Citations

Abstract The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 μmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo. (Cancer Res 2006; 66(1): 362-71)

The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations. It shows no recombination over a region of 2 Mb with the more common H1 haplotype. The distribution of the haplotype and analysis of the slippage of dinucleotide repeat markers within the haplotype suggest that it entered Homo sapiens populations between approx. 10000 and 30000 years ago. However, sequence comparison of the H2 haplotype with the H1 haplotype and with the chimp sequence suggests that the common founder of the H1 and H2 haplotypes was far earlier than this. We suggest that the H2 haplotype is derived from Homo neanderthalensis and entered H. sapiens populations during the co-existence of these species in Europe from approx. 45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease.

PurposeThis multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.Patients and MethodsPatients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.ResultsThirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).ConclusionThe favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.

Abstract Bronchiolar abnormalities are relatively common and occur in a variety of clinical settings. Various histopathologic patterns of bronchiolar injury have been described and have led to confusing nomenclature with redundant and overlapping terms. Some histopathologic patterns of bronchiolar disease may be relatively unique to a specific clinical context but others are nonspecific with respect to either etiology or pathogenesis. Herein, we present a scheme separating (1) those disorders in which the bronchiolar disease is the predominant abnormality (primary bronchiolar disorders) from (2) parenchymal disorders with prominent bronchiolar involvement and (3) bronchiolar involvement in large airway diseases. Primary bronchiolar disorders include constrictive bronchiolitis (obliterative bronchiolitis, bronchiolitis obliterans), acute bronchiolitis, diffuse panbronchiolitis, respiratory bronchiolitis, mineral dust airway disease, follicular bronchiolitis, and a few other rare variants. Prominent bronchiolar involvement may be seen in several interstitial lung diseases, including hypersensitivity pneumonitis, respiratory bronchiolitis–associated interstitial lung disease, cryptogenic organizing pneumonia (idiopathic bronchiolitis obliterans organizing pneumonia), and pulmonary Langerhans' cell histiocytosis. Large airway diseases that commonly involve bronchioles include bronchiectasis, asthma, and chronic obstructive pulmonary disease. The clinical relevance of a bronchiolar lesion is best determined by identifying the underlying histopathologic pattern and assessing the correlative clinico–physiologic–radiologic context.

Abstract Tissue structural cells are known in some situations to play a role in the presentation of antigen and in immunoregulation. We assessed the expression of B7 homologs, known to be involved in antigen presentation and lymphocyte costimulation, in human airway epithelial cells. Flow cytometry performed on the airway epithelial cell line BEAS-2B, as well as primary bronchial epithelial cells (PBEC), showed that B7-H2 was constitutively expressed on both BEAS-2B and PBEC, whereas B7-1 and B7-2 were undetectable on either epithelial cell type. B7-H2 expression was confirmed by Western blot using a specific antibody. Stimulation with various cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-4, slightly downregulated B7-H2 expression detected by flow cytometry, but did not significantly alter the apparent level of protein as assessed by Western blotting. Northern blotting detected mRNA for B7-H2 and B7-1, but not B7-2. B7-H2 was cloned from BEAS-2B cells and the sequence verified. Expression of B7-H2 mRNA was detected by real-time reverse transcriptase–polymerase chain reaction in PBEC from three independent donors. Immunohistochemical analysis of airway derived from autopsies revealed expression of B7-H2 in human airway epithelial cells. These results demonstrate that airway epithelial cells express the costimulatory molecule B7-H2, and suggest the possibility that B7-H2 may participate in antigen presentation by epithelial cells.