43 results on '"Saurabh V. Laddha"'
Search Results
2. A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme
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Deepanjan Paul, Ashis Narayan Sinha, Arjun Ray, Megha Lal, Subhashree Nayak, Anchal Sharma, Bharati Mehani, Debasish Mukherjee, Saurabh V. Laddha, Ashish Suri, Chitra Sarkar, and Arijit Mukhopadhyay
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Medicine ,Science - Abstract
Abstract Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than −6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A – C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patients identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain.
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- 2017
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- View/download PDF
3. Supplementary Video 1 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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MOV file - 7511KB, Acute autophagy ablation causes progressive motor and behavioral deficits.
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- 2023
4. Supplementary Table 2 from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
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PDF file - 1442KB, Table S2. TCGA cancers with available somatic mutation data from whole genome or exome sequencing and the total number of mutations found for BECN1 and BRCA1.
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- 2023
5. Supplementary Table 4 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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PDF file - 2587KB, Comparison of collapsed expression of all muscle genes during fasting.
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- 2023
6. Supplementary Table 4 from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
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PDF file - 1450KB, Table S4. The types of somatic mutations found for BRCA1.
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- 2023
7. Supplementary Table 1 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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PDF file - 145KB, Differential expression analysis for significant biological processes by GO term DAVID Analysis for liver tissues during fasting.
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- 2023
8. Data from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
- Abstract
Evidence suggests that the catabolic process of macroautophagy (autophagy hereafter) can either suppress or promote cancer. The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been implicated as a haploinsufficient tumor suppressor in breast, ovarian, and prostate cancers. The proximity of BECN1 to the known breast and ovarian tumor suppressor breast cancer 1, early onset, BRCA1, on chromosome 17q21, has made this determination equivocal. Here, the mutational status of BECN1 was assessed in human tumor sequencing data from The Cancer Genome Atlas (TCGA) and other databases. Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers. Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers.Implications: Contrary to previous reports, BECN1 is not significantly mutated in human cancer and not a tumor-suppressor gene, as originally thought.Visual Overview: http://mcr.aacrjournals.org/content/early/2014/04/01/1541-7786.MCR-13-0614/F1.large.jpg. Mol Cancer Res; 12(4); 485–90. ©2014 AACR.
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- 2023
9. Supplementary Table 3 from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
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PDF file - 1462KB, Table S3. The types of somatic mutations found for BECN1.
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- 2023
10. Supplementary Table 5 from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
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PDF file - 1483KB, Table S5. Gene expression levels of BECN1 across different cancer types.
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- 2023
11. Supplementary Table 2 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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PDF file - 116KB, Differential expression analysis for significant biological processes by GO term DAVID Analysis for muscle tissues during fasting.
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- 2023
12. Supplementary Data from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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PDF file - 3190KB, Supplementary Figures (S1-S6) provide additional characterization about effects of systemic autophagy ablation in normal adult tissues and tumors. Supplementary Methods supply detailed information of experiments.
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- 2023
13. Supplementary Table 1 from Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
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Eileen White, Chang S. Chan, Shridar Ganesan, and Saurabh V. Laddha
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PDF file - 1833KB, Table S1. TCGA cancers with available SNP or CGH array data for CNV analysis.
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- 2023
14. Supplementary Table 3 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
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PDF file - 2193KB, Comparison of collapsed expression of all liver genes during fasting.
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- 2023
15. Supplementary File 5 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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LC gene signature classifier and gene list
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- 2023
16. Supplementary File 6 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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TMA data for ASCL1 and S100 of 173 LCs
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- 2023
17. Supplementary File 7 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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Differentially expressed genes between AC and TC of LC1
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- 2023
18. Supplementary Data from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
- Abstract
Supplementary Figure 1: Subtype LC2 specific MEN1 loss of heterozygosity. Supplementary Figure 2: PCA on gene expression for top variable number of genes. Supplementary Figure 3: Pearson correlation on top 3000 variable genes. Supplementary Figure 4: Heatmap of top 100 variable genes. Supplementary Figure 5: PCA of top variable number of CpG sites. Supplementary Figure 6: Boxplot of gene expression of HNF1A, FOXA3 and HNF4A across three LC subtypes. Supplementary Figure 7: Low expression of HOX family members in LC2 subtype. Supplementary Figure 8: Heatmap of LCs classifier from 30 LC dataset on independent lung carcinoids cohort from Fernandez-Cuesta et al. Supplementary Figure 9: Heatmap of HNF1A, FOX3 and FEV on Fernandez-Cuesta et al gene expression dataset. Supplementary Figure 10: Key targets of ASCL1 transcription factor. Supplementary Figure 11: Clinical features of three LC subtypes for median age of diagnosis. Supplementary Table1: Tumor purity scores for 30 LC samples using gene expression profile. Supplementary Table2: Significant Pathways/Gene Ontologies for top 100 variable genes. Supplementary Table3: Global methylation CpG count under hypo (beta =0.7) methylated probes for 18 LC samples. Supplementary Table4: IHC staining results for ASCL1 and S100 biomarker in 20 LC dataset
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- 2023
19. Supplementary File 4 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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Differentially methylated CpG probes and CpG islands
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- 2023
20. Supplementary File 3 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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Differentially expressed genes between three LC subtypes and pathway analysis
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- 2023
21. Supplementary File 1 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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Clinical characterization and tumor purity
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- 2023
22. Data from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
- Abstract
Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management.Significance:Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.
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- 2023
23. Supplementary File 2 from Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Chang S. Chan, Laura H. Tang, William D. Travis, John T. Poirier, Natasha Rekhtman, Hua Ke, Brian R. Untch, Kenneth Robzyk, Edaise M. da Silva, and Saurabh V. Laddha
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Mutational profile of lung carcinoid and gene ontology of mutated genes
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- 2023
24. Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response
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Joshua A. Vieth, Laura Poillet-Perez, Janice M. Mehnert, Yang Yang, Praveen K. Bommareddy, Jun-Lin Guan, Shridar Ganesan, Eileen White, Maria Ibrahim, Jian Cao, Chang S. Chan, Michael Haas, Joshua D. Rabinowitz, Zhixian Sherrie Hu, Daniel W. Sharp, Marcus Bosenberg, Saurabh V. Laddha, and Edmund C. Lattime
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Cancer Research ,Autophagy ,Cancer ,Inflammation ,Biology ,medicine.disease ,Article ,Immune tolerance ,Immune system ,Oncology ,Stimulator of interferon genes ,Cancer research ,medicine ,medicine.symptom ,Intracellular ,Function (biology) - Abstract
Macroautophagy (hereafter autophagy) degrades and recycles intracellular components to sustain metabolism and survival during starvation. Host autophagy promotes tumor growth by providing essential tumor nutrients. Autophagy also regulates immune cell homeostasis and function and suppresses inflammation. Although host autophagy does not promote a T-cell antitumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that autophagy, especially in the liver, promotes tumor immune tolerance by enabling regulatory T-cell function and limiting stimulator of interferon genes, T-cell response and interferon-γ, which enables growth of high-TMB tumors. We have designated this as hepatic autophagy immune tolerance. Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load and autophagy inhibition is an effective means to promote an antitumor T-cell response in high-TMB tumors. White and colleagues identify a role for host autophagy in restraining T-cell-dependent immune responses, specifically against tumors with high mutational burden.
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- 2020
25. The Zebrafish GenomeWiki: a crowdsourcing approach to connect the long tail for zebrafish gene annotation.
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Meghna Singh, Deeksha Bhartiya, Jayant Maini, Meenakshi Sharma, Angom Ramcharan Singh, Subburaj Kadarkaraisamy, Rajiv Rana, Ankit Sabharwal, Srishti Nanda, Aravindhakshan Ramachandran, Ashish Mittal, Shruti Kapoor, Paras Sehgal, Zainab Asad, Kriti Kaushik, Shamsudheen Karuthedath Vellarikkal, Divya Jagga, Muthulakshmi Muthuswami, Rajendra K. Chauhan, Elvin Leonard, Ruby Priyadarshini, Mahantappa Halimani, Sunny Malhotra, Ashok Patowary, Harinder Vishwakarma, Prateek Rakeshkumar Joshi, Vivek Bhardwaj, Arijit Bhaumik, Bharat Bhatt, Aamod Jha, Aalok Kumar, Prerna Budakoti, Mukesh Kumar Lalwani, Rajeshwari Meli, Saakshi Jalali, Kandarp Joshi, Koustav Pal, Heena Dhiman, Saurabh V. Laddha, Vaibhav Jadhav, Naresh Singh, Vikas Pandey, Chetana Sachidanandan, Stephen C. Ekker, Eric W. Klee, Vinod Scaria, and Sridhar Sivasubbu
- Published
- 2014
- Full Text
- View/download PDF
26. Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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Edaise M da Silva, William D. Travis, Laura H. Tang, Chang S. Chan, Brian R. Untch, Hua Ke, Saurabh V. Laddha, Natasha Rekhtman, Kenneth Robzyk, and John T. Poirier
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Carcinoid Tumor ,Biology ,Gene mutation ,medicine.disease_cause ,Article ,Chromatin remodeling ,Epigenesis, Genetic ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,Basic Helix-Loop-Helix Transcription Factors ,Biomarkers, Tumor ,medicine ,Humans ,RNA, Messenger ,Exome sequencing ,Regulation of gene expression ,Gene Expression Profiling ,Cell Cycle ,S100 Proteins ,Reproducibility of Results ,DNA Methylation ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030104 developmental biology ,MRNA Sequencing ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,DNA methylation ,Cancer research ,Carcinogenesis - Abstract
Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management. Significance: Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.
- Published
- 2019
27. Publisher Correction: Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response
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Michael Haas, Janice M. Mehnert, Chang S. Chan, Joshua D. Rabinowitz, Shridar Ganesan, Edmund C. Lattime, Praveen K. Bommareddy, Maria Ibrahim, Daniel W. Sharp, Yang Yang, Joshua A. Vieth, Jun-Lin Guan, Laura Poillet-Perez, Jian Cao, Zhixian Sherrie Hu, Saurabh V. Laddha, Marcus Bosenberg, and Eileen White
- Subjects
Cancer Research ,Oncology ,business.industry ,Autophagy ,Cancer research ,T cell immunity ,medicine ,Cancer ,medicine.disease ,business - Published
- 2021
28. Peer review of 'A molecular map of lung neuroendocrine neoplasms'
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Saurabh V Laddha
- Abstract
This is the open peer reviewers comments and recommendations regarding the submitted GigaScience article and/or dataset.
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- 2019
- Full Text
- View/download PDF
29. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
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Laura H. Tang, Peter W. Lewis, Promita Bose, Kenneth Robzyk, Timothy A. Chan, Brian R. Untch, Saurabh V. Laddha, David S. Klimstra, Janet Y. Li, Edaise M da Silva, Matthew S. Koletsky, Paula J. Torres, Chang S. Chan, and C. David Allis
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0301 basic medicine ,X-linked Nuclear Protein ,endocrine system ,Cell type ,Science ,Mutant ,General Physics and Astronomy ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Death-associated protein 6 ,Proto-Oncogene Proteins ,Gene expression ,Humans ,Prospective Studies ,Allele ,Promoter Regions, Genetic ,lcsh:Science ,Gene ,ATRX ,Adaptor Proteins, Signal Transducing ,Retrospective Studies ,Multidisciplinary ,Nuclear Proteins ,General Chemistry ,DNA Methylation ,Immunohistochemistry ,Molecular biology ,Neuroendocrine Tumors ,030104 developmental biology ,PDX1 ,lcsh:Q ,Co-Repressor Proteins ,Molecular Chaperones - Abstract
The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value, In pancreatic neuroendocrine tumors (PanNETs) ATRX, DAXX, and MEN1 are commonly mutated (A-D-M mutant PanNETs). Here, the authors find in a cohort of PanNETS 58% are A-D-M mutant PanNETs, with a worse clinical outcome and differences in gene expression and methylation compared to A-D-M wild type cases- these gene expression differences suggest that A-D-M mutant PanNETs potentially originate from a cell type similar to alpha cells.
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- 2018
30. Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma
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Y Sun, Mireia Castillo-Martin, Saurabh V. Laddha, Carlos Cordon-Cardo, Arnold J. Levine, Chang S. Chan, and Anna M. Puzio-Kuter
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Male ,Liposarcoma ,Mice ,medicine ,PTEN ,Animals ,Molecular Biology ,Cyclin ,Original Paper ,biology ,Cyclin-dependent kinase 4 ,Microarray analysis techniques ,Cell growth ,PTEN Phosphohydrolase ,Cyclin-Dependent Kinase 4 ,Cell Biology ,Cyclin-Dependent Kinase 6 ,medicine.disease ,3. Good health ,biology.protein ,Cancer research ,Mdm2 ,Female ,Cyclin-dependent kinase 6 ,Tumor Suppressor Protein p53 ,Cell Division - Abstract
Liposarcoma (LPS) is a type of soft tissue sarcoma that mostly occurs in adults, and in humans is characterized by amplifications of MDM2 and CDK4. The molecular pathogenesis of this malignancy is still poorly understood and, therefore, we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease. We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS (from well-differentiated LPS to pleomorphic LPS). In addition, progression of the tumors is further characterized by the expression of D cyclins and CDK4/6, which allow for continued cell division. Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS, which could aid in understanding the disease and to unravel potential new therapeutic targets.
- Published
- 2015
31. Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma
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Mona A. M. Awad, Michele Patrizii, Cindy Kui, Mervat El Ansary, Rachel A. Bigos, Eric Huselid, Kathleen Flaherty, David Augeri, Monica Bartucci, Saurabh V. Laddha, Hatem E. Sabaawy, Mohamed Hussein, S. David Kimball, and John A. Gilleran
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Antineoplastic Agents ,macromolecular substances ,Article ,Small Molecule Libraries ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Viability assay ,Clonogenic assay ,Zebrafish ,Polycomb Repressive Complex 1 ,business.industry ,Cell growth ,HEK 293 cells ,Liver Neoplasms ,Cancer ,Cell migration ,Hep G2 Cells ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,030104 developmental biology ,HEK293 Cells ,BMI1 ,030220 oncology & carcinogenesis ,Liver cancer ,business - Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC. METHODS: We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds. RESULTS: Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo. CONCLUSIONS: This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.
- Published
- 2017
32. A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme
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Arijit Mukhopadhyay, Ashis Narayan Sinha, Megha Lal, Arjun Ray, Bharati Mehani, Debasish Mukherjee, Ashish Suri, Subhashree Nayak, Saurabh V. Laddha, Chitra Sarkar, Deepanjan Paul, and Anchal Sharma
- Subjects
0301 basic medicine ,Small RNA ,Adenosine ,Adenosine Deaminase ,Science ,RNA Stability ,Biology ,Article ,Corpus Callosum ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,microRNA ,Humans ,Genomic library ,Gray Matter ,Gene ,Base Pairing ,Gene Library ,Regulation of gene expression ,Genetics ,Multidisciplinary ,Brain Neoplasms ,RNA-Binding Proteins ,White Matter ,Inosine ,Frontal Lobe ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,HEK293 Cells ,chemistry ,RNA editing ,Case-Control Studies ,Medicine ,Nucleic Acid Conformation ,Thermodynamics ,Autopsy ,RNA Editing ,Glioblastoma ,Cytosine - Abstract
Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than −6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A – C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patients identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain.
- Published
- 2017
33. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells
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Stephen C. Van Nostrand, Xin Teng, Jessie Yanxiang Guo, Joshua D. Rabinowitz, Eileen White, Saurabh V. Laddha, Sinan Khor, Chang S. Chan, Yang Yang, and Sirui Ma
- Subjects
0301 basic medicine ,Lung Neoplasms ,Bioenergetics ,Glutamine ,Biology ,Mitochondrion ,Autophagy-Related Protein 7 ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,Genetics ,Autophagy ,Animals ,Nucleotide ,Energy charge ,chemistry.chemical_classification ,Reactive oxygen species ,Nucleotides ,Genetic Variation ,Nucleosides ,Cell biology ,Mitochondria ,Citric acid cycle ,030104 developmental biology ,chemistry ,Biochemistry ,Genome, Mitochondrial ,ras Proteins ,Energy Metabolism ,Oxidation-Reduction ,Gene Deletion ,Developmental Biology ,Research Paper - Abstract
Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7−/−) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.
- Published
- 2016
34. Micro RNA: New aspect in pathobiology of preeclampsia?
- Author
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Natalia C. Pedroza, Diky Mudhakir, Mohd Andalas, Saurabh V. Laddha, Harapan Harapan, and Jay R. Anand
- Subjects
MicroRNA ,Preeclampsia pathogenesis ,Biology ,Preeclampsia ,medicine.disease ,Bioinformatics ,female genital diseases and pregnancy complications ,Pathogenesis ,Mirna expression ,embryonic structures ,microRNA ,medicine ,Genetics(clinical) ,reproductive and urinary physiology ,Genetics (clinical) ,miRNA - Abstract
The discovery of miRNA in 1993, by Ambros et al. has had a huge influence in pathogenesis theory; diagnosis and treatment approach to some diseases. Some scientifically proven theories have been proposed to seek the association of alterations of miRNA expression to incidences and severity of preeclampsia (PE). In this review we explore the result of such investigations that discuss the association of miRNA and PE along with the role of various mRNAs in PE pathogenesis. Keywords : Preeclampsia; MicroRNA; miRNA; Preeclampsia pathogenesis
- Published
- 2012
35. miRvar: A comprehensive database for genomic variations in microRNAs
- Author
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Vinod Scaria, Arijit Mukhopadhyay, Saurabh V. Laddha, and Deeksha Bhartiya
- Subjects
Internet ,Database ,Genome, Human ,Genetic Variation ,Genomics ,Biology ,computer.software_genre ,Genome ,MicroRNAs ,microRNA ,Genetic variation ,Genetics ,Humans ,Human genome ,Databases, Nucleic Acid ,computer ,Genetics (clinical) - Abstract
microRNAs are a recently discovered and well studied class of small noncoding functional RNAs. The regulatory role of microRNAs (miRNAs) has been well studied in a wide variety of biological processes but there have been no systematic effort to understand and analyze the genetic variations in miRNA loci and study its functional consequences. We have comprehensively curated genetic variations in miRNA loci in the human genome and established a computational pipeline to assess potential functional consequences of these variants along with methods for systematic curation and reporting of variations in these loci. The data is made available on the Leiden Open (source) Variation Database (LOVD) platform at http://genome.igib.res.in/mirlovd to provide ease of aggregation and analysis and is open for community curation efforts.
- Published
- 2011
36. Abstract 1799: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct 'alpha-cell signature' subgroup
- Author
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Chang S. Chan, Promita Bose, Edaise M da Silva, Laura H. Tang, Kenneth Robzyk, Peter W. Lewis, Timothy A. Chan, David C. Allis, Saurabh V. Laddha, David S. Klimstra, Brian R. Untch, Matthew S. Koletsky, and Paula J. Torres
- Subjects
Cancer Research ,Mutant ,Cancer ,Neuroendocrine tumors ,Biology ,medicine.disease ,Death-associated protein 6 ,Oncology ,Tumor progression ,DNA methylation ,medicine ,Cancer research ,MEN1 ,ATRX - Abstract
Pancreatic neuroendocrine tumors (PanNETs) or islet cell tumors are a rare neuroendocrine malignancy with an annual incidence of less than 1 per 100,000 per year. Current classification scheme for PanNETs include grade and stage. While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs. A greater understanding of the cells of origin of PanNETs, tumor progression and pathway pathogenesis may guide the development of novel therapeutic options. The most commonly mutated genes in PanNETs are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing (n=33) and Illumina 450K DNA methylation (n=32) analysis on randomly selected PanNETs to reveal two distinct subgroups with one group consisting exclusively of A-D-M mutant PanNETs. Pair-wise correlation of gene expression between all PanNETs, showed A-D-M mutant PanNETs are more homogeneous as a group than A-D-M WT PanNETs. Among A-D-M mutant PanNETs, mutants with the same genotype (mutations in ATRX/DAXX/MEN1) did not show greater gene expression correlation. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature similar to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. We validated our subtype classification and A-D-M mutant panNET alpha signature using two independent PanNETs expression dataset. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. Citation Format: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup [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;78(13 Suppl):Abstract nr 1799.
- Published
- 2018
37. microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis
- Author
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Wenwei Hu, Cen Zhang, Chunwen Tan, Xiaolong Wang, Juan Liu, Yuhan Zhao, Xuetian Yue, Shu Zheng, Chang S. Chan, Zhaohui Feng, Jiaping Peng, and Saurabh V. Laddha
- Subjects
0301 basic medicine ,Male ,p53 ,Apoptosis ,medicine.disease_cause ,Immunoenzyme Techniques ,negative feedback loop ,Mice ,0302 clinical medicine ,Tumor Cells, Cultured ,3' Untranslated Regions ,Regulation of gene expression ,Mice, Inbred BALB C ,biology ,microRNA ,Reverse Transcriptase Polymerase Chain Reaction ,Proto-Oncogene Proteins c-mdm2 ,Prognosis ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Mdm2 ,Signal transduction ,Colorectal Neoplasms ,Signal Transduction ,Research Paper ,tumor suppressor ,Blotting, Western ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,MDM2 ,medicine ,Animals ,Humans ,RNA, Messenger ,Cell Proliferation ,Neoplasm Staging ,Three prime untranslated region ,Molecular biology ,Xenograft Model Antitumor Assays ,MicroRNAs ,030104 developmental biology ,Tissue Array Analysis ,biology.protein ,Cancer research ,Tumor Suppressor Protein p53 ,Carcinogenesis - Abstract
The tumor suppressor p53 plays a central role in tumor prevention. The E3 ubiquitin ligase MDM2 is the most critical negative regulator of p53, which binds to p53 and degrades p53 through ubiquitation. MDM2 itself is a transcriptional target of p53, and therefore, MDM2 forms a negative feedback loop with p53 to tightly regulate p53 levels and function. microRNAs (miRNAs) play a key role in regulation of gene expression. miRNA dysregulation plays an important role in tumorigenesis. In this study, we found that miRNA miR-1827 is a novel miRNA that targets MDM2 through binding to the 3'-UTR of MDM2 mRNA. miR-1827 negatively regulates MDM2, which in turn increases p53 protein levels to increase transcriptional activity of p53 and enhance p53-mediated stress responses, including apoptosis and senescence. Overexpression of miR-1827 suppresses the growth of xenograft colorectal tumors, whereas the miR-1827 inhibitor promotes tumor growth in mice in a largely p53-dependent manner. miR-1827 is frequently down-regulated in human colorectal cancer. Decreased miR-1827 expression is associated with high MDM2 expression and poor prognosis in colorectal cancer. In summary, our results reveal that miR-1827 is a novel miRNA that regulates p53 through targeting MDM2, and highlight an important role and the underlying mechanism of miR-1827 in tumor suppression.
- Published
- 2015
38. Autophagy is required for glucose homeostasis and lung tumor maintenance
- Author
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Sinan Khor, Jessie Yanxiang Guo, Joshua D. Rabinowitz, Saurabh V. Laddha, Tyler Jacks, Xin Teng, Sandy M. Price, Gizem Karsli-Uzunbas, Eileen White, Nada Y. Kalaany, Chang S. Chan, MIT Kavli Institute for Astrophysics and Space Research, and Jacks, Tyler E.
