共查询到20条相似文献,搜索用时 15 毫秒
1.
Urvi M. Parikh Kerri J. Penrose Amy L. Heaps Elias K. Halvas B. Jay Goetz Kelley C. Gordon Russell Hardesty Rahil Sethi William Schwarzmann Daniel W. Szydlo Marla J. Husnik Uma Chandran Thesla PalaneePhillips Jared M. Baeten John W. Mellors the MTN Study Team 《Journal of the International AIDS Society》2021,24(11)
2.
Ujjwal Neogi Anita Shet Pravat Nalini Sahoo Irene Bontell Maria L Ekstrand Akhil C Banerjea Anders Sonnerborg 《Journal of the International AIDS Society》2013,16(1)
Introduction
Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).Methods
In 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G-mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations.Results
hA3G/F-mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naïve individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naïve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA.Conclusions
hA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo. 相似文献3.
Kevin E. Fisher Jigna C. Jani Sarah B. Fisher Cora Foulks Charles E. Hill Collin J. Weber Cynthia Cohen Jyotirmay Sharma 《The Journal of surgical research》2013
Background
Epidermal growth factor receptor (EGFR) overexpression (EGFR-H) is implicated in thyroid carcinoma disease progression; however, the clinicopathologic significance of EGFR-H in tumors that harbor EGFR and/or v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)(V600E) mutations is unknown.Methods
Tissue microarrays from 81 patients who had undergone thyroidectomy for carcinoma from 2002–2011 were scored for EGFR expression using immunohistochemistry. Somatic mutations in EGFR exons 19 and 21 and BRAF were analyzed. Correlations between the EGFR immunohistochemistry, EGFR, and BRAF(V600E) mutations and the clinicopathologic features were assessed.Results
EGFR-H was detected in 39.5% of carcinomas (n = 32) from patients with papillary (PTC, 46.2%, n = 18), follicular (29.6%, n = 8), and anaplastic (100.0%, n = 6) but not medullary (0.0%, n = 9) thyroid carcinoma. BRAF(V600E) mutations were identified in 22.2% of the carcinoma cases (n = 18, 15 PTCs and 3 anaplastic thyroid carcinomas). No somatic EGFR mutations were detected in any subtype. On PTC univariate analysis, EGFR-H correlated with increasing stage, extrathyroid extension, tumor capsule invasion, adverse pathologic features (any demonstration of extrathyroid extension, tumor capsule invasion, lymphovascular invasion, lymph node metastasis, and/or distant metastasis), and BRAF(V600E) mutations. On multivariate analysis, EGFR-H correlated with BRAF(V600E) mutations. In BRAF wild-type PTCs, the correlation between EGFR-H and adverse pathologic features approached statistical significance (P = 0.065).Conclusions
EGFR-H could be an important biomarker for aggressive PTCs, particularly in BRAF wild-type PTCs. Despite EGFR-H in PTC, follicular thyroid carcinoma, and anaplastic thyroid carcinoma by immunohistochemistry, somatic EGFR mutations were absent. Therefore, future investigations of EGFR should consider histologic and immunohistochemical methods, in addition to molecular profiling of thyroid carcinomas. This multimodal approach is particularly important for future clinical trials testing anti-EGFR therapy. 相似文献4.
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Stéphanie Moreau MD Philippe Saiag MD PhD Philippe Aegerter MD PhD Daphné Bosset MD Christine Longvert MD Zofia Hélias-Rodzewicz PhD Cristi Marin MD Frédérique Peschaud MD PhD Sophie Chagnon MD PhD Utte Zimmermann MD Thierry Clerici MD Jean-Fran?ois Emile MD PhD 《Annals of surgical oncology》2012,19(13):4314-4321
Purpose
BRAF V600 mutations are frequent in melanomas, and BRAFV600-targeted therapy have dramatic, but often transitory, efficacy in stage IV patients. Prognosis of patients with American Joint Committee on Cancer (AJCC) stage III melanoma is heterogeneous. We aimed to determine the overall survival (OS) of stage III patients with a nodal deposit of ??2?mm according to BRAF V600 mutations and other previously reported prognostic criteria.Methods
This retrospective study included 105 consecutive patients with stage III cutaneous melanomas. Most patients underwent a prospective follow-up. BRAF V600 mutations were detected by sequencing and pyrosequencing of DNA in samples containing >60?% melanoma cells.Results
BRAF mutations (p.V600E and p.V600K in 83 and 14?% of cases, respectively) were detected in 40?% of the patients. For patients with and without BRAF mutations, death occurred in 83.3 and 60.3?%, with a median OS of 1.4 and 2.8?years, respectively. Patient age, primary melanoma ulceration, number of invaded lymph nodes, AJCC staging at study entry, and BRAF status were linked to OS in the univariate analysis. The only characteristics associated with OS in the multivariate analysis were number of invaded lymph nodes (P?=?0.005, hazard ratio 2.2, 95?% confidence interval 1.3?C3.9) and BRAF status (P?=?0.005, hazard ratio 1.9, 95?% confidence interval 1.2?C3.1).Conclusions
BRAF V600 status could be used to stage melanoma patients with nodal deposits. Our results may also help to plan adjuvant trials in these patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. 相似文献7.
Turun Song Lei Fu Zixing Huang Shaofeng He Ruining Zhao Tao Lin Qiang Wei 《International urology and nephrology》2014,46(4):743-747
Purpose
Uninephrectomy would induce compensatory hypertrophy in the remaining kidney. We investigated the relationship between changes in renal parenchymal volume (RPV) and renal function after nephrectomy in living kidney donors.Methods
From July 2011 and January 2012, 45 kidney donors were enrolled in this study. Magnetic resonance scanning was performed before surgery, 3 and 7 days postoperatively, and RPV was calculated through disc summarize methods. Participants were followed up for 1 year.Results
The RPV of the remaining kidney was 118.06 ± 23.51 cm3 and then increased by 21.23 % to 143.13 ± 25.52 cm3 at 3 days and by 24.17 % to 146.60 ± 25.86 cm3 at 7 days. Multivariate regression analysis showed that preoperative RPV is positively related to its initial function (p = 0.037); the RPV at 7 days is directly related to its initial, preoperative size (p < 0.001). With respect to change in postoperative RPV, there is bigger gain in size in smaller kidneys (p = 0.005). The kidneys that has ≥20 % increase RPV after 7 days are more likely to show further increase in GFR at 1 year (p = 0.024).Conclusions
Uninephrectomy induced immediately increment in RPV of the remaining kidney. Donors with RPV increase of ≥20 % at 1 week have a more favourable renal function adaptation at 1 year. 相似文献8.
9.
Aim Biallelic MutY human homologue (MUTYH) germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH‐associated polyposis (MAP), and colorectal cancer (CRC). The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants of MUTYH in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in a prospective cohort of unselected patients with different colorectal diseases. Method The hotspot mutations p.Y179C and p.G396D were genotyped in 352 consecutive patients undergoing colonoscopy at our tertiary referral centre. Exons 2–14 were sequenced in hotspot mutation carriers to exclude additional variants. Results Overall, we identified five heterozygous p.Y179C mutations and three heterozygous p.G396D mutations in seven hotspot mutation carriers (risk allele frequencies 0.7% and 0.4%, respectively). Two of these hotspot mutation carriers harboured a heterozygous p.Q338H variant, which is of uncertain clinical significance, on the other allele. Three individuals were biallelic MUTYH variant carriers (p.Y179C/p.G382D: typical MAP; p.Y179C/p.Q338H: atypical MAP with late onset and lower polyp burden; p.G382D/p.Q338H: inflammatory bowel disease), and four subjects were monoallelic mutation carriers. Conclusion MUTYH‐associated disease, and hence genetic counselling and MUTYH genetic testing, should be considered in the clinical routine of an endoscopy unit, but the wide range of phenotypes represents a challenge for patient identification. The clinical significance of p.Q338H should be evaluated in future case–control studies because compound heterozygotes for pathogenic mutations and p.Q338H may be at increased risk for mild polyposis or CRC. In addition, MUTYH should be assessed as a potential susceptibility gene for the development of colitis‐associated CRC in future. 相似文献
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Khairun I. Abdul-Jalil MRCSI Katherine M. Sheehan FRCPath Sinead Toomey PhD Jasmin Schmid MSc Jochen Prehn PhD Anthony O’Grady PhD Robert Cummins BSc Brian O’Neill FFRRCSI Deborah A. McNamara FRCSI Joseph Deasy FRCSI Oscar Breathnach FRCPI Liam Grogan FRCPI Ailin Rogers MRCSI Glen Doherty FRCPI Des Winter FRCSI John Ryan FRCPath Sherif El-Masry FRCSI David Gibbons FCAP Kieran Sheahan FRCPath Peter Gillen FRCSI Elaine W. Kay FRCPath Bryan T. Hennessy MD 《Annals of surgical oncology》2014,21(8):2642-2649
Background
Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes.Methods
We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway–related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform. DNA samples were extracted from pretreatment LARC biopsy samples taken from 201 patients who were then treated with long-course neoadjuvant CRT followed by surgical resection.Results
