المؤلفون: Anand Pathak, Anand Kolatkar, Amir Ali Talasaz, Julia A. Beaver, Daniel Edelstein, Matthew Ryder, Jerry S.H. Lee, Peter Kuhn, Lea M. Salvatore, Justin Johnson, Seema Singh Bhan, Allison Welsh, David A. Eberhard, James H Godsey, Howard I. Scher, Melanie Hullings, Carolyn Compton, James W. Hicks, Matthew Smalley, Robert L. Grossman, Jonathan W. Simons, Jake Vinson, Gideon M. Blumenthal, David Reese, Sean E. Hanlon, Walt Wells, Rebecca Levine, Phillip G. Febbo, Wendy Royalty, Lauren C. Leiman, Bryan Moy, Hsian-Rong Tseng, Ryan Dittamore, Daniel H. Hovelson, Daniel P. Miller, Anne-Marie Martin, Donald J Johann, Andrew E. Schade, J. Carl Barrett, Hakan Sakul, Carissa Moore, Stella Somiari, Kelli Bramlett, Paul J. Beresford, Andrew Gruen, Reena Philip, John K. Simmons, Angela Silvestro, Jean-Francois Martini, Muneesh Tewari

المصدر: Clinical Pharmacology and Therapeutics

مصطلحات موضوعية: Pharmacology, medicine.medical_specialty, Databases, Factual, Extramural, business.industry, MEDLINE, Public-Private Sector Partnership, Liquid Biopsy, Public-Private Sector Partnerships, Perspective, Medicine, Humans, Pharmacology (medical), Medical physics, Liquid biopsy, business, Perspectives, Data Management

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::021e87ff08b0cace4490eeb5f6d29110Test
http://europepmc.org/articles/PMC7158216Test

المؤلفون: Melanie Hullings, Ryon P. Graf, Howard I. Scher, Ryan Dittamore, Emily Carbone, Ethan Barnett

المصدر: Eur Urol

مصطلحات موضوعية: Male, Oncology, medicine.medical_specialty, Urology, medicine.medical_treatment, Clinical Decision-Making, 030232 urology & nephrology, Lower risk, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Circulating tumor cell, Internal medicine, Phenylthiohydantoin, medicine, Humans, Liquid biopsy, Chemotherapy, Taxane, business.industry, Neoplastic Cells, Circulating, medicine.disease, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, 030220 oncology & carcinogenesis, Cohort, Biomarker (medicine), business, Biomarkers

الوصف: Background Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used. Objective To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane. Design, setting, and participants The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3 yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes. Outcome measurements and statistical analyses We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status. Results and limitations Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; p =0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; p = 0.041). AR-V7–negative patients had superior survival on ARSIs over taxanes (p = 0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7–positive men. Conclusions Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures. Patient summary Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d38c7b42df0eb29e3fb1207006f9376fTest
https://doi.org/10.1016/j.eururo.2019.08.020Test

المؤلفون: Erin L Williams, Helen G. Mayo, Mitchell S. von Itzstein, Melanie Hullings, M. Shaalan Beg, David E. Gerber

المصدر: JAMA oncology. 7(10)

مصطلحات موضوعية: Protocol (science), Cancer Research, medicine.medical_specialty, business.industry, Medical record, Patient Selection, Information technology, Telehealth, Clinical trial, Patient recruitment, Clinical research, Oncology, Drug development, Artificial Intelligence, Neoplasms, Medicine, Humans, business, Intensive care medicine, Information Technology, Natural Language Processing

الوصف: Importance: As cancer treatment has become more individualized, oncologic clinical trials have become more complex. Increasingly numerous and stringent eligibility criteria frequently include tumor molecular or genomic characteristics that may not be readily identified in medical records, rendering it difficult to best match clinical trials with clinical sites and to identify potentially eligible patients once a clinical trial has been selected and activated. Partly because of these factors, enrollment rates for cancer clinical trials remain low, creating delays and increased costs for drug development. Information technology (IT) platforms have been applied to the implementation and conduct of clinical trials to improve efficiencies in several medical fields, and these platforms have recently been introduced to oncologic studies. Observations: This review summarizes cancer and noncancer studies that used IT platforms for assistance with clinical trial site selection, patient recruitment, and patient screening. The review does not address the use of IT in other aspects of clinical research, such as wearable physical activity monitors or telehealth visits. A large number of IT platforms (which may be patient facing, site or investigator facing, or sponsor facing) are now commercially available. These applications use artificial intelligence and/or natural language processing to identify and summarize protocol eligibility criteria, institutional patient populations, and individual electronic health records. Although there is an expanding body of literature examining the role of this technology, relatively few studies to date have been performed in oncologic settings. Conclusions and Relevance: This review found that an increasing number and variety of IT platforms were available to assist in the planning and conduct of clinical trials. Because oncologic clinical care and clinical trial protocols are particularly complex, nuanced, and individualized, published experience with this technology in other fields may not be fully applicable to cancer settings. The extent to which these services will overcome ongoing and increasing challenges in cancer clinical research remains unclear.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d298940670e663e678fcc26975fbe15fTest
https://pubmed.ncbi.nlm.nih.gov/34236403Test

المؤلفون: Vijay Ramani, Shruthi Nooka, Yu-An Zhang, Serena Gibbs, Hai-Cheng Huang, Melanie Hullings, Suzanne Conzen, Carlos L. Arteaga, Isaac Chan, Sangeetha M. Reddy

المصدر: Cancer Research. 82:4197-4197

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Introduction: Triple negative breast cancers (TNBC) have shown limited responses to immune checkpoint blockade (ICB). Breast cancer is associated with defects in antigen presentation which may contribute to resistance to ICB. Flt3 ligand (Flt3L) is a growth factor that increases differentiation of DC1 dendritic cells, critical mediators of antigen presentation. CD40 agonist activates all 3 classes of antigen presenting cells - dendritic cells, B cells, and macrophages. Synergy has been demonstrated between Flt3L and CD40 agonist as well as between CD40 agonist and chemotherapy in other cancers, however the combination of all three has not been studied in breast cancer. Methods: 6-8 week old Balb/c mice were injected with 4T1 triple negative breast cancer cells. When tumors were 50 mm3, mice were first treated with intraperitoneal pegylated liposomal doxorubicin (PLD) once and subcutaneous Flt3L daily for 5 days in different sequencing schedules (PLD first followed by Flt3L immediately or 4 days later or Flt3L first followed by PLD 7 days or 10 days later). Based on optimal scheduling of PLD and Flt3L, mice were treated with PLD alone, Flt3L alone, CD40 agonist alone, PLD + Flt3L, PLD + CD40 agonist, PLD + PD-1 blockade, or PLD + CD40 agonist + Flt3L. In addition to serial tumor measurements, mice were sacrificed and tumors and lymphoid organs harvested for flow cytometry analyses. Results: Treatment with PLD at least 4 days before Flt3L led to an optimal increase in intra-tumoral DC1 cells (p=0.0002), increase in polyfunctional CD8 T cell response (p Conclusions: Novel triplet combination with PLD, CD40 agonist, and Flt3L leads to enhanced tumor control in the 4T1 TNBC mouse model. A clinical trial with this combination in metastatic TNBC patients is expected to begin recruitment soon (NCT05029999). Citation Format: Vijay Ramani, Shruthi Nooka, Yu-An Zhang, Serena Gibbs, Hai-Cheng Huang, Melanie Hullings, Suzanne Conzen, Carlos L. Arteaga, Isaac Chan, Sangeetha M. Reddy. Treatment with chemotherapy, CD40 agonist, and Flt3 ligand triplet combination enhances antigen presentation and leads to cures in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4197.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::dcf2843009e3da1a8915f7f52b27f1d0Test
https://doi.org/10.1158/1538-7445.am2022-4197Test

المؤلفون: Sangeetha M. Reddy, Meredith Carter, Isaac Chan, Melanie Hullings, Nisha Unni, Jessica Medina, Shahbano Shakeel, Susan Armstrong, Lakeisha Cade, Farjana J. Fattah, Chul Ahn, Yisheng V. Fang, Nan Chen, Heather L. McArthur, Nicole Sinclair, Michael Jay Yellin, Joyce O'Shaughnessy, Rita Nanda, Suzanne D. Conzen, Carlos L. Arteaga

المصدر: Journal of Clinical Oncology. 40:TPS1126-TPS1126

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: TPS1126 Background: Only a subset of patients with metastatic triple-negative breast cancer demonstrate response to currently approved PD-1 immune checkpoint blockade, and few have durable responses. Antigen presentation defects may be a reason for this low response because deficiency of antigen-presenting DC1 dendritic cells is associated with poor anti-tumor immunity. CD40 agonists are a class of agents that activate antigen presenting cells including dendritic cells and B cells and also repolarize macrophages. Flt3 ligand is a growth factor that increases dendritic cells. In line with this, we recently demonstrated in pre-clinical models that the combination of liposomal-doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes of breast cancer compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal-doxorubicin, CDX-1140 (CD40 agonist), and CDX-301 (Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic triple-negative breast cancer. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, liposomal-doxorubicin only) prior to receiving full triplet therapy with fresh tissue biopsies before and after the lead-in treatment. CDX-301 will be discontinued after 2 cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase 2 dose based on treatment-related adverse events including dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal-doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV triple-negative breast cancer (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line metastatic treatment setting (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites. Clinical trial information: NCT05029999.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7bf8e9ffec885106c1d93420bdb3655eTest
https://doi.org/10.1200/jco.2022.40.16_suppl.tps1126Test

المؤلفون: Arthur E. Frankel, Melanie Hullings, Nisha Unni, Melissa Rodriguez, Thomas W. Froehlich, Dawn Klemow, Kiran Batra, Sunati Sahoo, Barbara Haley, Chul Ahn

المصدر: Clinical breast cancer. 21(5)

مصطلحات موضوعية: 0301 basic medicine, Oncology, Adult, Bridged-Ring Compounds, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, Pyridines, Antineoplastic Agents, Breast Neoplasms, Palbociclib, Ado-Trastuzumab Emtansine, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Trastuzumab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Taxane, business.industry, Cancer, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Neratinib, Toxicity, Female, Taxoids, Pertuzumab, business, medicine.drug

الوصف: Background Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. Patients and Methods A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. Results From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1–22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%–59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5–11.6). Conclusions The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::666730afbfe1b3f83663ea32957a94b3Test
https://pubmed.ncbi.nlm.nih.gov/33836974Test

المؤلفون: Joseph D. Schonhoft, Angel E. Dago, Ryan Dittamore, Jimmy L. Zhao, Melanie Hullings, Mithat Gonen, Jerry Lee, Ethan Barnett, Adam Jendrisak, Yipeng Wang, Audrey Gill, Emily Carbone, Samuel F. Bakhoum, Mark Landers, Howard I. Scher, Ramsay Sutton

المصدر: Cancer Res

مصطلحات موضوعية: 0301 basic medicine, Genetic Markers, Male, Cancer Research, DNA Copy Number Variations, Cell, Sensitivity and Specificity, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Circulating tumor cell, Chromosome instability, Chromosomal Instability, Biopsy, medicine, Humans, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Reproducibility of Results, Chromosome Breakage, Middle Aged, medicine.disease, Neoplastic Cells, Circulating, Prognosis, High-Throughput Screening Assays, Androgen receptor, Prostatic Neoplasms, Castration-Resistant, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Genomic Structural Variation, Cancer research, Disease Progression, Biomarker (medicine), Chromosome breakage, business, Algorithms

الوصف: Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes. Significance: A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::752bdfef1da6f8dcab84a6c08482f6dfTest
https://pubmed.ncbi.nlm.nih.gov/32816908Test

المؤلفون: Philip W. Kantoff, Wassim Abida, Ethan Barnett, Konrad H. Stopsack, Chloe J. Kim, Melanie Hullings, David B. Solit, Emily Weg, Samuel Haywood, Samantha E. Vasselman, Howard I. Scher, Subhiksha Nandakumar, Bastien Nguyen, Emily Carbone, Nikolaus Schultz, Michael J. Morris, Andreas Wibmer

المصدر: Clin Cancer Res

مصطلحات موضوعية: 0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Disease, Kaplan-Meier Estimate, SPOP, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Castration Resistance, Internal medicine, medicine, Biomarkers, Tumor, Humans, Orchiectomy, Aged, Neoplasm Staging, business.industry, Hazard ratio, Wnt signaling pathway, Genetic Variation, Prostatic Neoplasms, Genomics, Oncogenes, Cell cycle, Middle Aged, medicine.disease, Prognosis, 030104 developmental biology, Phenotype, Treatment Outcome, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Neoplasm Grading, business

الوصف: Purpose: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. Experimental Design: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. Results: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. Conclusions: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac311e6ba3427642a54d6c52cc588aacTest
https://pubmed.ncbi.nlm.nih.gov/32220891Test

المؤلفون: María Concepción Gil-Rodríguez, Angela E. Scheuerle, Kathleen A. Leppig, Hane Lee, Miguel Del Campo, Peter Diakumis, Katsuhiko Shirahige, Encarna Guillén-Navarro, Juliane Eckhold, Sally Ann Lynch, Holly Dubbs, A. Micheil Innes, Joe Ann S. Moser, Sulagna C. Saitta, Naohito Nozaki, Fabiola Quintero-Rivera, Helger G. Yntema, Antonie D. Kline, Antonio Perez-Aytes, Dinah Clark, Patrick Willems, Lynette S. Penney, Bryan D. Hall, David A. Dyment, Samuel P. Strom, Matthew A. Deardorff, Maninder Kaur, Kathleen A. Williamson, Diana Braunholz, Ieva Micule, Jennifer M. Hunter, Jose Ferreira, Laird G. Jackson, Sarah Ernst, Paldeep S. Atwal, Raoul C.M. Hennekam, Shane McKee, Sarju G. Mehta, David R. FitzPatrick, Sarah E. Noon, David J. Amor, Yolanda Gyftodimou, David W. Christianson, Louanne Hudgins, Christopher T. Fincher, Melanie Hullings, Inga Vater, Victoria Mok Siu, Feliciano J. Ramos, Michael B. Petersen, Christophe Decroos, Antonio Musio, Morad Ansari, Elizabeth Roeder, Nicole Revencu, Heidi Thiese, Shehla Mohammed, Beatriz Puisac, Louise C. Wilson, John Pappas, Lauren J. Francey, Zita Krumina, Zornitza Stark, Karen L. Schindeler, Juan Pié, Ellen Moran, Jolanta Wierzba, Nataliya Di Donato, Hakon Hakonarson, Frank J. Kaiser, Gabriele Gillessen-Kaesbach, Geert Mortier, Han G. Brunner, Linda Mannini, Melanie Bahlo, Jonathan J. Wilde, Masashige Bando, Jacquelyn J. Bradley, Mark B. Mallozzi, Ulrike Gehlken, Christine M. Bowman, Luis Nunes, Ian D. Krantz

المساهمون: Amsterdam Neuroscience, Amsterdam Public Health, Human Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, CareRare Canada Consortium, University of Washington Center for Mendelian Genomics

المصدر: Kaiser, F J, Ansari, M, Braunholz, D, Concepción Gil-Rodríguez, M, Decroos, C, Wilde, J J, Fincher, C T, Kaur, M, Bando, M, Amor, D J, Atwal, P S, Bahlo, M, Bowman, C M, Bradley, J J, Brunner, H G, Clark, D, Del Campo, M, Di Donato, N, Diakumis, P, Dubbs, H, Dyment, D A, Eckhold, J, Ernst, S, Ferreira, J C, Francey, L J, Gehlken, U, Guillén-Navarro, E, Gyftodimou, Y, Hall, B D, Hennekam, R, Hudgins, L, Hullings, M, Hunter, J M, Yntema, H, Innes, A M, Kline, A D, Krumina, Z, Lee, H, Leppig, K, Lynch, S A, Mallozzi, M B, Mannini, L, McKee, S, Mehta, S G, Micule, I, Mohammed, S, Moran, E, Mortier, G R, Moser, J-A S, Petersen, M B & Care4Rare Canada Consortium 2014, ' Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance ', Human Molecular Genetics, vol. 23, no. 11, pp. 2888-2900 . https://doi.org/10.1093/hmg/ddu002Test
Human molecular genetics, 23(11), 2888-2900. Oxford University Press
Human molecular genetics, vol 23, iss 11
Human Molecular Genetics, 23, 11, pp. 2888-900
Human Molecular Genetics, 23, 2888-900
HUMAN MOLECULAR GENETICS
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
Human Molecular Genetics, Vol. 23, no. 11, p. 2888-2900 (2014)
Human molecular genetics

