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  • 1
    Keywords: CANCER ; CELLS ; RISK ; TUMORS ; FAMILY ; BIOLOGY ; SUSCEPTIBILITY ; BREAST ; BREAST-CANCER ; STEM-CELLS ; MULTIPLE-MYELOMA ; MAMMARY-GLAND ; MUTATION CARRIERS ; ADHERENS JUNCTIONS ; EPITHELIUM ; MISSENSE MUTATIONS ; genetic variation ; MITOTIC SPINDLE ; BRCA1-DEPENDENT UBIQUITINATION ; CENTROSOMAL MICROTUBULE NUCLEATION ; PROGENITOR-CELL FATE
    Abstract: Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
    Type of Publication: Journal article published
    PubMed ID: 22110403
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  • 2
    ISSN: 1573-0972
    Keywords: Biosorbent ; biosorption ; metal ions ; Phormidium valderianum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Alkali-extracted biomass of Phormidium valderianum BDU 30501, a marine filamentous, non-heterocystous cyanobacterium adsorbed more than 90% of cadmium ions from solutions containing 0.1–40 mM. Cadmium binding accounted up to 18% of biomass weight (w/w). The algal biosorbent was also efficient is sequestering metal ions (Cd2+, Co2+, Cu2+, Ni2+) from a mixture. Biosorbent placed in dialysis tubing could concentrate Cd2+ (50–65%) from 1l solution (10 and 100 ppm) at equilibrium. Biosorbent immobilized in polyvinyl foam also removed cadmium and cobalt efficiently, but required longer contact times (24 h). Most of the bound metal ions (〉 80%) could be desorbed with 0.1 M HCl or EDTA, while other reagents were less efficient in the order: H2SO4 〉 NH4Cl 〉 CaCl2 〉 Na2SO 4 〉 KSCN 〉 KCl 〉 NH4OH 〉 NaHCO3. The regenerated biosorbent retained 80% of the initial binding capacity for Cd2+ and 50% binding capacity for Co2+ up to three cycles of reuse. Infrared spectra of the biosorbent preparation suggested carboxyl groups to be the primary sites for metal binding.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1572-8773
    Keywords: biosorption ; decontamination ; cadmium ; calcium ; magnesium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Alkali extracted mycelial biomass from Aspergillus niger, referred to as Biosorb, was found to sequester metal ions (Cd2+, Cu2+, Zn2+, Ni2+ and Co2+) efficiently both from dilute and concentrated solutions upto 10% of its weight (w/w). Sequestration of metal ions from a mixture was also efficient but with attendant antagonisms. The kinetics of metal binding by Biosorb indicated that it is a rapid process and about 70–80% of the metal is removed from solution in 5 min followed by a slower rate. The mechanism of metal binding is shown to be due to exchange of calcium and magnesium ions of the Biosorb during which equimolar concentrations of both the ions were released into the medium. Following this an efficient procedure for the regeneration and reuse of Biosorb was standardized by washing the biosorbent with calcium and magnesium solution (0.1 m). Biosorbents prepared from Neurospora, Fusarium and Penicillium also exhibited similar mechanisms for metal ion binding, though they had a lower metal binding capacity when compared with Biosorb. Chemical modification of carboxylic acid functional groups of the Biosorb resulted in loss of 90% of metal binding capacity which could not be restored even on regeneration. The significance of this finding on the metal sequestration mechanisms of microbial biosorbents is discussed.
    Type of Medium: Electronic Resource
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