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Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR ( FCAR ) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced ( P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ 1–40 . Thus, topical application of Aβ 1–40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36 0/0 ). The cerebrovascular effects of infusion of Aβ 1–40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36 0/0 mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ 1–40 . CD36 is also required for the vascular oxidative stress induced by exogenous Aβ 1–40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ 1–40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.

Unilateral renal artery stenosis (RAS) leads to atrophy of the stenotic kidney and compensatory enlargement of the contralateral kidney. Although the two-kidney, one-clip (2K1C) model has been extensively used to model human RAS, the cellular responses in the stenotic and contralateral kidneys, particularly in the murine model, have received relatively little attention. We studied mice 2, 5, and 11 wk after unilateral RAS. These mice became hypertensive within 1 wk. The contralateral kidney increased in size within 2 wk after surgery. This enlargement was associated with a transient increase in expression of phospho-extracellular signal-regulated kinase (p-ERK), the proliferation markers proliferating cell nuclear antigen and Ki-67, the cell cycle inhibitors p21 and p27, and transforming growth factor-β, with return to baseline levels by 11 wk. The size of the stenotic kidney was unchanged at 2 wk but progressively decreased between 5 and 11 wk. Unlike the contralateral kidney, which showed minimal histopathological alterations, the stenotic kidney developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Surprisingly, the stenotic kidney showed a proliferative response, which involved largely tubular epithelial cells. The atrophic kidney had little evidence of apoptosis, despite persistent upregulation of p53; expression of cell cycle regulatory proteins in the stenotic kidney was persistently increased through 11 wk. These studies indicate that in the 2K1C model, the stenotic kidney and contralateral, enlarged kidney exhibit a distinct temporal expression of proteins involved in cell growth, cell survival, apoptosis, inflammation, and fibrosis. Notably, an unexpected proliferative response occurs in the stenotic kidney that undergoes atrophy.

PurposeTwenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components.MethodsTo develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants.ResultsWe applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.ConclusionOur models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.

Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavioral deficits observed in these mice. We found that 12- to 15-month-old Tg2576 mice lacking the catalytic subunit Nox2 of NADPH oxidase do not develop oxidative stress, cerebrovascular dysfunction, or behavioral deficits. These improvements occurred without reductions in brain amyloid-β peptide (Aβ) levels or amyloid plaques. The findings unveil a previously unrecognized role of Nox2-derived radicals in the behavioral deficits of Tg2576 mice and provide a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology.