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mRNA gene expression correlates with histologically diagnosed chemotherapy-induced hepatic injury.

INTRODUCTION: Chemotherapy-induced hepatic injuries (CIHI) are an increasing problem facing hepatic surgeons. It may be possible to predict the risk of developing CIHI by analysis of genes involved in the metabolism of chemotherapeutics, previously established as associated with other forms of toxicity. METHODS: Quantitative reverse transcriptase-polymerase chain reaction methodology (q-RT-PCR) was employed to quantify mRNA expression of nucleotide excision repair genes ERCC1 and ERCC2, relevant in the neutralization of damage induced by oxaliplatin, and genes encoding enzymes relevant to 5-f

Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts.

Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the

XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription.

Nucleotide excision repair is a highly versatile DNA repair system responsible for elimination of a wide variety of lesions from the genome. It is comprised of two subpathways: transcription-coupled repair that accomplishes efficient removal of damage blocking transcription and global genome repair. Recently, the basic mechanism of global genome repair has emerged from biochemical studies. However, little is known about transcription-coupled repair in eukaryotes. Here we report the identification of a novel protein designated XAB2 (XPA-binding protein 2) that was identified by virtue of its ab

A phase II trial of irinotecan in patients with advanced or recurrent endometrial cancer and correlation with biomarker analysis.

OBJECTIVE: Chemotherapy for advanced or recurrent endometrial cancer requires further development. Irinotecan hydrochloride (CPT-11) suppresses tumor growth in several endometrial cancer strains. The present study evaluated the anti-tumor activity and toxicity of CPT-11 in patients with advanced or recurrent endometrial cancer. METHODS: Enrolled patients had advanced endometrial cancer with measurable lesions and received 2 pretreatment regimens. A 90-minute intravenous infusion of CPT-11 (100 mg/m2) was given on days 1, 8, and 15 of a 4-week cycle, aiming for an effect with ≤2 cycles. Treatm

Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN.

Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPR

Ocular manifestations of genetic skin disorders.

Genetic skin diseases, or genodermatoses, often have extracutaneous manifestations. Ocular manifestations in particular can have significant clinical implications, like blindness. Other manifestations, such as the corneal opacities that occur in X-linked ichthyosis, are asymptomatic but characteristic of a particular genodermatosis. Ophthalmologic examination can aid in diagnosis when characteristic findings are seen. The genodermatoses with ocular manifestations will be reviewed, but neurocutaneous, syndromes, genetic pigmentary disorders, and genetic metabolic diseases are not included becau

XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma.

The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case-control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genot

Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression.

BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression. METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Bio

Association of XRCC1, XRCC3, and XPD genetic polymorphism with an increased risk of hepatocellular carcinoma because of the hepatitis B and C virus.

OBJECTIVE: The south-east Asian and sub-Saharan African populations are the most susceptible to hepatocellular carcinoma (HCC). We aimed to establish whether XRCC1, XRCC3, and XPD are associated with liver cancer in Pakistan and to examine the interaction of hepatitis B virus (HBV) or hepatitis C virus (HCV) with repaired genes in the occurrence of liver cancer. MATERIALS AND METHODS: We enrolled 74 healthy individuals, 75 had either HBV or HCV, and 50 were HCC patients. The characteristic information of all the study participants were collected through a standard interviewer-administered que

Pretreatment selection of regimen according to genetic analysis improves the efficacy of chemotherapy in the first line treatment of metastatic colorectal cancer.

BACKGROUND AND OBJECTIVES: Metastatic colon cancer patients are treated with the chemotherapy regimens, FOLFOX and FOLFIRI, in either order. So far, we cannot predict the response of chemotherapeutic agent, so it is necessary to find which regimen is adequate before starting chemotherapy. METHODS: Enrolled patients are randomized into either conventional treatment or planned treatment preceded by pretreatment genetic analysis. Blood samples of patients in planned treatment group (N = 53) were analyzed for the genetic polymorphism before selection of chemotherapeutic agents. Target genes were

Benzo[a]pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: toxicokinetics is essential for in vivo-in vitro comparisons.

The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests. The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens. Recently, the differential gene expression response in wild-type and cancer-prone Xpa (-/-) p53 (+/-) primary mouse hepatocytes after exposure to benzo[a]pyrene (B[a]P) revealed downregulation of cancer-related pathways in Xpa (-/-) p53 (+/-) hepatocytes only. Here, we investigated pathway regulation upon in vivo B[a]P exposure of wild-type and Xpa

Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.

PURPOSE: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751

Translesion synthesis of 7,8-dihydro-8-oxo-2'-deoxyguanosine by DNA polymerase eta in vivo.

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) is one of the most common DNA lesions induced by oxidative stress. This lesion can be bypassed by DNA polymerase eta (Pol eta) using in vitro translesion synthesis (TLS) reactions. However, the role that Pol eta plays in vivo contributing to 8-oxo-dG mutagenesis remains unclear. To clarify the role of Pol eta in 8-oxo-dG mutagenesis, we have used an siRNA knockdown approach in combination with a supF shuttle vector (pSP189) which replicates in mammalian cells. The pSP189 plasmid was treated with methylene blue plus light (MBL), which produces pred

Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma.

INTRODUCTION: Younger women with breast carcinoma (BC) exhibits more aggressive pathologic features compared to older women; young age could be an independent predictor of adverse prognosis. To find any existing differences in the molecular pathogenesis of BC in both younger and older women, alterations at chromosomal (chr.) 9q22.32-22.33 region were studied owing to its association in wide variety of tumors. Present work focuses on comparative analysis of alterations of four candidate genes; PHF2, FANCC, PTCH1 and XPA located within 4.4 Mb region of the afore-said locus in two age groups of B

Mammographic density and candidate gene variants: a twins and sisters study.

BACKGROUND: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants. METHODS: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, I

[Expression of extraneuronal monoamine transporter gene and DNA repair gene vis-à-vis with antitumor efficacy of SarCNU in human tumor xenografts].

OBJECTIVE: To clarify if there are any correlations between extraneuronal monoamine transmitters (EMT), DNA repair gene expressions and SarCNU antitumor efficacy. METHODS: EMT, DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) and excision repair cross-complementing rodent repair deficiency gene (ERCC1-6) expressions in 9 human xenograft tumor models were determined by RT-PCR. The results were compared with the antitumor effects of SarCNU on these tumor xenografts. RESULTS: Multiple regression analysis revealed significant correlations of SarCNU antitumor activity with different

Molecular structure of human TFIIH.

TFIIH is a multiprotein complex required for both transcription and DNA repair. Single particles of human TFIIH were revealed by electron microscopy and image processing at a resolution of 3.8 nm. TFIIH is 16 x 12.5 x 7.5 nm in size and is organized into a ring-like structure from which a large protein domain protrudes out. A subcomplex assembled from five recombinant core subunits also forms a circular architecture that can be superimposed on the ring found in human TFIIH. Immunolabeling experiments localize several subunits: p44, within the ring structure, forms the base of the protruding pr

mRNA levels of the hypoxia inducible factor (HIF-1) and DNA repair genes in perinatal asphyxia of the rat.

Hypoxia inducible factor 1 (HIF-1) is a transcription factor which is expressed, when mammalian cells are subjected to hypoxia, activating the transcription of genes encoding proteins thought important for maintaining oxygen hemostasis. The aim of the study was to evaluate HIF-1 mRNA levels in a non-invasive model of perinatal asphyxia (PA). Brain was taken for studies on HIF-1 alpha and beta 10 min following the asphyctic period. To rule out influences by the redox status we also determined antioxidant enzyme mRNA levels for superoxide dismutase, catalase, glutathion peroxidase and performed

Targeting the DNA Damage Response for Cancer Therapy.

Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these mechanisms play a pivotal role in maintaining genomic stability. Defects in the DNA damage response pathways can give rise to various diseases, including cancer. The DNA damage response (DDR) system is instrumental in safeguarding genomic stability. The accumulation of DNA damage and the weakening of DDR function both promote the initiation and progression of tumors. Simultaneously, they offer opportunities and targets for cancer therapeutics. This article primarily elucid

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… Essential contributors to NER include the seven xeroderma pigmentosum (XP) complementation groups, spanning from XPA to XPG proteins, as well as the excision repair cross-complementing group 1 protein (ERCC1), the human counterpart of yeast RAD23 (hHR23B), the replication protein A (RPA), the subunits … Human xeroderma pigmentosum group D gene encodes a DNA helicase Nature 1993 365 852 855 10.1038/365852a0 8413672 32. Wang M. Chen S. Ao D. Targeting DNA repair pathway in cancer: Mechanisms and clinical application MedComm 2021 2 654 691 10.1002/mco2.103 34977872 PMC8706759 33. Spivak G. …

Grzybowski's Generalized Eruptive Keratoacanthomas in a Patient with Terminal Kidney Disease-An Unmet Medical Need Equally Ameliorated by Topical Imiquimod Cream and Lapacho Tea Wraps: A Case Report.

IntroductionDevelopment of singular keratoacanthoma (KA) is generally considered a benign condition as it has a tendency to regress spontaneously in spite of histological similarity to squamous cell carcinoma. Most KAs undergo excision to rule out differential diagnoses. Several alternative treatment modalities (keratinolytic, ablative, immunomodulating, antiproliferative, or targeted therapy) have been described in the past with varying success, underlining the therapeutic challenges associated with large or multiple lesions. Isomorphic response (Koebner phenomenon) may limit the efficacy of

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… Of note, genodermatoses such as Muir–Torre syndrome and xeroderma pigmentosum bear a dramatically increased risk for different cutaneous neoplasms, including KA. …