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PubMed2006

Elevation of thyroid cancer risk among cutaneous melanoma survivors.

Recent molecular studies have identified recurrent BRAF mutations in both cutaneous melanoma and thyroid malignancies. This relatively selective shared genetic vulnerability raises the possibility that these 2 tumors are connected through a common undisclosed pathogenic mechanism. To assess for possible associations between these 2 genetically related tumors at the population level, we calculated standardized incidence ratios (SIRs) for thyroid cancer (TC) among cutaneous melanoma (CM) survivors and CM among TC survivors using the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) database. Between 1973 and 2000, there were 73,274 and 27,138 cases of CM and TC cases, respectively. Overall, we found a 2.17-fold increase (p < 0.0000001) in the risk of TC after a diagnosis of CM. This augmented risk of TC is somewhat higher for males, for those diagnosed more recently and for the first 3 years after the CM diagnosis. We also detected a considerably smaller and borderline significant increased risk of CM (25%, p = 0.063) among the post-TC survivors. Of note, TC patients who received radiation therapy had a 57% increased risk of a subsequent CM (p = 0.034). Our study documents a strong unilateral risk of TC after CM. More studies are clearly needed to better delineate this mechanism.

Adult↗
PubMed2003

Virological and biochemical relapse according to YMDD motif mutant type during long-term lamivudine monotherapy.

Whether the type of lamivudine-resistant virus in hepatitis B virus (HBV) influences the clinical outcome, it is not completely understood. We evaluated the serial changes in YMDD motif mutant in 60 Japanese genotype C-HBV patients who received long-term lamivudine monotherapy. YIDD or YVDD alone tended to stop shifting to the mixed type (YVDD and YIDD) within 12 months after the detection of mutant virus. Hence, the characteristics, virological relapse (DNA breakthrough) and biochemical relapse (breakthrough hepatitis) of 49 patients, who could be classified into three types (continuous YVDD, continuous YIDD, and the mixed type), were investigated. YVDD and YIDD type tended to have the opposite background with regard to age, histology, and viral load. The mixed and YIDD types tended to have similar backgrounds, except for viral load. In the mixed type, both the HBeAg-positive rate and viral load as risk factors for emergence of the mutant tended to be high. Mutant virus, DNA breakthrough and breakthrough hepatitis emerged significantly earlier in the mixed type than the two other types. The incidence of severe breakthrough hepatitis accompanied by icteric flare-up tended to be higher in the mixed type than the other types. Our results suggest that the YMDD motif mutant type might emerge from different backgrounds and modulate the virological and biochemical relapse after the emergence. Large-scale studies of each mutant type should be conducted in the future to confirm these findings.

Adult↗
PubMed1997

Environmental stress and evolution: a theoretical study.

A haploid population subject to recurrent deleterious mutations and two environments that provide two different profiles of selection coefficients over loci are modeled. The population is supposed to inhabit one "home" environment where it evolves the corresponding genetic constitution. One generation of the population is then exposed to the second, "foreign" environment. The decline in the mean population fitness is considered as a measure of stress in the population caused by the foreign environment. I define the relative strength of stress as 1 minus the ratio of the mean fitnesses in the foreign and home environments, and give the corresponding analytical expression. The stress strength is composed of three different contributors: the environmental component of stress, which is determined by purely external, non-genetic factors of the foreign environment (its carrying capacity), and two genetic components. The latter consists of the environment x genetic component, caused by the direct influence of the foreign environment on selection coefficients, and of the evolutionary component that is due to the adaptation of the population to the home environment. Among others, it is shown that even if the home and foreign environments were equivalent, so that both the environmental and environmental x genetic components of stress were absent, stress would still occur in the foreign environment due to the evolutionary component. The model also predicts that stressful foreign environments cause an increase in the genotypic variance of fitness. Some other features of population variability in stressful environments are discussed. A general conclusion that can be drawn from this model is that a certain environment may be claimed as stressful only if considered with respect to both a given population and the environment in which the population has evolved.

