140 research outputs found
sj-docx-1-tam-10.1177_17588359231206259 – Supplemental material for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations
No full textSupplemental material, sj-docx-1-tam-10.1177_17588359231206259 for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations by Jui Wan Loh, Abner Herbert Lim, Jason Yongsheng Chan and Yoon-Sim Yap in Therapeutic Advances in Medical Oncology</p
sj-xlsx-2-tam-10.1177_17588359231206259 – Supplemental material for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations
No full textSupplemental material, sj-xlsx-2-tam-10.1177_17588359231206259 for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations by Jui Wan Loh, Abner Herbert Lim, Jason Yongsheng Chan and Yoon-Sim Yap in Therapeutic Advances in Medical Oncology</p
Germline and Somatic Neurofibromatosis Type 1 Aberrations in Breast Cancer
No full textTitle: Germline and Somatic Neurofibromatosis Type 1 Aberrations in Breast Cancer Overview: These studies were initiated after seeing a series of women with Neurofibromatosis Type 1 (NF1) and breast cancer (BC) at National Cancer Centre Singapore (NCCS) from 2006 to 2009. Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. NF1 is usually a clinical diagnosis as individuals with NF1 typically develop multiple neurofibromas which can be cosmetically disfiguring, in addition to other features such as café-au-lait spots, skin tags and Lisch nodules. These patients under my care had aggressive HER2-positive breast cancers that did not seem to respond to standard systemic therapies as well as in individuals without NF1 syndrome. Individuals with NF1, an autosomal dominant genetic disorder, are known to be at increased risk of developing various tumours, such as malignant peripheral nerve sheath tumour (MPNST), phaeochromocytoma, glioma, and rhabdomyosarcoma. In 2007, the first study which reported an increased risk of breast cancer in women with NF1 was published. Since then, there have been a number of other epidemiological studies with the consistent finding that women with NF1 are have a three- to eight-fold increased risk of breast cancer, especially for women aged less than 50 years. Data on the characteristics of BC in NF1 patients is currently still limited. Our group was the first to discover the higher frequency of HER2-positive, hormone receptor negative and grade 3 breast cancers in women with NF1 compared to breast cancers in women without NF1. We have also performed genomic profiling of these NF1-associated breast cancers. Over the course of my candidature, large-scale exome or genome sequencing studies led by various groups such as The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and METABRIC, have revealed somatic NF1 aberrations in different sporadic tumours from individuals in the absence of a clinical diagnosis of NF1. These somatic NF1 alterations appear to be associated with resistance to standard therapy and adverse outcomes, similar to the breast cancers in women with clinical NF1 syndrome. Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies. In Asia, women with breast cancer are on average younger than in Western populations, resulting in higer rates of poor prognosis breast cancers in premenopausal women. Since somatic NF1 mutations in BC are associated with poor prognosis, we also aimed to explore the potential role of NF1 and neurofibromin in the sporadic BCs from patients without NF1. This included immunohistochemical staining of tissue micrroarrays, and targeted gene sequencing (with NF1 in the gene panel). Structure of Thesis and Research Questions: Chapter 1: Systematic Review: This literature review focused on the germline NF1 disorder, the biology of the NF1 gene and neurofibromin, tumours associated with NF1 as well as sporadic tumours harbouring somatic NF1 aberrations in individuals without NF1 disorder. This review identified an important role of NF1 in carcinogenesis as well as the challenges of detecting NF1 aberrations and deficiency or dysfunction of the encoded protein neurofibromin. It also highlights the need to pursue further research, especially in the area of therapeutic strategies for individuals with germline NF1 syndrome and for sporadic tumours with somatic NF1 aberrations. Chapter 2: Whole exome sequencing of multiple tumours from an NF1 patient: This paper describes the exome sequencing of BC, MPNST, and neurofibroma from a patient with NF1. Apart from the germline NF1 mutation, we demonstrated independent somatic NF1 mutations in all three tumors. Each tumor had a distinct genomic profile with mutually exclusive aberrations in different genes. Although second-hit NF1 mutation may be critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors. Chapter 3: Comprehensive case series of BCs in women with NF1 with molecular insights into its aggressive phenotype: The aim was to elucidate the clinical, pathological and molecular characteristics of NF1-associated BCs at National Cancer Centre Singapore. There was a higher frequency of grade 3, oestrogen receptor (ER) negative and human epidermal growth factor receptor 2 (HER2) positive tumours among NF1 patients with inferior overall survival compared to non-NF1 BCs. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all NF1-associated BC specimens, but without any discernable consistent pattern in the intensity or extent of staining. It appears that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes. Chapter 4: Immunohistochemical expression of neurofibromin in sporadic breast cancers: From the initial discovery cohort of 314 sporadic breast cancers of all subtypes, tumours with both nuclear and cytoplasmic expression of neurofibromin seemed to have better outcomes, especially in the triple negative subset. However, there was no correlation between expression of neurofibromin and survival outcomes in a larger validation cohort of triple negative breast cancers. Chapter 5: Elucidating therapeutic molecular targets in premenopausal Asian women with recurrent breast cancers: Targeted sequencing was performed on a separate cohort of premenopausal poor prognosis BCs. The most prevalent alterations included TP53 (65%). PIK3CA (32%), GATA3 (29%), ERBB2 (27%), MYC (25%) and KMT2C (21%). The frequency of NF1 mutations was 2%. Detecting changes in dosage of the NF1 gene in formalin-fixed paraffin-embedded specimens was not feasible. Chapter 6: Conclusion and future directions: The final chapter summarises the findings of these studies and highlights future directions that are clinically relevant.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201
Towards a Biosemiotic Model of National Literature: Samples from Singaporean Writers
No full textSingapore has four official languages and they are Malay, Chinese, Tamil, and English with respect to each ethnic group. English is the working language and the other languages are considered mother tongues of each individual ethnic group. While examining the broad social, educational, political, cultural, and economic forces that shaped the writers’ destiny in order to provide background and contexts, this dissertation is concerned with how the notion of identity is constructed and maintained in the literary works. History, myth, and fable coalesce with sharp social commentary are evident in the literature after the attainment of nationhood.
By placing the writers and their literary works in the sociological context and using the methodology proposed in this dissertation, I will present in a systematic way how individual entity or unity interacts in Singaporean literature. Firstly, it is observed that two (sometimes more than two) entities/unities from the same domain, for example, language, culture, ethnicity, and so on, are selected by the author in his literature. The entities/unities exist in the first-order and interact based on the first-order structural coupling. The “medium” is the domain in which the entity comes from in the first-order. Secondly, it is observed that interactions generally do not stop at first-order. The first-order coupling is the initial state to start off a successive reaction. The second-order structural coupling then follows, in which the triggering or interfering entity acts upon the coupled structure. This triggering or interfering entity is labeled “environment” to indicate an external force triggering an internal response of the couple. The third-order coupling is the structural coupling of the unities with its medium. In this case, the social domain is where all entities are immersed. The complex web of relationships created by the superposition of political, economic, historical, and cultural relation in the social domain are reflected in the literary works to produce a distinctive Singaporean spectrum.Abstract………………………………………………………………………….……………….1
Acknowledgements………………………………………………………………………………2
Table of Contents………………………………………………………………………………...3
Foreword…………………………………………………………………………………………7
Part One
Chapter One: Introduction
The Purpose of the Dissertation………………………………………………………….....9
Methodology………………………………………………………………………………12
A. Biological Nature of Singaporean Literature…………………………………….14
B. Semiotic Nature of Singaporean Literature………………………………………23
C. Linguistic Nature of Singaporean Literature……………………………………..29
D. Sociological Nature of Singaporean Literature…………………………………..31
Contemporary Malay Literature in Singapore……………………………………………..33
Contemporary Chinese Literature in Singapore…………………………………………...36
Contemporary Tamil Literature in Singapore……………………………………………...40
Contemporary English Literature in Singapore…………………………………………....44
Chapter Two: Biosocial System
