Статті в журналах: "T-ARMS-PCR"

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Piccioli, Patrizia, Martina Serra, Viviana Gismondi, Simona Pedemonte, Fabrizio Loiacono, Sonia Lastraioli, Lucio Bertario, Maria De Angioletti, Liliana Varesco, and Rosario Notaro. "Multiplex Tetra-Primer Amplification Refractory Mutation System PCR to Detect 6 Common Germline Mutations of the MUTYH Gene Associated with Polyposis and Colorectal Cancer." Clinical Chemistry 52, no. 4 (April 1, 2006): 739–43. http://dx.doi.org/10.1373/clinchem.2005.060137.

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Abstract Background: We describe a simple tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) for detecting MUTYH mutations, which are associated with colorectal adenomas and colorectal cancer. Methods: We designed specific T-ARMS-PCR assays for 6 mutations (Y165C, G382D, 1395_7delGGA, Y90X, 1103delC, and R231H) selected on the basis of the frequency of their occurrence. We also designed a set of 3 multiplex T-ARMS PCR assays, each for detection of 2 mutations. We tested DNA samples from patients with attenuated or classic adenomatous polyposis coli and no detectable APC germline mutations. Results: All mutations were easily detected with both the specific and multiplex T-ARMS-PCR assays. Results were confirmed by DNA HPLC analysis in all 54 patients, and each mutation was confirmed by direct DNA sequencing. Conclusions: T-ARMS-PCR does not require any special equipment, and it provides rapid, reproducible, and cost-effective detection of common MUTYH mutations. Multiplex T-ARMS-PCR allows the detection of 6 common MUTYH mutations with use of as few as 3 single tube PCR reactions. It could be useful to carry out large population-based epidemiologic studies.

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Paul, Saikat, Rajneesh Dadwal, Shreya Singh, Dipika Shaw, Arunaloke Chakrabarti, Shivaprakash M. Rudramurthy, and Anup K. Ghosh. "Rapid detection of ERG11 polymorphism associated azole resistance in Candida tropicalis." PLOS ONE 16, no. 1 (January 13, 2021): e0245160. http://dx.doi.org/10.1371/journal.pone.0245160.

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Increasing reports of azole resistance inCandida tropicalis, highlight the development of rapid resistance detection techniques. Nonsynonymous mutations in the lanosterol C14 alpha-demethylase (ERG11) gene is one of the predominant mechanisms of azole resistance inC.tropicalis. We evaluated the tetra primer-amplification refractory mutation system-PCR (T-ARMS-PCR), restriction site mutation (RSM), and high-resolution melt (HRM) analysis methods for rapid resistance detection based onERG11polymorphism inC.tropicalis. Twelve azole-resistant and 19 susceptible isolates ofC.tropicaliswere included. DNA sequencing of the isolates was performed to check theERG11polymorphism status among resistant and susceptible isolates. Three approaches T-ARMS-PCR, RSM, and HRM were evaluated and validated for the rapid detection ofERG11mutation. The fluconazole MICs for the 12 resistant and 19 susceptible isolates were 32–256 mg/L and 0.5–1 mg/L, respectively. The resistant isolates showed A339T and C461T mutations in theERG11gene. The T-ARMS-PCR and RSM approaches discriminated all the resistant and susceptible isolates, whereas HRM analysis differentiated all except one susceptible isolate. The sensitivity, specificity, analytical sensitivity, time, and cost of analysis suggests that these three methods can be utilized for the rapid detection ofERG11mutations inC.tropicalis. Additionally, an excellent concordance with DNA sequencing was noted for all three methods. The rapid, sensitive, and inexpensive T-ARMS-PCR, RSM, and HRM approaches are suitable for the detection of azole resistance based onERG11polymorphism inC.tropicalisand can be implemented in clinical setups for batter patient management.

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Pua, Jing Yit, Ang Lee, Vienna Zi Wei Khor, Thanaseelan Pushpanathan, Abdul Aziz Mohamed Yusoff, Zamzuri Idris, and Azim Patar. "Development of a sensitive, specific and cost-effective T-ARMS PCR assay for the genotyping of R132H of IDH1 gene in glioma patients." Asian Journal of Medicine and Biomedicine 6, S1 (November 9, 2022): 61–63. http://dx.doi.org/10.37231/ajmb.2022.6.s1.528.

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The discovery of isocitrate dehydrogenase isoform 1 (IDH1) mutation as a key molecular marker has resulted in a change in glial tumour classification [1]. IDH1 mutations are commonly in gliomas, particularly in low-grade gliomas and secondary glioblastoma [2]. IDH1 p.R132H (c.395G>A) accounted for more than 90% of the mutation in IDH1/2 mutation and had a significant association with clinical outcomes. IDH1/2 mutations cause gain-of-function resulting in the formation of an oncometabolite, R-2-hydroxyglutarate instead of α-ketoglutarate implying a disruption of oxidative decarboxylation of Kreb’s cycle and other cellular mechanisms [3,4,5]. Immunohistochemistry (IHC) and Sanger sequencing is the most common approach used in molecular diagnostics. Nevertheless, both IHC and Sanger sequencing methods have shortcomings. IHC is prone to miss out on the mutation if the tumour samples are of poor quality, and it has also been reported to have low sensitivity when compared to sequencing-based techniques [6,7]. This study aimed to develop a sensitive, specific and cost-effective assay for genotyping IDH1 p.R132H mutations in glioma patients in order to shorten the time required for confirmatory diagnosis to be made. The tetra primer amplification refractory mutation system polymerase chain reaction (T-ARMS PCR) was used in this study to develop and validate the clinical applicability of the assay. A total of 61 glial specimens were collected and genomic DNA was isolated from all of them. All the samples were subjected to endpoint PCR and Sanger sequencing for mutation detection. T-ARMS PCR was developed and optimized prior to the screening of all the samples, and comparative mutation analysis was carried out. Overall, IDH1 p.R132H mutation was found to be 45.90% (n=28/61) prevalent and was found to be significantly associated with gender, tumour subtypes and grading, and location of the lesions (p=<0.05). With an F1 score of 0.966, we reported T-ARMS PCR with sensitivity, specificity and accuracy of 100% (95% CI: 87.94-100.00%), 93.94% (95% CI: 80.39-98.92%) and 96.72%, respectively. To compare with published studies, a meta-analysis is T-ARMS PCR detected one case with IDH1 p.R132C (c.394C>T), howbeit the case could have a double mutation of p.R132C (c.394C>T) and p.R132H (c.395G>A) or single mutation of p.R132Y (c.394_395CG>TA). However, this study was able to detect IDH1 p.R132G (c.394C>G) mutation via PCR by Sanger sequencing whereas T-ARMS PCR excluded the mutation, suggesting the assay is very specific to IDH1 p.R132HH (c.395G>A) only. Hereby, the performance of the T-ARMS PCR assay sheds a light that can be adapted for preoperative or intraoperative diagnosis.

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Harbeck, Nadia, Raquel von Schumann, Ronald Ernest Kates, Michael Braun, Sherko Kuemmel, Claudia Schumacher, Jochem Potenberg, et al. "Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer." Cancers 13, no. 19 (September 29, 2021): 4884. http://dx.doi.org/10.3390/cancers13194884.

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Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.

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Li, Mingxun, Xiaomei Sun, Jing Jiang, Yujia Sun, Xianyong Lan, Chuzhao Lei, Chunlei Zhang, and Hong Chen. "Tetra-primer ARMS-PCR is an efficient SNP genotyping method: An example from SIRT2." Anal. Methods 6, no. 6 (2014): 1835–40. http://dx.doi.org/10.1039/c3ay41370e.

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We have successfully genotyped a new identified bovine SIRT2 SNP g.4140A > G by T-ARMS-PCR method and validated the accuracy by PCR-RFLP assay using 1255 animals representing the five main Chinese breeds.

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Nagayama, Aiko, Tetsu Hayashida, Koji Okabayashi, Hiromitsu Jinno, Maiko Takahashi, Tomoko Seki, Akiko Matsumoto, Takeshi Murata, and Yuko Kitagawa. "A network meta-analysis assessing the comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e11598-e11598. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e11598.

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e11598 Background: The growing number of anti-HER2 agents suggests the eventual need for defining the optimal choice of neoadjuvant therapy for HER2-positive breast cancer. Multiple-treatments meta-analysis synthesizes information from a network of trials and combines direct and indirect evidence on the relative effectiveness. An indirect estimate of the benefit of A over B can be obtained by comparing trials of A v C with trials of B v C. In this study, we assessed the efficacy and safety of neoadjuvant therapy for HER2-positive breast cancer by conducting the direct and indirect comparisons from multiple RCTs. Methods: The primary outcome of the study was the number of the patients who achieved pathological complete response (pCR) defined as no invasive residual in breast or node. Secondary objectives were the number of patients who completed the treatment as planned and adverse events including diarrhea, neutropenia, cardiac events and skin disorder. Results: We identified 1047 articles by database search and 10 studies met our criteria. A total of 2247 patients in 7 different treatment arms were assessed; chemotherapy (CT) alone, CT with single or dual anti-HER2 agents and dual anti-HER2 agents without CT. Anti-HER2 agents evaluated were trastuzumab (T-mab), lapatinib, pertuzumab (P-mab). There was no significant difference between dual targeting treatment arms (CT + T-mab + lapatinib v CT + T-mab + P-mab, OR; 1.11, [0.42-2.86], p=0.41), however, lapatinib reduced the treatment completion mainly due to adverse events. Patients in dual targeting arms had significantly higher incidence of pCR than in other treatment arms. (CT + T-mab + P-mab v CT + T-mab, OR; 2.29, [1.02-5.02], p=0.02) Surface under the cumulative ranking probability curve (SUCRA) also indicated that CT + T-mab + P-mab had the highest probability of being the best treatment arm for pCR followed by CT + T-mab + lapatinib and CT + T-mab. Conclusions: This study provides evidence that combining two anti-HER2 agents with chemotherapy are the most effective treatment arms. Considering the cost and limited medical resources, CT + T-mab showed a well-balanced profile for efficacy, completion and safety.

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Muñoz-García, Canuto, Obdulia L. Segura-León, Julio C. Gómez-Vargas, Juan González-Maldonado, Juan A. Quintero-Elisea, Juan F. Martínez-Montoya, and Cesar Cortez-Romero. "Investigating mutations in the genes GDF9 and BMP15 in Pelibuey sheep through the amplification-refractory mutation system with tetra-primers." Austral Journal of Veterinary Sciences 55, no. 3 (September 22, 2023): 182–88. http://dx.doi.org/10.4206/ajvs.553.04.

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Single Nucleotide Polymorphisms (SNP) or mutations are variations with a broad distribution in the genome and, as part of genetic studies, SNP allow the identification of allelic variants related to characteristics of economic importance in sheep production. However, the identification of SNP and their genotypes through sequencing is expensive, as it requires specialized materials and equipment. The objective of this study was to identify polymorphisms and their genotypes in the growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes in Pelibuey sheep using the tetra-primer amplification-refractory mutation system through polymerase chain reaction (T-ARMS-PCR). DNA extraction and amplification of BMP15 and GDF9 were conducted from blood samples contained in WhatmanTM FTATM cards from 60 multiparous Pelibuey ewes with reproductive records. The T-ARMS-PCR methodology allowed the identification of wild-type genotypes and mutated homozygous genotypes in polymorphisms G4 and G6 of GDF9, whereas mutations in the BMP15 gene were not found. These results were confirmed by sequencing. In conclusion, the T-ARMS-PCR methodology allowed the identification of mutated and wild-type genotypes in SNP G4 and G6 of GDF9, although no mutations were found in BMP15 in Pelibuey sheep. This technique was found to be reliable, rapid, and easily applied to identify polymorphic genotypes.

