Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease

The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer’s disease. Indole-3-propionic acid (IPA, OXIGON™) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer’s disease.     

Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x(L) is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x(L) protein as a potential therapeutic target in melanoma, the influence of Bcl-x(L) expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x(L) in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p < or = 0.05). In a parallel approach, reduction of Bcl-x(L) protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x(L) is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x(L) expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.     

Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma

Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.     

The influence of the suppression of gastrooesophageal reflux on the gene expression pattern in Barrett's oesophagus

About 10% of Barrett's patients develop an adenocarcinoma in the course of life. There is increasing evidence that persistent gastrooesophageal reflux is involved in carcinogenesis. We investigated whether the gene expression pattern of Barrett's epithelium cells changes upon suppression of gastrooesophageal reflux compared to unsuppressed reflux. Biopsies from various regions of Barrett's segments and, further, during and without proton pump inhibitor therapy were collected in 5 patients. The reflux profile was assessed by simultaneous 24-h oesophageal pH and bile reflux testing. m-RNA was extracted from the specimens, and integrity and absence of DNA proven by gel electrophoresis and ALU-PCR. Using the micro array technique 1,176 genes were analysed and assigned an expression level. The number of genes detected in each experiment varied from 86 to 136. There was a 91% concordance of the gene expression pattern in distal and proximal biopsies from an individual Barrett's segment. Concordance was much less (68%) between biopsies of the same patient taken during and without proton pump inhibitor therapy. The gene expression pattern in a Barrett's oesophagus varies dependent upon different reflux situations. Other factors like the location of biopsy are of minor importance. The micro array technique allows for selection of candidate genes important in carcinogenesis.     

Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas

Oligodendrogliomas typically show loss of heterozygosity (LOH) on chromosomes 1p and 19q, which correlates with their response to chemotherapy, whereas low-grade astrocytomas are characterized by frequent TP53 mutations and lack of sensitivity to alkylating therapeutic agents. Unequivocal histological distinction of low-grade diffuse astrocytomas from oligodendrogliomas and oligoastrocytomas is often difficult. To elucidate the relationships between morphological phenotype and genetic profile, we screened 19 oligodendrogliomas (WHO grade II) and 23 low-grade diffuse astrocytomas (WHO grade II) for TP53 mutations and LOH on 1p and 19q. In oligodendrogliomas, LOH on chromosomes 1p and/or 19q was found in 15 cases (79%) and TP53 mutation was detected in 4 cases (21%). The presence of a typical perinuclear halo in >50% of tumour cells and a chicken-wire vascular pattern were significantly associated with LOH on 1p or 19q (93% of cases). This suggests that oligodendrogliomas with classical histologic features are likely to have a better prognosis. In low-grade diffuse astrocytomas, LOH on chromosomes 1p and/or 19q was found in three cases (13%) and TP53 mutation was detected in ten cases (43%). Histologically, five low-grade astrocytomas (22%) contained small areas with oligodendroglial differentiation, but this did not correlate with the presence of TP53 mutations or LOH on 1p and 19q. In both oligodendrogliomas and astrocytomas, LOH on chromosomes 1p or 19q and TP53 mutation were mutually exclusive. Methylation of the promoter of the gene for O (6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, which confers resistance to chemotherapy with alkylating agents, was detected in 47% of oligodendrogliomas and 48% of low-grade diffuse astrocytomas. There was no correlation with LOH on chromosomes 1p/19q, suggesting that MGMT may not be a prognostic marker for oligodendrogliomas.     

Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression

Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer.     

Functional and morphologic evaluation of congenital urinary tract dilatation by using combined static-dynamic MR urography: findings in kidneys with a single collecting system

