Biomedical subjects

Soma Das

Publications and source records attributed to Soma Das.

At least 19 recordsLinked to original sources

PubMed2026

Early-Onset Colorectal Cancer: Clinical and Molecular Features with Emerging Insights from Comprehensive Genomic Profiling.

Early‑onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before 50 years of age, is increasing globally. Colorectal cancer is currently the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide, with GLOBOCAN 2024 estimating approximately 2.04 million new cases and 917,895 deaths in 2024. Recent studies indicate a sustained rise in EOCRC incidence across multiple regions and birth cohorts, with the greatest increases observed among younger adults. Although hereditary cancer syndromes account for 20-25% of EOCRC cases, most occur in the absence of known genetic predispositions or established risk factors. Emerging evidence implicates the gut microbiome as a potential contributor to EOCRC, with distinct microbial signatures differentiating it from late‑onset colorectal cancer (LOCRC) diagnosed after 50 years of age. This review synthesizes current evidence on clinical, molecular, and diagnostic features distinguishing EOCRC from LOCRC, including differences in anatomical distribution, histopathology, genomic and epigenetic alterations, microbiome composition, and immune landscape, and discusses their implications for personalised screening and therapeutic strategies. We performed a retrospective secondary analysis of comprehensive genomic and immune profiling data from 1737 patients with colorectal cancer tested between June 2021 and June 2023. The analysis showed that tumours arising in patients with EOCRC had lower tumour mutational burden than tumours diagnosed as LOCRC, whereas other immune-related biomarkers, including tumour immunogenicity score, did not remain significantly different after correction for multiple testing. Despite these emerging biological differences, current screening strategies remain largely dependent on an age threshold of 50 years, and EOCRC is not addressed by age‑specific treatment approaches. We therefore review the translational potential of emerging biomarkers, including microbial signatures and liquid biopsy approaches, and propose a framework for integrating molecular profiling into clinical practice. Finally, we highlight the unmet need for coordinated efforts to improve screening in younger populations, address fertility preservation considerations, and ensure adequate psychosocial support for patients with EOCRC.

Early-onset colorectal cancer↗

PubMed2006

Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes.

UGT1A1 is induced by phenobarbital. We investigated whether three common UGT1A1 variants are associated with the variability in UGT1A1 inducibility. Human hepatocytes were incubated with 2 mM phenobarbital for 2 and 6 days followed by 5 microM SN-38 (1 h), a UGT1A1 probe. SN-38 glucuronidation in the cell media was measured by high-performance liquid chromatography. Three UGT1A1 promoter variants [-53(TA)(6>7), -3156G > A and -3279T > G] were genotyped. Significant induction of UGT1A1 catalytic activity was observed in 82% and 100% of the cultures treated with phenobarbital for 2 days (median fold-induction = 1.6, range 1.3-2.8; n = 28) and 6 days (median fold-induction = 2.8, range 1.6-6.4; n = 16), respectively. After 2 days of treatment, a negative correlation was observed between the UGT1A1 basal activities and the fold-induction (Spearman r = -0.52, P < 0.005). By contrast, the UGT1A1 activities in the basal and induced states were highly correlated (Spearman r = 0.95, P < 0.0001). Similar results were observed after 6 days of treatment. The allele frequencies were not significantly different between induced (n = 22) and non-induced preparations (n = 6) (P > 0.05). The fold-induction was not associated with any variants (P > 0.05). The basal and induced activities were correlated with -53(TA)(6>7) (and with -3156G > A due to almost complete linkage with the -53 indel) (P = 0.001). No association was found with the -3279T > G single nucleotide polymorphism (P > 0.05). The indel at -53 affects the basal phenotype and appears to limit the hepatocyte capability of maximal induction after phenobarbital. However, variants at -53, -3156 and -3279 are not associated with variability in UGT1A1 inducibility.

Adolescent↗

PubMed2005

BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy.

