ORCID Profile
0000-0003-3598-7733
Current Organisations
University at Buffalo, State University of New York
,
Garvan Institute of Medical Research
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Publisher: American Chemical Society (ACS)
Date: 06-04-2004
DOI: 10.1021/JA0495213
Abstract: We report here the ability of an alcohol dehydrogenase (ADH) ribozyme to reduce a benzaldehyde. While the ribozyme was initially evolved in vitro based on the activity for the NAD+-dependent oxidation of the benzyl alcohol, we found that this ADH ribozyme is also capable of reducing the aldehyde in the presence of NADH and Zn2+. The rate acceleration gained by ribozyme catalysis was more than 6 orders of magnitude larger than the spontaneous reaction. Although the reversibility of phosphordiester and acyl transfer reactions catalyzed by ribozymes was known, that of other chemical reactions has not been well established. This study has demonstrated the reversibility of a hydride transfer chemistry catalyzed by the ADH ribozyme. Most interestingly, the ribozyme shares many features with the protein ADHs, e.g., reversibility and NADH/Zn2+ dependence.
Publisher: Springer Science and Business Media LLC
Date: 20-03-2019
DOI: 10.1038/S41467-019-09312-9
Abstract: ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast s les from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1 , placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1 , as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1 . Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.
Publisher: Wiley
Date: 19-07-2019
DOI: 10.1111/IMCB.12281
Publisher: Springer Science and Business Media LLC
Date: 19-11-2018
DOI: 10.1038/S41591-018-0243-Z
Abstract: Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1038/S41375-021-01246-W
Abstract: The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline s les of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9% p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5% p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-04-2019
Abstract: The exclusion of immune cells from the tumor microenvironment has been associated with poor prognosis in the majority of cancers. We report that when considering 21 solid cancer types, immune cell exclusion is widely associated with the presence of a stem cell-like phenotype in tumors (“stemness”). Stemness positively correlates with higher intratumoral heterogeneity, possibly by protecting antigenic clones from elimination by the immune system. The activation of a stemness program appears to limit antitumor immune responses via tumor cell-intrinsic silencing of endogenous retrovirus expression, repression of type I interferon signaling, and up-regulation of immunosuppressive checkpoints. Our work suggests that targeting the stemness phenotype in cancer will promote T cell infiltration and render tumors more responsive to immune control.
Publisher: Public Library of Science (PLoS)
Date: 06-01-2012
Publisher: Springer Science and Business Media LLC
Date: 05-02-2014
Abstract: The rapid advancements in the field of genome sequencing are aiding our understanding on many biological systems. In the last five years, computational biologists and bioinformatics specialists have come up with newer, better and more efficient tools towards the discovery, analysis and interpretation of different genomic variants from high-throughput sequencing data. Availability of reliable simulated dataset is essential and is the first step towards testing any newly developed analytical tools for variant discovery. Although there are tools currently available that can simulate variants, none present the possibility of simulating all the three major types of variations (Single Nucleotide Polymorphisms, Insertions and Deletions and Copy Number Variations) and can generate reads taking a realistic error-model into consideration. Therefore, an efficient simulator and read generator is needed that can simulate variants taking the error rates of true biological s les into consideration. We report SInC ( S np, In del and C nv) an open-source variant simulator and read generator capable of simulating all the three common types of biological variants taking into account a distribution of base quality score from a most commonly used next-generation sequencing instrument from Illumina. SInC is capable of generating single- and paired-end reads with user-defined insert size and with high efficiency compared to the other existing tools. SInC, due to its multi-threaded capability during read generation, has a low time footprint. SInC is currently optimised to work in limited infrastructure setup and can efficiently exploit the commonly used quad-core desktop architecture to simulate short sequence reads with deep coverage for large genomes. We have come up with a user-friendly multi-variant simulator and read-generator tools called SInC. SInC can be downloaded from rojects/sincsimulator .
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2017
Abstract: Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Plasma and tumor s les were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma s les were available for most patients (24 of 30). Targeted licon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor s les from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2019
Publisher: Springer Science and Business Media LLC
Date: 24-04-2019
Publisher: Springer Science and Business Media LLC
Date: 10-08-2003
DOI: 10.1038/NSB964
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-01-2023
Abstract: Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.
Publisher: Wiley
Date: 05-2018
DOI: 10.1111/IMCB.12043
Publisher: F1000 Research Ltd
Date: 05-11-2015
DOI: 10.12688/F1000RESEARCH.7302.1
Abstract: Oral tongue squamous cell carcinomas (OTSCC) are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population ( yrs) is on the rise many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs), indels, regions with loss of heterozygosity (LOH), and copy number variations (CNVs) from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV) infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant lifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence.
Publisher: Elsevier BV
Date: 07-2011
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1538-7445.AM2018-3393
Abstract: Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent disease who have been extensively treated with chemotherapy or newer targeted agents, such as anti-angiogenics or PARP inhibitors (PARPi). We previously identified four mechanisms of acquired resistance from whole-genome sequencing (WGS) of 23 HGSC patients with recurrent disease a resistance mechanism of any kind was only identified in half of the patients. Since 2012, we have collected tumor s les from 16 HGSC patients through our rapid-autopsy program. On average, we collect 17 tumor sites per patient during the autopsy, and to date we have performed WGS on 28 autopsy s les from 8 patients. These data are allowing us to understand HGSC at end-stage, by examining the complete catalog of resistance mechanisms within an in idual patient and reconstructing the natural history of HGSC. One acquired resistance mechanism we identified in HGSC involves transcriptional fusion of the drug efflux pump ABCB1 to an upstream gene that causes its overexpression. ABCB1 encodes the multidrug resistance transporter MDR1, also known as P-glycoprotein. Through WGS and targeted RNA sequencing on end-stage tumor s les as well as recurrent ascites s les, we identified multiple fusion partners to ABCB1, with more than 15% of recurrent HGSC patients harboring ABCB1 transcriptional fusions. A number of HGSC patients carry multiple ABCB1 fusions, demonstrating convergent evolution within patients and the strong selective advantage of ABCB1 overexpression by gene fusion. Extending our analysis to recurrent and autopsy s les from breast and prostate cancer patients also identified ABCB1 transcriptional fusions as a resistance mechanism in these cancers. Our findings suggest that ABCB1 transcriptional fusions are a common mechanism of acquired chemotherapy resistance in ovarian, breast and prostate cancer patients, and that characterizing end-stage disease is particularly informative for understanding resistance mechanisms. Citation Format: Elizabeth L. Christie, Swetansu Pattnaik, Sian Fereday, Australian Ovarian Cancer Study, Heather Thorne, Andrea Bild, David D. Bowtell. Characterizing recurrent high-grade serous ovarian cancer through whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018 2018 Apr 14-18 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2018 (13 Suppl):Abstract nr 3393.
Location: United States of America
No related grants have been discovered for Swetansu Pattnaik.