Prospective investigation of amino acid transport and PSMA-targeted positron emission tomography for metastatic lobular breast carcinoma.

Purpose: To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or F-FDG positron-emission-tomography (PET)-CT].

Methods: 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with F-fluciclovine and Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and F-FDG PET-CT in 7 patients).

Evaluation of percutaneous vacuum assisted intact specimen breast biopsy device for ultrasound visualized breast lesions: Upstage rates and long term follow-up for high risk lesions and DCIS.

Objective: Percutaneous core biopsy of ultrasound visualized breast lesions is standard for diagnosis. Large gauge vacuum-assisted core needles have improved accuracy; but a significant underestimation of malignancy remains. The Intact device was assessed for upstaging and subsequent malignancy at the biopsy site.

Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells.

Multidrug resistance remains a major obstacle in the effective treatment of metastatic breast cancer. One mechanism by which multidrug resistance is conferred is the decreased intracellular drug accumulation due to the upregulation of the ATP-binding cassette (ABC) transporters. We have previously demonstrated that jadomycins, polyketide-derived natural products produced by Streptomyces venezuelae ISP5230, inhibit the growth of the human breast ductal carcinoma cell lines T47D and MDA-MB-435.

Copper-mediated nuclease activity of jadomycin B.

The natural product jadomycin B, isolated from Streptomyces venezeulae ISP5230, has been found to cleave DNA in the presence of Cu(II) ions without the requirement for an external reducing agent. The efficiency of DNA cleavage was probed using supercoiled plasmid DNA in buffered solution as a model environment. EC₅₀ and t(½) values for cleavage were 1.

Diverse DNA-cleaving capacities of the jadomycins through precursor-directed biosynthesis.

Gel mobility assays were used to establish that some members of the jadomycin family of natural products act as DNA cleaving agents. Moreover, it was found that subtle structural changes generated through the use of precursor-directed biosynthesis lead to marked effects on the DNA-damaging properties of these glycosylated polyketide-derived natural products.

Antimicrobial activities of jadomycin B and structurally related analogues.

Natural products are leads for new antibiotics as a result of their structural complexity and diversity. We have isolated a series of structurally related polyketide-derived natural products from Streptomyces venezuelae ISP5230. The most active of these jadomycin analogues showed good activity against a variety of staphylococci, including methicillin-resistant Staphylococcus aureus.

Stereochemical integrity of oxazolone ring-containing jadomycins.

The jadomycins are a series of natural products produced by Streptomyces venzuelae ISP5230 in response to ethanol shock. A unique structural feature of these angucyclines is the oxazolone ring, the formation of which is catalyzed by condensation of a biosynthetic aldehyde intermediate and an amino acid. The feeding of enantiomeric forms of alpha-amino acids indicates that the amino acid is incorporated by S.

Substrate flexibility of a 2,6-dideoxyglycosyltransferase.

We report the first 2,6-dideoxysugar-O-glycosyltransferase with substrate flexibility at the 2 position, confirm the function of a putative NDP-hexose 2,3-dehydratase in the jadomycin B biosynthetic gene cluster and deduce the substrate flexibility of downstream enzymes in l-digitoxose assembly, enabling reprogramming of biosynthetic gene clusters to modify sugar substituents.

Culture conditions improving the production of jadomycin B.

The jadomycins are a unique family of benzoxazolophenanthridine antibiotics produced by Streptomyces venezuelae ISP5230 following heat or ethanol shock or phage infection. We have modified the culture conditions by altering the carbon source, buffer, inoculum size, and timing of ethanol shock, thereby reducing growing times and improving jadomycin B production. Our optimized conditions use glucose as the carbon source, MOPS as buffer, low concentrations of phosphate, a defined inoculum concentration and an immediate ethanol shock to induce jadomycin B production; results that contrast previous studies.

Ring-opening dynamics of jadomycin A and B and dalomycin T.

[structure: see text] A novel oxazolone ring-opening and interconversion process between the two jadomycin diastereomeric forms has been characterized by NMR spectroscopy. An analogue, dalomycin T, has been isolated for the first time and does not undergo interconversion.

Novel and expanded jadomycins incorporating non-proteogenic amino acids.

Jadomycin B is a secondary metabolite produced, in response to stress, by Streptomyces venezuelae ISP5230 grown in nutrient-deprived media. We present definitive electrospray ionization mass spectrometry data identifying a series of novel jadomycins with non-proteogenic amino acids incorporated into the oxazolone ring of the secondary metabolite, and strengthening evidence for the existence of an aldimine intermediate in the biosynthetic pathway. We also demonstrate that the size of the oxazolone ring can be expanded by incorporating beta-amino acids.