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Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.
Arai, H, Xiao, Y, Millstein, J, Wang, J, Battaglin, F, Kawanishi, N, Jayachandran, P, Soni, S, Zhang, W, Mancao, C, et al
British journal of cancer. 2022;(1):72-78
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BACKGROUND The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.
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Whole-genome sequencing revealed an interstitial deletion encompassing OCRL and SMARCA1 gene in a patient with Lowe syndrome.
Zheng, B, Chen, Q, Wang, C, Zhou, W, Chen, Y, Ding, G, Jia, Z, Zhang, A, Huang, S
Molecular genetics & genomic medicine. 2019;(9):e876
Abstract
BACKGROUND Lowe syndrome is a rare X-linked syndrome that is characterized by involvement of the eyes, central nervous system, and kidneys. The aim of the present study was to determine the molecular basis of four patients with congenital cataract, infantile congenital hypotonia, and proximal renal tubular defect. METHODS Four children who met the clinical manifestations of Lowe syndrome were enrolled in this study. Patients' clinical information on eyes, central nervous system, kidneys, and family histories, etc., were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of OCRL gene using direct sequencing. Because of failure of PCR amplification, low coverage shortread whole genome sequencing (CNVseq) analysis was performed on one proband. Real-time PCR was subsequently performed to confirm the CNV that was detected from the CNVseq results. RESULTS We identified three OCRL allelic variants, including two novel missense mutations (c.1423C>T/p.Pro475Ser, c.1502T>G/p.Ile501Ser) and one recurrent nonsense mutation (c.2464C>T/p.Arg822Ter). Various bioinformatic tools revealed scores associated with potential pathogenic effects for the two missense variants, and protein alignments revealed that both variants affected an amino acid highly conserved among species. Since deletion of the entire gene was suspected in a patient, CNVseq was used, identifying an interstitial deletion to approximately 190 kb, encompassing OCRL, and SMARCA1 gene. Moreover, the hemizygous CNV was confirmed by qPCR. Reviewing another case reported in the literature, we found that the deletion of OCRL and nearby genes may contribute to a more severe phenotype and premature death. CONCLUSIONS This is the first report of an interstitial deletion encompassing OCRL and SMARCA1 gene in Lowe syndrome. Our results expand the spectrum of mutations of the OCRL gene in Chinese population. Moreover, whole-genome sequencing presents a comprehensive and reliable approach for detecting genomic copy number variation in patients or carriers in the family with rare inherited disorders.
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HIF1A (rs11549465) and AKNA (rs10817595) Gene Polymorphisms Are Associated with Primary Sjögren's Syndrome.
Hernández-Molina, G, Rodríguez-Pérez, JM, Fernández-Torres, J, Lima, G, Pérez-Hernández, N, López-Reyes, A, Martínez-Nava, GA
BioMed research international. 2017;:5845849
Abstract
Objective. To evaluate the allele and genotype frequencies of polymorphic sites of HIF1A and ANKA genes in primary Sjögren's syndrome (pSS). Methods. We included 110 patients with pSS and 141 ethnically matched healthy controls. Three HIF1A gene polymorphisms (Pro582Ser, Ala588Thr, and C191T) and two AKNA gene polymorphisms (-1372C>A and Pro624Leu) were genotyped using TaqMan probes in a Real-Time PCR instrument. Associations between pSS and genotypes, alleles, and inheritance models of the SNPs of interest were evaluated by logistic regression adjusted by age and gender. Results. The C/T genotype and the T allele of the HIF1A Pro582Ser polymorphism protected against pSS (OR = 0.22; 95% CI = 0.09-0.52; P < 0.01; OR = 0.26; 95% CI = 0.12-0.58; P < 0.01, resp.), whereas under a recessive model adjusted by age and gender, the AKNA -1372C>A polymorphism A/A genotype was associated with an increased risk of pSS (OR = 2.60; 95% CI = 1.11-6.12; P = 0.03). Conclusions. We identified HIF1A Pro582Ser T allele and C/T genotype as well as AKNA -1372C>A polymorphism A/A genotype as genetic factors associated with pSS. Further studies in other populations are needed to validate our findings and research is warranted in order to shed some light on their functional implications across biological pathways in this disease.
