Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.     

Enterovirus Infection, CXC Chemokine Ligand 10 (CXCL10), and CXCR3 Circuit: A Mechanism of Accelerated ��-Cell Failure in Fulminant Type 1 Diabetes

OBJECTIVE

Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated β-cell failure are unclear.

RESEARCH DESIGN AND METHODS

Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2–5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR.

RESULTS

Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor–bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-γ and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including β-cells and α-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells.

CONCLUSIONS

These results strongly suggest the presence of a circuit for the destruction of β-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-γ and CXCL10 in β-cells. CXCL10 secreted from β-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-γ in the islets, not only damaging β-cells but also accelerating CXCL10 generation in residual β-cells and thus further activating cell-mediated autoimmunity until all β-cells have been destroyed.Fulminant type 1 diabetes is characterized by abrupt onset of severe hyperglycemia and ketoacidosis preceded by flu-like symptoms including fever, abdominal pain, and headache (1–3). Due to the rushed clinical course in most cases, patients with fulminant type 1 diabetes are sometimes untreated until becoming comatose and/or entering a critical, life-threatening state (4). Endogenous insulin secretion is completely abolished over time and diabetic microangiopathies develop over a short duration (5,6). The mechanisms underlying the aggressive and rapid destruction of β-cells have remained one of the major questions regarding this subtype of type 1 diabetes. However, in situ human data on affected islets and pancreas and possible mechanisms have been completely lacking for fulminant type 1 diabetes.Viral infection with subsequent immunological mechanisms represents one of the leading candidates for destruction of β-cells in fulminant type 1 diabetes (3,7). Some studies on the mouse model of lymphocytic choriomeningitis virus–induced type 1 diabetes have demonstrated that islet β-cells can be destroyed as follows: within 1 day after virus infection, CXC chemokine ligand 10 (CXCL10) (8), a key chemoattractant for activated T-cells and macrophages, is produced in β-cells and secreted from islets (9). Activated T-cells bearing the receptor for CXCL10, named CXCR3 (8), infiltrate and accumulate in islets secreting CXCL10 (10). Accumulated T-cells at the islets then destroy β-cells through cell-mediated mechanisms (11). With this mechanism, CXCL10 is necessary and sufficient for accelerated T-cell response with complete β-cell destruction and resulting type 1 diabetes (10,12,13). We have recently found that serum CXCL10 levels are increased at the onset of fulminant type 1 diabetes, suggesting a crucial role of the CXCL10-CXCR3 axis in the aggressive β-cell destruction in this syndrome (14). We therefore examined in situ status with regard to enterovirus infection, CXCL10-CXCR3 axis, major histocompatibility complex (MHC) molecule expression, and islet dysfunction in pancreata from patients with fulminant type 1 diabetes who died due to diabetic ketoacidosis within 2–5 days after outset of flu-like symptoms. Our in situ findings for affected pancreata provide new insights into understanding the pathogenesis of and developing interventional strategies against human type 1 diabetes.     

Bone edema determined by magnetic resonance imaging reflects severe disease status in patients with early-stage rheumatoid arthritis

OBJECTIVE: To determine the significance of bone edema, detected by magnetic resonance imaging (MRI), in early-stage rheumatoid arthritis (RA). METHODS: We simultaneously examined serologic variables, MRI of wrist sites and finger joints of both hands, clinical disease activity score (DAS), and HLA-DR typing at entry in 80 patients with early-stage RA. RESULTS: The number of bones scored as positive for bone edema correlated with the number of sites scored as positive for MRI synovitis and MRI bone erosion, rate of enhancement (E-rate), and serum C-reactive protein (CRP), matrix metalloproteinase 3 (MMP-3), and interleukin 6 (IL-6). Findings for MRI synovitis and MRI bone erosion, E-rate, CRP, MMP-3, IL-6, seropositivity, and titer of anti-cyclic citrullinated peptide antibody (anti-CCP antibody), DAS28-CRP and HLA-DRB1*0405 allele carriership, were significantly higher in the positive versus the negative bone edema group. CONCLUSION: Bone edema based on our scoring system may reflect severe disease status in patients with early-stage RA. However, its clinical value at entry in prognostication of RA should be examined through prospective clinical followup studies.     

Toxoplasmosis encephalitis following severe graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group

Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.     

Small-cell lung carcinoma produces salivary-type amylase: a case report with review

A 53-year-old woman diagnosed with small-cell lung carcinoma (SCLC) was referred to our hospital because of general malaise and inappetence. Serum amylase levels were drastically elevated at 13,920 IU/l, with the salivary type dominating. She suffered multiple liver metastases and presented with disseminated intravascular coagulation (DIC). She succumbed to progressive malaise one month after admission. The amylase level was increased to 18,630 IU/l just before her death. Necropsy of the right supraclavicular lymph node confirmed SCLC with partial necrosis. Immunohistological analysis revealed that the SCLC produced salivary-type amylase. A rare case of salivary-type amylase-producing SCLC with a futile outcome was reported with review of the previous literature.     

Chronic sclerosing pyelitis with an increased number of IgG4-positive plasma cells

IgG4-related disease has been recently described. This disease occurs in various anatomic locations including pancreas, biliary tract, liver, retroperitoneum, kidney, breast, lung, thyroid gland, prostate, salivary gland, lacrimal gland, and lymph node. In this article, we report the first case of IgG4-related disease arising in the renal pelvis. A 49-year-old Japanese woman was found to show left hydronephrosis by a medical checkup. Histological examination of the renal pelvic tumor showed IgG4-related disease. Her postoperative serum IgG4 was elevated, and this was compatible with IgG4-related disease. Systemic examination showed swelling of major and minor salivary glands and the lacrimal glands, and biopsy of the minor salivary gland revealed the finding of IgG4-related disease. Finally, pathologists and clinicians should be aware of the possibility that the renal pelvis may be involved in IgG4-related systemic disease.     

Skeletal Class III and open bite treated with bilateral sagittal split osteotomy and molar intrusion using titanium screws

Two-jaw surgery has been performed for the treatment of severe skeletal open bite cases to obtain stability of occlusion after treatment. If molar intrusion with titanium screws could be performed instead of surgical superior repositioning of the maxilla, the incidence of surgical invasion would be reduced. However, there have been few reports of such a therapy. This case report describes treatment for skeletal Class III and open bite with bilateral sagittal split osteotomy and intrusion of the molars using titanium screws. The patient had a concave profile, a long lower facial height, Class III malocclusion, and excessive anterior open bite following mandibular protrusion and a high mandibular plane angle. The mandible autorotated closed 3.5° following intrusion of the upper and lower molars using titanium screws during the presurgical orthodontic treatment phase. After the autorotation of the mandible, a mandibular setback with a bilateral sagittal split osteotomy was performed. The posttreatment records showed a good facial profile and occlusion. The mandible was stable 1 year after surgery. These results demonstrate that surgical orthodontic treatment combined with bilateral sagittal split osteotomy and intrusion of the molars using titanium screws can reduce the need for surgical invasion by avoidance of maxillary surgery and was effective for correcting the facial profile and occlusion in a skeletal Class III and open bite patient.