مصطلحات موضوعية: Male, Care4Rare Canada Consortium, medicine.disease_cause, Bioinformatics, Medical and Health Sciences, Cohort Studies, Congenital, Genes, X-Linked, De Lange Syndrome, 2.1 Biological and endogenous factors, Missense mutation, Eye Abnormalities, Aetiology, Hypertelorism, Child, Genetics (clinical), X-linked recessive inheritance, Pediatric, Genetics & Heredity, Genetics, screening and diagnosis, Mutation, Genetic disorder, Articles, General Medicine, Biological Sciences, Chemistry, Detection, Phenotype, Child, Preschool, Female, medicine.symptom, Cornelia de Lange Syndrome, Cohesin complex, Intellectual and Developmental Disabilities (IDD), Molecular Sequence Data, Cranial Fontanelles, Mutation, Missense, Biology, Histone Deacetylases, Rare Diseases, medicine, Humans, Amino Acid Sequence, Dental/Oral and Craniofacial Disease, Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12], University of Washington Center for Mendelian Genomics, Preschool, Molecular Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Infant, NIPBL, X-Linked, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Repressor Proteins, Genes, Human medicine, Missense, Sequence Alignment

الوصف: Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. © The Author 2014. Published by Oxford University Press. All rights reserved.Published by Oxford University Press. All rights reserved.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9d5b1ff2bb16729d8da56fa773419cfeTest
https://doi.org/10.1093/hmg/ddu002Test

المؤلفون: Nicole A. Schreiber, Emily Carbone, Nikolaus Schultz, Michael F. Berger, Mark Landers, Nadia Ebrahim, Melanie Hullings, Howard I. Scher, David B. Solit, Angel E. Dago, Ethan Barnett, Ryan Dittamore, Jerry Lee, Yipeng Wang, Ramsay Sutton

المصدر: Journal of Clinical Oncology. 37:3050-3050

مصطلحات موضوعية: Oncology, Cancer Research, Mutation profiling, medicine.medical_specialty, Concordance analysis, medicine.diagnostic_test, Somatic cell, business.industry, Cancer, medicine.disease, Internal medicine, Biopsy, medicine, business

الوصف: 3050 Background: MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a high throughput, targeted-DNA-sequencing panel for somatic mutations created by the Department of Pathology at Memorial Sloan Kettering Cancer Center (MSK). The MSK-IMPACT is FDA approved for tumor tissue profiling to guide treatment selection. Recognizing access to tumor tissue in many cancers is difficult and may harbor inter & intra lesional heterogeneity, we sought to evaluate concordance of sequencing single CTCs vs. paired biopsy analyzed by MSK-IMPACT, to assess CTC vs. tumor clonality, and their relationship to outcomes. Methods: 148 biopsy samples from 138 mCRPC pts were submitted for IMPACT analysis and a blood draw within 30-day prior to initiation of a new line of treatment. Blood samples were sent to Epic Sciences for CTC detection. The detected CTCs underwent single cell low pass whole genome sequencing for copy number variation (CNV). For each set of matched samples, DNA copy number profiles from IMPACT and CTC sequencing were compared for similarity. Results: Of the 114 successfully sequenced samples 58 were from lymph nodes, 23 from bone, 25 from liver or lung, and 8 from other soft tissue. Of the 111 patients with CTCs analyzed, a total of 1073 CTCs were sequenced (range 1-27, median = 4 per pt). Of patients with both IMPACT & CTC, >80% pts had multiple subclones with distinguishable CNV. Concordance of genomics clones was found in 63%, and discordant in 37% cases. The clonal concordance between tissue biopsy and CTC was higher when the biopsy was obtained from bone marrow or a visceral site (71% concordance) than from a lymph node (53% concordance). Conclusions: Single CTC sequencing is often concordant to metastatic tissue, but unique CTC clones and the presence of multi-clonal disease highlight the potential to be underrepresented through tissue biopsy, especially when taken from the lymph node.[Table: see text]

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1a663397bb19fb396291ac33ade63ffdTest
https://doi.org/10.1200/jco.2019.37.15_suppl.3050Test