Animals↗
PubMed1992

Mhc-DRB diversity of the chimpanzee (Pan troglodytes).

Fifty-four chimpanzee Patr-DRB and five human HLA-DRB second exons were cloned and sequenced from thirty-five chimpanzees and four human B-cell lines and compared with known Mhc-DRB sequences of these two species. Equivalents of the HLA-DRB1*02, -DRB1*03, -DRB1*07 allelic lineages and the HLA-DRB3, -DRB4, -DRB5, -DRB6, and -DRB7 loci were all found in the chimpanzee. In addition, two chimpanzee Patr-DRB lineages (Patr-DRBX and -DRBY) were found for which no human counterparts have been described. None of the Patr-DRB sequences is identical to known HLA-DRB sequences. The Patr-DRB1*0702 and HLA-DRB1*0701 alleles are the most similar sequences in a comparison between the two species and differ by only two nucleotides out of 246 sequenced. Equivalents of the HLA-DRB1*01, -DRB1*04, and -DRB1*09 alleles were not found in our sample of chimpanzees. A per locus comparison of the number of Patr-DRB alleles with the HLA-DRB alleles shows that the Patr-DRB3, -DRB4, -DRB5, and -DRB6 locus are, thus far, more polymorphic than their human homologs. The polymorphism of the Patr-DRB1 locus seems to be less extensive than that reported for the HLA-DRB1 locus. Nevertheless, the Patr-DRB1 locus seems to be the most polymorphic of the Patr-DRB loci. Phylogenetic analyses indicate that the HLA-DRB1*09 allele may have originated from a recombination between a Mhc-DRB5 allele and the DRB1 allele of a Mhc-DR7 haplotype. Although recombination seems to increase the diversity of the Patr-DRB alleles, its contribution to the generation of Patr-DRB variation is probably low. Hence, most Patr-DRB diversity presumably accumulated via recurrent point mutations. Finally, two distinct Patr-DRB haplotypes are deduced, one of which (the chimpanzee equivalent of the HLA-DR7 haplotype) is probably older than 6-8 million years.

Amino Acid Sequence↗
PubMed2006

Early reduction of infected hepatocytes by activated immunity at the time of interferon withdrawal hepatitis followed by lamivudine administration resulted in higher seroconversion in hepatitis Be antigen-positive patients with chronic hepatitis B.

BACKGROUND: It has been found that the efficacy of lamivudine (LAM) therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal. Because of the side effects of corticosteroid, we tested the effect of a short course of interferon (IFN) as the primer instead of prednisolone, which was followed by LAM when the hepatitis flare occurred. The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied. METHODS: Patients treated with interferon (IFN)-LAM therapy (n=73) were compared to those treated with IFN alone (n=117). The IFN-LAM group received IFN-alpha MU/day, t.i.w. for a 3-month period. LAM (10mg/day during 1 year) was started when IFN withdrawal hepatitis occurred during 2-10 months after stopping IFN. The LAM-resistant, core promoter, and precore mutations were examined by sequencing. RESULTS: (1) The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy. The seroconversion (SC) rate was significantly higher in the IFN-LAM group than in the IFN-alone group (61% vs 26%, P=0.0001). (2) The LAM resistance mutation rate was 31% at 1 year after initiating LAM therapy. (3) In a stepwise discriminant-function analysis, decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe (P = 0.0073 and 0.004, respectively). (4) The reappearance rate of HBeAg within 6 months after the therapy (relapse) was 33% in the IFN-LAM group and 10% in the IFN-alone group. The prevalence of core promoter and precore mutations did not change before and after the therapy, nor did these mutations correlate with the relapse after stopping IFN-LAM therapy. CONCLUSIONS: (1) Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy. (2) The emergence of LAM-resistant mutations was similar to the previously reported rate, and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.

Adult↗
PubMed2002

Interferon for treatment of breakthrough infection with hepatitis B virus mutants developing during long-term lamivudine therapy.

BACKGROUND: We aimed to treat patients with chronic hepatitis B on long-term treatment with lamivudine who developed lamivudine-resistant hepatitis B virus (HBV) mutants along with clinical relapses. METHODS: Of 217 patients with chronic hepatitis B who had been treated with lamivudine for 1-6 years, 23 (11%) developed lamivudine-resistant hepatitis B virus (HBV) mutants. Seven of them, including 1 whose case was previously reported, received interferon (IFN) daily for 4 weeks and then two or three times a week thereafter to cope with exacerbation of hepatitis. We investigated the efficacy of this IFN therapy in 6 patients, excluding the 1 previously reported. RESULTS: In 4 patients, HBV DNA decreased to below the detectable limit of the branched DNA assay (<0.7 MEq/ml) accompanied by normalization of transaminase levels. During IFN therapy, 2 patients seroconverted to antibody to hepatitis B e antigen (HBeAg) and showed normalized transaminase levels. Interferon was required in 7 of the 111 (6%) patients with chronic hepatitis B who were positive for HBeAg, but in none of the 106 who were positive for antibody to HBeAg ( P = 0.014). CONCLUSIONS: The efficacy of IFN in controlling virological breakthroughs and exacerbation of hepatitis by infection with lamivudine-resistant HBV mutants in patients with HBeAg-positive chronic hepatitis B could enhance the versatility of lamivudine, which may have to be given to them indefinitely.

Adolescent↗
PubMed2026

Genomic, transcriptomic, and molecular predictors of response to neoadjuvant therapy in locally advanced rectal cancer: a narrative review.

Total neoadjuvant therapy (TNT) has emerged as a key treatment paradigm for locally advanced rectal cancer, reducing distant metastasis rates and facilitating organ preservation in selected patients. However, treatment response remains heterogeneous, highlighting the need for biomarkers that can guide treatment selection and optimise outcomes. This narrative review synthesises the current evidence regarding tumour-intrinsic genomic biomarkers associated with response to neoadjuvant therapy, encompassing somatic mutations, germline polymorphisms, gene expression profiles, mismatch repair (MMR) status, protein expression, epigenetic markers, and circulating tumour-derived biomarkers across conventional chemoradiotherapy (CRT) and TNT paradigms. Across the reviewed literature, individual somatic mutations, including KRAS, TP53, and BRAF, demonstrated limited reproducibility as predictive biomarkers, although KRAS mutations were recurrently associated with lower pathological complete response (pCR) rates in CRT-era cohorts. Germline polymorphisms in DNA repair (XRCC1) and folate metabolism (MTHFR) genes showed inconsistent associations with treatment response. In contrast, transcriptomic biomarkers demonstrated greater biological coherence, with proliferative, epithelial-mesenchymal transition, and metabolic signatures frequently associated with treatment resistance, while multi-gene classifiers generally outperformed single-gene markers. Among currently available tumour-intrinsic biomarkers, MMR deficiency was the most consistently reported biomarker associated with reduced response to fluoropyrimidine-based regimens, including TNT, although TNT-specific evidence remains comparatively limited. Dynamic circulating tumour DNA (ctDNA) monitoring, particularly ctDNA clearance during or after therapy, was consistently associated with pathological response and long-term oncologic outcomes across reviewed studies, whereas baseline ctDNA levels showed limited predictive value. Overall, the reviewed literature suggests that biomarker research in rectal cancer has evolved from single-gene analyses towards pathway-level and dynamic biomarkers. The integration of transcriptomic signatures, MMR status, and dynamic ctDNA monitoring may represent a promising strategy for personalising neoadjuvant therapy, improving patient selection for organ-preserving approaches, and enhancing oncologic outcomes in locally advanced rectal cancer. Nevertheless, the evidence base remains heterogeneous, and further prospective validation, assay standardisation, and evaluation within contemporary TNT cohorts are required before these biomarkers can be routinely incorporated into clinical decision-making.