The Multiracial and Multi-ethnical………………………………………………………...50
The Political and Institutional……………………………………………………………...56
The Transformational and Irreversible…………………………………………………….66
The National and Historical……………………………………………………………….70
The Polygonal and Variational…………………………………………………………….79
A Final Word………………………………………………………………………………83
Chapter Three: Biosocio Linguistic System
Ethnic Symbiosis: Evolution of Language in Singaporean Literature…………………….89
Emergent Voices: Up to 1970……………………………………………………………...86
New Voices: 1970-1990……………………………………………………………………93
Diverse Voices: 1990-present………………………………………………………………95
One Voice: Emergent Tongue in Singaporean Literature…………………………………..97
A Final Word……………………………………………………………………………....102
Part Two
Chapter Four: Close Readings of a Multilingual Anthology
A Biosemiotic Analysis of Rhythms: A Singaporean Millennial Anthology of Poetry……103
1. “Neighbours” by Alfian Bin Sa’at………………………………………………..104
2. “Running” by Boey Kim Cheng…………………………………………………..111
3. “What is it to Write?” (For Anna) by Felix Cheong………………………………116
4. “By the Sea at Sarimboon” by Goh Poh Seng………………………………….....123
5. “Speaking in Tongues—Singapore Style” by Goh Sin Tub……………………....126
6. “Moon Fall” by Gwee Li Sui……………………………………………………...140
7. “Cross Cultural Exchange”
(dedicated to the late Mr. Ee Tiang Hong)………………………………………..142
8. “Rain Tree” by Ho Poh Fun……………………………………………………...147
9. “Cheng Zhong Shi, First Generation” by Roger Jenkins………………………...149
10. “Island” by Koh Buck Song…………………………………………………….153
11. “The Road Taken” by Agnes Lam………………………………………………154
12. “Outlander: Hirundo Rustica” by Aaron Lee…………………………………...156
13. “You, Travelling” (for Ee Tiang Hong) by Lee Tzu Pheng……………………..159
14. “Banana Tree” by David Leo…………………………………………………...162
15. “Love is Not Enough” by Leong Liew Geok…………………………………...163
16. “A Fool’s Game” by Theodore Lim Li…………………………………………166
17. “First Vision” by Lin Hsin Hsin………………………………………………...169
18. “There is a Moment” by Alvin Pang……………………………………………171
19. “How to Fly the Singapore Flag” by Daren Shiau……………………………...173
20. “Kueh Belanda” by Desmond Sim……………………………………………...175
21. “Walking Down the Streets” by Kirpal Singh…………………………………..177
22. “我是 (I am)” by Paul Tan……………………………………………………..180
23. “Two Figures When One is Sick” by Simon Tay…………………………….....184
24. “Outing” by Edwin Thumboo…………………………………………………..185
25. “Women’s Song (1979)” (for Mum) by Angeline Yap………………………….189
26. “An Afternoon Nap” by Arthur Yap…………………………………………….190
27. “Boys in Jungle Green” by Robert Yeo………………………………………....193
28. “Before the Rain” by Yong Shu Hoong………………………………………...195
A Final Word……………………………………………………………………………...198
Chapter Five: Birth of a Legend
A Biosemiotic Analysis of the Merlion…………………………………………………...201
Close Readings of the Merlion Poems……………………………………………………205
1. “Ulysses by the Merlion” by Edwin Thumboo………………………………......205
2. “Merlion” by Liang Yue………………………………………………………….209
3. “The Merlion” by Alfian Bin Sa’at………………………………………………211
4. “Merlign” by Alvin Pang………………………………………………………....215
A Final Word………………………………………………………………………………219
Afterword
Convergence and Consolidation………………………………………………………….220
Bibliography…………………………………………………………………………………...224
Appendices
Appendix I: “By the Sea at Sarimboon” translated by Ho Chee Lick〈莎林邦海岸〉….238
Appendix II: “Merlion” by Liang Yue 梁鉞〈魚尾獅〉………………………..……….23
Abstract 2923: Label-free enrichment and integrated full-length mRNA transcriptome analysis of single live circulating tumor cells from breast cancer patients
No full textAbstract
Background Label-free methods for isolating circulating tumor cells (CTCs) are attractive because they provide an opportunity to analyze a larger set of CTCs that may otherwise be missed due to variable or no expression of protein (label) markers. Understanding genetic and functional heterogeneity in CTCs allows us to gain insight into the mechanisms underscoring metastasis, drug resistance, and tumor aggressiveness. Currently, a simple workflow for isolation and molecular characterization of single CTCs by mRNA sequencing is lacking. In order to address this challenge, we developed a label-free workflow to isolate CTCs from breast cancer patients for full-length mRNA sequencing analysis by integrating the ClearCell® FX System with the Polaris™ system. The ClearCell FX system processes blood samples from cancer patients and enriches for CTCs in a label-free antibody-independent manner. The low level of nonspecifically isolated white blood cells from ClearCell FX is further depleted on the Polaris system by negative enrichment of viable CTCs. This unique integration of systems will enable researchers to perturb single CTCs in a controlled environment, monitor and measure the response due to perturbation, and link these response measurements to downstream genomic and transcriptomic analysis.
Method and Results CTCs from 7.5 mL of peripheral blood sample from breast cancer patients were enriched using ClearCell FX. To differentiate larger blood cells from putative CTCs, we stained the enriched cells with Alexa Fluor® 647-conjugated CD45 and CD31 to identify leukocytes and endothelial cells, respectively. Calcein AM (live cell marker) and CellTracker™ Orange (universal cell marker) were added to identify live cells. Single CTCs were selected on Polaris (Fluidigm) system, lysed and reverse-transcribed, and cDNA were preamplified on the Polaris integrated fluidic circuit (IFC). Sequencing libraries were generated using the Nextera® kit and sequenced on Illumina® MiSeq™ and NextSeq™ systems. We successfully processed blood samples from four patients. Sequenced data showed high-quality metrics, with read depth of up to 2.5 million reads (MiSeq) or 60 million reads (NextSeq), with a low percentage of mapped reads to ribosomal RNA and mitochondrial RNA. Unsupervised hierarchical clustering of gene expression data showed clustering by patient, but considerable heterogeneity was also observed among the CTCs from the same patient. We will provide insights into full-length mRNA transcriptome of single CTCs from triple negative breast cancer patient.
Conclusion We present the feasibility of integrating two microfluidics platforms to capture single CTCs for transcriptome and functional study. Our data suggests that the heterogeneity of tumor sample and characterization of metastatic processes can be elucidated from single-cell mRNA sequencing of CTCs.
Citation Format: Naveen Ramalingam, Yi Fang Lee, Lukasz Szpankowski, Anne Leyrat, Brian Fowler, Jovina Tan, Chong Tracy Lu, Ninez Delos Angeles, Chad Sanada, Cassandra Greene, Kyle Hukari, Andrew Wu, Yoon-Sim Yap, Jay West, Ali Asgar Bhagat. Label-free enrichment and integrated full-length mRNA transcriptome analysis of single live circulating tumor cells from breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2923. doi:10.1158/1538-7445.AM2017-2923</jats:p
Aggressive mixed epithelial-stromal tumour of the kidney treated with chemotherapy and radiotherapy
No full textAbstract CT045: Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers
No full textAbstract
Background: Cyclin D-cyclin-dependent kinase (CDK) 4/6 complexes promote cell proliferation through phosphorylation of retinoblastoma protein (Rb). In breast cancer, cyclin D-CDK4/6 activity can be increased through cyclin D gene (CCND1) amplification or loss of the CDK4/6 negative regulator p16. Here we present efficacy data from the Phase III MONALEESA-2 study of ribociclib (CDK4/6 inhibitor) + letrozole vs. placebo + letrozole for first-line treatment of HR+, HER2- ABC, assessed in baseline tumors by protein levels of Rb, p16, the cell proliferation marker Ki67, and by gene expression levels of CDKN2A (p16) and CCND1.
Methods: Postmenopausal women with HR+, HER2- ABC with no prior systemic therapy for advanced disease were randomized 1:1 to receive ribociclib or placebo (600 mg/day 3-weeks-on/1-week-off) + letrozole (2.5 mg/day continuous). The primary endpoint was investigator-assessed progression-free survival (PFS). Provision of a representative baseline tumor biopsy or archival tissue at screening was mandatory if available. Baseline tumor tissue was evaluated for protein biomarkers (immunohistochemistry) and gene expression (NanoString nCounter® Human Cancer Reference panel).