Sixty-two mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (47 %), PIK3CA (14 %), STK11 (6.5 %), and CTNNB1 (6 %). Mutations were detected in BRAF, NRAS, AKT1, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK, and TNK2, but at frequencies of <5 %. As expected, a pathologic complete response (pCR) was associated with improved 5-year recurrence-free survival (RFS; hazard ratio, 0.074; 95 % CI 0.01–0.54; p = 0.001). Mutations in PI3K pathway–related genes (odds ratio, 5.146; 95 % CI 1.17–22.58; p = 0.030), but not MAPK pathway–related genes (p = 0.911), were associated with absence of pCR after neoadjuvant CRT. In contrast, in patients who did not achieve pCR, mutations in PI3K pathway–related genes were not associated with recurrence-free survival (p = 0.987). However, in these patients, codon 12 (G12D/G12 V/G12S) and 13 mutations in KRAS were associated with poor recurrence-free survival (hazard ratio, 1.579; 95 % confidence ratio, 1.00–2.48; p = 0.048).Conclusions
Mutations in kinase signaling pathways modulate treatment responsiveness and clinical outcomes in LARC and may constitute rational targets for novel therapies. 相似文献11.
Satoru Yamaguchi Hideo Ogata Daisuke Katsumata Masanobu Nakajima Takaaki Fujii Soichi Tsutsumi Takayuki Asao Kinro Sasaki Hiroyuki Kuwano Hiroyuki Kato 《Surgery today》2014,44(4):593-600
MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10–100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis. 相似文献
12.
Andrea Kerti Rózsa Csohány Attila Szabó Ottó Árkossy Péter Sallay Vincent Moriniére Virginia Vega-Warner Gábor Nyírő Orsolya Lakatos Tamás Szabó Beata S. Lipska Franz Schaefer Corinne Antignac George Reusz Tivadar Tulassay Kálmán Tory 《Pediatric nephrology (Berlin, Germany)》2013,28(5):751-757
Background
The most frequently mutated gene of steroid-resistant nephrotic syndrome (SRNS) is NPHS2. Current guidelines propose the sequencing of all NPHS2 exons only in childhood-onset SRNS.Methods
A cohort of 38 Hungarian patients with childhood-onset nephrotic-range proteinuria was screened for NPHS2 mutations. The frequency of the p.V290M mutation in late-onset SRNS was examined in the French and PodoNet cohorts.Results
Of the 38 Hungarian patients screened, seven carried NPHS2 mutations on both alleles, of whom two—diagnosed with proteinuria through school screening programs at the age of 9.7 and 14 years, respectively—did not develop nephrotic syndrome in childhood. The first, an 18-year-old boy, homozygous for p.V290M, has never developed edema. The second, a 31-year-old woman—compound heterozygous for p.V290M and p.R138Q—was first detected with hypoalbuminemia (<30 g/l) and edema at the age of 24.3 and 27.5 years, respectively. Both patients currently have a normal glomerular filtration rate. The mutation p.V290M was carried by three of the 38 patients in the Hungarian cohort, by two of the 95 patients with late-onset SRNS in the PodoNet cohort and by none of the 83 patients in the French cohort.Conclusions
We propose that not only the p.R229Q variant, but also the p.V290M mutation should be screened in Central and Eastern European patients with late-onset SRNS. 相似文献13.
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Jennifer Guimbellot George M. Solomon Arthur Baines Sonya L. Heltshe Jill VanDalfsen Elizabeth Joseloff Scott D. Sagel Steven M. Rowe 《Journal of cystic fibrosis》2019,18(1):102-109
Background
The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non-G551D gating mutations.Methods
Patients with non-G551D gating mutations were recruited to an open-label study evaluating ivacaftor. Primary outcomes included: lung function, sweat chloride, weight gain, and quality of life scores.Results
Twenty-one subjects were enrolled and completed 6?months follow-up on ivacaftor; mean age was 25.6?years with 52% <18. Baseline ppFEV1 was 68% and mean sweat chloride 89.6?mEq/L. Participants experienced significant improvements in ppFEV1 (mean absolute increase of 10.9% 95% CI?=?[2.6,19.3], p?=?0.0134), sweat chloride (?48.6 95% CI?=?[?67.4,-29.9], p?<?0.0001), and weight (5.1?kg, 95% CI?=?[2.8, 7.3], p?=?0.0002).Conclusions
Patients with non-G551D gating mutations experienced improved lung function, nutritional status, and quality of life. This study supports ongoing use of ivacaftor for patients with these mutations. 相似文献15.
