sequencing of bacterial 16S rRNA was performed to characterize the microbiome. Results Specific microbiomes were not detected in either peritoneal fluid or ovarian cystic fluid regardless of the presence or absence of endometriosis and the type of cyst. When the cutoff value of infectious bacterial abundance in the vagina was set as 64.3%, there were many cases more than a cutoff value in the endometriosis group significantly (p = 0.01). When the cutoff value of infectious bacterial abundance in the endometrium was set as 18.6%, there were many cases more than a cutoff level in the endometriosis cases significantly (p = 0.02). Conclusion Peritoneal fluid and ovarian cystic fluid are almost sterile, although dysbiosis may occur in the vaginal and endometrial microbiome in women with endometriosis