PURPOSE: To assess combined static-dynamic magnetic resonance (MR) urography in the evaluation of congenital urinary tract dilatation in infants and children. MATERIALS AND METHODS: Sixty-two patients with urinary tract dilatation underwent prospective examination with combined static-dynamic MR urography. A combination examination involved use of a static T2-weighted three-dimensional inversion-recovery fast spin-echo sequence and a dynamic T1-weighted two-dimensional fast field-echo sequence with gadopentetate dimeglumine-DTPA and furosemide application. Twelve additional patients underwent examination with only static MR urography. Thus, both image quality and morphologic features were assessed in 74 patients with the use of MR urography. The results were compared with those of ultrasonography and, when available, conventional urography or surgery. In 62 patients, the dynamic sequence was used to calculate split renal function from renograms generated from parenchymal regions of interest and to assess urinary excretion from whole-kidney renograms. Results were compared with those of diuretic renal scintigraphy (DRS) for split function (Spearman rank correlation coefficient) and urinary excretion (kappa coefficient). RESULTS: Stenoses at the ureteropelvic (n = 33) and ureterovesical (n = 31) junctions and within the ureter (n = 3) and nonstenotic dilatation (n = 23) were clearly depicted, while the normal urinary tract (n = 51) was depicted in its entirety in 47 of 51 examinations. Image quality was considered good or excellent in 95% of the kidney-ureter units. For split renal function, dynamic MR urography and DRS showed significant correlation (r = 0.92, P <.001). For urinary excretion, MR urography and DRS showed strong agreement (kappa = 0.67), with concordant classification of urinary excretion in 59 (81%) of 73 abnormal kidney-ureter units and in all 47 (100%) normal kidney-ureter units. CONCLUSION: Combined static-dynamic MR urography provides high-quality depiction of the urinary tract in infants and children, while allowing accurate determination of single-kidney function and reliable evaluation of urinary excretion.     

Noninvasive grading of untreated gliomas: a comparative study of MR imaging and 3-(iodine 123)-L-alpha-methyltyrosine SPECT

PURPOSE: To compare the accuracy of magnetic resonance (MR) imaging scores with that of 3-(iodine 123)-L-alpha-methyltyrosine ((123)I-IMT) single photon emission computed tomography (SPECT) in the noninvasive grading of untreated gliomas. MATERIALS AND METHODS: The study comprised 15 patients with low-grade gliomas (grades I-II, according to World Health Organization criteria) and 33 patients with high-grade gliomas (grades III-IV). The lesions were evaluated by using an MR imaging score based on nine criteria. The (123)I-IMT uptake was quantified as the ratio between the amino acid uptake in the tumor and that in the contralateral hemisphere. To test for potentially significant differences in diagnostic performance between contrast material-enhanced MR imaging and (123)I-IMT SPECT, binormal receiver operating characteristic curves were fitted to the data and compared by using the area test. RESULTS: The accuracy of MR imaging in the noninvasive grading of untreated gliomas was higher than that of (123)I-IMT SPECT (88% vs 79%). However, the difference in diagnostic performance was not significant on the basis of findings at receiver operating characteristic analysis (P >.2). Neither MR imaging nor (123)I-IMT SPECT allowed differentiation between high-grade gliomas (grades III and IV). CONCLUSION: Although (123)I-IMT uptake is significantly higher in high-grade gliomas than in low-grade gliomas, the performance of (123)I-IMT SPECT adds little to the accuracy of determining tumor grade when MR imaging is performed.     

3-[123I]Iodo-L-alpha-methyl tyrosine transport into human fibroblasts and comparison with Ewing's sarcoma cells

The cellular transport systems and the transport kinetics of [123I]IMT uptake into non-malignant extracranial cells were characterized for the first time. Human fibroblasts were chosen as non-malignant extracranial cells as they are found ubiquitous in the body. [123I]IMT is exclusively transported into fibroblasts via the sodium independent system L. An apparent Michaelis constant K(m) = 116.2 +/- 18.9 microM and a maximum transport velocity V(max) = 191.6 +/- 13.9 pmol x (10(6) cells)(-1) x min(-1) were calculated for the sodium-independent transport. These results were compared with those determined in two malignantly transformed extracranial cell lines, the human Ewing's sarcoma cell lines VH-64 and CADO-ES-1.     

Proximal myotonic myopathy: clinical, electrophysiological and pathological findings in a family

Proximal myotonic myopathy (PROMM) is an autosomal dominant muscle disorder characterized by proximal weakness, myotonia, muscle pain and cataract. It resembles Steinert myotonic dystrophy (MD), but weakness is proximal, without facial muscle involvement, and the chromosome 19 CTG trinucleotide repeat expansion characteristic of MD is not present. We describe a further family with PROMM. Affected members complained of weakness of lower limbs or of myotonia. EMG revealed diffuse myotonic discharges. Muscle histology showed dystrophic abnormalities. The PROMM phenotype varies, even in the same pedigree, and may mimic MD or limb-girdle muscle dystrophy. EMG is particularly useful, since it may disclose myotonic discharges even in the absence of overt myotonia. Thus far it is not known whether PROMM is a single entity, or if it represents a heterogeneous group of disorders. This question will probably soon be settled through genetic analysis.