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1. Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes.

Author

Thibaud, Santiago, Subaran, Ryan, Newman, Scott, Lagana, Alessandro, Melnekoff, David, Bodnar, Saoirse, Ram, Meghana, Soens, Zachry, Genthe, William, Brander, Tehilla, Mouhieddine, Tarek, Van Oekelen, Oliver, Houldsworth, Jane, Cho, Hearn, Richard, Shambavi, Richter, Joshua, Rodriguez, Cesar, Rossi, Adriana, Sanchez, Larysa, Chari, Ajai, Moshier, Erin, Jagannath, Sundar, Parekh, Samir, and Onel, Kenan

Subjects
Humans, Multiple Myeloma, Germ-Line Mutation, Female, DNA Repair, Male, Genetic Predisposition to Disease, Middle Aged, Aged, Adult
Abstract

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.

Published
2024

2. Benchmarking Embedding Aggregation Methods in Computational Pathology: A Clinical Data Perspective

Author

Chen, Shengjia, Campanella, Gabriele, Elmas, Abdulkadir, Stock, Aryeh, Zeng, Jennifer, Polydorides, Alexandros D., Schoenfeld, Adam J., Huang, Kuan-lin, Houldsworth, Jane, Vanderbilt, Chad, and Fuchs, Thomas J.

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Recent advances in artificial intelligence (AI), in particular self-supervised learning of foundation models (FMs), are revolutionizing medical imaging and computational pathology (CPath). A constant challenge in the analysis of digital Whole Slide Images (WSIs) is the problem of aggregating tens of thousands of tile-level image embeddings to a slide-level representation. Due to the prevalent use of datasets created for genomic research, such as TCGA, for method development, the performance of these techniques on diagnostic slides from clinical practice has been inadequately explored. This study conducts a thorough benchmarking analysis of ten slide-level aggregation techniques across nine clinically relevant tasks, including diagnostic assessment, biomarker classification, and outcome prediction. The results yield following key insights: (1) Embeddings derived from domain-specific (histological images) FMs outperform those from generic ImageNet-based models across aggregation methods. (2) Spatial-aware aggregators enhance the performance significantly when using ImageNet pre-trained models but not when using FMs. (3) No single model excels in all tasks and spatially-aware models do not show general superiority as it would be expected. These findings underscore the need for more adaptable and universally applicable aggregation techniques, guiding future research towards tools that better meet the evolving needs of clinical-AI in pathology. The code used in this work is available at \url{https://github.com/fuchs-lab-public/CPath_SABenchmark}., Comment: 10 pages, 2 figures

Published
2024

3. A Clinical Benchmark of Public Self-Supervised Pathology Foundation Models

Author

Campanella, Gabriele, Chen, Shengjia, Verma, Ruchika, Zeng, Jennifer, Stock, Aryeh, Croken, Matt, Veremis, Brandon, Elmas, Abdulkadir, Huang, Kuan-lin, Kwan, Ricky, Houldsworth, Jane, Schoenfeld, Adam J., and Vanderbilt, Chad

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

The use of self-supervised learning (SSL) to train pathology foundation models has increased substantially in the past few years. Notably, several models trained on large quantities of clinical data have been made publicly available in recent months. This will significantly enhance scientific research in computational pathology and help bridge the gap between research and clinical deployment. With the increase in availability of public foundation models of different sizes, trained using different algorithms on different datasets, it becomes important to establish a benchmark to compare the performance of such models on a variety of clinically relevant tasks spanning multiple organs and diseases. In this work, we present a collection of pathology datasets comprising clinical slides associated with clinically relevant endpoints including cancer diagnoses and a variety of biomarkers generated during standard hospital operation from two medical centers. We leverage these datasets to systematically assess the performance of public pathology foundation models and provide insights into best practices for training new foundation models and selecting appropriate pretrained models., Comment: arXiv admin note: text overlap with arXiv:2310.07033

Published
2024

4. Multiparametric MRI Texture Analysis in Prediction of Glioma Biomarker Status: Added Value of MR Diffusion

Author

Kihira, Shingo, Tsankova, Nadejda, Bauer, Adam, Sakai, Yu, Mahmoudi, Keon, Zubizarreta, Nicole, Houldsworth, Jane, Khan, Fahad, Salamon, Noriko, Hormigo, Adilia, and Nael, Kambiz

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Neurosciences, Brain Disorders, Rare Diseases, Brain Cancer, Biomedical Imaging, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, glioma, MR diffusion, multiparametric MRI, radiogenomics, texture analysis
Abstract