- Subjects
Cachexia ,Lung Neoplasms ,Biology ,Autophagy-Related Protein 7 ,Article ,Proto-Oncogene Proteins p21(ras) ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Autophagy ,Glucose homeostasis ,Animals ,Homeostasis ,Humans ,Lung cancer ,Neurodegeneration ,Cancer ,medicine.disease ,humanities ,Hypoglycemia ,Gene Expression Regulation, Neoplastic ,Glucose ,Oncology ,Cancer research ,Tumor Suppressor Protein p53 ,Microtubule-Associated Proteins - Abstract
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers., Val Skinner Foundation, National Institutes of Health (U.S.) (RC1 CA147961), Rutgers Cancer Institute of New Jersey, Rutgers Cancer Institute of New Jersey (P30 CA072720), National Institutes of Health (U.S.) (R01 CA163591), National Institutes of Health (U.S.) (R37 CA53370), National Institutes of Health (U.S.) (R01 CA130893)
- Published
- 2014
39. Mutational landscape of the essential autophagy gene BECN1 in human cancers
- Author
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Eileen White, Saurabh V. Laddha, Shridar Ganesan, and Chang S. Chan
- Subjects
Cancer Research ,endocrine system diseases ,Gene Expression ,Biology ,Article ,law.invention ,Ovarian tumor ,Breast cancer ,Germline mutation ,law ,Neoplasms ,medicine ,Autophagy ,Humans ,Genes, Tumor Suppressor ,skin and connective tissue diseases ,Molecular Biology ,Gene ,Germ-Line Mutation ,BRCA1 Protein ,Membrane Proteins ,BECN1 ,medicine.disease ,Oncology ,Cancer research ,Suppressor ,Beclin-1 ,Haploinsufficiency ,Apoptosis Regulatory Proteins - Abstract
Evidence suggests that the catabolic process of macroautophagy (autophagy hereafter) can either suppress or promote cancer. The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been implicated as a haploinsufficient tumor suppressor in breast, ovarian, and prostate cancers. The proximity of BECN1 to the known breast and ovarian tumor suppressor breast cancer 1, early onset, BRCA1, on chromosome 17q21, has made this determination equivocal. Here, the mutational status of BECN1 was assessed in human tumor sequencing data from The Cancer Genome Atlas (TCGA) and other databases. Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers. Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers. Implications: Contrary to previous reports, BECN1 is not significantly mutated in human cancer and not a tumor-suppressor gene, as originally thought. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/04/01/1541-7786.MCR-13-0614/F1.large.jpg. Mol Cancer Res; 12(4); 485–90. ©2014 AACR.
- Published
- 2014
40. The Zebrafish GenomeWiki: a crowdsourcing approach to connect the long tail for zebrafish gene annotation
- Author
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Prerna Budakoti, Paras Sehgal, Ashok Patowary, Meenakshi Sharma, Rajendra K. Chauhan, Kriti Kaushik, Eric W. Klee, Heena Dhiman, Mukesh Kumar Lalwani, Sunny Malhotra, Subburaj Kadarkaraisamy, Rajiv Rana, Harinder Vishwakarma, Ashish Mittal, Koustav Pal, Vinod Scaria, Meghna Singh, Sridhar Sivasubbu, Saakshi Jalali, Ankit Sabharwal, Vikas Pandey, Jayant Maini, Shamsudheen Karuthedath Vellarikkal, Vivek Bhardwaj, Zainab Asad, Mahantappa Halimani, Stephen C. Ekker, Srishti Nanda, Aravindhakshan Ramachandran, Prateek Joshi, Divya Jagga, Shruti Kapoor, Ruby Priyadarshini, Aamod Jha, Muthulakshmi Muthuswami, Naresh Singh, Rajeshwari Meli, Aalok Kumar, Elvin Leonard, Saurabh V. Laddha, Bharat Bhatt, Angom Ramcharan Singh, Kandarp Joshi, Vaibhav Jadhav, Arijit Bhaumik, Deeksha Bhartiya, and Chetana Sachidanandan
- Subjects
Crowdsourcing ,Internet and science and learning ,General Biochemistry, Genetics and Molecular Biology ,Zoological sciences ,World Wide Web ,Annotation ,Databases, Genetic ,Animals ,Genetics (life sciences) ,Zebrafish ,Bioinformatics (life sciences) ,Internet ,Genome ,biology ,business.industry ,Semantic search ,Molecular Sequence Annotation ,Gene Annotation ,biology.organism_classification ,Database Tool ,Linked data structure ,Zebrafish Information Network genome database ,General Agricultural and Biological Sciences ,business ,Information Systems - Abstract