Humans↗
PubMed1989

A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells.

Herpes simplex virus encodes a ribonucleotide reductase that is not essential for virus growth in dividing cells at 37 degrees. This enzyme has been proposed as a target for antiviral drugs; its utility in this regard could depend upon its importance in vivo. To test the requirement of viral ribonucleotide reductase in a mammalian host, we tested a mutant virus, lacking most of the gene encoding the ribonucleotide reductase large subunit, in a mouse eye model of pathogenesis and latency where the wild-type virus establishes reactivatable latent infections in trigeminal ganglia following corneal inoculation. The deletion mutant was severely impaired in its ability to replicate acutely in the eye and in the trigeminal ganglion and failed to establish reactivatable latent infections. In contrast, a recombinant virus in which the deleted sequences were restored was competent for both acute and latent infections. The defects of the deletion mutant in the mouse may be related to its severely impaired growth at 38 degrees in mouse cells relative to its growth in Vero cells. These results indicate that ribonucleotide reductase is critical for productive acute and reactivatable latent infections in mice and replication in mouse cells at 38 degrees and suggest that caution be exercised in extrapolating from studies conducted in mice to human infections when judging the utility of this enzyme as a target for antiviral chemotherapy.

Acute Disease↗
PubMed2005

Biallelic deletion and loss of expression analysis of genes at FRA2G common fragile site in tumor-derived cell lines.

Common fragile sites (CFS) are regions of chromosome instability that show gaps or breaks when cells are exposed to particular culture condition. Much evidence suggests that CFSs are causally related to cancer as breakpoints in recurrent chromosome mutations and as sites of viral integration. We investigated the FRA2G CFS (2q31) for biallelic deletions and loss of expression in a panel of 19 tumor-derived cell lines. We found that Burkitt lymphoma-derived cell line DAUDI has a biallelic deletion of eight of the nine analyzed genes. Moreover, we observed loss of expression (LOE) of the DHRS9 gene (alias RDHL), one of the deleted genes in the DAUDI cell line, in MOLT-14 and Raji cell lines derived from Burkitt lymphoma and from T-cell acute lymphoblastic leukemia, respectively. DHRS9 is involved in development and differentiation pathways.

Cell Line, Tumor↗
PubMed2006

JAK2, the JAK2 V617F mutant and cytokine receptors.

Recently, a unique recurrent somatic mutation was identified as a major molecular event in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Expression of this mutant in cytokine-dependent hematopoietic cell lines induces autonomous growth. This effect is enhanced by overexpression of cytokine receptors, and can be inhibited by co-expression at higher levels of the wild type JAK2, which may compete for a limited pool of receptors. In JAK2-deficient cells, we showed that JAK2 V617F can transmit signals from ligand-activated TpoR or EpoR. Furthermore, the mutant JAK2 can be demonstrated to stimulate traffic of the EpoR. Thus, JAK2 V617F mutant must be able to interact via its intact FERM-SH2 domains with the cytosolic domains of cytokine receptors. A synergy between JAK2 V617F and insulin-like growth factor 1 receptor (IGF1R) can be detected in cytokine-dependent cell proliferation. Once cells are rendered autonomous by expression of JAK2 V617F, IGF1 acquires the ability to activate the JAK-STAT pathway. Thus, expression of JAK2 V617F may explain the described hypersensitivity of PV erythroid progenitors to IGF1. The V617 is conserved in two other mammalian JAKs, JAK1 and Tyk2. The homologous mutants JAK1 V658F and Tyk2 V678F are also active in proliferation and transcriptional assays. Such mutants may be found in human cancers or autoimmune diseases. In contrast, the JAK3 M592F does not lead to activation of JAK3. Current hypotheses on how JAK2 V617F contributes to three myeloproliferative diseases, and which other events may favor one disease versus another, are discussed.

