Convertases other than furin cleave β‐secretase to its mature form

An aspartyl protease, Beta‐Site APP cleaving enzyme (BACE), was identified as the β‐secretase responsible for generating the Amyloid β protein that is believed to cause Alzheimer’s disease. BACE has a short propeptide domain that is absent in the mature enzyme because of proteolytic cleavage after the sequence RLPR. This sequence is a predicted substrate for proprotein convertases such as furin. To determine the role of furin and other proprotein convertases, we expressed proBACE in a furin‐deficient mutant Chinese hamster ovary (CHO‐K1) line, RPE.40. ProBACE signal was higher in RPE.40 than in the CHO‐K1 parent, which confirmed that furin plays a role in propeptide removal. However, two independent approaches showed that proBACE is cleaved to mature BACE in RPE.40: proBACE was rapidly turned over in RPE.40 although total BACE was stable, and decanoyl‐RVKR‐chloromethylketone, an inhibitor of the proprotein convertase family, substantially increased proBACE levels in both RPE40 and CHO‐K1. Transient transfection shows that furin, PACE4, PC5/6, and PC7 mediate BACE cleavage in vivo, at least when overexpressed. RPE.40 is proficient in BACE activity despite its furin deficiency. Therefore, our finding that proBACE is cleaved in this mutant leaves open the possibility that maturation is an important regulatory step and a therapeutic target.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154385/1/fsb2fj000891fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154385/2/fsb2fj000891fje-sup-0001.pd

MULTI-UUV MISSIONS USING RANGER MicroUUVs

ABSTRACT Groups of four UUVs have been used to validate a plume source localization algorithm and map the 3-D movement of a salinity front over time. These missions have demonstrated that not only are multi-vehicle deployments possible, but by using teams of cooperating vehicles, difficult tasks such as plume source localization can be performed quickly and that small volumes of the ocean can be simultaneously sampled with unprecedented spatial and temporal resolution. The key to the success of these missions is the small, inexpensive and easy to operate Ranger MicroUUV from Nekton Research. We report on the results of recent multi-agent missions and provide information about the UUVs used during these missions

An international multicenter retrospective analysis of patients with extranodal marginal zone lymphoma and histologically confirmed central nervous system and dural involvement

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty-six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26-78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2-year progression-free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2-year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation

Characterisation of hepcidin response to holotransferrin treatment in CHO TRVb-1 cells

Iron overload coupled with low hepcidin levels are characteristics of hereditary haemochromatosis. To understand the role of transferrin receptor (TFR) and intracellular iron in hepcidin secretion, Chinese hamster ovary transferrin receptor variant (CHO TRVb-1) cells were used that express iron-response-element-depleted human TFRC mRNA (TFRC∆IRE). Results showed that CHO TRVb-1 cells expressed higher basal levels of cell-surface TFR1 than HepG2 cells (2.2-fold; p < 0.01) and following 5 g/L holotransferrin treatment maintained constitutive over-expression at 24h and 48 h, contrasting the HepG2 cells where the receptor levels significantly declined. Despite this, the intracellular iron content was neither higher than HepG2 cells nor increased over time under basal or holotransferrin-treated conditions. Interestingly, hepcidin secretion in CHO TRVb-1 cells exceeded basal levels at all time-points (p < 0.02) and matched levels in HepG2 cells following treatment. While TFRC mRNA expression showed expected elevation (2h, p < 0.03; 4h; p < 0.05), slc40a1 mRNA expression was also elevated (2 h, p < 0.05; 4 h, p < 0.03), unlike the HepG2 cells. In conclusion, the CHO TRVb-1 cells prevented cellular iron-overload by elevating slc40a1 expression, thereby highlighting its significance in the absence of iron-regulated TFRC mRNA. Furthermore, hepcidin response to holotransferrin treatment was similar to HepG2 cells and resembled the human physiological response

Ferroportin and hepcidin: a new hope in diagnosis, prognosis, and therapy for breast cancer

Breast cancer is the most prevalent malignancy in women. The success of breast cancer treatment relies on the ability to detect the disease and correct molecular abnormalities at an early stage of disease development. A recent article describes a marked decrease in the levels of ferroportin in breast cancer. More importantly, the presented results demonstrate convincingly the incredible diagnostic and prognostic value of ferroportin and hepcidin gene expression in breast cancer and suggest that determination of these two molecular markers may be used as guidance toward individualized therapy for breast cancer patients

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

AbstractMore active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days −8 to −3). Gemcitabine was infused continuously at 10 mg/m2/minute over 4.5 hours (days −8 and −3). Busulfan dosing targeted 4000 μM-minute/day (days −8 to −5). Melphalan was infused at 60 mg/m2/day (days −3 and −2). Patients with CD20+ tumors received rituximab (375 mg/m2, days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography–positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting