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1
Perfecto-Avalos, Yocanxochitl, Jose R. Borbolla Escoboza, Luis M. Villela-Martiez, et al. "Correlation between FOXP3 Gene Polymorphisms in Donors, and the Severity of Acute Graft-Versus-Host Disease in Patients after Related Allogeneic Stem Cell Transplantation." Blood 110, no. 11 (2007): 3233. http://dx.doi.org/10.1182/blood.v110.11.3233.3233.
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Abstract INTRODUCTION: Acute Graft-versus-host disease (aGVHD) is a major complication of allogeneic stem cell transplantation (alloSCT). Risk factors include patient age, sex matching, CMV status and degree of match. Regulatory T cells are critical for immune tolerance processes such as aGVHD, and express the transcription factor FOXP3, a member of the forkhead/winged-helix family, identified as a key regulatory gene required for the development and activity of these cells. It has been suggested that genetic expression of FOXP3 is inversely correlated with the severity of the GVHD. We studied donor’s DNA looking for 5 polymorphisms on the promoter region of the FOXP3 gene, and we tried to correlate them with presence and degree of aGVHD. PATIENTS AND METHODS: We studied donors of stem cells for allogeneic stem cell transplants. We looked for the presence of the following polymorphisms by PCR: POL01 −5906 T/A rs2869211; POL03 −3279 A/C rs3761548 ; POL04 −2383 C/T rs3761549 ; POL05 −1383 C/T rs2232364 ; POL06 −924 A/G rs2232365. RESULTS: Our sample consisted of 31 donors, all siblings. In them we found only 2 of the 5 FOXP3 polymorphisms, either as homozygous or heterozygous. These polymorphisms were found in 15/31 donors, with 12 being homozygous (38.7%), and 3 heterozygous (9.7%). These genes polymorphisms were POL03 y POL06. The most observed polymorphism was POL-06 with 9 cases, while POL-03 was found in 6 donors. Only sex difference and CMV status had an elevated hazard ratio for developing GVHD (HR=1.18, CI95%: 0.18 to 7.64; p=0.85) and (HR=3.0, CI95%: 0.07 to 126; p=0.46) respectively. We found no statistically significant difference in the incidence of GVHD between patients who had received cells from donor with or without a FOXP3 polymorphism (p=0.87). When we analyzed the risk of presenting GVHD, results suggest that having one of the 2 positive polymorphisms of the FOXP3 gene could have a protective effect for the patient. For POL03 HR=0.87, CI95%:0.18 to 4.14; p=0.86, and for POL06, HR=1, CI95%: 0.37 to 2.64, p=0.67. CONCLUSIONS: Even though our sample is still small to make conclusive remarks, we believe that our results point toward some level of “protection” from acute GVHD in patients receiving cells from donors expressing POL03 and POL06. It is also worthwhile mentioning the relatively high frequency of these polymorphisms, as well as the absence of the other 3.
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Pachlopnik Schmid, Jana, Roxane Lemoine, Nadine Nehme та ін. "Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)". Journal of Experimental Medicine 209, № 13 (2012): 2323–30. http://dx.doi.org/10.1084/jem.20121303.
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DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.
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TUBAU, SUSAGNA. "The asymmetric behavior of English negative quantifiers in negative sentences." Journal of Linguistics 56, no. 4 (2020): 775–806. http://dx.doi.org/10.1017/s0022226719000495.
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In this paper, the unexpected behavior of object negative quantifiers in some diagnostic tests of sentential negation is accounted for within a Minimalist framework assuming that: (i) negative quantifiers decompose into negation and an existential quantifier; (ii) negative quantifiers are multidominant phrase markers, as Parallel Merge allows the verb to c-select their existential part but not their negative part, thus giving negation remerge flexibility; (iii) tag questions involve or-coordination of TPs, and neither/so clauses involve and-coordination of TPs; (iv) two positions for sentential negation are available in English, one below TP (PolP2), and one above TP (PolP1). Activation of either PolP1 or PolP2 in the absence of other scope-taking operators corresponds to two distinct grammars. If PolP1 is active, the negative part of an object negative quantifier remerges in its Specifier valuing the [upol: ] feature of Pol1 as negative ([upol:neg]) while skipping the TP-domain. As no negative formal feature is present in the TP, a negative question tag is required, as well as so-coordination, too-licensing and Yes, I guess so ‘expression of agreement’. Conversely, if PolP2 is active, the negative part of the object negative quantifier remerges in the TP-domain (in Spec, PolP2), thus requiring a positive question tag, neither-coordination, either-licensing, and No, I guess not.
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Shimada, Kenji, Monika Tsai-Pflugfelder, Niloofar Davoodi Vijeh Motlagh, et al. "The stabilized Pol31–Pol3 interface counteracts Pol32 ablation with differential effects on repair." Life Science Alliance 4, no. 9 (2021): e202101138. http://dx.doi.org/10.26508/lsa.202101138.
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DNA polymerase δ, which contains the catalytic subunit, Pol3, Pol31, and Pol32, contributes both to DNA replication and repair. The deletion of pol31 is lethal, and compromising the Pol3–Pol31 interaction domains confers hypersensitivity to cold, hydroxyurea (HU), and methyl methanesulfonate, phenocopying pol32Δ. We have identified alanine-substitutions in pol31 that suppress these deficiencies in pol32Δ cells. We characterize two mutants, pol31-T415A and pol31-W417A, which map to a solvent-exposed loop that mediates Pol31–Pol3 and Pol31–Rev3 interactions. The pol31-T415A substitution compromises binding to the Pol3 CysB domain, whereas Pol31-W417A improves it. Importantly, loss of Pol32, such as pol31-T415A, leads to reduced Pol3 and Pol31 protein levels, which are restored by pol31-W417A. The mutations have differential effects on recovery from acute HU, break-induced replication and trans-lesion synthesis repair pathways. Unlike trans-lesion synthesis and growth on HU, the loss of break-induced replication in pol32Δ cells is not restored by pol31-W417A, highlighting pathway-specific roles for Pol32 in fork-related repair. Intriguingly, CHIP analyses of replication forks on HU showed that pol32Δ and pol31-T415A indirectly destabilize DNA pol α and pol ε at stalled forks.
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Miyabayashi, Hiroka, Hiroyuki D. Sakai, and Norio Kurosawa. "DNA Polymerase B1 Binding Protein 1 Is Important for DNA Repair by Holoenzyme PolB1 in the Extremely Thermophilic Crenarchaeon Sulfolobus acidocaldarius." Microorganisms 9, no. 2 (2021): 439. http://dx.doi.org/10.3390/microorganisms9020439.