A large repertoire of gene-centric data has been generated in the field of zebrafish biology. Although the bulk of these data are available in the public domain, most of them are not readily accessible or available in nonstandard formats. One major challenge is to unify and integrate these widely scattered data sources. We tested the hypothesis that active community participation could be a viable option to address this challenge. We present here our approach to create standards for assimilation and sharing of information and a system of open standards for database intercommunication. We have attempted to address this challenge by creating a community-centric solution for zebrafish gene annotation. The Zebrafish GenomeWiki is a ‘wiki’-based resource, which aims to provide an altruistic shared environment for collective annotation of the zebrafish genes. The Zebrafish GenomeWiki has features that enable users to comment, annotate, edit and rate this gene-centric information. The credits for contributions can be tracked through a transparent microattribution system. In contrast to other wikis, the Zebrafish GenomeWiki is a ‘structured wiki’ or rather a ‘semantic wiki’. The Zebrafish GenomeWiki implements a semantically linked data structure, which in the future would be amenable to semantic search. Database URL: http://genome.igib.res.in/twiki
- Published
- 2014
41. Genome-wide analysis reveals downregulation of miR-379/miR-656 cluster in human cancers
- Author
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Charu Sharma, Prerana Jha, Rajasekhara Reddy, Arijit Mukhopadhyay, Saurabh V. Laddha, Manoj Hariharan, Deepanjan Paul, Chitra Sarkar, Anurag Agrawal, Shantanu Chowdhury, and Subhashree Nayak
- Subjects
Male ,Immunology ,Breast Neoplasms ,Locus (genetics) ,In Vitro Techniques ,Biology ,Real-Time Polymerase Chain Reaction ,GBM ,General Biochemistry, Genetics and Molecular Biology ,Downregulation and upregulation ,Neoplasms ,Glioma ,microRNA ,medicine ,Humans ,DLK1-DIO3 ,Ecology, Evolution, Behavior and Systematics ,Cancer ,Ovarian Neoplasms ,Genetics ,Regulation of gene expression ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) ,Research ,Applied Mathematics ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Real-time polymerase chain reaction ,Cluster ,Modeling and Simulation ,DNA methylation ,Cancer research ,Female ,MiRNAs ,Human genome ,MEF2 ,General Agricultural and Biological Sciences ,Tumor Suppressor - Abstract
Background MicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls. Results We found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10-6, FDRMEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster. Conclusion We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs. Reviewers Reviewed by: Prof. Gregory J Goodall and Dr. Alexander Max Burroughs
- Published
- 2013
42. Exosome-enclosed microRNAs in exhaled breath hold potential for biomarker discovery in patients with pulmonary diseases
- Author
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Debasis Dash, Arijit Mukhopadhyay, Amit Kumar Yadav, Manish Kumar, Gaurav Malik, Samarpana Chakraborty, Ankur Kulshreshtha, Anirban Sinha, S. K. Kabra, Balaram Ghosh, Rakesh Lodha, Rajesh Pandey, Saurabh V. Laddha, Anurag Agrawal, and Tavpritesh Sethi
- Subjects
Lung Diseases ,business.industry ,Immunology ,Bioinformatics ,Exosomes ,Exosome ,MicroRNAs ,Breath Tests ,microRNA ,Immunology and Allergy ,Medicine ,Humans ,In patient ,Biomarker discovery ,business ,Biomarkers - Published
- 2012
43. The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors
- Author
-
Chung Wong, Chris R. Harris, E Normant, Laura H. Tang, Arnold J. Levine, Eugenia Y. Xu, P Sandy, Evan Vosburgh, Chang S. Chan, and Saurabh V. Laddha
- Subjects
Cancer Research ,Immunology ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Biology ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins c-myc ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Line, Tumor ,Acetamides ,Humans ,Protein kinase B ,Transcription factor ,Cell Proliferation ,Sirolimus ,Cell growth ,Nuclear Proteins ,RNA-Binding Proteins ,Cell Biology ,Azepines ,G1 Phase Cell Cycle Checkpoints ,3. Good health ,Bromodomain ,Neuroendocrine Tumors ,chemistry ,Cancer research ,Original Article ,Growth inhibition ,G1 phase ,Transcription Factors - Abstract
Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.
- Published
- 2014
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