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Skin collagen fluorophore LW-1 versus skin fluorescence as markers for the long-term progression of subclinical macrovascular disease in type 1 diabetes.
Sell, DR, Sun, W, Gao, X, Strauch, C, Lachin, JM, Cleary, PA, Genuth, S, , , Monnier, VM
Cardiovascular diabetology. 2016;:30
Abstract
BACKGROUND Skin collagen Long Wavelength Fluorescence (LWF) is widely used as a surrogate marker for accumulation of advanced glycation end-products. Here we determined the relationship of LWF with glycemia, skin fluorescence, and the progression of complications during EDIC in 216 participants from the DCCT. METHODS LW-1 and collagen-linked fluorescence (CLF) were measured by either High Performance Liquid Chromatography (HPLC) with fluorescence detection (LW-1) or total fluorescence of collagenase digests (CLF) in insoluble skin collagen extracted from skin biopsies obtained at the end of the DCCT (1993). Skin intrinsic fluorescence (SIF) was noninvasively measured on volar forearm skin at EDIC year 16 by the SCOUT DS instrument. RESULTS LW-1 levels significantly increased with age and diabetes duration (P < 0.0001) and significantly decreased by intensive vs. conventional glycemic therapy in both the primary (P < 0.0001) and secondary (P < 0.037) DCCT cohorts. Levels were associated with 13-16 year progression risk of retinopathy (>3 sustained microaneurysms, P = 0.0004) and albumin excretion rate (P = 0.0038), the latter despite adjustment for HbA1c. Comparative analysis for all three fluorescent measures for future risk of subclinical macrovascular disease revealed the following significant (P < 0.05) associations after adjusting for age, diabetes duration and HbA1c: coronary artery calcium with SIF and CLF; intima-media thickness with SIF and LW-1; and left ventricular mass with LW-1 and CLF. CONCLUSIONS LW-1 is a novel risk marker that is robustly and independently associated with the future progression of microvascular disease, intima-media thickness and left ventricular mass in type 1 diabetes. Trial registration NCT00360815 and NCT00360893 at clinicaltrials.gov.
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Immunocytochemical study of TOP2A and Ki-67 in cervical smears from women under routine gynecological care.
Peres, AL, Paz E Silva, KM, de Araújo, RF, de Lima Filho, JL, de Melo Júnior, MR, Martins, DB, de Pontes Filho, NT
Journal of biomedical science. 2016;(1):42
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BACKGROUND Cervical cancer is one of the most common female cancers and is caused by human papillomavirus (HPV). Viral infection leads to cell cycle deregulation by inactivating p53 and retinoblastoma protein by viral oncoproteins E6 and E7, respectively. Then, nuclear proteins such as DNA topoisomerase type IIa (TOP2A) and Ki-67 show increased expression because of increased cell division. These molecules are used as biomarkers for immunohistochemistry analysis of cervical tissue. METHODS In this cross-sectional study, we recruited 110 women receiving regular gynecological surveillance at public health centers in Olinda - PE, Brazil. Cervicovaginal cells were collected to determine the presence of cytological abnormalities and HPV infection. Pap smear slides were used to evaluate the expression of TOP2A and Ki-67 using immunocytochemistry techniques. RESULTS Of the 110 women, 75.4 % showed HPV-DNA(+) infection (83/110) and 29.1 % showed cellular abnormalities (32/110). Two atypical cells of undetermined significance, one low-grade squamous intraepithelial lesion, and one high-grade squamous intraepithelial lesion samples showed no HPV-DNA. TOP2A was positive in 71.9 % of samples, while Ki-67 was positive in 81.2 %. Immunocytochemistry results were positive in 4 of 5 atypical cells of undetermined significance samples. In HPV-DNA(+) samples with cytological abnormalities, immunocytochemistry results were positive 96.4 % of samples (p < 0.0001; odds ratio = 28.0). Among the samples infected with HR-HPV, TOP2A(+) was effective in 71 % samples, while and Ki-67(+) was 77.4 %. Ki-67 and TOP2A were positive for all samples infected with HPV6, HPV11, and HPV18. Ki-67 was also positive for all HPV16 samples, except for one negative sample in cytopathology analysis. CONCLUSIONS TOP2A and Ki-67 antibodies may be used in combination for cervical cancer screening in immunocytochemistry assays.