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Motta, B. M., P. Dongiovanni, S. Fargion, and L. Valenti. "T-ARMS-PCR for the evaluation of rs12979860 IL28B genotype: an optimized protocol." Journal of Viral Hepatitis 19, no. 3 (February 13, 2012): 228. http://dx.doi.org/10.1111/j.1365-2893.2012.01582.x.

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Marty, M. E., J. Guinebretiere, M. Mathieu, B. Sigal-Zafrani, A. De Roquancourt, M. Spielmann, S. Giacchetti, P. De Cremoux, F. Spyratos, and B. Asselain. "Triple-negative phenotype is a strong predictor of sensitivity to epirubicin-cyclophosphamide (EC) then docetaxel (D) (ECD) primary chemotherapy (PCT) for localized breast cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21128. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21128.

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21128 Background: Molecular markers (GEP, p53 mutations,) could overcome usual predictors (size, pathology, Hormone receptors, HER2) in identifying patients (pts) experiencing complete pathological response (pCR) with anthracyclin based chemotherapy (Clin.Cancer Res., 2004, 10 6789). We aimed at validating and refining these finding in pts treated with ECD. Methods: From 05/2004 to 04/2006 170 pts not amenable to Breast Conserving Therapy and/or with high evolutive potential were randomly allocated to EC (75/750mg/sqm)x4 then D (100 mg/sqm)x 4 (with or without celecoxib in HER2-ve or trastuzumab (T) in HER2+ve. The primary endpoint - absence of residual invasive breast carcinoma and of nodal involvement (pCR)- was to be correlated with usual predictors , phenotype, GEP and p53 mutations assessed from core biopsies. pCR ranged from 13 to 14% in the arms without T thus without suggestion of a difference between these arms. pCR in the 30 HER2+ve pts having received ECD + T was 30% (NS). Results in 135 fully evaluable pts not allocated to T and having undergone secondary surgery are analyzed. Results: Main predictors and related pCR are shown in the table below Results of ongoing molecular analysis will be reported. Conclusions: Expression of ER appears to be the major prognosticator for ECD induced pCR. Triple negative breast cancers experience the highest pCR rate (p< 0.0001) (chi2 test with Yates correction). Molecular studies to be presented will show if GEP and/or p53 mutations could allow to improve such prediction. [Table: see text] No significant financial relationships to disclose.

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Poe, Brian L., Doris M. Haverstick, and James P. Landers. "Warfarin Genotyping in a Single PCR Reaction for Microchip Electrophoresis." Clinical Chemistry 58, no. 4 (April 1, 2012): 725–31. http://dx.doi.org/10.1373/clinchem.2011.180356.

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Abstract BACKGROUND Warfarin is the most commonly prescribed oral anticoagulant medication but also is the second leading cause of emergency room visits for adverse drug reactions. Genetic testing for warfarin sensitivity may reduce hospitalization rates, but prospective genotyping is impeded in part by the turnaround time and costs of genotyping. Microfluidics-based assays can reduce reagent consumption and analysis time; however, no current assay has integrated multiplexed allele-specific PCR for warfarin genotyping with electrophoretic microfluidics hardware. Ideally, such an assay would use a single PCR reaction and, without further processing, a single microchip electrophoresis (ME) run to determine the 3 single-nucleotide polymorphisms (SNPs) affecting warfarin sensitivity [i.e., CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) *2, CYP2C9 *3, and the VKORC1 (vitamin K epoxide reductase complex 1) A/B haplotype]. METHODS We designed and optimized primers for a fully multiplexed assay to examine 3 biallelic SNPs with the tetraprimer amplification refractory mutation system (T-ARMS). The assay was developed with conventional PCR equipment and demonstrated for microfluidic infrared-mediated PCR. Genotypes were determined by ME on the basis of the pattern of PCR products. RESULTS Thirty-five samples of human genomic DNA were analyzed with this multiplex T-ARMS assay, and 100% of the genotype determinations agreed with the results obtained by other validated methods. The sample population included several genotypes conferring warfarin sensitivity, with both homozygous and heterozygous genotypes for each SNP. Total analysis times for the PCR and ME were approximately 75 min (1-sample run) and 90 min (12-sample run). CONCLUSIONS This multiplexed T-ARMS assay coupled with microfluidics hardware constitutes a promising avenue for an inexpensive and rapid platform for warfarin genotyping.

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Gluz, Oleg, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Johannes Holtschmidt, Jan Priel, Andreas Hartkopf, et al. "De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 515. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.515.

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515 Background: HR+/HER2+ breast cancer (BC) is a distinct entity associated with better prognosis compared to HR-/HER2+ BC. However, combination of chemotherapy (CT) with (dual) anti-HER2 blockade is standard in HER2+ early BC (EBC), irrespective of HR-status. Despite of some promising data on combination of endocrine therapy (ET) with dual anti-HER2 blockade in EBC and metastatic HR+/HER2+ BC, no prospective comparison of neoadjuvant CT vs. ET + dual HER2-blockade has yet been performed. Methods: In the prospective WSG TP-II phase II-trial (NCT03272477; Sponsor: Palleos GmbH, Wiesbaden, Germany), 207 patients (pts) (257 screened; 40 centers) with centrally confirmed HR+/HER2+ EBC were randomized to 12 weeks of standard ET (n=100) vs. paclitaxel 80 mg/m2 weekly (n=107) +trastuzumab+pertuzumab q3w for all pts. Primary endpoint was pCR (ypT0/is/ypN0). Secondary endpoints include safety, disease-free and overall survival, translational research, and quality of life (QoL). Omission of further CT was allowed in all pts with pCR; dual HER2-blockade was administered in the adjuvant setting in all pts. Results: Baseline characteristics were well balanced between the arms. Median age was 53 years; 58% had cT2-4, 28% had cN+; 43% had G3 tumors. pCR data were available in 198 pts (ET: n=96; Pac: n=102). pCR was observed in 24% (95% CI: 16-34%) with ET+T+P vs. 57% (95% CI:47-67%) with Pac+T+P (OR 0.24, 95% CI: 0-0.46, p<0.001). In multivariable logistic regression analysis and corresponding sensitivity analysis (bootstrap/subsample inclusion frequencies and lasso regression) including study arm, BMI, menopausal, cT, and cN status, histological grade, HER2-status, Ki67, ER, PR as continuous variables, only study arm and HER2 3+ status were significantly associated with pCR. Neoadjuvant treatment was well tolerated in both study arms and completed per protocol in 93/92 (ET+P+T/Pac+P+T) patients. Only 9/13 SAEs (ET+P+T/Pac+P+T) were reported during neoadjuvant therapy. PAM50 and QoL analysis are ongoing. Conclusions: WSG TP-II is the first randomized prospective trial comparing two neoadjuvant de-escalation treatments in HR+/HER2+ EBC. The excellent pCR rate of 57% after only 12 weeks of Pac+P+T was clearly superior to the still promising 24% pCR rate in pts treated by ET+P+T. In both arms, treatment efficacy was most pronounced in HER2 3+ tumors. Survival results need to be awaited before definite recommendations for a de-escalated regimen in HR+/HER2+ EBC can be made. Clinical trial information: 2016-005157-21 .

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Sadia, Haleema, Waqas Ahmed Khan, Misbah Hussain, and Iqra Murtza. "Development of T-ARMS-PCR to Detect MYBPC3 Gene Variation in Hypertrophic Cardiomyopathy (HCM) Patients." Current Trends in OMICS 3, no. 1 (June 15, 2023): 60–72. http://dx.doi.org/10.32350/cto.31.04.

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Hypertrophic cardiomyopathy (HCM) is a common and complex, genetically inherited, cardiovascular disorder. It is typically inherited in an autosomal dominant manner with variable penetrance and mutable expression. Mutations in MYBPC3 gene is one of the genetic causes of HCM. Only 0.2% of general population suffers from HCM. The MYBPC3 gene provides instructions for making cardiac myosin binding protein C, which is imperative for the maintenance and regulation of normal cardiac functions. This study aims to explore the reported SNP rs1052373 from exon 30 of MYBPC3 gene in the population of Punjab, Pakistan. The reported SNP rs1052373 was analysed using Tetra Amplification Refractory Mutation System Polymerase Chain Reaction (T-ARMS-PCR) to find the allelic frequency in the selected population. T-ARMS-PCR is a cost effective, flexible, rapid, and accurate tool for genotyping. The specific sequences of MYBPC3 gene from exons 30 and 31 and introns 29, 30, and 31 were retrieved from NCBI (https://www.ncbi.nlm.nih.gov/). A tetra primer designing tool known as Primer 1 (http://primer1.soton.ac.uk/primer1.html) was used to design the primers for the targeted region of MYBPC3 gene. In this study, the genotyping of previously reported SNP rs1052373 showed variation in the disease group, giving CC, CT, and TT genotypes with the frequency of 0.04. The genotyping analysis of rs1052373 showed that the allelic frequency of homozygous condition T/T was 0.02 and the allelic frequency of heterozygous condition C/T was 0.02 in disease group as compared to the control group. In the latter, the homozygous T/T and heterozygous C/T genotypes were not observed in any individuals. All the individuals in control group carried homozygous C/C genotype. While, the frequency of homozygous C/C genotype was 0.96 in disease group. The findings of this study would help to find novel molecular markers for HCM diagnosis.

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Mahdi, Yasmin, and Haidar Kadhim. "Evaluation of Cytotoxic T-Lymphocyte Antigen-4 (+49A/G) Gene Polymorphism in Chronic Hepatitis B Virus Infection." Iraqi Journal of Medical Sciences 18, no. 2 (December 31, 2020): 101–9. http://dx.doi.org/10.22578/ijms.18.2.3.

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Background: Chronic hepatitis B (CHB) infection is associated with the depletion of T cells, resulting in weak or absent virus specific T cells reactivity, which is described as ‘exhaustion’. This exhaustion is characterized by impaired cytokine production and sustained expression of multiple coinhibitory molecules. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is one of many coinhibitory molecules that can attenuate T cell activation by inhibiting stimulation and transmitting inhibitory signals to T cells. Objective: To explore the effect of CTLA-4+49A/G single nucleotide polymorphism (SNP) on the progression CHB in Iraqi patients. Methods: Blood serum and genomic DNA was isolated from 90 patients with CHB. Tetra-Primer Amplification Refractory System-Polymerase Chain Reaction (ARMS-PCR) was used for amplification and genotyping of CTLA-4 gene using specific primers, and plasma hepatitis B virus (HBV) viral load was investigated by real time PCR, in addition to estimate the hepatitis B e antigen (HBeAg) and anti-HBe by enzyme-linked immunosorbent assay (ELISA). Results: AA genotype was more frequent among uncomplicated than complicated CHB (44.83% versus 28.12%) with a significant difference (OR= 0.315, 95%CI=1.0-0.99, p= 0.048). Conclusion: These data strongly suggested the persistence role of CTLA-4+49 polymorphism against HBV among Iraqi patients. Keywords: CTLA 4, SNP, ARMS-PCR Citation: Mahdi YS, Kadhim HS. Evaluation of cytotoxic T-lymphocyte Antigen-4 (+49A/G) gene polymorphism in chronic hepatitis B virus infection. Iraqi JMS. 2020; 18(2): 101-109. doi: 10.22578/IJMS.18.2.3

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Alshemmari, Salem H., Mohmd Edrees, and Marwa Almusailaik. "Comparative Analysis Between Molecular Techniques Used for the Detection of JAK2V617F Mutation in Patients with Chronic Myeloproliferative Disorders." Blood 118, no. 21 (November 18, 2011): 5178. http://dx.doi.org/10.1182/blood.v118.21.5178.5178.