To explore the molecular mechanisms for the similarities between inherited and noninherited forms of breast cancer, we tested the hypothesis that inactivation of BRCA1 by promoter hypermethylation is associated with reduced gene copy number and chromosome 17 aneusomy as observed in tumors from BRCA1 mutation carriers. Using a combination of methylation-specific PCR analysis and fluorescence in situ hybridization, we observed varying degrees of promoter methylation in 39 of 131 (29.8%) primary tumors. Despite significant tumor heterogeneity, mean copy numbers of BRCA1 and CEP17 per cell were lower in methylated cases compared with unmethylated cases [1.78 versus 2.30 (P = 0.001) and 1.85 versus 2.29 (P = 0.005), respectively]. Methylation was more frequently observed in younger women (P = 0.05) with high-grade (P = 0.001), estrogen receptor-negative (P = 0.04), and progesterone receptor-negative (P = 0.01) tumors. Moreover, methylation was associated with reduced or absent BRCA1 transcripts, which was reversible in the heavily BRCA1-methylated cell line UACC3199 following treatment with 5-aza-2'-deoxycytidine and trichostatin A. We identified five CpGs at positions -533, -355, -173, -21, and +44 as critical in the reexpression of BRCA1. We conclude that BRCA1 methylation contributes to a subset of sporadic breast cancers with the resulting molecular and clinicopathologic phenotype similar to that of hereditary BRCA1-associated breast cancers. Our data support a model of carcinogenesis in which BRCA1 promoter methylation may serve as a "first hit," much like an inherited germ line mutation, and promote tumor progression down a restricted set of molecular pathways.

Aneuploidy↗

PubMed2005

Acrylamide inhibits dopamine uptake in rat striatal synaptic vesicles.

Evidence suggests that acrylamide (ACR) neurotoxicity is mediated by decreased presynaptic neurotransmitter release. Defective release might involve disruption of neurotransmitter storage, and therefore, we determined the effects of in vivo and in vitro ACR exposure on 3H-dopamine (DA) transport into rat striatal synaptic vesicles. Results showed that vesicular DA uptake was decreased significantly in rats intoxicated at either 50 mg/kg/day x 5 days or 21 mg/kg/day x 21 days. ACR intoxication also was accompanied by a reduction in KCl-evoked synaptosomal DA release, although consistent changes in presynaptic membrane transport were not observed. Silver stain and immunoblot analyses suggested that reduced vesicular uptake was not due to active nerve terminal degeneration or to a reduction in the synaptic vesicle content of isolated striatal synaptosomes. Nor did the in vivo presynaptic effects of ACR involve changes in synaptosomal glutathione concentrations. In vitro exposure of striatal vesicles showed that both ACR and two sulfhydryl reagents, N-ethylmaleimide (NEM) and iodoacetic acid (IAA), produced concentration-dependent decreases in 3H-DA uptake. Although ACR was significantly less potent than either NEM or IAA, all three chemicals caused comparable maximal inhibitions of vesicular uptake. Kinetic analysis of DA uptake showed that in vitro exposure to either ACR or NEM decreased V(max) and increased K(m). Determination of radiolabel efflux from 3H-DA-loaded vesicles indicated that in vitro ACR did not affect neurotransmitter retention. These data suggest that ACR impaired neurotransmitter uptake into striatal synaptic vesicles, possibly by interacting with sulfhydryl groups on functionally relevant proteins. The resulting disruption of neurotransmitter storage might mediate defective presynaptic release.

Acrylamide↗

PubMed2005

Low frequency of BRAF and CDKN2A mutations in endometrial cancer.

Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage (p = 0.04), high histologic grade (p = 0.02), estrogen receptor negativity (p = 0.05), pathologic expression of p53 (p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival (p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types (p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied.

Aged↗

PubMed2005

Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations.

We identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing NSD1 (referred to as "NSD1-positive individuals"), through analyses of 530 subjects with diverse phenotypes. Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (P < 2 x 10(-16)). Sotos syndrome was clinically diagnosed in 99% of NSD1-positive individuals, independent of the molecular analyses, indicating that NSD1 aberrations are essentially specific to this condition. Furthermore, our data suggest that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. We reviewed the clinical phenotypes of 239 NSD1-positive individuals. Facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of the individuals. However, both the height and head circumference of 10% of the individuals were within the normal range, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype, since individuals with identical mutations had different phenotypes. We compared the phenotypes of patients with intragenic NSD1 mutations with those of patients with 5q35 microdeletions. Patients with microdeletions had less-prominent overgrowth (P = .0003) and more-severe learning disability (P = 3 x 10(-9)) than patients with mutations. However, all features present in patients with microdeletions were also observed in patients with mutations, and there was no correlation between deletion size and the clinical phenotype, suggesting that the deletion of additional genes in patients with 5q35 microdeletions has little specific effect on phenotype. We identified only 13 familial cases. The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases (P = .005) to carry missense mutations, suggesting that the underlying NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness.

Amino Acid Sequence↗

PubMed2005

Global gene expression as a function of germline genetic variation.

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P< or =0.0031; GSTM1: 112 probe sets, FDR=42.5%, P< or =0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.

Child↗

PubMed2005

Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.

Alleles↗

PubMed2005

Clinical outcome and follow-up of the first reported case of Russell-Silver syndrome with the unique combination of maternal uniparental heterodisomy 7 and mosaic trisomy 7.