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DNA polymerase B1 (PolB1) is a member of the B-family DNA polymerase family and is a replicative DNA polymerase in Crenarchaea. PolB1 is responsible for the DNA replication of both the leading and lagging strands in the thermophilic crenarchaeon Sulfolobus acidocaldarius. Recently, two subunits, PolB1-binding protein (PBP)1 and PBP2, were identified in Saccharolobus solfataricus. Previous in vitro studies suggested that PBP1 and PBP2 influence the core activity of apoenzyme PolB1 (apo-PolB1). PBP1 contains a C-terminal acidic tail and modulates the strand-displacement synthesis activity of PolB1 during the synthesis of Okazaki fragments. PBP2 modestly enhances the DNA polymerase activity of apo-PolB1. These subunits are present in Sulfolobales, Acidilobales, and Desulfurococcales, which belong to Crenarchaea. However, it has not been determined whether these subunits are essential for the activity of apo-PolB1. In this study, we constructed a pbp1 deletion strain in S. acidocaldarius and characterized its phenotypes. However, a pbp2 deletion strain was not obtained, indicating that PBP2 is essential for replication by holoenzyme PolB1. A pbp1 deletion strain was sensitive to various types of DNA damage and exhibited an increased mutation rate, suggesting that PBP1 contribute to the repair or tolerance of DNA damage by holoenzyme PolB1. The results of our study suggest that PBP1 is important for DNA repair by holoenzyme PolB1 in S. acidocaldarius.
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Yao, Jianfei, Shiying Dang, Lifeng Li, et al. "Characteristics of POLE and POLD1 gene variations in Chinese cancer patients." Journal of Clinical Oncology 37, no. 15_suppl (2019): e14031-e14031. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14031.
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e14031 Background: POLE and POLD1 gene variations have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutation burden (TMB), an effective indicator for response prediction in immunotherapy. Methods: In this study, we systematically studied the spectrum and characteristics of POLE and POLD1 gene variations from 1,392 Chinese cancer patients, and their correlation with existing immunotherapeutic markers and cancer associated genes. Results: We found that the frequency of POLE variations was not statistically different from that in COSMIC database, while the frequency of POLD1 variations in Chinese lung cancer patients was significantly higher than that in COSMIC database. Variations frequency analysis showed that c.857C > G and c.2091dupC were potential high frequency variations in Chinese cancer patients. Patients carrying POLE damaging variations were significantly younger, and patients carrying POLD1 damaging variations exhibited significantly higher frequency of MSI than POLE/POLD1 WT patients. Further studies found that patients carrying POLE exonuclease domain damaging variations, POLD1 exonuclease and non-exonuclease domain damaging variations exhibited significantly higher TMB than POLE/POLD1 WT patients, while no such difference was found in patients carrying POLE and POLD1 neutral variations. Moreover, patients with POLE exonuclease domain damaging variations showed significantly higher frequency of MMR gene and driver gene variations than POLE/POLD1 WT patients, including genes associated with RTK/RAS/RAF pathway. Patients with damaging POLD1 variations also exhibited higher frequency of MMR gene variations than POLE/POLD1 WT patients. The high frequency variant genes in patients with POLE exonuclease domain damaging variations or POLD1 damaging variations were associated with MMR, RTK/RAS/RAF, TGFβ, WNT, PI3K-Akt and TP53 pathways. Conclusions: This study identified key characteristics and domains of POLE and POLD1 gene variations that related to TMB, MSI, MMR gene variations and key driver gene variations, and provided theoretical and practical basis for patient selection based on POLE or POLD1 gene status in immunotherapy.
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Tian, Junjie, Cheng Cheng, Jianguo Gao, et al. "POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma." International Journal of Molecular Sciences 24, no. 7 (2023): 6849. http://dx.doi.org/10.3390/ijms24076849.
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DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis.
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Coston, Tucker, Elizabeth Mauer, Jeremy Clifton Jones, et al. "Characterizing the genomic landscape of POLE/POLD1-mutated colorectal adenocarcinoma." Journal of Clinical Oncology 41, no. 4_suppl (2023): 199. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.199.
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199 Background: The progression of neoplasia in colorectal cancer (CRC) has been well characterized, with the evolution typically involving mutations in APC, KRAS, and p53, among others. POLE/POLD1 genes encode for proteins essential in enzymatic DNA polymerase function, yet POLE/POLD1 mutations in tumors are poorly characterized. Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H) independent of deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). Studies have shown associations between this hypermutated phenotype and susceptibility to immune checkpoint inhibition, which may be attributable to neoantigen creation. As such, these tumors are a clinically relevant phenotype requiring further investigation. Here, we characterized POLE/POLD1 alterations in a large, real-world cohort of patients with CRC. Methods: We retrospectively analyzed de-identified records of 9,136 primary CRC patients profiled with the Tempus xT assay. The assay includes DNA-seq of 595-648 genes at 500x to evaluate single-nucleotide variants, insertions/deletions, and copy number changes. Immunological markers analyzed included tumor mutational burden (TMB), MSI, and dMMR. MSI-H was determined by the assay through assessment of 239 loci. dMMR was determined by immunohistochemistry. Results: A total of 217 patient tumors harbored somatic POLE/POLD1 mutations (n = 203 POLE, n = 13 POLD1, and n = 1 POLE and POLD1; none germline), with no differences noted in baseline demographics including gender and age. Among the POLE/POLD1-mutant cohort, POLE copy number losses accounted for most mutations (n = 127, 59%), with short variants and copy number amplifications accounting for 35% (n = 76). The remainder of tumors exhibited POLD1 copy number changes (n = 14), including one with both POLE and POLD1 copy number loss. POLE/POLD1-mutated tumors presented with a lower frequency of MSI-H compared to wild-type (1.8% vs 6.1%, P= 0.018). Conversely, there was a higher frequency of TMB-high cases ( > 10 mut/Mb) for POLE/POLD1-mutated compared to wild-type tumors (22% vs 9.9%, P< 0.001). Differences between POLE/POLD1-mutated and wild-type tumors were also observed among many co-mutated genes, including APC (80% vs 65%, P< 0.001), ALK (31% vs 11%, P< 0.001), ATM (12% vs 3.6%, P< 0.001), BRCA2 (12% vs. 3.2%), and RET (24% vs 8.9%, P< 0.001). Conclusions: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC.
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Jia, Yongning, Yaqun Xin, Hongling Yuan, et al. "Abstract 5751: Comprehensive analysis of POLE/POLD1 variants, MMR deficient/MSI, and tumor mutational burden in Chinese population." Cancer Research 82, no. 12_Supplement (2022): 5751. http://dx.doi.org/10.1158/1538-7445.am2022-5751.
