New magnetic resonance imaging techniques for the detection of breast cancer

Summary The importance of contrast agents in enhancing diagnoses from magnetic resonance images has been established in numerous cases. However, the development of a potent tissue-specific contrast agent, as a sensitive probe for early detection and investigation of the physiological characteristics of a tumor, has not yet been realized in MR imaging (MRI). In nuclear scintigraphy the technique has been demonstrated; however, the poor spacial resolution inherent to the modality and the substantial dose of radioactivity administered to the patient has hindered its widespread use. This article will review the different classes of contrast agents in MRI, with special focus on the strategies involved in the development of targeted tissue-specific MRI contrast agents for the early detection of breast cancer. The features of a new class of contrast agents for targeted MR imaging will be described. Gadolinium-containing melanin polymers (GMP's) have been synthesized as MR contrast agents in our laboratory. These GMP's demonstrate significantly higher relaxivities than any other paramagnetic contrast agents reported; consequently, they are extremely effective contrast enhancing, imaging agents by themselves. The successful coupling of these potent GMP's to a monoclonal antibody specific for breast carcinoma, the 323/A3 monoclonal antibody, suggests thatin vivo tissue-specific MR imaging, at the receptor level, will become feasible in the near future.     

Pharmacological basis for cladribine resistance

The inherent or acquired resistance of leukemic cells to cytostatic agents is a major clinical challenge. The purpose of this review was to elucidate and analyse the available data concerning mechanisms of resistance of cladribine with emphasis on recent advances in the characterization of activating and inactivating enzymes in the induction of resistance to cladribine. All available in vitro and clinical data on cladribine was undertaken. Cladribine, unlike many other drugs, is toxic to both dividing and indolent lymphoid malignancies. Cladribine is a prodrug and must be phosphorylated intracellularly to cladribine-monophosphate (MP) by the nuclear/cystosol enzyme deoxycytidine kinase (dCK) and the mitochondrial enzyme deoxyguanosine kinase. The cytotoxicity mainly depends on the accumulation of cladribine-triphosphates (TP) after phosphorylation of cladribine-MP by nucleoside monophosphate kinase and nucleoside diphosphate kinase. 5'-Nucleotidase (5'-NT) dephosphorylates cladribine-MP and the accumulation of cladribine-TP depends on the ratio of dCK and 5'-NT in the cells. The mechanisms underlying cladribine resistance are multifactorial, e.g. decreased nucleoside transport, decreased activity or deficiency of dCK, altered intracellular pools of competing nucleotides, altered regulation of ribonucleotide reductase and increased drug inactivation by 5'-NT. Finally, cladribine resistance may be a consequence of a defective induction of apoptosis. In spite of the fact that more than one mechanism can contribute to a cladribine resistance phenotype, a reduction in dCK activity is probably the major determinant of cladribine resistance. Insight into the mechanism of action and resistance to cladribine is crucial for its optimal use as well as for the development of newer analogues.     

Follicular large cell lymphoma localized to the testis in children

PURPOSE: Primary follicular lymphoma of the testis in childhood is rare with only 6 cases previously reported. We present 3 additional cases. MATERIALS AND METHODS: We extensively analyzed primary follicular lymphoma of the testis in 3 boys. Clinical data were obtained by reviewing patient charts. RESULTS: The patients were 4, 5 and 11 years old, respectively. Two patients presented with painless unilateral testicular enlargement and 1 presented with unilateral hydrocele. Laboratory findings were within normal limits in all patients. Radical orchiectomy was done in all cases. The excised testes were partially or completely replaced by tumor. In all cases the features were those of follicular, large cell-type malignant lymphoma. Tumor cells in all cases were CD20 and CDw75 positive, focally CD23 positive and bcl-2 negative, while in 2 they were CD10 positive and bcl-6 positive. Surface Ig was absent in the 2 cases studied. Karyotyping in 1 case showed a normal karyotype. Staging revealed no evidence of extratesticular disease. All patients underwent combination chemotherapy and were in complete remission 7 to 59 months after therapy. CONCLUSIONS: We present 3 cases of pediatric primary follicular lymphoma of the testis. Pathological findings and clinical features were similar to those in the 6 previously reported cases and suggest that primary pediatric testicular follicular lymphoma may represent unique subset of follicular lymphoma with a particularly good prognosis.     

A photopolymerized sealant for corneal lacerations

PURPOSE: To determine whether a novel photocrosslinkable polymer synthesized from hyaluronic acid would seal experimental full-thickness corneal lacerations in a rabbit model. METHODS: A solution of hyaluronic acid was modified with methacrylate groups (HA-MA), precipitated, dried, reconstituted in an aqueous solution, and sterilized before use. The viscous polymer solution was applied to 38 of 43 experimental corneal lacerations in rabbits and subsequently irradiated with a low-intensity argon laser beam to produce a clear flexible polysaccharide hydrogel patch. The ability of this sealant to repair corneal lacerations was evaluated in four types of full-thickness, 3-mm corneal wounds (linear, linear + epithelium removed, stellate, and stellate + epithelium removed). Slit-lamp examinations, measurements of intraocular pressure, Seidel tests, and histologic studies were performed at selected intervals to evaluate the wound and determine the rate of healing. RESULTS: Corneal perforations were completely sealed and the anterior chambers had reformed by 6 hours in HA-MA-treated eyes. There was no evidence of leakage at this or later times in 37 of the 38 eyes. Intraocular pressure had risen to near-normal levels by day 7 in all four groups, and the sealant was still present in most eyes at day 7. In contrast, the anterior chambers did not re-form in control eyes (five) with untreated perforations because of aqueous leakage through the wounds. Minimal inflammation was observed clinically or in histologic sections of treated corneas. There was extensive proliferation of stromal cells and formation of new extracellular matrix at the wound edges, which became tightly adherent between days 4 and 7. CONCLUSION: Our novel photocrosslinkable methacrylated hyaluronan polymer sealed 97% (37/38) of the experimental corneal lacerations. HA-MA may prove useful for sealing corneal lacerations in patients and for other sutureless ophthalmic surgical procedures.     

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis

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UCHL-1 gene in multiple system atrophy: a haplotype tagging approach.

To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case-control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease.     

NR4A2 genetic variation in sporadic Parkinson's disease: a genewide approach.

The NR4A2 gene, which may cause autosomal dominant Parkinson's disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotype-tagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population.