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Abstract Abstract 5178 Several somatic mutations have been known to result in an individual to suffer from one or more classes of MPDS. JAK2V617F mutation is the most common somatic mutation that is known as a major contributor to MPDs. Extraction of Total Genomic DNA from Whole Peripheral Blood Blood samples were collected from each subject in vacutainer tubes containing 1.8mg/ml K3-EDTA. Extraction of total genomic DNA was carried following the protocol of a standard QIAGEN DNA Extraction Kit (QIAGEN, USA). Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) for the Detection of JAK2V617FMutation Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) technique was used in this study to amplify three DNA bands, control (463bp), wild type (229bp), and mutant (279bp) if existent, in which the latter represents cells with JAK2V617F mutation. A 100 ng of DNA template was used for the amplification of the three fragments. HotStart Taq Polymerase Master Mix (Qiagen) was utilized for the amplification JAK2V617FAllele-Specific Real-Time PCR (RT-PCR). Qualitative real-time PCR (RT-PCR) was performed in this study on 100 patients suffering from MPDs, fifty of which were negative and fifty were positive, for the detection of as low as 5% of mutant cells. Standard JAK2 MutaScreen™ Kit (IPSOGEN Cancer Profiler) was used in this procedure, containing JAK2V617F mutant positive control (100%), negative control (0.00%), and a reference sample for the discrimination of negative and very low positive cells. Genomic DNA of MPD samples was diluted in TE buffer (AMBION) to 5.0 ng/μl in concentration. For the amplification of the mutant fragment, TaqMan Universal Master Mix (Applied Biosystems) was added to the mixture of 10x probe/primers and DNA. Polymerase Chain Reaction (PCR) for Direct Sequencing A fragment of 349bp was amplified to include the JAK2 mutational site (V617FG>T) in exon 14. AmpliTaq Gold® PCR Master Mix (Applied Biosystems, USA) was used in this procedure. In this comparative analysis, we diagnosed a total number of 385 MPD patients using three major molecular techniques, direct DNA sequence analysis, ARMS-PCR, and RT-PCR. Out of the 385 patients, 285 were run for DNA sequencing, in which 50 negatives and 50 positives were randomly tested using ARMS-PCR. In comparison, a separate randomized set of 100 (50 negatives & 50 positives) patients that were diagnosed through ARMS-PCR, were also run for RT-PCR for comparative investigation. For the 100 MPD cases that were randomly chosen from the 285 diagnosed set, the 50 positive individuals confirm positivity for JAK2V617F mutation (true positives), whereas 47 were confirmed negative (true negatives) and three patients, in which their somatic cells tested negative using DNA sequencing, were proven positive using ARMS-PCR (false negatives). As shown in Figure (X), well 13–15 display clear 279bp mutant band that represents the presence of JAK2V617F positive cells, whereas the 229bp reflect on the presence of wild type cells. Overall, out of the 100 samples that were run for DNA sequence analysis, misdiagnosis accounts for 3% of the total sample number. On another set of patients, 50 randomly chosen negatives and 50 positives that were assessed using ARMS-PCR were also confirmed for their JAK2V617F somatic mutation through RT-PCR. Results revealed that diagnosis of JAK2V617F mutation utilizing RT-PCR is parallel to the outcome if DNA is tested for positivity using ARMS-PCR. Out of the 100 MPD patients, 50 indicated true negativity, and 50 showed true positivity. Thereby, usage of ARMS-PCR as a diagnostic molecular technique is comparable to RT-PCR. The somatic nature of JAK2V617F mutation has a 3% chance in being misdiagnosed for an MPD when DNA sequencing is implemented over ARMS-PCR based on our results. This is most probably due to the small number of mutant cells that result in a small chromatographic peak on the DNA sequence in response to mutant DNA, hence the false negative diagnosis. Whereas, by utilizing ARMS-PCR as a molecular diagnostic assay, we were able to synthesize mutant DNA of such small number of mutant cells, hence eliminating any chance of misdiagnosis. Intensity of the mutant band displayed on the agarose gel in comparison to the wild type is a reflection of the amount of mutant DNA found in each case. Disclosures: No relevant conflicts of interest to declare.

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Hameed, Taha, Zahid Khan, Muhammad Imran, Saif Ali, Abdullah Abdo Albegali, Muhammad Ikram Ullah, and Hasan Ejaz. "Associations of transcription factor 7-Like 2 (TCF7L2) gene polymorphism in patients of type 2 diabetes mellitus from Khyber Pakhtunkhwa population of Pakistan." African Health Sciences 21, no. 1 (April 16, 2021): 15–22. http://dx.doi.org/10.4314/ahs.v21i1.4.

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Background: Type 2 diabetes mellitus (T2DM) is the most prevalent component of metabolic syndrome. Environmental factors and various complex genes like transcription factor 7-like 2 (TCF7L2) gene have involved in the disease development. Objective: To determine TCF7L2 genetic association (rs7903146C/T and rs12255372G/T) in T2DM patients of Khyber Pakhtunkhwa population of Pakistan. Subjects and methods: This study comprised of 176 subjects including 118 T2DM patients and 58 healthy controls. Genomic DNA was extracted and genotype of common variants (rs7903146 C/T and rs12255372 G/T) was carried out by amplification-refractory mutation system (ARMS)-PCR of sequence specific oligonucleotides. Results: The distribution of genotype of TCF7L2 SNPs (rs7903146 C/T and rs12255372 G/T) was significantly associated with T2DM as compared to the controls (p <0.0001). The genetic models of the rs7903146 (C/T) and rs12255372 (G/T) SNPs were significantly associated between cases and controls (p <0.0001). On the other hand, the significant association was observed between the two SNPs and different biochemical parameters like serum fasting glucose, lipid profile, creatinine and blood HbA1c levels (p <0.05). Conclusion: It is concluded that the SNPs of the TCF7L2 gene are significantly associated with T2DM disease susceptibil- ity in the population of Khyber Pakhtunkhwa of Pakistan. Keywords: T2DM; TCF7L2; Genetic association, ARMS-PCR, Single nucleotide Polymorphism (SNPs), Khyber Pakh- tunkhwa.

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de Sa Filho, D. J., D. F. de Castro, L. H. Gagliani, and M. M. Caseiro. "Discordant results using T-ARMS-PCR and sequencing for the evaluation of rs12979860 IL28B genotype." Journal of Viral Hepatitis 19, no. 3 (February 13, 2012): 227. http://dx.doi.org/10.1111/j.1365-2893.2011.01585.x.

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Heidar, Mohammad Mehdi, and Mehri Khatami. "Designing and Validation of One-Step T-ARMS-PCR for Genotyping the eNOS rs1799983 SNP." Iranian Journal of Biotechnology 15, no. 3 (September 27, 2017): 208–12. http://dx.doi.org/10.15171/ijb.1307.

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Harbeck, Nadia, Oleg Gluz, Matthias Christgen, Ronald Ernest Kates, Michael Braun, Sherko Küemmel, Claudia Schumacher, et al. "De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor–Positive Phase II Randomized Trial—Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET." Journal of Clinical Oncology 35, no. 26 (September 10, 2017): 3046–54. http://dx.doi.org/10.1200/jco.2016.71.9815.

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Purpose Human epidermal growth factor receptor 2 (HER2)–positive/hormone receptor (HR)–positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported. Conclusion The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.

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Liu, D., Z. Wang, W. Ma, Y. Gao, A. Li, X. Lan, C. Lei, and H. Chen. "Tetra-primer ARMS-PCR identified a missense mutation of the bovine <i>NRIP1</i> gene associated with growth traits." Archives Animal Breeding 58, no. 1 (April 28, 2015): 165–69. http://dx.doi.org/10.5194/aab-58-165-2015.

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Abstract. Nuclear receptor-interacting protein 1 (NRIP1) specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors to inhibit transcription. Previous work has demonstrated this protein to be a key regulator in modulating transcriptional activity of many transcription factors, some of which are closely related to development and growth. In this study, we have successfully genotyped two newly identified bovine NRIP1 single-nucleotide polymorphisms (SNPs) (c.605A > G and c.1301G > A) using the T-ARMS-PCR method and validated the accuracy by means of PCR-RFLP assay using 1809 individuals of 9 different cattle breeds. The association analyses results indicated that c.605A > G locus was significantly associated with body weight and average daily gain in Nanyang cattle at 18 months (P < 0.05). Thus it can be inferred that T-ARMS-PCR is a rapid, reliable, and cheap method for SNP genotyping and that c.605A > G polymorphism in bovine NRIP1 is associated with growth traits. These findings will be of benefit for the application of DNA markers related to growth traits in marker-assisted selection (MAS), and will improve the promotion of beef cattle.

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Chiu, Rossa W. K., Michael F. Murphy, Carrie Fidler, Benny C. Y. Zee, James S. Wainscoat, and Y. M. Dennis Lo. "Determination of RhD Zygosity: Comparison of a Double Amplification Refractory Mutation System Approach and a Multiplex Real-Time Quantitative PCR Approach." Clinical Chemistry 47, no. 4 (April 1, 2001): 667–72. http://dx.doi.org/10.1093/clinchem/47.4.667.

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Abstract Background: Rh isoimmunization and hemolytic disease of the newborn still occur despite the availability of Rh immunoglobulin. For the prenatal investigation of sensitized RhD-negative pregnant women, determination of the zygosity of the RhD-positive father has important implications. The currently available molecular methods for RhD zygosity assessment, in general, are technically demanding and labor-intensive. Therefore, at present, rhesus genotype assessment is most commonly inferred from results of serological tests. The recent elucidation of the genetic structure of the prevalent RHD deletion in Caucasians, as well as the development of real-time PCR, allowed us to explore two new approaches for the molecular determination of RhD zygosity. Methods: Two methods for RhD zygosity determination were developed. The first was based on the double Amplification Refractory Mutation System (double ARMS). The second was based on multiplex real-time quantitative PCR. For the double ARMS assay, allele-specific primers were designed to directly amplify the most prevalent RHD deletion found in RhD-negative individuals in the Caucasian population. The multiplex real-time quantitative PCR assay, on the other hand, involved coamplification and quantification of RHD-specific sequences in relation to a reference gene, albumin, in a single PCR reaction. A ratio, ΔCt, based on the threshold cycle, was then determined and reflects the RHD gene dosage. Results: The allele-specific primers of the double ARMS assay reliably amplified the RHD-deleted allele and therefore accurately distinguished homozygous from heterozygous RhD-positive samples. The results were in complete concordance with serological testing. For the multiplex real-time quantitative PCR assay, the ΔCt values clearly segregated into two distinct populations according to the RHD gene dosage, with mean values of 1.70 (SD, 0.17) and 2.62 (SD, 0.29) for the homozygous and heterozygous samples, respectively (P <0.001, t-test). The results were in complete concordance with the results of serological testing as well as with the double ARMS assay. Conclusion: Double ARMS and real-time quantitative PCR are alternative robust assays for the determination of RhD zygosity.