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Abstract Background: Mutations in genes encoding DNA polymerase epsilon (POLE) and delta 1 (POLD1) can lead to defects in the DNA replication, resulting in a hypermutated tumor phenotype, which might help identify potential responders to immunotherapy. This study aims to comprehensively investigate the different variants of POLE/POLD1 mutants and how it related to MSI/MMR status and TMB levels within a large Chinese population. Methods:Among 15640 Chinese patients who underwent NGS testing, the prevalence of POLE/POLD1 mutants was analyzed and the high frequencies of POLE/POLD1 variants as well as their relations with MMR/MSI and TMB were explored. Results: POLE and POLD1 mutations were highly distributed in endometrial cancer (11.1% and 9.3%), colorectal cancer (5.9% and 4.5%), and gastric cancer (4.6% and 3.3%). In our study, the mutation frequency of POLE was 3.4%, including p.Ala252Val (9.2%), p.Pro286Arg (2.7%), p.Val411Leu (1.3%), p.Asp601Glu (6.0%), p.Lys425Gln (2.9%) and p.Phe1849Val (1.8%). Variants of p.Ala252Val, p.Pro286Arg and p.Val411Leu displayed high TMB levels (median 71.4 muts/Mb, 236.7 muts/Mb and 220 muts/Mb, respectively) while variants of p.Asp601Glu, p.Lys425Gln, p.Phe1849Val and p.Asn2098His had a rather low TMB, ranging from 5.2-8.1 muts/Mb. It is worth mentioning that 37.5% of p. Pro286Arg and 87.5% of Val411Leu variants had concurrent loss-of-function mutations of MMR (MMRLOF), while MMRLOF rarely occurred in the other variants.For POLD1, the mutation frequency in Chinese patients was 2.8%, including p.Arg119His (18.8%), p.Glu57del (16.5%) and p.Asp987Thrfs (3.3%). p.Arg119His variants showed a high TMB level of 65.6 muts/Mb and most occurred in lung cancer. Variants of p.Asp987Thrfs, p.Pro116Hisfs and p.Arg19His had similar TMB levels (p&gt;0.05), while much lower TMB levels was found in p.Glu57del (3.3 muts/Mb, p&lt;0.001) compared to p.Arg119His.Compared with POLE/POLD1 wild-type (POLDE/POLD1-WT), the percentage of MSI-H samples in POLE/POLD1 mutants was much higher (14% vs 0.7, p&lt;0.001). About 10% of POLE/POLD1 mutations carried MMRLOF mutations while it was barely observed in POLE/POLD1-WT (0.5%). The TMB levels of POLE/POLD1 mutations were significantly higher than that of the POLE/POLD1-WT (17.7 vs 2.9 muts/Mb, p&lt;0.001). Furthermore, POLE/POLD1 mutations was found to be a main cause leading to high levels of TMB. Among samples with TMB &gt;10 muts/Mb, 22.6% of them were POLE/POLD1 mutations. And in samples with TMB &gt;100 muts/Mb, as high as 82% of samples were found carrying POLE/POLD1 mutations. Conclusion: POLE/POLD1 mutations were found in Chinese patients in multiple tumors. Different POLE/POLD1 variants were associated with different MMR status and TMB levels. In addition to MMR, POLE/POLD1 mutations might be another distinct means of inducing high TMB. Citation Format: Yongning Jia, Yaqun Xin, Hongling Yuan, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Comprehensive analysis of POLE/POLD1 variants, MMR deficient/MSI, and tumor mutational burden in Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5751.
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Syed, Masood Pasha, Morgan Ferrell, Svea Cheng, et al. "Molecular and clinical characteristics of POLE/POLD1 alterations among patients with colorectal cancer." Journal of Clinical Oncology 42, no. 3_suppl (2024): 184. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.184.
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184 Background: POLE and POLD1 alterations (DNA polymerase ε and DNA polymerase δ) are key biomarkers of immune response for patients with MSS colorectal cancers (CRC). The clinical and molecular characteristics of POLE/POLD1 alterations are not yet well defined across CRCs. In this study, we investigated the clinical/molecular features of POLE and POLD1 alterations and its association with MSI-H CRC. Methods: All the patients and mutation data were selected from the cBioPortal database (https://www.cbioportal.org). All nonsynonymous mutations including missense, frameshift, nonsense, nonstop, splice site, and translation start site changes of POLE/POLD1 were considered. 21 studies were used in the analysis. 7179 data samples were obtained from 7179 patients. Tumors included were from all stages of CRCs. POLE/POLD1 mutations were from mutation tables, only protein-changing mutations were kept. MSI-H status was based on mutation data (presence of MLH1/PMS2/MSH2/MSH6 mutations). Results: Of 7179 patients with all stage CRCs, 6.1% (439) were found to harbor mutated POLE/POLD1 genes. Among those, 3446 patients had known MSI status and 14.9% (514/3446) had MSI-H disease. Notably, 3.3% patients with POLE/POLD1 mutations were found to have concurrent MSI-H disease (co-existence) and only 1.1% of patients with POLE/POLD1 mutations had MSS CRC. MSI status was unknown for 1.7% of patients with POLE/POLD mutant CRC. The mean age for patients with POLE/POLD1 + with or without MSI-H disease was 67. POLE/POLD mutations were exceedingly more common in colon than rectum regardless of MSI-H status (85% vs 15% overall and 88% vs 12% in MSI-H subgroup). No difference was seen among genders for the distribution of POLE/POLD1 mutations. Conclusions: POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.
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Niu, Yanling, Tonghui Ma, Yanling Niu, and Tao Li. "Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (2021): 2606. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2606.
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2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.
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Lin, Xia. "PO01." Brachytherapy 20, no. 3 (2021): S56. http://dx.doi.org/10.1016/j.brachy.2021.06.089.
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Tsao, Wei-chung, Raquel Buj, Katherine M. Aird, Julia M. Sidorova, and Kristin A. Eckert. "Overexpression of oncogenic H-Ras in hTERT-immortalized and SV40-transformed human cells targets replicative and specialized DNA polymerases for depletion." PLOS ONE 16, no. 5 (2021): e0251188. http://dx.doi.org/10.1371/journal.pone.0251188.
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DNA polymerases play essential functions in replication fork progression and genome maintenance. DNA lesions and drug-induced replication stress result in up-regulation and re-localization of specialized DNA polymerases η and κ. Although oncogene activation significantly alters DNA replication dynamics, causing replication stress and genome instability, little is known about DNA polymerase expression and regulation in response to oncogene activation. Here, we investigated the consequences of mutant H-RAS G12V overexpression on the regulation of DNA polymerases in h-TERT immortalized and SV40-transformed human cells. Focusing on DNA polymerases associated with the replication fork, we demonstrate that DNA polymerases are depleted in a temporal manner in response to H-RAS G12V overexpression. The polymerases targeted for depletion, as cells display markers of senescence, include the Pol α catalytic subunit (POLA1), Pol δ catalytic and p68 subunits (POLD1 and POLD3), Pol η, and Pol κ. Both transcriptional and post-transcriptional mechanisms mediate this response. Pol η (POLH) depletion is sufficient to induce a senescence-like growth arrest in human foreskin fibroblast BJ5a cells, and is associated with decreased Pol α expression. Using an SV-40 transformed cell model, we observed cell cycle checkpoint signaling differences in cells with H-RasG12V-induced polymerase depletion, as compared to Pol η-deficient cells. Our findings contribute to our understanding of cellular events following oncogene activation and cellular transformation.
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Gutiérrez, Pedro J. A., and Teresa S.-F. Wang. "Genomic Instability Induced by Mutations in Saccharomyces cerevisiae POL1." Genetics 165, no. 1 (2003): 65–81. http://dx.doi.org/10.1093/genetics/165.1.65.
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Abstract Mutations of chromosome replication genes can be one of the early events that promote genomic instability. Among genes that are involved in chromosomal replication, DNA polymerase α is essential for initiation of replication and lagging-strand synthesis. Here we examined the effect of two mutations in S. cerevisiae POL1, pol1-1 and pol1-17, on a microsatellite (GT)16 tract. The pol1-17 mutation elevated the mutation rate 13-fold by altering sequences both inside and downstream of the (GT)16 tract, whereas the pol1-1 mutation increased the mutation rate 54-fold by predominantly altering sequences downstream of the (GT)16 tract in a RAD52-dependent manner. In a rad52 null mutant background pol1-1 and pol1-17 also exhibited different plasmid and chromosome loss phenotypes. Deletions of mismatch repair (MMR) genes induce a differential synergistic increase in the mutation rates of pol1-1 and pol1-17. These findings suggest that perturbations of DNA replication in these two pol1 mutants are caused by different mechanisms, resulting in various types of mutations. Thus, mutations of POL1 can induce a variety of mutator phenotypes and can be a source of genomic instability in cells.
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Pasli, Melisa, Sara Cowles, Jasmin Jo, et al. "Miscellaneous Posters PO101." Brachytherapy 22, no. 5 (2023): S119. http://dx.doi.org/10.1016/j.brachy.2023.06.202.
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Yang, Gao, Jian'An Huang, Yukun Zu, et al. "Analysis of mutation detection of POLD1/pole in pan-cancer." Journal of Clinical Oncology 38, no. 15_suppl (2020): 3142. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3142.
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3142 Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.
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Lin, Xia. "Physics PO01." Brachytherapy 20, no. 3 (2021): S5. http://dx.doi.org/10.1016/j.brachy.2021.05.104.
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Gola, Michał, Przemysław Stefaniak, Janusz Godlewski, Barbara Alicja Jereczek-Fossa, and Anna Starzyńska. "Prospects of POLD1 in Human Cancers: A Review." Cancers 15, no. 6 (2023): 1905. http://dx.doi.org/10.3390/cancers15061905.
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Cancer is the second leading cause of death globally, exceeded only by cardiovascular disease. Despite the introduction of several survival-prolonging treatment modalities, including targeted therapy and immunotherapy, the overall prognosis for the metastatic disease remains challenging. Therefore, the identification of new molecular biomarkers and therapeutic targets related to cancer diagnosis and prognosis is of paramount importance. DNA polymerase delta 1 (POLD1), a catalytic and proofreading subunit of the DNA polymerase δ complex, performs a crucial role in DNA replication and repair processes. Recently, germline and somatic mutations of the POLD1 gene have been acknowledged in several malignancies. Moreover, diversified POLD1 expression profiles have been reported in association with clinicopathological features in a variety of tumor types. With this review, we aim to summarize the current knowledge on the role of POLD1 in cancers. In addition, we discuss the future prospects and clinical applications of the assessment of POLD1 mutation and expression patterns in tumors.
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Zheng, Shuhua, Eric D. Donnelly, and Jonathan B. Strauss. "Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer." JAMA Network Open 7, no. 1 (2024): e2351906. http://dx.doi.org/10.1001/jamanetworkopen.2023.51906.
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ImportanceBlack patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied.ObjectiveTo explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups.Design, Setting, and ParticipantsThis retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering–Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups.ExposurePatients of different racial groups with EC and with or without POLE or POLD1 alterations.Main Outcomes and MeasuresThe main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected.ResultsA total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients.Conclusions and RelevanceIn this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.
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Siraj, Abdul K., Rong Bu, Maham Arshad, et al. "POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer." Endocrine Connections 9, no. 9 (2020): 923–32. http://dx.doi.org/10.1530/ec-20-0258.
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Thyroid cancer is the most frequent endocrine cancer with an increasing incidence rate worldwide and is the second most common malignancy among females in Saudi Arabia. Papillary thyroid cancer (PTC) is the most common subtype. Germline pathogenic variants in the proofreading domain of the POLE and POLD1 genes predispose to several types of cancers. However, the role of pathogenic variants of these two genes in PTC remains unknown. Capture sequencing, Sanger sequencing and immunohistochemistry were performed on 300 PTC cases from the Middle Eastern region. One germline pathogenic variant each of POLE (1/300, 0.33%) and POLD1 (1/300, 0.33%) genes was identified. Low expression of POLD1 was detected in 46.5% (133/286) of cases and was significantly associated with the follicular variant of PTC (P = 0.0006), distant metastasis (P = 0.0033) and stage IV tumours (P = 0.0081). However, no somatic pathogenic variant was detected in POLE gene. Furthermore, low expression of POLE was noted in 61.7% (175/284) of cases with no significant clinicopathological associations. Our study shows that pathogenic variant in the POLE and POLD1 proofreading domain is a cause of PTC and low expression of POLD1 is associated with poor prognostic markers in the Middle Eastern population. Further studies from different geographic populations are needed to determine the frequency and spectrum of proofreading domain pathogenic variants in POLE and POLD1 genes and in PTC from different ethnicities.
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Bappy, Md Nazmul Islam, Anindita Roy, Md Gulam Rabbany Rabbi, et al. "Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene." Genetics Research 2022 (May 11, 2022): 1–12. http://dx.doi.org/10.1155/2022/1740768.
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POLD1 (DNA polymerase delta 1, catalytic subunit) is a protein-coding gene that encodes the large catalytic subunit (POLD1/p125) of the DNA polymerase delta (Polδ) complex. The consequence of missense or nonsynonymous SNPs (nsSNPs), which occur in the coding region of a specific gene, is the replacement of single amino acid. It may also change the structure, stability, and/or functions of the protein. Mutation in the POLD1 gene is associated with autosomal dominant predisposition to colonic adenomatous polyps, colon cancer, endometrial cancer (EDMC), breast cancer, and brain tumors. These de novo mutations in the POLD1 gene also result in autosomal dominant MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy). In this study, genetic variations of POLD1 which may affect the structure and/or function were analyzed using different types of bioinformatics tools. A total of 17038 nsSNPs for POLD1 were collected from the NCBI database, among which 1317 were missense variants. Out of all missense nsSNPs, 28 were found to be deleterious functionally and structurally. Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.
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Pätzold, LA, D. Bērziņa, Z. Daneberga, J. Gardovskis, and E. Miklaševičs. "Detection of allelic variants of the POLE and POLD1 genes in colorectal cancer patients." Balkan Journal of Medical Genetics 20, no. 2 (2017): 83–87. http://dx.doi.org/10.1515/bjmg-2017-0028.