Results: Of 668 patients randomized, 479 were evaluable for total Rb, and 416 (87%) displayed high levels (H-score ≥100). p16 protein levels were evaluable in 405 patients; 165 (41%) had low (H-score &lt;50), 182 (45%) medium (H-score ≥50-149), and 58 (14%) had high (H-score ≥150) p16 levels. Ki67 was detected in ≤14% of tumor cells in 216 (47%) patients and in &gt;14% of cells in 247 (53%) patients. The median messenger RNA expression level was used as the cut-off to define patients with low or high baseline CDKN2A and CCND1 gene expression. An improved PFS was observed by the addition of ribociclib to letrozole in all the above patient subgroups, with hazard ratios ranging from 0.40 (high p16 by H-score; 95% confidence interval [CI] 0.16-1.0; p=0.06) to 0.64 (≤14% Ki67-positive cells; 95% CI 0.39-1.0; p=0.07). Patients with less or greater than 14% Ki67-positive cells, lower or higher p16 levels, Rb levels, or CDKN2A or CCND1 gene expression benefitted from the addition of ribociclib to letrozole to a similar extent.
Conclusions: A consistent benefit from ribociclib + letrozole vs. placebo + letrozole was observed irrespective of baseline Rb, p16, and Ki67 levels or CDKN2A and CCND1 gene expression levels. Hormone receptor positivity remains the only established biomarker of response to CDK4/6 inhibitors.
Citation Format: Fabrice Andre, Salomon M. Stemmer, Mario Campone, Katarina Petrakova, Shani Paluch-Shimon, Yoon-Sim Yap, Norbert Marschner, Arlene Chan, Cristian Villanueva, Lowell L. Hart, Carlos L. Arteaga, Gabe S. Sonke, Eva-Maria Grischke, Emilio Alba, Arnd Nusch, Denise A. Yardley, Erik Jakobsen, Sibel Blau, Sara M. Tolaney, Faye Su, Wei He, Caroline Germa, Gabriel N. Hortobagyi. Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT045. doi:10.1158/1538-7445.AM2017-CT045</jats:p
Regulatory and operational challenges in conducting Asian International Academic Trial for expanding the indications of cancer drugs
No full textThere are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications.ope
Reducing the risk of peripherally inserted central catheter line complications in the oncology setting
No full textClassification of HER2-negative breast cancers by copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations
No full textBackground: Recently, HER2-negative breast cancers have been reclassified by protein expression into ‘HER2-low’ and ‘HER2-zero’ subgroups, but the consideration of HER2-low breast cancer as a distinct biological subtype with differing prognoses remains controversial. By contrast, non-neutral ERBB2 copy number alteration (CNA) status is associated with inferior survival outcomes compared to ERBB2 CNA-neutral breast cancer, providing an alternative approach to classification. Methods: Here, we investigated the molecular landscape of non-metastatic HER2-negative BCs in relation to ERBB2 CNA status to elucidate biological differences. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) TCGA-BRCA datasets ( n = 1875) were analyzed. Results: Nearly two-fifths of the cohort harbored ERBB2 CNAs (39.4%), which were significantly enriched within hormone receptor-negative (56.1%) than within hormone receptor-positive BCs (35.5%; p < 0.0001). Globally, CNAs across the genome were significantly higher in ERBB2 non-neutral compared to neutral cohorts ( p < 0.0001). Notably, genetic aberrations on chromosome 17 – BRCA1 , NF1 , TP53 , MAP2K4, and NCOR1 – were widespread in the ERBB2 non-neutral cases. While chromosome 17q arm-level alterations were largely in tandem with ERBB2 CNA status, arm-level loss in chromosome 17p was prevalent regardless of ERBB2 gain, amplification, or loss. Differential gene expression analysis demonstrated that pathways involved in the cell cycle, proteasome, and DNA replication were upregulated in ERBB2 non-neutral cases. Conclusion: Classification of HER2-negative BCs according to ERBB2 CNA status reveals differences in the genomic landscape. The implications of concurrent aberrations in other genes on chromosome 17 merit further research in ERBB2 non-neutral BCs
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