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Effect of lyso-phosphatidylcholine and Schnurri-3 on osteogenic transdifferentiation of vascular smooth muscle cells to calcifying vascular cells in 3D culture.
Castro-Chavez, F, Vickers, KC, Lee, JS, Tung, CH, Morrisett, JD
Biochimica et biophysica acta. 2013;(6):3828-34
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BACKGROUND In vitro cell culture is a widely used technique for investigating a range of processes such as stem cell behavior, regenerative medicine, tissue engineering, and drug discovery. Conventional cell culture is performed in Petri dishes or flasks where cells typically attach to a flat glass or plastic surface as a cell monolayer. However, 2D cell monolayers do not provide a satisfactory representation of in vivo conditions. A 3D culture could be a much better system for representing the conditions that prevail in vivo. METHODS AND RESULTS To simulate 3D conditions, vascular smooth muscle cells (VSMCs) were loaded with gold-polyvmer-iron oxide hydrogel, enabling levitation of the cells by using spatially varying magnetic fields. These magnetically levitated 3D cultures appeared as freely suspended, clustered cells which proliferated 3-4 times faster than cells in conventional 2D cultures. When the levitated cells were treated with 10nM lysophosphatidylcholine (LPC), for 3days, cell clusters exhibited translucent extensions/rods 60-80μm wide and 200-250μm long. When 0.5μg/μl Schnurri-3 was added to the culture containing LPC, these extensions were smaller or absent. When excited with 590-650nm light, these extensions emitted intrinsic fluorescence at >667nm. When the 3D cultures were treated with a fluorescent probe specific for calcium hydroxyapatite (FITC-HABP-19), the cell extensions/rods emitted intensely at 518nm, the λmax for FITC emission. Pellets of cells treated with LPC were more enriched in calcium, phosphate, and glycosaminoglycans than cells treated with LPC and Schnurri-3. CONCLUSIONS In 3D cultures, VSMCs grow more rapidly and form larger calcification clusters than cells in 2D cultures. Transdifferentiation of VSMC into calcifying vascular cells is enhanced by LPC and attenuated by Schnurri-3. GENERAL SIGNIFICANCE The formation of calcified structures in 3D VSMC cultures suggests that similar structures may be formed in vivo.
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Associations between TS, TTF-1, FR-α, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy.
Grønberg, BH, Lund-Iversen, M, Strøm, EH, Brustugun, OT, Scott, H
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2013;(10):1255-64
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INTRODUCTION Pemetrexed is effective in the treatment of non-small-cell lung cancer, mainly in nonsquamous cell carcinomas. Inhibition of thymidylate synthase (TS) is considered the key mechanism of action. Folate receptor-α facilitates uptake of pemetrexed. Polyglutamation by folylpolyglutamate synthetase enhances activity and prolongs cellular retention of pemetrexed. Thyroid transcription factor-1 (TTF-1) is mainly positive in nonsquamous cell carcinoma and has been proposed as a marker for sensitivity to pemetrexed. The aim was to investigate associations between these biomarkers and survival in patients who participated in a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer (n = 436). In this study, there was no difference in overall survival between the two regimens. METHODS Formalin-fixed, paraffin-embedded biopsies were collected. Percentages of tumor cells positive and highly positive for the biomarkers were assessed using immunohistochemistry (IHC) and an IHC score was calculated (range, 0-200). RESULTS Two hundred thirty-six biopsies were analyzed (pemetrexed plus carboplatin: n = 114, gemcitabine plus carboplatin: n = 122). There was a significant difference in overall survival between those with TTF-1-positive and -negative tumors (10.4 versus 6.0 months; p < 0.001) and those with a low and a high TS IHC score (9.7 versus 6.2 months; p < 0.001). Folate receptor-α and folylpolyglutamate synthetase were not significant prognostic factors. In multivariate analyses adjusting for established prognostic characteristics, TS (p = 0.002) and TTF-1 (p = 0.003) remained significant. There were no differences in survival between the treatment arms depending on biomarker scores. CONCLUSIONS TTF-1 positivity and low TS level were associated with prolonged survival. The associations between the biomarkers and overall survival were similar for both chemotherapy regimens.