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Abstract Incidence of colorectal cancer is high worldwide and it mostly occurs as an accumulation of environmental factors and genetic alterations. Hereditary colorectal cancer can develop as a part of a hereditary syndrome. There is a suspected correlation between colorectal cancer and allelic variants of the POLE and POLD1 genes. The aim of the present study was to look for associations between the allelic variants in the POLE and POLD1 genes and colorectal cancer. One thousand, seven hundred and forty-nine DNA samples from colorectal cancer patients were collected from 2002 to 2013. Samples were divided in three groups: hereditary colorectal cancer patients, patients with different hereditary cancer syndromes in their families and patients with no cancer history in their families. The DNA samples were screened for allelic variants of POLE rs483352909 and POLD1 rs39751463 using denaturing high performance liquid chromatography (DHPLC). All patients were negative for allelic variants rs483352909 of the POLE gene and rs397514632 of the POLD1 gene. One allelic variant rs373243003 in the POLE gene and one novel duplication of four nucleotides at the excision site between intron and exon (c.1384-5dupCCTA) in the POLD1 gene, was found. We could not detect or confirm the connection between the genetic variants in the POLD1 and POLE genes and colorectal cancer patients, but we detected a novel genetic variant with an unknown significance.
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Isohanni, P., A. H. Hakonen, L. Euro, et al. "POLG1 manifestations in childhood." Neurology 76, no. 9 (2011): 811–15. http://dx.doi.org/10.1212/wnl.0b013e31820e7b25.
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Venkatesan, Ranga N., Piper M. Treuting, Evan D. Fuller та ін. "Mutation at the Polymerase Active Site of Mouse DNA Polymerase δ Increases Genomic Instability and Accelerates Tumorigenesis". Molecular and Cellular Biology 27, № 21 (2007): 7669–82. http://dx.doi.org/10.1128/mcb.00002-07.
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ABSTRACT Mammalian DNA polymerase δ (Pol δ) is believed to replicate a large portion of the genome and to synthesize DNA in DNA repair and genetic recombination pathways. The effects of mutation in the polymerase domain of this essential enzyme are unknown. Here, we generated mice harboring an L604G or L604K substitution in highly conserved motif A in the polymerase active site of Pol δ. Homozygous Pold1 L604G/L604G and Pold1 L604K/L604K mice died in utero. However, heterozygous animals were viable and displayed no overall increase in disease incidence, indicative of efficient compensation for the defective mutant polymerase. The life spans of wild-type and heterozygous Pold1 +/L604G mice did not differ, while that of Pold1 +/L604K mice was reduced by 18%. Cultured embryonic fibroblasts from the heterozygous strains exhibited comparable increases in both spontaneous mutation rate and chromosome aberrations. We observed no significant increase in cancer incidence; however, Pold1 +/L604K mice bearing histologically diagnosed tumors died at a younger median age than wild-type mice. Our results indicate that heterozygous mutation at L604 in the polymerase active site of DNA polymerase δ reduces life span, increases genomic instability, and accelerates tumorigenesis in an allele-specific manner, novel findings that have implications for human cancer.
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Stopińska, Katarzyna, Tomasz Grzybowski, Boris A. Malyarchuk, Miroslava V. Derenko, and Danuta Miścicka-Sliwka. "Optimization of the Y831C mutation detection in human DNA polymerase gamma by allelic discrimination assay." Acta Biochimica Polonica 53, no. 3 (2006): 591–95. http://dx.doi.org/10.18388/abp.2006_3332.
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Many well-defined mutations in the gene for the catalytic subunit of polymerase gamma (POLG1) have been found to be associated with disease, whereas the status of several mutations remains unresolved due to the conflicting reports on their frequencies in populations of healthy individuals. Here, we have developed a highly sensitive, real-time allelic discrimination assay enabling detection of the Y831C mutation in the POLG1 gene. The Y831C mutation is present in the Polish population at a frequency of 2.25%. The new assay is well suited to both extensive population studies and molecular diagnostics of POLG1.
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Robinson, Philip S., Tim H. H. Coorens, Claire Palles, et al. "Increased somatic mutation burdens in normal human cells due to defective DNA polymerases." Nature Genetics 53, no. 10 (2021): 1434–42. http://dx.doi.org/10.1038/s41588-021-00930-y.
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AbstractMutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
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YÖNTEM, Ahmet, İbrahim BAYRAM, Gülay SEZGİN, Serhan KÜPELİ, Ayşe ÖZKAN, and Atila TANYEL,İ. "DNA polymerase delta (POLD1 and POLD2) gene expression in pediatric acute lymphoblastic leukemia patients and its relationship with prognosis." Cukurova Medical Journal 48, no. 2 (2023): 377–84. http://dx.doi.org/10.17826/cumj.1221593.
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Purpose: This study aimed to investigate the status of DNA polymerase delta (POLD1 and POLD2) gene expression at the time of diagnosis in pediatric acute lymphoblastic leukemia (ALL) patients, compared with the normal population, and its relationship with prognosis and other clinical findings.
 Materials and Methods: Seventy-three patients diagnosed with ALL between January 2008 and November 2015 and 29 healthy control subjects were included in the study. Gene expression profiling of peripheral blood samples was performed using Real-time PCR.
 Results: The mean value of POLD1 gene expression was found to be significantly higher in ALL patients at the time of diagnosis than the control group (376.5± 685.8 and 17.9± 19.8, respectively), but there was no difference in POLD2 gene expression (511.5± 898.1 and 125.4± 132.7, respectively). POLD1 and POLD2 gene expressions were found to be low in patients with relapse and exitus, but the results were not statistically significant. Patients with low levels of POLD1 expression had lower survival rates in the 5th year than those with high levels of expression (54% and 68%, respectively), and similarly, patients with low levels of POLD2 expression had lower survival rates in the 5th year compared to those with high levels of expression (58% and 68%, respectively).
 Conclusion: Lower POLD1 and POLD2 expressions at the time of diagnosis in ALL patients may adversely affects the prognosis.
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van Well, Evelien, Tim Govers, Stavroula Giannouli, et al. "GYN Posters PO01." Brachytherapy 22, no. 5 (2023): S65—S66. http://dx.doi.org/10.1016/j.brachy.2023.06.102.
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Sharma, Manish R., James T. Auman, Nirali M. Patel, et al. "Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1." JCO Precision Oncology, no. 1 (November 2017): 1–12. http://dx.doi.org/10.1200/po.16.00015.
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Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.
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Meira, Bruna, Rafael Roque, Miguel Pinto, and André Caetano. "Late-onset presentation of POLG1-associated mitochondrial disease." BMJ Case Reports 12, no. 3 (2019): e228482. http://dx.doi.org/10.1136/bcr-2018-228482.
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Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.
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Yu, Lijun, Meiyan Wei, and Fengyan Li. "Longitudinal Analysis of Gene Expression Changes During Cervical Carcinogenesis Reveals Potential Therapeutic Targets." Evolutionary Bioinformatics 16 (January 2020): 117693432092057. http://dx.doi.org/10.1177/1176934320920574.