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Wolf, Denise M., Christina Yau, Michael J. Campbell, Annuska M. Glas, Lorenza Mittempergher, Midas M. Kuilman, Andrei Barcaru, et al. "Biomarkers predicting response to 5 immunotherapy arms in the neoadjuvant I-SPY2 trial for early-stage breast cancer (BC): Evaluation of immune subtyping in the response predictive subtypes (RPS)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 102. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.102.

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102 Background: Previously, we showed that in our first PD1-inhibitor (PD1-inh) arm of I-SPY2, pCR associates with high STAT1/chemokine/dendritic signatures in TN and with high B-cell/low mast cell in HR+. From these results, we defined a research-grade Immune classifier incorporated into the RPS (PMID: 35623341), a schema designed to increase pCR if used to prioritize treatment. A clinical-grade version of the Immune (ImPrint) and other RPS biomarkers are now used in I-SPY2.2. Here we evaluate immune markers in 5 Immune-Oncology (IO) therapy arms (2 PD1-inh, 2 PD1-inh combinations, and 1 PDL1-inh combination). Methods: 343 patients with HER2-negative BC with information on pCR and mRNA in 5 IO arms (n 60-72 pts) plus controls (Ctr: 343) were considered. 32 continuous markers including 30 immune (7 checkpoint genes, 14 immune cell, 3 T/B-cell prognostic, 1 TGFB and 5 tumor-immune) and ESR1/PGR and proliferation signatures, were assessed for association with pCR using logistic regression. p-values were adjusted using the Benjamini-Hochberg method (BH p<0.05). Correlations to multiplex immunofluorescence (mIF) data from our initial arm (immune cell and spatial proximity markers) were calculated. Performance of ImPrint, developed with Agendia Inc, was characterized overall and within HR subsets. Results: A larger number of the research-grade immune markers predict response to IO in HR+ than in TN, with the most for HR+ in combination-IO arms (27/32 biomarkers). Tumor-immune signatures dominated by chemokines/cytokines were most consistently associated with pCR across IO arms and across receptor status. Moreover, we found that these markers correlate to mIF spatial proximity measures reflecting high spatial co-localization of PD1+ immune and PDL1+ tumor cells, in TN especially (r=0.59; p=0.003). The ImPrint classifier was evaluated in the IO arms. In HR+, 28% were ImPrint+; and pCR rates were 76% in ImPrint+ vs. 16% in ImPrint-. In TN, 46% were ImPrint+; and pCR rates were 75% in ImPrint+ and 37% in ImPrint-. Overall (HR+ and TN, in all IO arms), pCR rates were 75% in ImPrint+ and 23% in ImPrint-. Performance varied by arm, with the highest pCR rates for HR+/ImPrint+ >90%; and for TN/ImPrint+ >81%. In contrast, pCR rates in the control arm were 34% for ImPrint+ (HR+:33%; TN: 34%) and 13% for ImPrint- (HR+: 21%; TN:8%). Conclusions: Tumor-immune signaling signatures predict response for IO drug class in both TN and HR+HER2-. The ImPrint single-sample classifier predicts response to a variety of IO regimens in both subsets and may inform prioritization of IO vs other treatments and best balance likely benefit vs risk of serious immune-related adverse events. Clinical trial information: NCT01042379 .

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Hussain, Misbah, Haq Nawaz Khan, and Fazli Rabbi Awan. "Development and application of low-cost T-ARMS-PCR assay for AGT and CYP11B1 gene polymorphisms." Molecular Biology Reports 46, no. 1 (November 26, 2018): 443–49. http://dx.doi.org/10.1007/s11033-018-4493-0.

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Mehrabi Pour, Mahsa, Mahboobeh Nasiri, Hajar Kamfiroozie, and Mohammad Javad Zibaeenezhad. "Association of the ATG9B gene polymorphisms with coronary artery disease susceptibility: A case-control study." Journal of Cardiovascular and Thoracic Research 11, no. 2 (June 25, 2019): 109–15. http://dx.doi.org/10.15171/jcvtr.2019.19.

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Introduction: Endothelial nitric oxide synthase (eNOS), the main regulator of cardiac cell functioning, is regulated post-transcriptionally by autophagy-related 9B (ATG9B) gene. The proper function of the heart is partly determined by the intact interaction of these molecules. The present study aimed to investigate the effects of ATG9B rs2373929 and rs7830 gene polymorphisms on the predisposition to coronary artery disease (CAD). Methods: In this hospital-based case-control study, 150 patients with CAD compared with 150 healthy subjects for the genotype distributions of rs2373929 and rs7830 polymorphisms using T-ARMS PCR and ARMS PCR, respectively. Results: Considering rs2373929 polymorphism, increased risk of CAD observed in the presence of TT genotype (OR: 3.65; 95% CI: 1.77-7.53; P < 0.001) and also in the recessive model for T allele (OR: 3.41; 95% CI: 1.76- 6.60; P < 0.001). The frequency of the T allele was higher in cases compared to controls (OR: 1.71; 95% CI: 1.24-2.28; P = 0.001). The genotype and allele frequencies of the rs7830 polymorphism did not differ between the two study groups. Conclusion: The ATG9B gene rs2373929 polymorphism might involve in the pathogenesis of the CAD and can be considered as a screening molecular marker in the subjects prone to CAD.

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Sayaman, Rosalyn W., Denise M. Wolf, Christina Yau, Julia Wulfkhule, Emanuel F. Petricoin, Lamorna Brown-Swigart, Tam Binh Bui, et al. "Abstract A066: Machine learning elucidates biology of response within and outside the mechanisms of action of therapeutic agents in the I-SPY2 breast cancer TRIAL." Cancer Research 84, no. 3_Supplement_1 (February 1, 2024): A066. http://dx.doi.org/10.1158/1538-7445.advbc23-a066.

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Abstract Background: Machine learning (ML) in translational medicine has led to prediction of clinical outcomes and identification of new biomarkers. We employ ML in prediction of pathologic complete response (pCR) in high-risk breast cancer patients in the neoadjuvant I-SPY2 TRIAL where not all novel agents have strong predictive biomarkers. Leveraging a ML approach using progressively expanded candidate genes, we explore the limitations of using only known mechanisms of action in predicting pCR, and the extent to which biology outside known drug action improves response prediction in the first 10 arms of the trial. Methods: ML random forest models were developed in I-SPY2 patients (n=982) with pre-treatment gene expression and pCR data across 10 treatment arms (PMID: 35623341), including inhibitors of HER2: neratinib (N), pertuzumab (P), TDM1/P; AKT (MK-2206); IGF1R (ganitumab); HSP90 (ganetespib); PARP/DNA repair (veliparib/carboplatin, VC); ANG1/2 (trebananib, T); immune checkpoints (PD1-inh); and Control (Ctr). Each HR/HER2 receptor/treatment arm subset (m=27) was evaluated independently. We employed a three-pronged feature-selection approach using (1) genes restricted to known mechanism of action of individual I-SPY2 agents (k=10 to 88 genes); (2) genes expanded to include targeted pathways for all 10 agents/combinations (k=282); and (3) an unbiased whole genome approach (k=17,990). Samples were partitioned with 75% used for training and cross-validation, and 25% held out as test sets. Predictive ML models were defined as those with performance ≥ 0.90 based on different performance metrics (e.g., AUC, sensitivity, specificity). Results: For each of the 27 subtype-treatment subsets, at least one high performing model was identified. In 6 subtype-treatment subsets, mechanism of action genes were sufficient to predict pCR: AKT/PI3K/HER genes in HR+HER2- N and HR-HER2+ P; DNA repair genes in HR+HER2- VC; angiogenesis-associated genes in HR+HER2+ T; and immune-associated genes in both HR+HER2- and HR-HER2- PD1-inh subsets. Expanded targeted pathway models were required to identify predictive models in 8 additional subtype-treatment pairs from the N, T-DM1/P, MK-2206, VC, T, and HER2+ Ctr arms, with significant contribution of DNA repair, immune, and HSP90 genes for multiple arms. A genome-wide approach was required for the remaining 13 subtype-treatment pairs with no previous models from the N, P, MK-2206, ganitumab, ganetespib, T, and HER2- Ctr arms. Even for subtype-treatment pairs where mechanism of action gene sets was sufficient for reasonable models, expanded gene sets resulted in improved performance. For instance, metabolism genes improved model performance for HR-HER2+ in N and Ctr, and for HR+HER2- in the PD1-inh arm; and mitochondrial and protein folding dysfunction genes improved response prediction in HR-HER2- in the ganetespib arm. Conclusion: Our study identifies mechanism of action biomarkers associated with response to each drug and elucidates possible off-target effects contributing to observed drug sensitivity and resistance. Citation Format: Rosalyn W. Sayaman, Denise M. Wolf, Christina Yau, Julia Wulfkhule, Emanuel F. Petricoin, Lamorna Brown-Swigart, Tam Binh Bui, Gillian L. Hirst, Diane Heditsian, W. Fraser Symmans, Angela DeMichele, Mark LaBarge, Laura J. Esserman, Laura van ‘t Veer. Machine learning elucidates biology of response within and outside the mechanisms of action of therapeutic agents in the I-SPY2 breast cancer TRIAL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A066.

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Untch, Michael, Gunter von Minckwitz, Bernd Gerber, Christian Schem, Mahdi Rezai, Peter A. Fasching, Hans Tesch, et al. "Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44)." Journal of Clinical Oncology 36, no. 13 (May 1, 2018): 1308–16. http://dx.doi.org/10.1200/jco.2017.75.9175.

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Purpose The GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline–taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Here, we report the long-term outcomes. Methods Patients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months. Results Three-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor–positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor–negative patients; however, the small number of events limits this interpretation. Within the hormone receptor–negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively). Conclusion pCR correlated with long-term outcome. In patients with hormone receptor–positive tumors, prolonged anti-HER2 treatment—neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months—significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.

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Badshah, Yasmin, Maria Shabbir, Khushbukhat Khan, Maha Fatima, Iqra Majoka, Laiba Aslam та Huda Munawar. "Manipulation of Interleukin-6 (IL-6) and Transforming Growth Factor Beta-1(TGFβ-1) towards viral induced liver cancer pathogenesis". PLOS ONE 17, № 10 (10 жовтня 2022): e0275834. http://dx.doi.org/10.1371/journal.pone.0275834.

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Hepatocellular carcinoma (HCC) is the most common liver malignancy. Early diagnosis of HCC has always been challenging. This study aims to assess the pathogenicity and the prevalence of IL-6 -174G/C (rs1800795) and TGFβ-1 +29C/T (rs1800470) polymorphisms in HCV-infected HCC patients. Experimental strategies are integrated with computational approaches to analyse the pathogenicity of the TGFβ-1 +29C/T and IL-6–174 G/C polymorphisms in HCV-induced HCC. AliBaba2 was used to predict the effect of IL-6–174 G/C on transcription factor binding site in IL-6 gene. Structural changes in the mutant TGFβ-1 structure were determined through project HOPE. To assess the polymorphic prevalence of IL-6 -174G/C and TGFβ-1 +29C/T genotypes in HCC and control subjects, amplification refractory mutation system PCR (ARMS-PCR) was performed on 213 HCC and 216 control samples. GraphPad Prism version 8.0 was used for the statistical analysis of the results. In-silico analysis revealed the regulatory nature of both IL-6 -174G/C and TGFβ-1 +29C/T polymorphisms. ARMS-PCR results revealed that the individuals carrying TT genotype for TGFβ-1 gene have an increased risk of developing HCC (p<0.0001, OR = 5.403, RR = 2.062) as compared to individuals with CT and CC genotype. Similarly, GC genotype carriers for IL-6 gene exhibit an increased risk of HCC susceptibility (p<0.0001, OR = 2.276, RR = 1.512) as compared to the people carrying the GG genotype. Genotype TT of TGFβ-1 gene and genotype GC of IL-6 gene are found to be associated with HCV-induced HCC. IL-6 polymorphism may alter its transcription that leads to its pathogenicity. TGFβ-1 polymorphism may alter protein structure stability.