BACKGROUND: Russell-Silver syndrome (RSS) has been associated with maternal uniparental disomy (UPD) for chromosome 7 although the etiology of the syndrome is still unknown. Cases of RSS associated with maternal UPD7 have involved isodisomies, heterodisomies, and mixed isodisomy with heterodisomy simultaneously. This publication is a follow-up report of the postnatal clinical outcome of the first prenatally suspected case of combined mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 (UPD7). CASE: The diagnosis of RSS in the proband was suspected prenatally because trisomy 7 mosaicism (47,XX,+7[13]/46,XX[19]) and maternal uniparental heterodisomy 7 were both found in amniotic fluid cells. Cord blood karyotype analysis showed only disomic cells (46,XX[50]), whereas postpartum chorionic villus analysis was completely trisomic for chromosome 7 (47,XX,+7[19]). Postnatally, the diagnosis of RSS was confirmed by physical findings, her trisomy 7 mosaicism was confirmed by cytogenetic analysis of her skin biopsy (47,XX,+7[9]/46,XX[20]) and her UPD7 was confirmed on both peripheral blood and skin biopsy using microsatellite markers. During infancy, the proband experienced growth deficiency, persistent hypoglycemia, and psychomotor developmental delay. CONCLUSIONS: Trisomic rescue as a life-saving mechanism, with subsequent chromosomal mosaicism in combination with UPD may occur more frequently in RSS than has been reported. Systematic testing of cases suspected prenatally or postnatally would be informative regarding the individual contribution of each factor. Imprinting, loss of heterozygosity for recessive genes, and mosaicism may explain the short stature, asymmetry, and the variable expression of the phenotype. The contribution of these mechanisms to the syndrome should be evaluated in these cases.

Chromosomes, Human, Pair 7↗

PubMed2005

Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome).

PURPOSE: The onset of pantothenate kinase-associated neurodegeneration (PKAN) occurs in the first and second decade of life and a pigmentary retinal degeneration is a feature of the disorder. Since the neuro-ophthalmologic and electroretinographic (ERG) features have never been well delineated, we describe them in 16 patients with PKAN. DESIGN: Observational case series. METHODS: Sixteen patients with genetic and neuroimaging-confirmed PKAN were examined. Ten underwent neuro-ophthalmologic examination and all had ERGs. RESULTS: Of the 10 who underwent neuro-ophthalmologic examination, all showed saccadic pursuits and eight showed hypometric or slowed vertical saccades. Seven of eight had inability to suppress the vestibulo-ocular reflex; two patients could not cooperate. Two had square wave jerks and four had poor convergence. Vertical optokinetic responses were abnormal in five, and two patients had blepharospasm. Eight patients had sectoral iris paralysis and partial loss of the pupillary ruff consistent with Adie's pupils in both eyes. Only four of 10 examined patients showed a pigmentary retinopathy, but 11 of 16 had abnormal ERGs ranging from mild cone abnormalities to severe rod-cone dysfunction. No patient had optic atrophy. The PANK2 mutations of all of the patients were heterogeneous. CONCLUSIONS: Adie's-like pupils, abnormal vertical saccades, and saccadic pursuits were very common. These findings suggest that mid-brain degeneration occurs in PKAN more frequently than previously thought. ERG abnormalities were present in approximately 70% and no patient had optic atrophy. Although genotype-ocular phenotype correlations could not be established, allelic differences probably contributed to the variable clinical expression of retinopathy and other clinical characteristics in these patients.

Adolescent↗

PubMed2005

NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory.

PURPOSE: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. METHODS: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. RESULTS: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. CONCLUSIONS: The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated.

Child↗

PubMed2005

Technical standards and guidelines: molecular genetic testing for ultra-rare disorders.

These standards and guidelines are designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical molecular geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the laboratory record the rationale for any significant deviation from these standards and guidelines.

Genetic Testing↗

PubMed2005

Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes.

OBJECTIVES: Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in Asians and Caucasians and gain insights on their functional consequences. METHODS: Asian and Caucasian individuals were genotyped for UGT1A1 and UGT1A9 variants. RESULTS: A higher frequency of the UGT1A9 -118T10 allele was observed in Asians compared to Caucasians, while the -275T>A and -2152C>T variants were relatively uncommon in Caucasians and not found in Asians. The strongest linkage disequilibrium (LD) was observed between the UGT1A1 -53 and -3156 and between the UGT1A9 -275 and -2152 loci. Lower LD was observed between the -118 UGT1A9 variant and the UGT1A1 variants. Fourteen UGT1A9-UGT1A1 haplotypes were found in Asians, seven of them found to be shared by both populations. Common UGT1A9-UGT1A1 diplotypes were defined, and a difference was observed across the SN-38 glucuronidation rates in Caucasian livers stratified by diplotypes. CONCLUSION: This study for the first time described common UGT1A9-UGT1A1 haplotypes, highlighting important ethnic differences between Asians and Caucasians. If the functional effect of these haplotypes can be confirmed, this haplotypic information would be applicable to the correct design of prospective clinical studies of irinotecan, as well as of other drugs primarily metabolized by both UGT1A1 and UGT1A9.