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Genetic polymorphism of XRCC1 correlated with response to oxaliplatin-based chemotherapy in advanced colorectal cancer.
Lv, H, Li, Q, Qiu, W, Xiang, J, Wei, H, Liang, H, Sui, A, Liang, J
Pathology oncology research : POR. 2012;(4):1009-14
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To examine the association between genetic polymorphisms of XRCC1 Arg399Gln(G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients(37 stage III, 62 stage IV)with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by TaqMan-MGB probe allelic discrimination method. And clinical response of 62 patients in stage IVafter 2 to 3 cycles of chemotherapy were evaluated. Also time to progress (TTP) of all patients were evaluated. Of the genotype frequencies in all patients, up to 52.53 % were G/G genotype, 9.09 % were A/A genotype, and 38.38 % were G/A genotype. The response rate (CR+PR) of 62 patients in stage IV was 61.29 % (19/31). Patients with G/G genotype showed enhanced respond to chemotherapy compared to those with G/A+A/A (x(2) = 5.6, P = 0.029; OR = 3.845, 95 %CI = 1.231 ~ 12.01, P = 0.018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, those with the G/A+A/A genotype had an TTP of 5.0(4.26-5.74) months. The log-rank test was marginally significant (x(2) = 29.20, P < 0.01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen, showed that only XRCC1 G/G genotypes increases the OR significantly (OR = 3.555; 95 % CI, 2.119 ~ 5.963; P < 0.01). The results suggest that XRCC1 Arg399Gln polymorphisms is associated with the response to oxaliplatin-based chemotherapy and time to progression in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely benefit from oxaliplatin-based treatment.
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Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin.
Salek, L, Lutucuta, S, Ballantyne, CM, Gotto, AM, Marian, AJ
Journal of molecular medicine (Berlin, Germany). 2002;(11):737-44
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Sterol regulatory elements binding factor-1a (SREBF-1a) and SREBF cleavage activating protein (SCAP) regulate lipids homeostasis. Polymorphisms in SREBF-1a and SCAP could affect plasma levels of lipids and risk of atherosclerosis. We determined association of SREBF-1a -36del/G and SCAP 2386A/G genotypes with plasma levels of lipids, severity and progression/regression of coronary atherosclerosis, and response to treatment with fluvastatin in a well-characterized Lipoprotein Coronary Atherosclerosis Study population. Plasma lipids and quantitative indices of coronary atherosclerosis were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo in 372 subjects. Fluvastatin reduced plasma levels of total cholesterol by 16%, LDL-C by 25%, and ApoB by 16% and increased plasma levels of HDL-C by 9% and apoA-1 by 7%. Distributions of SREBF-1a SCAP genotypes were 60 GG, 172 del-G and 140 del-del and 88 GG, 188 GA and 96 AA, respectively. There were no significant differences in baseline plasma levels of lipids or indices of severity of atherosclerosis among the genotypes of each gene. There was a strong graded genotype-treatment interaction between SREBF-1a genotypes and change in apoA-I levels in response to fluvastatin (16.5% increase in GG, 10.5% in del/G, and 0.4% in del/del groups). Modest interactions between SREBF-1a genotypes and changes in HDL-C, and apoC-III levels in response to fluvastatin were also present. No genotype-treatment interaction for progression or regression of coronary atherosclerosis was detected. There were no significant interactions between SCAP genotypes and response to therapy. Thus we detected a strong graded interaction between SREBF-1a -36del/G genotypes and response of plasma apoA-I to treatment with fluvastatin.