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Al-askeri, Mohammed A., Ferdous A. Jabir, and Watheq Jaber. "INTERLEUKIN-18 GENE POLYMORPHISM AND SOME RISK FACTORS IN IRAQI PATIENTS WITH BREAST CANCER." Asian Journal of Pharmaceutical and Clinical Research 10, no. 1 (January 1, 2016): 140. http://dx.doi.org/10.22159/ajpcr.2017.v10i1.14487.

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ABSTRACTObjective: Breast cancer is the most diagnosed cancer in women, which leads to death in a lot of women with breast cancer. The major risk factorsassociated with breast cancer risk related to family history, age, clinical history, lifestyle factors, long-period hormonal exposure, and single nucleotidepolymorphisms in many genes showed possible links with breast cancer incidence risk in different people populations. Our study aimed to figure outthe correlation between smoking, lodging and family history, and other factors with the risk of breast cancer.Methods: Blood sample from female patients with breast cancer and healthy individuals were collected and subjected to tetra-amplification refractorymutation system–polymerase chain reaction (T-ARMS-PCR) technique for −607 C/A mutation of an interleukin (IL-18) gene and SPSS 18 softwareanalyzed the results statically.Results: Results showed no association between lodging and smoking with risk of breast cancer, (p>0.05), while the association between the risk andfamily history were obvious (p<0.05).Conclusion: The results obtained by T-ARMS-PCR technique did not show the association between −607 C/An alternation of IL-18 gene and breastcancer (p>0.05) in the individuals examined in our study.Keywords: Interleukin-18, Gene, Polymorphism, Tetra-amplification refractory mutation system–polymerase chain reaction, Mutations.

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Valero-Hervás, D. M., P. Morales, M. J. Castro, P. Varela, M. Castillo-Rama, E. Moreno, J. C. Meneu, S. Mora-Díaz, P. Talayero, and E. Paz-Artal. "Complement C3 Genotyping of Slow and Fast Variants by Real Time PCR-High Resolution Melting." European Journal of Inflammation 10, no. 3 (September 2012): 329–34. http://dx.doi.org/10.1177/1721727x1201000308.

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“Slow” and “Fast” C3 complement variants (C3S and C3F) result from a g.304C>G polymorphism that changes arginine to glycine at position 102. C3 variants are associated with complement-mediated diseases and outcome in transplantation. In this work C3 genotyping is achieved by a Real Time PCR - High Resolution Melting (RT-PCR-HRM) optimized method. In an analysis of 49 subjects, 10.2% were C3FF, 36.7% were C3SF and 53.1% were C3SS. Allelic frequencies (70% for C3S and 30% for C3F) were in Hardy-Weinberg equilibrium and similar to those published previously. When comparing RT-PCR-HRM with the currently used Tetraprimer-Amplification Refractory Mutation System PCR (T-ARMS-PCR), coincidence was 93.8%. The procedure shown here includes a single primer pair and low DNA amount per reaction. Detection of C3 variants by RT-PCR-HRM is accurate, easy, fast and low cost, and it may be the method of choice for C3 genotyping.

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JEON, H. K., K. H. LEE, K. H. KIM, U. W. HWANG, and K. S. EOM. "Complete sequence and structure of the mitochondrial genome of the human tapeworm, Taenia asiatica (Platyhelminthes; Cestoda)." Parasitology 130, no. 6 (February 3, 2005): 717–26. http://dx.doi.org/10.1017/s0031182004007164.

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The complete Taenia asiatica mitochondrial genome was amplified by long extension polymerase chain reaction (long PCR) to yield overlapping fragments that were then completely sequenced. The whole mitochondrial genome was 13703 bp long and contained 12 protein-encoding, 2 ribosomal RNA (small and large subunits), 22 transfer RNA genes and a short non-coding region. Thus, its gene contents are like those typically found in metazoan animal mitochondrial genomes (apart from the absence of atp8). All the genes were transcribed from the same strand. The 3′ end 34 bp region of nad4L overlapped with the 5′ end portion of nad4. The tRNA genes were 61–69 bp long, and the secondary structures of 18 tRNAs had typical clover-leaf shapes with paired DHU arms. However, trnC, trnS1, trnS2 and trnR had unpaired DHU arms that were 7–12 bp in length. The tRNAs that transferred serine lacked a DHU arm, as is also observed in a number of parasitic platyhelminths and metazoans. However, the trematode trnRs have paired DHU arms. The T. asiatica mtDNA non-coding region was like that in other cestodes since it was composed of a short non-coding region of 72 nucleotides and a long non-coding region of 176 nucleotides separated by a trnL1/, trnS2/, trnL2/, trnR/, nad5 gene cluster. The sequences of the cox1 genes between T. asiatica and T. saginata differ by 4·6%, while the T. asiatica cob gene differs by 4·1% and 12·9% from the cob genes of T. saginata and T. solium, respectively. In conclusion, the T. asiatica mitocondrial genome should provide a resource for comparative mitochondrial genomics and systematic studies of parasitic cestodes.

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Bahari, Gholamreza, Mohammad Hashemi, Mohsen Taheri, Mohammad Naderi, Ebrahim Eskandari-Nasab, and Mahdi Atabaki. "Association of IRGM Polymorphisms and Susceptibility to Pulmonary Tuberculosis in Zahedan, Southeast Iran." Scientific World Journal 2012 (2012): 1–5. http://dx.doi.org/10.1100/2012/950801.

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Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. IRGM1 is an important protein in the innate immune response against intracellular pathogens by regulating autophagy. Polymorphisms in the IRGM genes are known to influence expression levels and may be associated with outcome of infections. This case-control study was done on 150 patients with PTB and 150 healthy subjects to determine whether the IRGM polymorphisms at positions −1208 A/G (rs4958842), −1161 C/T (rs4958843), and −947 C/T (rs4958846) were associated with PTB. The polymorphisms were determined using tetra-amplification refractory mutation system-PCR (T-ARMS-PCR). The results showed that the IRGM −1161 C/T and −947 C/T polymorphisms were associated with decreased susceptibility to PTB (OR = 0.06, 95% CI = 0.03–0.13,P < 0.001 and OR = 0.27; 95% CI = 0.013–0.55,P < 0.001, resp.). No significant difference was found among the groups regarding −1208 A/G polymorphism. In conclusion we found that the IRGM −1161 C/T and −947 C/T polymorphisms but not −1208 A/G polymorphism provide relative protection against PTB in a sample of Iranian population.

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Song, Li, Fei, Zhang, Pan, Chen, Qu, and Lan. "Polymorphisms within the Boule Gene Detected by Tetra-Primer Amplification Refractory Mutation System PCR (T-ARMS-PCR) are Significantly Associated with Goat Litter Size." Animals 9, no. 11 (November 1, 2019): 910. http://dx.doi.org/10.3390/ani9110910.

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As a gene contributing to spermatogenesis, the Boule gene (also called Boll), whose mutations result in azoospermia and sterility of flies and mice, was conserved in reductional maturation divisions. However, in goats, the polymorphisms of Boule, especially with regard to their fundamental roles in female reproduction traits, are still unknown. Therefore, the aims of this study were to detect a potential mutation (rs661484476: g.7254T>C) located in intron 2 of the Boule gene by tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) and to explore its potential association with the litter size of Shaanbei White-Cashmere goats (SBWGs). In this study, g.7254T>C was firstly detected. The TT genotype was the dominant genotype in the single-lamb group, and T was also the dominant allele in all tested groups. Additionally, the detected locus displayed moderate polymorphism with polymorphism information content (PIC) values among all studied goats ranging from 0.303 to 0.344. Notably, according to the χ2 test, the distribution differences for the genotypic frequencies between the single- and multi-lamb groups was significant (p = 0.014). Furthermore, the polymorphisms of the goat Boule gene were significantly associated with the goat litter size in SBWGs (p < 0.05), which indicated that g.7254T>C could be a potential marker in the marker-assisted selection process for potential litter size in goats. These results also indicated that the Boule gene might exercise important functions in female goat reproduction, which provided new insight for female goat breeding and could accelerate the process of goat breeding.

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Islam, Md Rabiul, Tasnova Tasnim Nova, NAM Momenuzzaman, Sikder Nahidul Islam Rabbi, Ishrat Jahan, Thomas Binder, Mohammad Safiqul Islam, Abul Hasnat, and Zabun Nahar. "Prevalence of CYP2C19 and ITGB3 polymorphisms among Bangladeshi patients who underwent percutaneous coronary intervention." SAGE Open Medicine 9 (January 2021): 205031212110422. http://dx.doi.org/10.1177/20503121211042209.

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Introduction: Antithrombotic agents are the basic therapeutic option for patients with arterial thrombosis who underwent percutaneous coronary intervention (PCI). In Bangladesh, aspirin and clopidogrel are frequently prescribed as antithrombotics or platelet inhibitors. Studies reported the genetic polymorphisms of CYP2C19*2, CYP2C19*17, and ITGB3 cause an alteration of the pharmacodynamic and pharmacokinetic profile of aspirin and clopidogrel. Therefore, we aimed to assess the prevalence of CYP2C19*2, CYP2C19*17, and ITGB3 polymorphisms among Bangladeshi patients with cardiovascular disease (CVD) who underwent PCI. Methods: Here we assessed a total of 1,000 CVD patients (male 782 and female 218) who underwent PCI and were treated with clopidogrel and/or aspirin. We performed genotyping of patients treated with clopidogrel and aspirin by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) methods. The PCR products of clopidogrel-treated patients were screened with agarose gel electrophoresis and then digested with SmaI and NsiI-HF for CYP2C19*2 and CYP2C19*17, respectively. We genotyped aspirin-treated patients with T-ARMS-PCR for missense rs5918 (PlA1/A1) polymorphism of the ITGB3 gene. Then we ran the digested PCR products on 2% agarose gel electrophoresis to detect the mentioned polymorphisms. Results: Among the clopidogrel-treated patients, we observed 64.1% polymorphism (hetero + mutant) of CYP2C19*2 (loss-of-function allele) and 22.7% (hetero + mutant) of CYP2C19*17 (gain-of-function allele). On the other hand, among the aspirin-treated patients, polymorphisms of ITGB3 were 84.1% homozygous (PlA1/A1), 15.6% heterozygous (PlA1/A2), and 0.3% mutant homozygous. Conclusion: In the present study, we observed a high prevalence of genetic polymorphisms of CYP2C19 and ITGB3 genes. Therefore, we recommend genotyping of CVD patients before prescribing clopidogrel or aspirin to prevent coagulation. Based on the genotyping study, the adjustment of doses or alternative generics might require to avoid therapeutic failure or toxicity in some cases.