Asian People↗

PubMed2005

Denaturing high-performance liquid chromatography for mutation detection and genotyping.

Denaturing high-performance liquid chromatography (DHPLC) is an accurate and efficient screening technique used for detecting deoxyribonucleic acid sequence changes by heteroduplex analysis. It can also be used for genotyping of single-nucleotide polymorphisms. The high-sensitivity of DHPLC has made this technique one of the most reliable approaches to mutation analysis and is used in various areas of genetics, both in the research and clinical arena. This chapter describes the methods used for mutation detection analysis and the genotyping of single-nucleotide polymorphisms by DHPLC on the WAVETM system from Transgenomic Inc.

Chromatography, High Pressure Liquid↗

PubMed2005

Changing diversity of hymenopteran parasitoids from organically and conventionally managed tea-ecosystem of North Bengal, India.

Tea, Camellia sinensis (L.) O. Kuntze, is grown conventionally (application of chemical fertilizer and pesticides) as well as organically in Darjeeling hills and adjoining plains. Studies on parasitic Hymenoptera gain relevance due to their effective role as biocontrol agents for maintenance of ecological balance and as biological indicators of health of tea agro-ecosystem. Diversity of the hymenopterans was studied using Shannon-Weaver index (1963) both at morphospecies and family levels. The analysis reflected the changing diversity of this group with season, pesticide application and the condition of the tea crop. It further indicated that mainly four parasitoid groups such as braconids, ichneumonids, eulophids and scelionids, showed greater diversity in organic plantation as compared to conventional. Since species (= RTU: recognizable taxonomic unit) diversity and family diversity indices agreed with one another a surrogacy based system (family for RTU) could be adopted for diversity analysis.

Agriculture↗

PubMed2004

Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia.

PURPOSE: One of the adverse effects of therapy for acute lymphoblastic leukemia (ALL) is osteonecrosis of the hip. Putative risk factors for osteonecrosis have included being female, white race, and older age. Our goal was to define possible genetic risk factors for osteonecrosis among children treated for newly diagnosed ALL. METHODS: Using a candidate gene approach, we determined the genotypes for 16 common polymorphisms in genes likely to affect the pharmacokinetics or pharmacodynamics of antileukemic medications in 64 children with ALL. Therapy included glucocorticoids and antifolates. Magnetic resonance imaging of both hips was used to diagnose osteonecrosis, and was performed at similar times from the start of ALL therapy (P =.61) in the 25 patients with and the 39 patients without osteonecrosis (median, 447 days and 443 days, respectively). RESULTS: In addition to age older than 10 years (odds ratio [OR], 24.2; P =.0001) and white race (OR, 11.1; P =.037), host factors for osteonecrosis included the vitamin D receptor FokI start site CC genotype (OR, 4.5; P =.045), and the thymidylate synthase low activity 2/2 enhancer repeat genotype (OR, 7.4; P =.049). CONCLUSION: Because folate-related and vitamin D-receptor genetic variants have been associated with bone and vasculature morbidity, these pharmacogenetic associations likely reflect the interaction of antileukemic medications with germline sensitivity to drug actions, and might identify ALL patients at highest risk to develop osteonecrosis.

Age Factors↗

PubMed2004

Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.

PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

Antineoplastic Agents, Phytogenic↗

PubMed2004

LySDB - Lysozyme Structural DataBase.

LySDB (Lysozyme Structural DataBase) is an integrated database containing 740 three-dimensional structures of lysozyme available in the Protein Data Bank. The database can be used to visualize the three-dimensional structure of the entire protein model or the substructures in which the user is interested (for example, insertions and deletions of amino acids) using the three-dimensional atomic coordinates. The database is provided with a search engine with several useful built-in facilities. The public domain graphics program RASMOL has been deployed for visualization. The three-dimensional structures used to create the database are updated at regular intervals and hence the users are provided with the current information available in the literature. The database LySDB is available over the World Wide Web and can be accessed at the URL http://iris.physics.iisc.ernet.in/lysdb/ or http://144.16.71.2/lysdb/.

Computational Biology↗