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Despite advances in the treatment of cervical cancer (CC), the prognosis of patients with CC remains to be improved. This study aimed to explore candidate gene targets for CC. CC datasets were downloaded from the Gene Expression Omnibus database. Genes with similar expression trends in varying steps of CC development were clustered using Short Time-series Expression Miner (STEM) software. Gene functions were then analyzed using the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Protein interactions among genes of interest were predicted, followed by drug-target genes and prognosis-associated genes. The expressions of the predicted genes were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Red and green profiles with upward and downward gene expressions, respectively, were screened using STEM software. Genes with increased expression were significantly enriched in DNA replication, cell-cycle-related biological processes, and the p53 signaling pathway. Based on the predicted results of the Drug-Gene Interaction database, 17 drug-gene interaction pairs, including 3 red profile genes (TOP2A, RRM2, and POLA1) and 16 drugs, were obtained. The Cancer Genome Atlas data analysis showed that high POLA1 expression was significantly correlated with prolonged survival, indicating that POLA1 is protective against CC. RT-qPCR and Western blotting showed that the expressions of TOP2A, RRM2, and POLA1 gradually increased in the multistep process of CC. TOP2A, RRM2, and POLA1 may be targets for the treatment of CC. However, many studies are needed to validate our findings.
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Pang, Linrong, Tao Xu, Hua Tao, et al. "The landscape of POLE/POLD1 mutations in Chinese solid tumor patients." Journal of Clinical Oncology 37, no. 15_suppl (2019): e13050-e13050. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13050.
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e13050 Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p < 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.
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Dawan, Jirapat, and Juhee Ahn. "Variability in Adaptive Resistance of Salmonella Typhimurium to Sublethal Levels of Antibiotics." Antibiotics 11, no. 12 (2022): 1725. http://dx.doi.org/10.3390/antibiotics11121725.
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This study was designed to evaluate the adaptive resistance of Salmonella Typhimurium under continuous sublethal selective pressure. Salmonella Typhimurium ATCC 19585 (STATCC) and S. Typhimurium CCARM 8009 (STCCARM) were sequentially cultured for 3 days at 37 °C in trypticase soy broth containing 1/2 × MICs of cefotaxime (CEF1/2), chloramphenicol (CHL1/2), gentamicin (GEN1/2), and polymyxin B (POL1/2). The STATCC and STCCARM exposed to CEF1/2, CHL1/2, GEN1/2, and POL1/2 were evaluated using antibiotic susceptibility, cross-resistance, and relative fitness. The susceptibilities of STATCC exposed to GEN1/2 and POL1/2 were increased by a 2-fold (gentamicin) and 8-fold (polymyxin B) increase in minimum inhibitory concentration (MIC) values, respectively. The MIC values of STCCARM exposed to CEF1/2, CHL1/2, GEN1/2, and POL1/2 were increased by 4-fold (cefotaxime), 2-fold (chloramphenicol), 2-fold (gentamicin), and 8-fold (polymyxin B). The highest heterogeneous fractions were observed for the STATCC exposed to CEF1/2 (38%) and POL1/2 (82%). The STCCARM exposed to GEN1/2 was cross-resistant to cefotaxime (p < 0.05), chloramphenicol (p < 0.01), and polymyxin B (p < 0.05). The highest relative fitness levels were 0.92 and 0.96, respectively, in STATCC exposed to CEF1/2 and STCCARM exposed to POL1/2. This study provides new insight into the fate of persistent cells and also guidance for antibiotic use.
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Finsterer, Josef, and Sinda Zarrouk-Mahjoub. "POLG1 mutations in bipolar disorders." Psychiatry and Clinical Neurosciences 71, no. 8 (2017): 569. http://dx.doi.org/10.1111/pcn.12509.
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Tiangyou, W., G. Hudson, D. Ghezzi, et al. "POLG1 in idiopathic Parkinson disease." Neurology 67, no. 9 (2006): 1698–700. http://dx.doi.org/10.1212/01.wnl.0000238963.07425.d5.
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Miguel, Rita, Miguel Fernandes Gago, João Martins, Pedro Barros, José Vale, and Maria José Rosas. "POLG1-related levodopa-responsive parkinsonism." Clinical Neurology and Neurosurgery 126 (November 2014): 47–54. http://dx.doi.org/10.1016/j.clineuro.2014.08.020.
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Finsterer, Josef, and Fulvio A. Scorza. "Phenotypic spectrum of POLG1 mutations." Neurological Sciences 39, no. 3 (2017): 571–73. http://dx.doi.org/10.1007/s10072-017-3116-1.
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Wang, Tao, Dingwei Liu, Lin Wang, et al. "DNA Repair Genes Are Associated with Subtype Classification, Prognosis, and Immune Infiltration in Uveal Melanoma." Journal of Oncology 2022 (January 19, 2022): 1–18. http://dx.doi.org/10.1155/2022/1965451.
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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. DNA repair genes play a vital role in cancer development. However, there has been very little research about DNA repair genes in UM. This study aimed to evaluate the importance of DNA repair genes and established a signature for predicting prognosis and immune features of UM. In this study, we mined TCGA database through bioinformatics analysis, and the intersect was taken between DNA repair genes and prognosis related genes and yielded 52 genes. We divided 80 UM patients into C1 and C2 subtypes. GSEA results indicated that abundant cancer-promoting functions and signaling pathways were activated in C2 subtype and the proportion of SNVs was higher in C2 than in C1 which suggested a worse prognosis. We built a six DNA repair genes model including ITPA, CETN2, CCNO, POLR2J, POLD1, and POLA1 by LASSO regression to predict prognosis of UM patients and utilized the median value of risk scores as the cutoff point to differentiate high risk and low risk group. The survival analyses and the receiver operating characteristic (ROC) curves in the validation group and entire data set confirmed the accuracy of this model. We also constructed a nomogram based on age and risk scores to evaluate the relationship between risk scores and clinical outcome. The calibration curve of the overall survival (OS) indicated that the performance of this model is steady and robust. Finally, the enrichment analysis showed that there were complex regulatory mechanisms in UM patients. The immune infiltration analysis indicated that the immune infiltration in C2 in the high risk group was different from that in the low risk group. Our findings indicated that the DNA repair genes may be related to UM prognosis and provide new insight into the underlying mechanisms.
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Martin, Aegina Adams, Isabelle Dionne, Raymund J. Wellinger та Connie Holm. "The Function of DNA Polymerase α at Telomeric G Tails Is Important for Telomere Homeostasis". Molecular and Cellular Biology 20, № 3 (2000): 786–96. http://dx.doi.org/10.1128/mcb.20.3.786-796.2000.