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Zhang, Sihuan, Yonglong Dang, Qingfeng Zhang, Qiaomei Qin, Chuzhao Lei, Hong Chen, and Xianyong Lan. "Tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) rapidly identified a critical missense mutation (P236T) of bovine ACADVL gene affecting growth traits." Gene 559, no. 2 (April 2015): 184–88. http://dx.doi.org/10.1016/j.gene.2015.01.043.

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Wargo, Jennifer Ann, Rodabe Navroze Amaria, Peter A. Prieto, Miles Cameron Andrews, Michael T. Tetzlaff, Phillip Andrew Futreal, Patrick Hwu, et al. "Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9587. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9587.

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9587 Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p < 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.

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Qiu, Ling, Zong-xiang Tang, Meng Li, and Shu-lan Fu. "Development of new PCR-based markers specific for chromosome arms of rye (Secale cereale L.)." Genome 59, no. 3 (March 2016): 159–65. http://dx.doi.org/10.1139/gen-2015-0154.

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PCR-based rye (Secale cereale L.) chromosome-specific markers can contribute to the effective utilization of elite genes of rye in wheat (Triticum aestivum L.) breeding programs. In the present study, 578 new PCR-based rye-specific markers have been developed by using specific length amplified fragment sequencing (SLAF-seq) technology, and 76 markers displayed different polymorphism among rye Kustro, Imperial, and King II. A total of 427 and 387 markers were, respectively, located on individual chromosomes and chromosome arms of Kustro by using a set of wheat–rye monosomic addition lines and 13 monotelosomic addition lines, which were derived from T. aestivum L. ‘Mianyang11’ × S. cereale L. ‘Kustro’. In addition, two sets of wheat–rye disomic addition lines, which were derived from T. aestivum L. var. Chinese Spring × S. cereale L. var. Imperial and T. aestivum L. ‘Holdfast’ × S. cereale L. var. King II, were used to test the chromosomal specificity of the 427 markers. The chromosomal locations of 281 markers were consistent among the three sets of wheat–rye addition lines. The markers developed in this study can be used to identify a given segment of rye chromosomes in wheat background and accelerate the utilization of elite genes on rye chromosomes in wheat breeding programs.

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Zhang, Chong, Xiaohui Zhang, Zhengying Yao, Yaping Lu, Fengxia Lu, and Zhaoxin Lu. "A new method for multiple gene inactivations in Bacillus subtilis 168, producing a strain free of selectable markers." Canadian Journal of Microbiology 57, no. 5 (May 2011): 427–36. http://dx.doi.org/10.1139/w11-035.

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This study describes a novel method for repeated gene inactivation in Bacillus subtilis 168. A B. subtilis strain (BS-PS) that is conditionally auxotrophic for lysine was obtained by replacing the PlysA promoter with the Pspac promoter. The homologous recombination integration vector PLC-T was constructed to contain lacI, which encodes a Pspac promoter repressor, and the chloromycetin resistance gene. Target genes were manipulated by generating an insertion sequence with two homologous arms and the target gene in PLC-T to create a specific integrating vector. Integration into the BS-PS chromosome occurred by a single crossover at either of the two homologous arms. The resulting transitional strain (BS-PS-PI) was chloromycetin resistant and lysine auxotrophic and had an unstable genome structure because of the duplication. Excision of lacI and chloromycetin resistance gene was achieved by a second single crossover at the duplication. Recovery of a lysine prototroph functioned as counter-selection and was identified by PCR. In this work, we inactivated nprE and aprE, two protease genes secreted by B. subtilis 168 free of selectable markers.

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Khavandegar, Armin, Bahareh Tavakoli-Far, Sarina Ansari, Parisa Veis-Karami, Faezeh Ghasemi, Samira Sheibaninia, Roshanak Jazayeri, and Massoud Houshmand. "Allelic and Genotype Frequencies of CYP2B6∗2 (64C > T) and CYP2B6∗3 (777C > A) in Three Dominant Ethnicities of the Iranian Population." Genetics Research 2023 (February 9, 2023): 1–8. http://dx.doi.org/10.1155/2023/8283470.

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Background. Cytochrome P450 complex plays a key role in drug metabolism. CYP2B6 has an essential part in Cytochrome P450 complex metabolism. This study aims to determine the allelic distribution of CYP2B6∗2 and CYP2B6∗3 in three main Iranian ethnicities: Fars, Turk, and Kurd. Methods. The study was conducted on 174 unrelated healthy volunteers from three main Iranian ethnicities. After DNA extraction from peripheral blood samples, genotyping of CYP2B6∗2 and ∗3 was performed using tetra ARMS and ARMS PCR, respectively. Results. The average age of 174 cases was 40.69 ± 11.87 (mean ± SD) and 39.06 ± 11.63 (mean ± SD) for males and females. In the CYP2B6∗2 variant, the genotyping frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 8.7%, 86%, and 5.2%, respectively. The CYP2B6∗2 (c.64C > T) allele frequency was 48.2% (95% CI: (37.8–58.6)). In the CYP2B6∗3 variant, the frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 75.3%, 11%, and 13.6%, respectively. The CYP2B6∗3 (c.777C > A) allelic frequency was 19.1% (95% CI: (17.5–20.7)). Conclusion. Allelic distribution in three main Iranian ethnicities, i.e., Turk, Kurd, and Fars, is remarkably higher than that in other populations, even that in Southern Iran. High frequencies of CYP2B6∗2 and ∗3 in the Iranian population highly affect drug responsiveness. Understanding such variability could help to increase drug efficacy and reduce its toxicity.

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Sharma, Priyanka, Bruce F. Kimler, Anne O'Dea, Lauren Elizabeth Nye, Yen Y. Wang, Rachel Yoder, Lindsey Hastings Prochaska, et al. "Results of randomized phase II trial of neoadjuvant carboplatin plus docetaxel or carboplatin plus paclitaxel followed by AC in stage I-III triple-negative breast cancer (NCT02413320)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 516. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.516.

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516 Background: Addition of neoadjuvant carboplatin (Cb) to paclitaxel (T) followed by doxorubicin + cyclophosphamide (AC) improves pathologic complete response (pCR) rate compared to T/AC in TNBC. An anthracycline-free regimen of Cb plus docetaxel (D) also yields high pCR rates in TNBC, and patients achieving pCR with this regimen demonstrate excellent 3-year outcomes without adjuvant anthracycline. This study was designed to compare the efficacy of neoadjuvant regimens CbT→AC and CbD in TNBC. Methods: In this multicenter study, eligible patients with stage I–III TNBC were randomized (1:1) to either paclitaxel 80 mg/m2 every week X 12 + carboplatin (AUC 6) every 3 weeks X 4, followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 every 2 weeks X 4 (CbT→AC, Arm A), or to carboplatin (AUC 6) + docetaxel (75 mg/m2) every 21 days X 6 cycles (CbD, Arm B). The primary endpoint was pCR (no evidence of invasive tumor in the breast and axilla). The two regimens were compared for differences in pCR, residual cancer burden (RCB), treatment delivery, and toxicity. Results: Between 2015 and 2018, 100 patients were randomized; 48 to Arm A and 52 to Arm B. Median age was 52 years, median tumor size was 2.7 cm, 30% were lymph node-positive and 17% carried a BRCA1/2 mutation. Baseline demographic and tumor characteristics were balanced between two arms. pCR was 55% (95%CI: 41%-59%) in Arm A and 52% (95%CI: 39%-65%) in Arm B, p =0.84. RCB 0+1 rate was 67% in both arms. Grade 3/4 adverse events were more common in Arm A compared to Arm B (73% vs 21%, p < 0.0001), with most notable differences in rates of G3/4 neutropenia (Arm A = 60%, Arm B = 8%, p = 0.0001), febrile neutropenia (Arm A = 18%, Arm B = 0%, p = 0.0001), and G3/4 anemia (Arm A = 46%, Arm B = 4%, p = 0.0001). 81% of Arm A patients completed all 4 doses of AC and 4 doses of Cb, and 71% completed > 9 doses of T. 90% of Arm B patients completed all 6 doses of CbD (p = 0.034). Conclusions: The non-anthracycline platinum regimen of CbD yields pCR and RCB 0+1 rates similar to 4-drug regimen of CbTàAC, but with a more favorable toxicity profile and higher treatment completion rate. The CbD regimen should be further explored as a way to de-escalate therapy in TNBC. Clinical trial information: NCT02413320.

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Ghafer, Asmaa, Abdulameer M. Ghareeb, and Abdul Hussain M. Al-Faisal. "Association the allelic variation and SNP rs12917707 genotyping with UMOD serum level among Iraqi patients infected with uropathogenic Escherichia coli." Sumer 1 8, CSS 1 (August 15, 2023): 1–12. http://dx.doi.org/10.21931/rb/css/2023.08.01.83.

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: The current study included 90 samples collected and divided into (45) Urinary tract infections of E. coli patients and (45) controls with different ages of both genders. Patient samples were collected from UTI patients admitted to ALYarmouk Teaching Hospital, AL-Karama Teaching Hospital and Al Kidney Teaching Hospital from November 2020 to March 2021. The current study measured Tamm Horsfall protein (THP) concentration in patients with Urinary tract infections and healthy groups. The study also included the Relationship of Umod rs12917707 genotype and Uromodulin level in patients and control using Nested T-ARMS PCR. Our study had two objectives: First, to address whether urinary uromodulin concentration is associated with urinary tract infection with E. coli in a community-based study, and second, to determine whether a single-nucleotide polymorphism (SNP) in the UMOD region, rs12917707, is associated with urinary uromodulin concentrations. After statistical analysis, the results showed that there could be an association between having mutant homozygous GG polymorphism in the UMOD gene and having UTI of E. coli. At the same time, the mutant homozygous TT represents a risk factor compared to other genotypes (ORs: 0.4, 95% CI (0.17 - 0.93 and ORs: 4.4, 95% CI (1.47-13.26) respectively. The results also showed a significant decrease at P≤0.01 in the patients group with Urinary tract infection (1.38 ± 0.03) Ng/ml compared with the control sample, which was (1.83 ± 0.04) Ng/ml. Keywords: urinary tract infection, UPEC, UMOD-promoter region, SNPs, Nested T-ARMS PCR

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Heidari, Zahra, Hamidreza Mahmoudzadeh-Sagheb, Mohammad Hashemi, Somayeh Ansarimoghaddam, Bita Moudi та Nadia Sheibak. "Association between IFN-γ+874A/T and IFN-γR1 (-611A/G, +189T/G, and +95C/T) Gene Polymorphisms and Chronic Periodontitis in a Sample of Iranian Population". International Journal of Dentistry 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/375359.

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Background. Interferon gamma (IFN-γ) is an immune regulatory cytokine that acts through its receptor and plays important role in progression of inflammatory disease such as chronic periodontitis (CP). The purpose of this study was to determine the differences in the distribution of IFN-γ(+874A/T) and IFN-γR1 (-611A/G, +189T/G, and +95C/T) gene polymorphisms among CP and healthy individuals and to investigate relationships between these polymorphisms and susceptibility to CP.Materials and Methods. 310 individuals were enrolled in the study including 210 CP patients and 100 healthy controls. Single nucleotide polymorphisms at IFN-γ(+874A/T) and IFN-γR1 (-611A/G, +189T/G, and +95C/T) were analyzed by ARMS-PCR and PCR-RFLP methods.Results. The significant difference was found in genotype and allele frequency of IFN-γ(+874A/T) gene polymorphism in chronic periodontitis patients and healthy controls. The distribution of genotypes and allele frequencies for IFN-γR1 (-611A/G, +189T/G, and +95C/T) were similar among the groups and no differences in the frequencies of alleles or genotypes of IFN-γR1 genetic polymorphisms variants between case and control groups were detected.Conclusion.The finding of this study showed that IFN-γ+874A/T gene polymorphism may affect susceptibility to CP, whereas IFN-γR1 genetic polymorphisms at -611A/G, +189T/G, and +95C/T were not associated with this disease.