Amino Acid Substitution↗
PubMed2001

Severe hypertriglyceridemia with plasma inhibitory factor(s) on lipoprotein lipase activity in a patient with a common Ser(447)-Ter LPL mutation.

Severe hypertriglyceridemia is a major risk for acute pancreatitis. So far, several mutations on the lipoprotein lipase (LPL) gene causing type I hyperlipidemia have been identified. However, the common mutation Ser(447)-Ter has been recently proposed to have a lowering effect on serum triglyceride concentrations in the general population. In this study, we analyzed blood from a patient suffering from severe hypertriglyceridemia and pancreatitis with the mutation on the lipoprotein lipase gene, Ser(447)-Ter. The patient's plasma showed inhibitory effects on the LPL activities from normal subjects. The bottom fraction separated by ultracentrifugation revealed enhanced effects as an inhibitory factor. The inhibitory effect observed in the bottom fraction was dose-dependent, stable at treatment of 65 degrees C for 30 min, and decreased significantly after being dialyzed using membranes with a cut-off molecular weight of 3500 or 6000 Da. The inhibitory effect was significantly higher when the post-heparin plasma was used from the patient or a subject with the same LPL mutation as an LPL source, compared to that from normal subjects. These results suggest that the patient has inhibitory factors in his plasma. Such inhibitory factors might cause severe hypertriglyceridemia in a case with the common mutation, which has been proposed to show the lowing effect on serum triglyceride concentrations in the general population.

Acute Disease↗
PubMed1997

Shortened survival after relapse in T-cell acute lymphoblastic leukemia patients with p16/p15 deletions.

p16 Alterations were detected in > 60% of 103 primary T-ALL samples. In paired diagnosis-relapse patient samples, 80% of the relapse samples with p16 deletion were deleted at diagnosis. When p16 was homozygously deleted, p15 gene alterations were found in 72% of the diagnosis T-ALL patient samples, increasing significantly to 100% at relapse. Alterations of p18 were not detected. No clinical significance of p15/p16 gene deletion in diagnosis T-ALL was found with respect to white blood cell (WBC) count, incidence of mediastinal mass, rate of relapse, duration of first remission or event-free survival. In relapse T-ALL, however, patients with p16 deletion experienced a significantly shorter duration of post-relapse survival, demonstrating that p16 deletion is clinically significant in T-ALL.

Carrier Proteins↗
PubMed2001

Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection.

BACKGROUND/AIMS: Reinfection with hepatitis B virus (HBV) after liver transplantation (OLT) is associated with an unfavourable clinical course. Lamivudine/hepatitis B immune globulin (HBIG) combination treatment reduces reinfection rates. However, it is unclear at what time point lamivudine should be started and which HBIG doses are sufficient. METHODS: Twenty-one patients receiving combination treatment were studied. Lamivudine was started up to 16.5 months before OLT and continued thereafter. HBIG was started intraoperatively and continued according to anti-HBs-titers. Median follow-up after OLT was 20 months. RESULTS: Eleven patients received lamivudine pretreatment for >2 (median 6) months due to initial HBV-DNA-positivity (median 749 pg/ml). After initial lamivudine response HBV-DNA increased in two of them to concentrations above 10 pg/ml prior to OLT. Both had developed mutations in the YMDD motif and suffered from HBV reinfection 13 and 75 days postoperatively. Individual HBIG consumption was highly variable (range 787-4,766 lU/month). Twenty-two percent of anti-HBs titers measured before HBIG administration were below 100 IU/l. CONCLUSIONS: Combined reinfection prophylaxis with lamivudine and HBIG is effective in patients with controlled viral replication at the time of OLT. However, pretransplantation lamivudine resistance is a risk factor for reinfection. Low dose HBIG maintenance therapy individualized according to anti-HBs-titers appears to be tenable.

Adolescent↗