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ABSTRACT Telomere length control is influenced by several factors, including telomerase, the components of telomeric chromatin structure, and the conventional replication machinery. Although known components of the replication machinery can influence telomere length equilibrium, little is known about why mutations in certain replication proteins cause dramatic telomere lengthening. To investigate the cause of telomere elongation in cdc17/pol1 (DNA polymerase α) mutants, we examined telomeric chromatin, as measured by its ability to repress transcription on telomere-proximal genes, and telomeric DNA end structures in pol1-17 mutants. pol1-17 mutants with elongated telomeres show a dramatic loss of the repression of telomere-proximal genes, or telomeric silencing. In addition,cdc17/pol1 mutants grown under telomere-elongating conditions exhibit significant increases in single-stranded character in telomeric DNA but not at internal sequences. The single strandedness is manifested as a terminal extension of the G-rich strand (G tails) that can occur independently of telomerase, suggesting thatcdc17/pol1 mutants exhibit defects in telomeric lagging-strand synthesis. Interestingly, the loss of telomeric silencing and the increase in the sizes of the G tails at the telomeres temporally coincide and occur before any detectable telomere lengthening is observed. Moreover, the G tails observed incdc17/pol1 mutants incubated at the semipermissive temperature appear only when the cells pass through S phase and are processed by the time cells reach G1. These results suggest that lagging-strand synthesis is coordinated with telomerase-mediated telomere maintenance to ensure proper telomere length control.
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Peramachi Palanivelu. "Polymerase and Proofreading Exonuclease Domains in the DNA Polymerase γ and Nuclear-encoded RNA Polymerase of the Human Mitochondria and Identification of Mitochondrial Disease Mutations in the Polymerase Active Site Region of DNA Polymerase γ". World Journal of Advanced Research and Reviews 21, № 2 (2024): 979–1005. http://dx.doi.org/10.30574/wjarr.2024.21.2.0512.
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Recent reports have made it clear that mutations in the mitochondrial DNA (mtDNA) polymerase γ (POLG1) are a major cause of many human diseases. Mutations in the mtDNA polymerase leads to defective oxidative phosphorylation and ATP production, resulting in many mitochondrial diseases. For their mitochondrial genome replication, humans and animals use POLG1, whose catalytic site is essentially similar to the E. coli DNA polymerase I (DNA pol I). Multiple sequence alignment (MSA) analysis have shown that the POLG1 and E. coli DNA pol I use identical amino acids in their polymerase catalytic sites, viz. –943R-4EHAKI1FNYGRI955Y8G- (human DNA pol γ) as –R-4RSAKA1INFGLIY8G- (E. coli DNA pol I). However, the human POLG1 shows only 31.25% identity with the E. coli DNA pol I, suggesting a highly divergent evolution. Mutation(s) in the POLG1 gene is one of the most common causes of many inherited mitochondrial diseases in children and adults. Depending on their location within the enzyme, mutations either lead to mtDNA depletion or accumulation of multiple mtDNA deletions leading to various mitochondrial diseases. The most common POLG1 dominant mutation, viz. Y955→H/C, which lead to a severe, early-onset of multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure is located in the template-binding pair of the polymerase catalytic site region by MSA. Another dominant mutation, R943→H/C is observed in patients with Progressive External Ophthalmoplegia (adPEO, an autosomal, dominant, heritable mitochondrial disorder) is located in the nucleoside triphosphate (NTP) selection amino acid in the polymerase catalytic site region. The nuclear-encoded RNA polymerase (NEP) is imported from the nucleus and involves in the transcription of all the mitochondrial genes. The human mitochondrial NEP showed 39.30%, 40.12% and 26.98% identities to the NEPs of the mitochondria and chloroplasts of Arabidopsis thaliana, and T7 RNA polymerase, respectively, suggesting that the human and plant mitochondrial NEPs are distinctly different. Interestingly, the human NEP’s catalytic core is almost completely conserved in the plant mitochondrial and chloroplast NEPs, viz. –R-4KVVKQ1TVMTVVY8G- (Human) and –R-4KLVKQ1TVMTSVY8G- (A. Thaliana). Furthermore, the mitochondrial NEP’s catalytic core from human and different animal sources is remarkably conserved and is in close agreement with other NEPs of plant sources. Both the human DNA pol γ and NEP possess a typical template-binding pair (-YG-), a basic catalytic amino acid (K) to initiate catalysis and a basic nucleotide selection amino acid R at -4 from the catalytic K. The PR exonucleases of POLG1 and NEP belong to the DEDD-superfamily of exonucleases and uses a Y or H as the proton acceptor, respectively.
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Wei, Christina Hsiao, Edward Wenge Wang, Lingzi Ma, et al. "POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab." Cancers 15, no. 23 (2023): 5674. http://dx.doi.org/10.3390/cancers15235674.
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Background: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. Methods: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient’s tumor and engineered cell lines. Results: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient’s tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). Conclusion: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.
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Singh, Keshav K. "MITOCHONDRIA AS REVERSIBLE REGULATORS OF AGING ASSOCIATED SKIN WRINKLES AND HAIR LOSS IN MICE." Innovation in Aging 3, Supplement_1 (2019): S395. http://dx.doi.org/10.1093/geroni/igz038.1461.
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Abstract To evaluate the consequences of the decline in mtDNA content associated with aging we have created an inducible mouse model expressing, in the polymerase domain of POLG1, a dominant-negative mutation that induces depletion of mtDNA. We utilized this inducible mouse model to modulate mitochondrial function by depleting and repleting the mtDNA content. We demonstrate that, in mice, ubiquitous expression of dominant-negative mutant POLG1 leads to 1) reduction of mtDNA content in skin, 2) skin wrinkles, and 3) hair loss. By turning off the mutant POLG1 transgene expression in the whole animal, the skin and hair phenotypes revert to normal after repletion of mtDNA. Thus, we have developed whole-animal mtDNA depleter-repleter mice. These mice present evidence that mtDNA homeostasis is involved in skin aging phenotype and loss of hair and provide an unprecedented opportunity to create tissue-specific mitochondrial modulation to determine the role of the mitochondria in a particular tissue.
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Ito, Tetsuya, Tadashi Nomizu, Hidetaka Eguchi, et al. "The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan." Japanese Journal of Clinical Oncology 50, no. 9 (2020): 1080–83. http://dx.doi.org/10.1093/jjco/hyaa090.
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Abstract Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G&gt;A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.
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Chatre, Laurent, Denis S. F. Biard, Alain Sarasin, and Miria Ricchetti. "Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome." Proceedings of the National Academy of Sciences 112, no. 22 (2015): E2910—E2919. http://dx.doi.org/10.1073/pnas.1422264112.
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UV-sensitive syndrome (UVSS) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UVsS or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UVSS cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.
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Balasubramanian, S., T. Bettin Thomas, D. Mathavan, et al. "Isolation and Screening of Probiotic Bacteria from the Gut of Polychaetes as a Probiotic Potential for Fish Aquaculture." Nature Environment and Pollution Technology 22, no. 2 (2023): 861–68. http://dx.doi.org/10.46488/nept.2023.v22i02.028.