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Bear, H. D., G. Tang, P. Rastogi, C. E. Geyer, A. Robidoux, J. N. Atkins, L. Baez, et al. "The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40." Journal of Clinical Oncology 29, no. 18_suppl (June 20, 2011): LBA1005. http://dx.doi.org/10.1200/jco.2011.29.18_suppl.lba1005.

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LBA1005 Background: The addition of capecitabine (X), gemcitabine (G), and bevacizumab (B) to taxanes have each improved PFS in metastatic breast cancer. The primary aims of this trial were to determine if adding X or G to docetaxel (T) → AC will increase breast pathologic complete response (pCR) rates in operable, HER2-negative breast cancer and if adding B to T-based regimens →AC will increase pCR rates. Secondary aims included assessment of clinical complete response (cCR) rates. Methods: Pts received one of 3 T-based regimens, with or without B, 15mg/kg, q3wks x 4: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4, with or without B for the initial 2 cycles of AC. Pts randomized to B resumed B for 10 postop doses. The primary endpoint was pCR in the breast. The maximum of the standardized pairwise differences between pCR rate for the T → AC regimen and for the other 2 T-based regimens was used as the test statistic to adjust for multiple comparisons. Fisher’s exact test was used to compare the arms with and without B. Results: The groups were balanced, with 47% clinically node+, 56% poorly differentiated, and 59% HR+. Assessments for pCR were available from 1180 of 1206 randomized patients. pCR for TX and TG were 29.7% and 32% vs. 32.7% for T. Neither TX nor TG increased cCR rates relative to T (58.3% and 60.4% vs. 61.5%). TX and TG increased toxicity. Addition of B increased the pCR rate (28.4 vs. 34.5%, p=0.027) and the cCR rate (55.8 vs. 64.3%, p=0.007). The effect of B was predominantly in the HR+ subset (15.2 vs. 23.3%, p=0.008) with minimal effect in the HR- subset (47.3% vs. 51.3%, p=0.44). Grades 2/3/4 toxicities increased with B were HTN (1/<1/0% vs. 13/9/<1%), HFS (11/7/0% vs. 15/11/0%), and mucositis (10/3/0% vs. 20/5/0%). Conclusions: The addition of B to neoadjuvant chemotherapy improved pCR and cCR rates, but the addition of X or G to T did not improve outcomes. Follow-up for wound healing issues and DFS will help define the role of B in the treatment of early breast cancer. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-44066, and F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly.

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Abbasali, F. H., K. Sh Mahmoud, N. Hengameh, D. H. Mina, D. Setare, D. M. Hale, and D. M. Sima. "Rare and New Mutations of B-Globin in Azari Population of Iran, a Considerable Diversity." Balkan Journal of Medical Genetics 25, no. 2 (December 1, 2022): 51–62. http://dx.doi.org/10.2478/bjmg-2022-0016.

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ABSTRACT Background Thalassemia, as the most common single-gene genetic disorder, is related to a defect in the synthesis of one or more hemoglobin chains. More than 200 mutations have been identified in the β-globin gene. Globally, every susceptible racial group has its own specific spectrum of the common mutations that are well-known to a particular geographic region. On the other hand, varying numbers of diverse rare mutations may occur. Materials and Methods The subjects of the study included 2113 heterozygote or homozygote β-thalassemia cases selected among couples who participated in the Iranian national thalassemia screening program from January 2011 to November 2019. Molecular characterization of the β-thalassemia mutation was initially carried out by the amplification-refractory mutation system-polymerase chain reaction (ARMS–PCR) technique for common mutations, followed by sequencing, Gap PCR, and Multiple ligation-dependent probe amplification (MLPA) methods - in cases not detected by the ARMS-PCR. Results The existence of 39 rare and new point mutations and 4 large deletions were described in our cohort. Sicilian (-13,337bp) deletion, CD36/37 (-T), and CD15 TGG>TGA were encountered more often than the others in a decreasing order, in terms of frequency. The least frequent mutations/deletions were deletion from HBD exon 1 to HBB promoter, 619 bp deletion, Deletion from up HBBP1-Exon3 HBBP1 and up HBB-0.5Kb down HBB, CAP+8 C>A, CD37 (G>A), CD6 (-A), IVSI-2 (T>C), IVSII-705 T>G, and IVSII-772 (G>A). Each occurred once. Five mutations/variants were also determined which have not been reported previously in Iran. Conclusion According to the findings of the study, the Northwestern Iranian population displayed a wide variety of thalassemia allelic distributions. Identification of rare and new mutations in the β-thalassemia in the national population is beneficial for screening programs, genetic counseling, and prenatal diagnosis

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Purzycka-Bohdan, Dorota, Bogusław Nedoszytko, Marta Sobalska-Kwapis, Monika Zabłotna, Michał A. Żmijewski, Justyna Wierzbicka, Jolanta Gleń, Dominik Strapagiel, Aneta Szczerkowska-Dobosz, and Roman J. Nowicki. "Assessment of the Potential Role of Selected Single Nucleotide Polymorphisms (SNPs) of Genes Related to the Functioning of Regulatory T Cells in the Pathogenesis of Psoriasis." International Journal of Molecular Sciences 24, no. 7 (March 23, 2023): 6061. http://dx.doi.org/10.3390/ijms24076061.

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Recent studies have indicated a key role of the impaired suppressive capacity of regulatory T cells (Tregs) in psoriasis (PsO) pathogenesis. However, the genetic background of Treg dysfunctions remains unknown. The aim of this study was to evaluate the association of PsO development with selected single nucleotide polymorphisms (SNPs) of genes in which protein products play a significant role in the regulation of differentiation and function of Tregs. There were three study groups in our research and each consisted of different unrelated patients and controls: 192 PsO patients and 5605 healthy volunteers in the microarray genotyping group, 150 PsO patients and 173 controls in the ARMS–PCR method group, and 6 PsO patients and 6 healthy volunteers in the expression analysis group. The DNA microarrays analysis (283 SNPs of 57 genes) and ARMS–PCR method (8 SNPs in 7 genes) were used to determine the frequency of occurrence of SNPs in selected genes. The mRNA expression of selected genes was determined in skin samples. There were statistically significant differences in the allele frequencies of four SNPs in three genes (TNF, IL12RB2, and IL12B) between early-onset PsO patients and controls. The lowest p-value was observed for rs3093662 (TNF), and the G allele carriers had a 2.73 times higher risk of developing early-onset PsO. Moreover, the study revealed significant differences in the frequency of SNPs and their influence on PsO development between early- and late-onset PsO. Based on the ARMS–PCR method, the association between some polymorphisms of four genes (IL4, IL10, TGFB1, and STAT3) and the risk of developing PsO was noticed. Psoriatic lesions were characterized with a lower mRNA expression of FOXP3, CTLA4, and IL2, and a higher expression of TNF and IL1A in comparison with unaffected skin. In conclusion, the genetic background associated with properly functioning Tregs seems to play a significant role in PsO pathogenesis and could have diagnostic value.

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Revathi, Badiginchala, Palanki Satya Dattatreya, Attili Venkata Satya Suresh, Sharanabasappa Somanath Nirni, and Vindhya Vasini Andra. "Nanosomal docetaxel lipid suspension (NDLS) based (neo) adjuvant chemotherapy improves pathological complete response (pCR) in patients with breast cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e12591-e12591. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e12591.

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e12591 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS versus conventional docetaxel-based neo/adjuvant chemotherapy in patients with breast cancer. Methods: Patients with stage IIb-III breast cancer were randomized (1:1) to receive neoadjuvant doxorubicin and cyclophosphamide (AC) followed by conventional docetaxel (arm A) or NDLS (Doceaqualip; arm B) at a dose 75 mg/m2 IV every 3-weekly for 4 cycles as neo/adjuvant therapy. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received treatment as per clinical practice. The study outcomes included pathologic and clinical response rates (pCR, CR), and overall survival (OS). Results: 60 patients were randomized to arm A (n=30) or arm B (n=30). The baseline characteristics were similar in both groups. The pathological and clinical response rates were comparable between the NDLS and conventional docetaxel arms (P>0.05) (Table). The efficacy outcomes were not affected by the receptor (estrogen, progesterone, and HER2) status. The pCR and CR rates were higher in patients who received neoadjuvant AC followed by neoadjuvant NDLS/T versus neoadjuvant AC followed by adjuvant NDLS/T. At a follow-up of 6 months, median OS was not evaluable in both arms as all patients were alive at follow-up post study completion. Grade 3/4 infusion-related reactions, hyperglycemia and neuropathy were noted in 5, 8 and 3 patients, respectively, in the conventional docetaxel arm while it was not reported in any patient in the NDLS arm. Conclusions: NDLS based neo/adjuvant chemotherapy was efficacious in the treatment of breast cancer and showed comparable pCR, CR and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.[Table: see text]

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Revathi, Badiginchala, Palanki Satya Dattatreya, Attili Venkata Satya Suresh, Sharanabasappa Somanath Nirni, and Vindhya Vasini Andra. "Nanosomal docetaxel lipid suspension (NDLS) based (neo) adjuvant chemotherapy improves pathological complete response (pCR) in patients with breast cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e12591-e12591. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e12591.

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e12591 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS versus conventional docetaxel-based neo/adjuvant chemotherapy in patients with breast cancer. Methods: Patients with stage IIb-III breast cancer were randomized (1:1) to receive neoadjuvant doxorubicin and cyclophosphamide (AC) followed by conventional docetaxel (arm A) or NDLS (Doceaqualip; arm B) at a dose 75 mg/m2 IV every 3-weekly for 4 cycles as neo/adjuvant therapy. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received treatment as per clinical practice. The study outcomes included pathologic and clinical response rates (pCR, CR), and overall survival (OS). Results: 60 patients were randomized to arm A (n=30) or arm B (n=30). The baseline characteristics were similar in both groups. The pathological and clinical response rates were comparable between the NDLS and conventional docetaxel arms (P>0.05) (Table). The efficacy outcomes were not affected by the receptor (estrogen, progesterone, and HER2) status. The pCR and CR rates were higher in patients who received neoadjuvant AC followed by neoadjuvant NDLS/T versus neoadjuvant AC followed by adjuvant NDLS/T. At a follow-up of 6 months, median OS was not evaluable in both arms as all patients were alive at follow-up post study completion. Grade 3/4 infusion-related reactions, hyperglycemia and neuropathy were noted in 5, 8 and 3 patients, respectively, in the conventional docetaxel arm while it was not reported in any patient in the NDLS arm. Conclusions: NDLS based neo/adjuvant chemotherapy was efficacious in the treatment of breast cancer and showed comparable pCR, CR and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.[Table: see text]

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Bisseneva, Anar Kazbekovna, Gayane Pavlovna Pogossyan, and Constantin Grigoryevich Li. "Association of polymorphism rs12329760 of the TMPRSS2 gene with coronavirus infection." Bulletin of the Karaganda University. “Biology, medicine, geography Series” 109, no. 1 (March 30, 2023): 44–48. http://dx.doi.org/10.31489/2023bmg1/44-48.

