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PubMed2006

Hyperhomocysteinemia and venous thromboembolism.

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. Severe hyperhomocysteinemia (homocystinuria), due to inherited metabolic defects of Hcy metabolism, is associated with very high risk of venous thromboembolism (VTE); treatment with vitamins is associated with dramatic decrease of VTE risk. Several case-control and prospective studies showed that also mild/moderate hyperhomocysteinemia (which is caused by the interaction of environmental factors with mild genetic abnormalities of Hcy metabolism) is associated with heightened risk of VTE; however, it is uncertain whether treatment with vitamins also decreases the VTE risk in these patients.

Case-Control Studies↗
PubMed2004

Cancer of the ovary.

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed2005

Cystic fibrosis genotype and bacterial infection: a possible connection.

Patients with cystic fibrosis (CF) have repeated bacterial infection of the airways, which can lead to chronic infection. There is evidence that disease severity is determined by the genetic mutations present. This study aims to establish if CF genotype is related to the frequency and types of airway bacterial infection. Adult patients attending the regional CF unit are followed for two years and assigned to one of three groups depending on whether they are chronically infected with Burkholderia cepacia complex (BCC) organisms, Pseudomonas aeruginosa, or neither of these organisms. Genotype analysis is performed on all patients to determine which of the cystic fibrosis transmembrane regulator (CFTR) gene mutations are present. The numbers and types of organism with the CFTR mutations isolated from sputum are identified. Data are available on 59 patients: 15 colonised with BCC, 24 colonised with P. aeruginosa, and 20 not colonised with either organism. Twenty patients were homozygous for deltaF508, 25 were heterozygous, and the deltaF508 mutation was not present in the remaining 14 patients. Patients homozygous or heterozygous for the deltaF508 mutation had an increased likelihood of colonisation with BCC or P. aeruginosa, an increased number of positive sputum cultures and a higher frequency of multiple infecting organisms. Cystic fibrosis mutational analysis identified seven patients who had the R117H mutation. These patients were less likely to be colonised with BCC or P. aeruginosa. In conclusion, patients homozygous or heterozygous for the deltaF508 deletion are more likely to suffer airway colonisation with BCC or P. aeruginosa, with increased numbers of positive sputum cultures and infecting organisms. Those with the R117H mutation are less likely to be colonised by Gram-negative organisms.

Adult↗
PubMed1997

Molecular and cytogenetics of soft tissue sarcomas.

Molecular and cytogenetically soft tissue sarcomas are a well-characterized tumor entity with several tumor type specific changes understood also at the molecular level. Most likely, additional characteristic alterations will be detected, recurrent aberrations characterized at the molecular level, new clinical and histopathological correlations will be found, and little is known about how the genetic changes lead to tumor formation, promote progression and sometimes give tumor cells the ability to recur locally or distantly. The possibility to detect cells with these acquired genetic alterations may increase the reproducibility of tumor classification, yields promising possibilities for early diagnosis of tumor recurrences and/or metastasis, and may allow development of therapeutic regimens targeted at the genetically alterated cell.

Chromosome Aberrations↗
PubMed1977

Frequency of occurrence of idiotypes associated with anti-p-azophenylarsonate antibodies arising in mice immunologically suppressed with respect to a cross-reactive idiotype.

Inoculation of rabbit anti-idiotypic (anti-id) antibodies suppresses the subsequent appearance of a cross-reactive idiotype (CRI) associated with the anti-p-azophenylarsonate (anti-Ar) antibodies of A/J mice. Such suppressed mice produce normal concentrations of anti-Ar antibodies which lack the CRI, but against which anti-id antisera can be prepared. The anti-Ar antibodies of an individual, suppressed mouse do not in general share idiotype with anti-Ar antibodies of other A/J mice, either suppressed or nonsuppressed. The present experiments were undertaken to quantitate several "private idiotypes" in a large number of hyperimmunized A/J mice. Anti-Ar antibodies of three mice, suppressed for the CRI, were labeled with 125I and subjected to isoelectric focusing. Four single peaks, that were over 90% reactive with autologous antiid, were randomly selected for use as ligands in a radioimmunoassay, and ascitic fluids containing anti-Ar antibodies from 181 A/J mice were tested as inhibitors. Two of the four idiotypes could not be detected in any mouse other than the donor. The concentration of the idiotype was less than 1 part in 1,250 to less than 1 part in 25,000 of the anti-Ar antibody population; these are minimum values. A third idiotype was detected in 3 of the 181 mice, but at very low concentrations. The fourth idiotype was present in 28% of the mice, again at a low concentration. The data support the existence of a very large repertoire of anti-Ar antibodies in the A/J strain and are consistent with a process of random somatic mutation for generating diversity in hypervariable regions. It is proposed that the cross-reactive idiotype may be controlled by a germ line gene or a gene related to a germ line gene through a small number of somatic mutations; and that the idiotypes that were not detectable in other mice were the products of genes that had undergone extensive mutations, with a low probability of recurrence in other mice.

Animals↗
PubMed2003

Molecular biology of prostate cancer.

In spite of progress in diagnosis and treatment, prostate cancer has become one of the most frequent lethal cancers in males in many Western industrialized countries. Research on the molecular biology of prostate cancer is expected to reveal those aspects of Western lifestyle contributing to its high incidence with the aims of improving prevention, distinguishing slow-growing from aggressive clinically relevant cancers, and providing targets for treatment, particularly of locally advanced and of metastatic disease. Traditionally, prostate cancer research focused on androgens. More recently, tumour suppressors and proto-oncogenes important in other human cancers have been intensely investigated. Current approaches include the search for genes mutated in familial cases, identification of recurrent chromosomal alterations and their associated potential tumour suppressor genes, determination of gene expression profiles characterizing tumour stages and subclasses, and elucidation of the importance of epigenetic alterations. Results from such studies have begun to be translated into the clinic. Further successful transfer of results from molecular biology to the clinic will, however, require integration of the amassed molecular data into a biological framework model of prostate carcinoma.

Aged↗
PubMed1999

Early occlusion of coronary by-pass associated with the presence of factor V Leiden and the prothrombin 20210A allele: case report.

The presence of factor V Leiden mutation and the variation of the prothrombin gene 20210GA have been described as additional risk factors for arterial thrombosis when other acquired or metabolic risk factors are present. We report here a 56-year-old man who developed coronary artery disease since 1980 without any known risk factor and underwent a cardiopulmonary by-pass in 1997. In the first month after surgery, he became symptomatic, and an angiography showed complete occlusion of the grafts and some native coronary arteries. Three months after the second cardiopulmonary by-pass, a thrombophilic state was searched, and plasma levels of lipoprotein (a) (LPa) were measured. The patient is heterozygous for factor V Leiden mutation and has the variation 20210GA of the prothrombin gene and high levels of LPa. These findings induced us to add oral anticoagulation to the aspirin treatment, and the patient is in a good condition 11 months later.

Coronary Artery Bypass↗
PubMed2001

Transient relapses ("blips") of plasma HIV RNA levels during HAART are associated with drug resistance.

INTRODUCTION: In a large number of patients on HAART who achieved plasma HIV RNA levels below the limit of detection (50 copies/ml), transient relapses of HIV RNA levels ("blips") are observed. OBJECTIVE: To determine whether relapses of plasma HIV RNA during HAART are associated with development of drug resistance. METHODS: Plasma samples from 15 patients with a transient viral load relapse during HAART were studied. All regimens contained lamivudine (3TC). We used an ultrasensitive sequence approach to analyze the presence of drug resistance mutations during the relapse. RESULTS: The median plasma HIV RNA load of the relapse was 76 copies/ml (range 50-1239). In 11 of 15 cases, a genotype of HIV could be obtained. Mutations in the RT and protease gene conferring resistance to one or more drugs were observed in 8 of 11 patients, 6 of whom had the M184V substitution. During a median follow-up of 27 months after the relapse, plasma HIV RNA levels remained undetectable in 13 of 15 patients. CONCLUSIONS: Plasma HIV RNA blips during HAART can be associated with selection of drug-resistant HIV. This indicates that viral replication may occur during HAART, probably caused by a temporary decrease in active drug concentrations. A blip containing only wild-type virus is not necessarily caused by viral replication. In this situation the raise of HIV RNA could also originate from release of wild-type viruses, caused by activation of the latent virus reservoir. Independent of the mechanism, blips did not preclude successful inhibition of viral replication during 2-year follow-up in the majority of these cases.

Anti-HIV Agents↗
PubMed2003

Molecular detection of von Hippel-Lindau gene mutations in urine and lymph node samples in patients with renal cell carcinoma: potential biomarkers for early diagnosis and postoperative metastatic status.

PURPOSE: Organ confined renal cell carcinoma can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. Therefore, the development of a useful biomarker for early diagnosis as well as postoperative metastatic status would contribute to the appropriate therapy for renal cell carcinoma. To diagnose renal cell carcinoma preoperatively we developed a novel urinary test and detected occult lymph node micrometastasis using a molecular approach. MATERIALS AND METHODS: Urine samples were obtained preoperatively from 27 patients with renal cell carcinoma and von Hippel-Lindau (VHL) gene mutations in the tumors, and were analyzed for VHL gene mutations using a nested single strand conformational polymorphism analysis. Lymph nodes without evidence of histological metastasis were obtained from 15 patients with renal cell carcinoma and VHL gene mutations, and analyzed for VHL gene mutations using mutation specific nested reverse transcription polymerase chain reaction method. RESULTS: In urine samples 5 of 27 VHL gene mutations (18.5%) were found and each mutation pattern was the same as that detected in each renal cell carcinoma. One lymph node micrometastasis was found. CONCLUSIONS: These data indicate the presence of detectable levels of tumor derived DNA in the urine of patients with renal cell carcinoma and suggest that nested single strand conformational polymorphism analysis of VHL gene of urine samples provides a possible tool for the early detection of renal cell carcinoma. Furthermore, mutation specific nested reverse transcription polymerase chain reaction is useful to detect occult lymph node micrometastasis and may predict patients at risk for local recurrence. These 2 combined approaches using VHL gene mutations may contribute to the total therapy for and prognosis of renal cell carcinoma.

Biomarkers, Tumor↗
PubMed1998

Low-dose recombinant interferon therapy in anti-HBe-positive chronic hepatitis B in Asian Indians.

Approximately 15% of Indian patients with hepatitis B virus (HBV)-related chronic liver disease (CLD) have infection with precore mutant forms. These patients are likely to have an aggressive course. There are equivocal reports of success with interferon therapy of mutant infection in the West. This therapy has not been evaluated in precore mutant-related CLD in Asian Indians. Eighteen patients (mean age 38.2 +/- 12 years, M:F: 17:1) with biopsy proven CLD and precore mutant HBV infection (hepatitis B surface antige (HBsAg) positive, hepatitis B e antigen (HBeAg) negative, anti-HBe positive, HBV-DNA positive) were included. Interferon alpha 2b was given at 3 mIU on alternate days for 4 months. Serology, determination of HBV-DNA (both by dot-blot hybridization and polymerase chain reaction) and liver biopsy were repeated after completion of the therapy. Response to interferon therapy was defined as loss of HBV-DNA by dot-blot hybridization. Thirteen (72.2%) patients responded to the treatment (responders). Mean alanine aminotransferase levels (83 +/- 12 vs 55 +/- 29 IU/L, P < 0.01) and the histological activity index (15 +/- 1.4 vs 12 +/- 1.3, P < 0.01) significantly decreased in the responders compared with initial values. Serum albumin levels also improved at the end of the therapy (3.5 +/- 0.4 g/dL vs 3.8 +/- 0.4 g/dL, P = 0.07). During follow up, seven of the 13 (54%) responders relapsed; cirrhotics relapsed more often than chronic hepatitis patients (P < 0.05). All 18 patients, however, continued to be HBV-DNA positive at the end of follow up. This study concluded that: 1. Interferon therapy is beneficial, albeit to a limited extent, in HBV precore mutant-related chronic liver disease in Asian Indians. 2. It is ineffective in eliminating the mutant HBV infection, which explains the high relapse rate. 3. Prolonged low-dose interferon therapy alone or in combination with newer nucleoside analogues should be evaluated in these patients.

Adult↗
PubMed2000

Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome.

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.

Action Potentials↗
PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), &#x2265;10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NF&#x3ba;b pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗
PubMed2000

Mutations in the tropoelastin gene (ELN) were not found in patients with spontaneous cervical artery dissections.

BACKGROUND AND PURPOSE: The majority of patients with spontaneous cerebral artery dissection show ultrastructural alterations in dermal collagen and elastic fibers. METHODS: We studied the gene encoding tropoelastin (ELN) by reverse transcription-polymerase chain reaction and subsequent sequence analysis in 10 patients with abnormalities in their elastic fibers. RESULTS: No mutations were found in the whole coding region of the ELN gene. The simultaneous visualization and quantification of ELN splice variants by gene scanning enabled the analysis of the regulation of alternative splicing of ELN mRNA. No differences could be detected between fibroblast cultures of the patients and a control subject. CONCLUSIONS: Neither mutations in the ELN gene nor dysregulation of its activity appears to be the cause of the connective tissue disorder that is found in most patients with spontaneous dissections.

Adult↗
PubMed1998

Heat shock protein and p53 expression in head and neck squamous cell carcinoma.

BACKGROUND: Heat shock proteins have been associated with the mutant form of the tumor suppressor gene, TP53, and with resistance to cancer chemotherapy. METHODS: Archival tissues from 50 patients with head and neck squamous cell carcinoma who received primary surgical resection were examined for p53, HSP27, and HSP70 by immunohistochemistry and correlated with tumor stage, grade, and 5-year survival (alive or deceased). RESULTS: Both heat shock proteins were strongly expressed in normal mucosa and in small (T1 and T2) tumors. Thirty (60%) of tumors were positive for p53, 43 (86%) for HSP27, and 34 (68%) for HSP70, with no association between p53 and heat shock protein expression. Twenty-five patients were alive (4 with disease), and 25 patients were deceased (9 from other causes). p53 Protein overexpression correlated with low-grade tumors. Only primary tumor site (i.e., oral cavity > larynx > oropharynx/base of tongue) and N stage were significantly associated with survival. CONCLUSIONS: Heat shock proteins are expressed in normal upper respiratory tract squamous mucosa, and their role in carcinoma remains unclear. None of the markers, p53, HSP27, or HSP70, demonstrated prognostic significance for 5-year survival. We confirm the recognized association of cervical lymph node metastases with decreased survival.

Biomarkers, Tumor↗
PubMed2003

A second case of multidrug-resistant Mycobacterium leprae isolated from a Japanese patient with relapsed lepromatous leprosy.

Emergence of drug resistant strains of Mycobacterium leprae was reported soon after the introduction of dapsone (diamino-diphenyl sulphone, DDS) for leprosy treatment (6, 10, 11). Three cases of multidrug-resistant strains of M. leprae have been reported recently (2, 8, 9, 13). In order to prevent multiple drug resistant strains of M. leprae from developing, current leprosy control strategies are based on early detection of cases and treatment with multidrug therapy (MDT) as recommended by the World Health Organization (WHO). We report here the identification of a multidrug-resistant strain of M. leprae from a patient who received inadequate therapy for leprosy. The drug resistant profile of the isolated strain was confirmed by the mouse footpad method and the identification of mutations in genes previously shown to be associated with resistance to each drug was made.

Aged↗
PubMed1999

Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox.

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytes in which defective production of microbicidal oxidants leads to severe recurrent infections. CGD is caused by mutations in any of 4 genes encoding components of nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase, the multisubunit enzyme that produces the precursor of these oxidants, superoxide. Approximately 5% of CGD patients have an autosomal recessive form of disease caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the oxidase that appears to regulate electron transport within the enzyme. Here we report the biochemical and molecular characterization of 6 unrelated kindreds with p67-phox deficiency. These studies show that, as in gp91-phox and p22-phox deficiencies, the p67-phox CGD patients show a high degree of heterogeneity in the genetic defects that underlie their disease. Five different mutant alleles were identified: (1) a nonsense mutation in exon 4 (C(304) --> T); (2) a 5-nucleotide (nt) deletion in exon 13 (nts 1169-1173); (3) a splice mutation in the first nucleotide of intron 4 (G --> A); (4) a deletion of 1 nt in exon 9 (A(728)); and (5) a 9-nt in-frame deletion in exon 2 (nts 55-63). The splice mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 apparently unrelated families (both of Palestinian origin). Homozygosity was present in 4 of the kindreds, 2 of which had consanguineous parentage. In the isolated neutrophils of each of the affected patients in the 6 kindreds, there was no measurable respiratory burst activity and no p67-phox protein detected by immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot studies. Thus, this heterogeneous group of mutations in p67-phox all lead to marked instability of mRNA or protein (or both) that results in the complete loss of NADPH oxidase activity.

Adolescent↗