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In the present study, a total of 17 morphologically different gut-associated bacteria were isolated from four species of estuarine polychaetes: polychaetes Capitella capitata, Scalibregma inflatum, Dendronereis aesturiana, and Namalycastis abiuma. The isolated strains were evaluated for their probiotic activities, such as digestive enzymes including protease, amylase, and lipase, and antimicrobial activities by the agar well diffusion method against fish pathogens. Based on their better enzymatic and antibacterial activities, two bacterial strains, CMST Poly1 and CMST Poly2, were selected for further probiotic studies. Based on the biochemical and morphological characterization, both probiotic strains were characterized as Gram-positive, rod-shaped, non-motile, non-spore-forming, homofermentative, absence of catalyzing enzymes and notable proteolytic activity, and susceptibility to various antibiotics. Further, these two strains were confirmed by 16S rRNA gene sequence analysis as Bacillus subtilis CMST Poly1 and Priestia megaterium CMST Poly2. Our results revealed that strains Bacillus subtilis CMST Poly1 and Priestia megaterium CMST Poly2 can potentially be used as probiotic strains in aquaculture applications.
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Fujita, Takehiro, Masami Shuta, Mika Mano, et al. "Forced Gradient Copolymer for Rational Design of Mussel-Inspired Adhesives and Dispersants." Materials 16, no. 1 (2022): 266. http://dx.doi.org/10.3390/ma16010266.
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In recent years, there has been considerable research into functional materials inspired by living things. Much attention has been paid to the development of adhesive materials that mimic the adhesive proteins secreted by a mussel’s foot. These mussel-inspired materials have superior adhesiveness to various adherents owing to the non-covalent interactions of their polyphenolic moieties, e.g., hydrogen bonding, electrostatic interactions, and even hydrophobic interactions. Various factors significantly affect the adhesiveness of mussel-inspired polymers, such as the molecular weight, cross-linking density, and composition ratio of the components, as well as the chemical structure of the polyphenolic adhesive moieties, such as l-3,4-dihydroxyphenylalanine (l-Dopa). However, the contributions of the position and distribution of the adhesive moiety in mussel-inspired polymers are often underestimated. In the present study, we prepared a series of mussel-inspired alkyl methacrylate copolymers by controlling the position and distribution of the adhesive moiety, which are known as “forced gradient copolymers”. We used a newly designed gallic-acid-bearing methacrylate (GMA) as the polyphenolic adhesive moiety and copolymerized it with 2-ethylhexyl methacrylate (EHMA). The resulting forced gradient adhesive copolymer of GMA and EHMA (poly(GMA-co-EHMA), Poly1) was subjected to adhesion and dispersion tests with an aluminum substrate and a BaTiO3 nanoparticle in organic solvents, respectively. In particular, this study aims to clarify how the monomer position and distribution of the adhesive moiety in the mussel-inspired polymer affect its adhesion and dispersion behavior on a flat metal oxide surface and spherical inorganic oxide surfaces of several tens of nanometers in diameter, respectively. Here, forced gradient copolymer Poly1 consisted of a homopolymer moiety of EHMA (Poly3) and a random copolymer moiety of EHMA and GMA (Poly4). The composition ratio of GMA and the molecular weight were kept constant among the Poly1 series. Simultaneous control of the molecular lengths of Poly3 and Poly4 allowed us to discuss the effects on the distribution of GMA in Poly1. Poly1 exhibited apparent distribution dependency with regard to the adhesiveness and the dispersibility of BaTiO3. Poly1 showed the highest adhesion strength when the composition ratio of GMA was approximately 9 mol% in the portion of the Poly4 segment. In contrast, the block copolymer consisting of the Poly3 segment and Poly4 segment with only adhesive moiety 1 showed the lowest viscosity for dispersion of BaTiO3 nanoparticles. These results indicate that copolymers with mussel-inspired adhesive motifs require the proper design of the monomer position and distribution in Poly1 according to the shape and characteristics of the adherend to maximize their functionality. This research will facilitate the rational design of bio-inspired adhesive materials derived from plants that outperform natural materials, and it will eventually contribute to a sustainable circular economy.
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Jin, Ying, Run-jie Huang, Zong-jiong Mai, et al. "A phase II clinical trial of toripalimab in advanced solid tumors with POLE/POLD1 mutation." Journal of Clinical Oncology 41, no. 4_suppl (2023): 802. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.802.
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802 Background: Prior studies indicated that polymerase epsilon/polymerase delta (POLE/POLD1) exonuclease domain mutations (POL-EDMs) was associated with the efficacy of immune checkpoint inhibitor (ICI). However, there remains controversy about whether patients with POLE/POLD1 non-exonuclease domain mutations (POLE-non-EDMs), which occupied the majority of POLE/POLD1 mutations, could benefit from ICI. Currently, few prospective clinical trials have evaluated the predictive value of POLE/POLD1 mutation in ICI. Methods: We initiated a phase II clinical trial for non-microsatellite instability-high (non-MSI-H) patients with POLE/POLD1 mutant advanced solid tumors to investigate the treatment efficacy of toripalimab, an anti-PD-1 antibody. Eligible patients received one dose of 240mg toripalimab every three weeks for up to two years until disease progression or intolerable toxicity occurred. The primary endpoint was overall response rate, and secondary endpoints included disease control rate, overall survival, progression-free survival, and safety. Treatment responses were assessed using the RECIST v1.1 after each six-week treatment cycle. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. This study is registered on ClinicalTrials.gov, NCT03810339. Results: A total of 15 patients were enrolled to receive treatment, of whom 14 underwent response assessment. The overall response rate was 21.4%, and the disease control rate was 57.1%. The median overall survival and median progression-free survival were 2.5 months and 28.2 months, respectively. The overall response rate of the patients with POL-EDMs and POL-non-EDMs were 66.7% and 7.1%, while the disease control rates were 66.7% and 54.5%, respectively. Grade three or four treatment-related adverse events occurred in 20% of patients. Conclusions: This study showed that patients with POL-EDMs had a good response to ICI therapy, and those with POL-non-EDMs could clinically benefit from anti-PD-1 antibody monotherapy, urging the need for more investigations on immunotherapy combined with chemotherapy in patients with POL-non-EDMs. Clinical trial information: NCT03810339 .
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Finsterer, Josef. "Valproate Is Contraindicated in POLG1 Mutations." Pediatric Gastroenterology, Hepatology & Nutrition 22, no. 1 (2019): 105. http://dx.doi.org/10.5223/pghn.2019.22.1.105.
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El-Baba, Chirine, Zeinab Ayache, Mona Goli, et al. "The Antitumor Effect of the DNA Polymerase Alpha Inhibitor ST1926 in Glioblastoma: A Proteomics Approach." International Journal of Molecular Sciences 24, no. 18 (2023): 14069. http://dx.doi.org/10.3390/ijms241814069.
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Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.
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Keshinro, Ajaratu, Chad Vanderbilt, Jin K. Kim, et al. "Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer." JCO Precision Oncology, no. 5 (May 2021): 817–26. http://dx.doi.org/10.1200/po.20.00456.
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PURPOSE To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb ( P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.