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The article presents the results of genotyping of DNA samples obtained from study participants with the established status of coronavirus infection (COVID-19) using enzyme immunoassay for the single nucleotide polymorphism rs12329760 (C/T) of the TMPRSS2 gene. Genotyping was carried out by polymerase chain reaction (PCR) in real time using the technique “Amplification of the refractory mutation system” (ARMS). The distribution of frequencies of genotypes and alleles rs12329760 C>T of the TMPRSS2 gene in 80 people of the experimental and control groups was analyzed. The presence of the significance of the single nucleotide polymorphism rs12329760 of the TMPRSS2 gene in the homozygous state (CC) and heterozygous (CT) and the absence of the significance of the TT genotype was found. A statistically significant difference in the distribution of the T allele was found.

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47

Harbeck, Nadia, Oleg Gluz, Matthias Christgen, Sherko Kuemmel, Eva-Maria Grischke, Michael Braun, Jochem Potenberg, et al. "De-escalated neoadjuvant pertuzumab+trastuzumab with or without paclitaxel weekly in HR-/HER2+ early breast cancer: ADAPT-HR-/HER2+ biomarker and survival results." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 503. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.503.

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503 Background: Optimal use of de-escalated, particularly chemotherapy(CT)-free, neoadjuvant regimens in HER2+ early breast cancer (EBC) is currently unclear as there are limited survival data so far. In ADAPT-HR-/HER2+, we previously showed an excellent pCR rate of 90% after 12-week neoadjuvant paclitaxel (Pac) +pertuzumab (P) +trastuzumab (T) and a substantial and clinically meaningful pCR rate of 34% after P+T alone in HR-/HER2+ EBC. Here, we present first survival data. Methods: The prospective multicenter WSG-ADAPT-HR-/HER2+ phase II-trial is part of the ADAPT-umbrella protocol. Patients with cT1-cT4c, cN0-3 HR-/HER2+ EBC (n = 134) were randomized to 4 cycles of P+T +/- pac d1,8,15 q3w. All tumors were HR-negative (ER and PR < 1%) and HER2-positive (central lab, i.e., 2+ FISH positive or 3+ by immunohistochemistry. Primary endpoint was pCR (ypT0/is/ypN0); omission of further CT was allowed in pts with pCR. Trial objective was to compare pCR in P+T+pac arm vs. early responders in P+T arm (defined as low cellularity and/or Ki67 decrease >30% after 3 weeks). The trial was stopped early due to the observed pCR superiority in the P+T+pac arm. Secondary endpoints included safety, 5-y (distant)-DFS, OS and translational research. Cox-regression analysis was applied. PAM50 subtype was assessed using the BC360 panel. Results: 134 patients were randomized to P+T (n = 92) or P+T+pac (n = 42). 60% of tumors were cT2-4, 42% clinically node-positive. After a median follow-up of 5 years, no significant differences between study arms were observed regarding DFS, dDFS, and OS; only 13 iDFS events (7 dDFS) were observed in the whole ITT population. pCR (vs. non-pCR) after the 12-week study treatment (irrespective of study arm) was strongly associated with improved iDFS (5y DFS 98.5% vs. 82%, HR = 0.14, 95% CI 0.03-0.64). Of the 69 patients with pCR, 39 (56.5%) received no further CT (P+T arm: n = 9, 29% vs. (P+T+pac arm n = 30, 79%); only 1 distant relapse (1.4%) was observed in these patients. In the CT-free P+T arm, no pCR was observed in patients with low HER2 expression (IHC 1+/2+ and FISH positive) and/or basal-like subtype by PAM50 (n = 17, 19%). In the total study population, low HER2 expression and/or no early response was strongly associated with worse dDFS (p =.029) and iDFS (p =.068). No new safety signals were observed. Conclusions: For the first time, we have shown both excellent pCR and survival in patients treated by de-escalated neoadjuvant CT+P+T irrespective of further CT use in a prospective multicenter study. Investigation of CT-free regimens may need to be focussed on selected patients only (e.g. with high HER2 expression/non-basal-like tumors). In ADAPT HR-/HER2+, early pCR after only 12 weeks of neoadjuvant P+T+pac was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment (de)-escalation. Clinical trial information: NCT01779206.

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Chabas, Delphine, Nathalie Beaufils, Gerard Sebahoun, Regis Costello, J. Weiller, Jean-Robert Harle, and Jean Gabert. "New Detection Method of V617F JAK2 Mutation; Its Use in a Clinical Setting." Blood 108, no. 11 (November 16, 2006): 4889. http://dx.doi.org/10.1182/blood.v108.11.4889.4889.

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Abstract Background: A single point mutation in the Janus 2 tyrosine kinase gene leading to a V617F substitution has been described in a large group of hematological pathologies such as Polycythemia Vera (PV), Essential Thrombocytaemia (ET), Idiopathic Myelofibrosis (IM) and unclassified Myeloproliferative disorders (MPDs). Mutated JAK2 is an essential biomarker which improves the understanding and classification of MPDs and offers a new target for specific therapeutics. Methods: We adapted the V617F genotyping by amplification mutation system (ARMS) PCR described by AmyV Jones and Nicholas C.P Cross and combined it with a capillary electrophoresis performed on the Agilent Bioanalyseur 2100. DNA quantification was determined by βglobin gene amplification by quantitative PCR.100ng of samples and controls were genotyped by a DNA ARMS assay, using a primer pair that specifically amplifies the mutant sequence. We chose the homozygous HEL cell line as a positive control systematically tested in each run. We investigated the sensitivity of the method by testing serial dilutions of 100% V617F homozygous HEL DNA into a non mutated DNA of PBL. We compared the sensitivity of simplex ARMS PCR method using a primer pair that only amplifies the mutant sequence versus a multiplex ARMS PCR method using a two primer pairs to specifically amplify the normal and mutant sequence plus a positive control band in a single reaction. We genotyped over 6 months, 70 patients who had been screened for MPDs, BCR-ABL fusion negative, PV, ET, and isolated polycythaemia. Furthermore, we intend to collaborate with IPSOGEN SAS to compare our results with their new licensed JAK2 mutation test based on the pioneering work of Dr.Vainchenker. Results: Sensitivity of the mutliplex and simplex techniques respectively ranged from 100% to 1% and 100% to 0.1%. We found evidence that the sensitivity of the technique was imrpoved by using a simplex ARMS PCR followed by a capillary electrophoresis than a multiplex one. Of the 70 samples with a known or suspected diagnosis of MPD, 43(61%) were negative for V617F JAK2 mutation and 27(39%) were positive. The V617F JAK2 mutation was detected in 43% (3/7) PV, 42% (22/53) MPDs, BCR-ABL fusion gene negative, 25% (2/8) ET and none of isolated polycythaemia. Conclusions: The poor frequency of positive V617F V617F JAK2 mutation in patients screened for an evocated PV might be due to the inclusion in PV group of patients who do not meet diagnostic criteria for PV. The V617F JAK2 mutation in MPDs can be detected by various methods. ARMS associated with a capillary electrophoresis seems to be easy to use and reproductible for detection of single base G → T substitution in JAK2 mutation. In addition, the simplex approach improves the sensitivity of the technique leading to V617F JAK2 mutation. This qualitative test leads to the conclusions: presence of the V617F JAK2 mutation “or absence of detection of the V617F JAK2 mutation and is essential in diagnosis and classification of MPDs whereas quantitative approach will improve the management of therapeutic response when targeted therapy against V617F JAK2 mutation will be defined.

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Mokhtari, Mohammad Ali, Saman Sargazi, Ramin Saravani, Milad Heidari Nia, Shekoufeh Mirinejad, Kinga Hadzsiev, Judit Bene, and Mansoor Shakiba. "Genetic Polymorphisms in miR-137 and Its Target Genes, TCF4 and CACNA1C, Contribute to the Risk of Bipolar Disorder: A Preliminary Case-Control Study and Bioinformatics Analysis." Disease Markers 2022 (September 22, 2022): 1–14. http://dx.doi.org/10.1155/2022/1886658.

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Accumulating evidence has suggested that miR-137 and its target genes, CACNA1C, and TCF4, are amongst the most robustly implicated genes in psychiatric disorders. This preliminary study is aimed at investigating the effects of genetic variations in miR-137 (rs1625579A/C), TCF4 (rs1261084C/T), and CACNA1C (rs10774053A/G and rs10466907G/T) on BD susceptibility. We recruited 252 BD patients and 213 healthy subjects as the control group. Genotyping was performed using PCR-RFLP and ARMS-PCR methods. Enhanced risk of BD was found under the codominant homozygous, dominant, and allelic models of TCF4 rs1261084C/T, codominant homozygous and allelic models of CACNA1C rs10466907G/T polymorphisms, as well as codominant homozygous, dominant, recessive, and allelic models of the CACNA1C rs10774053A/G. Moreover, both TT/AG/GT/AA and TT/GG/GT/AC genotype combinations strongly increased the risk of BD in the participants. The bioinformatics analyses revealed that rs1261084C/T and rs10466907G/T created and disrupted binding sites of some miRNAs in the 3 ′ -untranslated region of TCF4 and CACNA1C genes. In contrast, the rs10774053A/G created a new binding site for a major splicing factor and might have an effective role in the function of the CACNA1C protein. We have found that all the studied SNPs are positively associated with BD susceptibility. Replicated studies on different ethnicities are required to confirm these findings.

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Olt, Serdar, Orhan Öznas, Haydar Bağış, and Eda Tahir Turanlı. "Chemerin rs17173608 Gene Polymorphism is not Associated with Type 2 Diabetes Mellitus: a Cross-sectional Study." Folia Medica 61, no. 1 (March 1, 2019): 69–75. http://dx.doi.org/10.2478/folmed-2018-0045.

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Abstract Background: Previous studies have shown that chemerin has important roles in the development of obesity, insulin resistance, metabolic syndrome, polycystic ovary syndrome (PCOS) and T2DM. The main goal of our study was to investigate the role of Chemerin rs17173608 gene polymorphism in T2DM (type 2 diabetes mellitus). Materials and methods: 100 patients with T2DM and 50 healthy volunteers were included in the present study. DNA isolation from blood samples was performed with K1820-02 DNA Mini Kit. Chemerin gene polymorphism was detected by Tetra- Amplification Refractory mutation system polymerase chain reaction (T-ARMS-PCR). At the end of T-ARMS-PCR, samples were run using gel electrophoresis. Some samples were validated by sequence analysis. Results: In the genotype analysis, 18.0% of patients had TT genotype and 81.0% of TG genotype was detected. GG genotype was not detected in any patient. Genotype of 1 patient was unidentified. Genotype distribution of healthy control group was 12.0% TT genotype and 88.0% TG genotype. Similar to the T2DM group, the GG genotype was not detected in the control group. There was no statistically significant difference between T2DM group and healthy control group for TG and TT genotypes. Conclusion: To our knowledge, chemerin rs17173608 gene polymorphism has been investigated in T2DM for the first time herein. In the present study, the TT genotype ratios were higher in the T2DM subjects than in healthy subjects. G allele frequency in the T2DM group was lower than that in the control group. However, there was no statistically significant difference between the groups.

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