Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Peer reviewe

Identification Of Inequalities In The Selection Of Liver Surgery For Colorectal Liver Metastases In Sweden

Background: Liver resection for colorectal liver metastases offers a 5-year survival rate of 25%–58%. This study aimed to analyze whether patients with colorectal liver metastases undergo resection to an equal extent and whether selection factors play a role in the selection process. Material and Methods: Data were retrieved from the Swedish Colorectal Cancer Registry (2007–2011) for colorectal cancer and colorectal liver metastases. The patients identified were linked to the Swedish Registry of Liver and Bile surgery and the National Patient Registry to identify whether liver surgery or ablative treatment was performed. Analyses for age, sex, type of primary tumor and treating hospital (university, county, or district), American Society of Anesthesiologists class, and radiology for detection of metastatic disease were performed. Results: Of 28,355 patients with colorectal cancer, 21.6% (6127/28,355) presented with liver metastases. Of the patients with liver metastases, 18.5% (1134/6127) underwent liver resection or ablation. The cumulative proportion of liver resection/ablation was 4% (1134/28,355) of all colorectal cancer. If “not bowel resected” were excluded, the proportion slightly increased to 4.7% (1134/24,262). Around 15% of the patients with metastases were registered as referrals for liver surgery. In a multivariable analysis patients treated at a university hospital for primary tumor were more frequently surgically treated for liver metastases (p 70 years and those with American Society of Anesthesiologists class >2 underwent liver resection less frequently. Magnetic resonance imaging of the liver was more often used in diagnostic work-up in men. Conclusion: Patients with colorectal liver metastases are unequally treated in Sweden, as indicated by the low referral rate. The proximity to a hepatobiliary unit seems important to enhance the patient’s chances of being offered liver surgery

Temples: Toji Temple, Kyoto, Japan [040]

Photograph of sculptures in hall, Toji Temple, Kyoto, JapanSculptures in hall, Toji Temple, Kyoto, Japan

Lack of aggregation of ischemic stroke subtypes within affected sibling pairs

ABSTRAK Rahmat,  Angga  Nur.  2014.  Pengembangan  Trainer  Sistem  Recloser  Berbasis Smart  Relay  Untuk  Menunjang  Matakuliah  Sistem  Distribusi  Dan Transmisi Di Jurusan Teknik Elektro Universitas Negeri Malang. Skripsi, Jurusan  Teknik  Elektro,  Fakultas  Teknik,  Universitas  Negeri  Malang. Pembimbing: (1) Yuni Rahmawati, S.T., M.T., (2) Sujito, S.T., M.T. Kata Kunci: Sistem Recloser, trainer, smart relay   Recloser  atau  Penutup  Balik  Otomatis  merupakan  salah  satu  peralatan proteksi pada jaringan distribusi tenaga listrik. Recloser peralatan yang berfungsi membuka  jaringan  ketika  terjadi  hubung  singkat  atau  arus  lebih  kemudian menutup balik secara otomatis ketika gangguan tersebut hilang dengan sendirinya. selain  itu  sebagai  pengaman  seksi  sehingga  dapat melokalisir/membatasi  daerah yang terganggu. Mata kuliah Sistem Distribusi dan Transmisi  Jurusan Teknik Universitas Negeri Malang merupakan mata  kuliah  yang  disajikan  untuk  program  keahlian Elektro  (Arus  Kuat). Media  pembelajaran  yang membantu  proses  pembelajaran mata kuliah  ini  sangat  terbatas. Keterbatasan  ini dikarenakan peralatan distribusi tidak mungkin  dihadirkan  secara  nyata  ketika  proses  pembelajaran.  berdasarkan observasi  dan  wawancara  kepada  dosen  pengampu  yang  telah  dilakukan  maka diperlukan  media  pembelajaran  yang  hampir  menyerupai  peralatan  distribusi tenaga listrik tersebut. Di Jurusan Teknik Elektro terdapat Trainer sistem recloser berbasis PLC, namun kondisi trainer tersebut sedang rusak, selain itu pengawatan trainer masih rumit dan pengontrolannya  terbatas, sehingga mahasiswa kesulitan dalam memahami  prinsip  kerja  recloser. Trainer  sistem  recloser  berbasis  smart relay  digunakan  sebagai  alternatif media  pembelajaran  yang mampu mengatasi kekurangan  media  pembelajaran  sebelumnya.  Smart  relay  merupakan  sebuah peralatan  elektronik  yang mampu menggantikan  fungsi  relay  konvensional  dan bisa  diberikan  instruksi  atau  program.  Trainer  sistem  recloser  berbasis  smart relay  ini, memiliki  kelebihan,  antara  lain:  pengawatan mudah  dan  pengontrolan lebih banyak.   Model  pengembangan  yang  digunakan  adalah  model  pengembangan Sugiyono  yang  dikombinasikan  dengan metode  Borg  dan  Gall.  Pemilihan  pada model pengembangan tersebut dikarenakan keruntutan dalam setiap tahapnya dan terdapat  beberapa  revisi  yang  justru  berguna  untuk membuat  produk  yang  lebih baik daripada sebelumnya. Tahap model pengembangan yang dilaksanakan, yaitu: (1) Potensi dan Masalah; (2) Pengumpulan Data; (3) Desain Produk; (4) Validasi Desain; (5) Revisi Desain; (6) Produksi; (7) Ujicoba Perseorangan; (8) Revisi; (9) Ujicoba Kelompok Kecil;  (10) Revisi;  (11) Ujicoba Lapangan;  (12) Revisi;  (13) Laporan; dan (14) Produksi Masal.    Berdasarkan  pelaksanaan  metode  penelitian  dan  pengembangan  maka diperoleh  data  hasil    dari  ahli  media  sebesar  95%,  ahli  materi  sebesar  91%, ujicoba kelompok kecil  sebesar 92%, dan ujicoba kelompok besar  sebesar 88%. Dapat  disimpulkan  bahwa  trainer  sistem  recloser  berbasis  smart  relay  telah memenuhi kriteria valid dan layak digunakan sebagai media pembelajaran