Mao-Song Tsai Chia-Jui Yang Nan-Yao Lee Szu-Min Hsieh Yu-Hui Lin Hsin-Yun Sun Wang-Huei Sheng Kuan-Yeh Lee Shan-Ping Yang Wen-Chun Liu Pei-Ying Wu Wen-Chien Ko Chien-Ching Hung 《Journal of the International AIDS Society》2014,17(1)
Introduction
The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated.Methods
In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance.Results
The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the macrolide resistance mutation (A2058G). In subgroup analyses confined to the 75 patients infected with T. pallidum lacking resistance mutation, a statistically significantly lower risk for the Jarisch-Herxheimer reaction following azithromycin treatment was noted.Conclusions
Treatment with azithromycin was associated with a lower risk for the Jarisch-Herxheimer reaction than that with benzathine penicillin G in HIV-positive patients with early syphilis. Previous benzathine penicillin G therapy for syphilis decreased the risk, whereas higher RPR titres increased the risk, for the reaction. 相似文献16.
Background
Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate‐resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?Methods
A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.Results
Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2‐4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.Conclusion
Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.17.
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Introduction
HIV-1 near full-length genome (HIV-NFLG) sequencing from plasma is an attractive multidimensional tool to apply in large-scale population-based molecular epidemiological studies. It also enables genotypic resistance testing (GRT) for all drug target sites allowing effective intervention strategies for control and prevention in high-risk population groups. Thus, the main objective of this study was to develop a simplified subtype-independent, cost- and labour-efficient HIV-NFLG protocol that can be used in clinical management as well as in molecular epidemiological studies.Methods
Plasma samples (n=30) were obtained from HIV-1B (n=10), HIV-1C (n=10), CRF01_AE (n=5) and CRF01_AG (n=5) infected individuals with minimum viral load >1120 copies/ml. The amplification was performed with two large amplicons of 5.5 kb and 3.7 kb, sequenced with 17 primers to obtain HIV-NFLG. GRT was validated against ViroSeq™ HIV-1 Genotyping System.Results
After excluding four plasma samples with low-quality RNA, a total of 26 samples were attempted. Among them, NFLG was obtained from 24 (92%) samples with the lowest viral load being 3000 copies/ml. High (>99%) concordance was observed between HIV-NFLG and ViroSeq™ when determining the drug resistance mutations (DRMs). The N384I connection mutation was additionally detected by NFLG in two samples.Conclusions
Our high efficiency subtype-independent HIV-NFLG is a simple and promising approach to be used in large-scale molecular epidemiological studies. It will facilitate the understanding of the HIV-1 pandemic population dynamics and outline effective intervention strategies. Furthermore, it can potentially be applicable in clinical management of drug resistance by evaluating DRMs against all available antiretrovirals in a single assay. 相似文献19.
《Renal failure》2013,35(8):1329-1337
AbstractWhile many previous studies have reported an association between the single-nucleotide polymorphisms (SNPs) of the podocin and proteinuria occurred, a conclusive relationship has not been defined in every oligoallelic state of amino acid (AA) mutations in podocin. In this study, we performed a meta-analysis of the published data to investigate the impact of the oligoallelic AA mutations of the podocin on proteinuria; a total 16 AA mutations were investigated for oligoallelic pathogenicity. Despite significant heterogeneity within some of the comparisons, the results revealed significantly higher risks of proteinuria in early-onset (onset age <16) individuals for five mutations (P118L, R138Q, R168H, V180M, and V260E), and in all onset ages individuals for five mutations (R138Q, G140X, R229Q, V260E, and V290M) compared to non-variant individuals. We also tested the steroid response in individuals with R229Q and E237Q. No statistically significant differences in the two mutations carrier rate were observed between steroid resistance patients and controls. No AA mutation was selected for meta-analysis on the recurrence of proteinuria after renal transplantation as lack of control data. In conclusion, our meta-analysis tested the pathogenicity of the oligoallelic AA mutations in podocin and suggested the potential causative mutations, and the alleles showing an association with protein susceptibility. The sensitivity and specificity of each causative mutation are pending further testing. 相似文献
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