BackgroundEarly identification of glioma molecular phenotypes can lead to understanding of patient prognosis and treatment guidance. We aimed to develop a multiparametric MRI texture analysis model using a combination of conventional and diffusion MRI to predict a wide range of biomarkers in patients with glioma.MethodsIn this retrospective study, patients were included if they (1) had diagnosis of gliomas with known IDH1, EGFR, MGMT, ATRX, TP53, and PTEN status from surgical pathology and (2) had preoperative MRI including FLAIR, T1c+ and diffusion for radiomic texture analysis. Statistical analysis included logistic regression and receiver-operating characteristic (ROC) curve analysis to determine the optimal model for predicting glioma biomarkers. A comparative analysis between ROCs (conventional only vs conventional + diffusion) was performed.ResultsFrom a total of 111 patients included, 91 (82%) were categorized to training and 20 (18%) to test datasets. Constructed cross-validated model using a combination of texture features from conventional and diffusion MRI resulted in overall AUC/accuracy of 1/79% for IDH1, 0.99/80% for ATRX, 0.79/67% for MGMT, and 0.77/66% for EGFR. The addition of diffusion data to conventional MRI features significantly (P < .05) increased predictive performance for IDH1, MGMT, and ATRX. The overall accuracy of the final model in predicting biomarkers in the test group was 80% (IDH1), 70% (ATRX), 70% (MGMT), and 75% (EGFR).ConclusionAddition of MR diffusion to conventional MRI features provides added diagnostic value in preoperative determination of IDH1, MGMT, and ATRX in patients with glioma.

Published
2021

5. Twenty-Five Years of Germline Genetic Testing and What May Lie Ahead

Author

Pratt, Victoria M., Akhavanfard, Sara, Houldsworth, Jane, Laffin, Jennifer J., Moyer, Ann M., Reddi, Honey V., Scott, Stuart A., Lebo, Matthew S., Lebo, Matthew S., Akhavanfard, Sara, Du, Xiaoli, Hawks, Tina Hambuch, Houldsworth, Jane, Laffin, Jennifer J., Moyer, Ann M., Pratt, Victoria M., Reddi, Honey V., Scott, Stuart A., and Williams, Eli

Published
2024
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9. Host Nuclear Genome Copy Number Variations Identify High-Risk Anal Precancers in People Living with HIV

Author

Mutetwa, Tinaye, primary, Liu, Yuxin, additional, Silvera, Richard, additional, Evans, Michelle, additional, Yurich, Michael, additional, Tripodi, Joseph, additional, Leonard, Issa, additional, Houldsworth, Jane, additional, Gümüş, Zeynep, additional, Bowcock, Anne M., additional, Sigel, Keith, additional, Gaisa, Michael, additional, and Polak, Paz, additional

Published
2024
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10. Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience

Author

Bryce, Clare, Grimes, Zachary, Pujadas, Elisabet, Ahuja, Sadhna, Beasley, Mary Beth, Albrecht, Randy, Hernandez, Tahyna, Stock, Aryeh, Zhao, Zhen, AlRasheed, Mohamed Rizwan, Chen, Joyce, Li, Li, Wang, Diane, Corben, Adriana, Haines, G. Kenneth, III, Westra, William H., Umphlett, Melissa, Gordon, Ronald E., Reidy, Jason, Petersen, Bruce, Salem, Fadi, Fiel, Maria Isabel, El Jamal, Siraj M., Tsankova, Nadejda M., Houldsworth, Jane, Mussa, Zarmeen, Veremis, Brandon, Sordillo, Emilia, Gitman, Melissa R., Nowak, Michael, Brody, Rachel, Harpaz, Noam, Merad, Miriam, Gnjatic, Sacha, Liu, Wen-Chun, Schotsaert, Michael, Miorin, Lisa, Aydillo Gomez, Teresa A., Ramos-Lopez, Irene, Garcia-Sastre, Adolfo, Donnelly, Ryan, Seigler, Patricia, Keys, Calvin, Cameron, Jennifer, Moultrie, Isaiah, Washington, Kae-Lynn, Treatman, Jacquelyn, Sebra, Robert, Jhang, Jeffrey, Firpo, Adolfo, Lednicky, John, Paniz-Mondolfi, Alberto, Cordon-Cardo, Carlos, and Fowkes, Mary E.

Published
2021
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11. Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms

Author

Livanos, Alexandra E., Jha, Divya, Cossarini, Francesca, Gonzalez-Reiche, Ana S., Tokuyama, Minami, Aydillo, Teresa, Parigi, Tommaso L., Ladinsky, Mark S., Ramos, Irene, Dunleavy, Katie, Lee, Brian, Dixon, Rebekah E., Chen, Steven T., Martinez-Delgado, Gustavo, Nagula, Satish, Bruce, Emily A., Ko, Huaibin M., Glicksberg, Benjamin S., Nadkarni, Girish, Pujadas, Elisabet, Reidy, Jason, Naymagon, Steven, Grinspan, Ari, Ahmad, Jawad, Tankelevich, Michael, Bram, Yaron, Gordon, Ronald, Sharma, Keshav, Houldsworth, Jane, Britton, Graham J., Chen-Liaw, Alice, Spindler, Matthew P., Plitt, Tamar, Wang, Pei, Cerutti, Andrea, Faith, Jeremiah J., Colombel, Jean-Frederic, Kenigsberg, Ephraim, Argmann, Carmen, Merad, Miriam, Gnjatic, Sacha, Harpaz, Noam, Danese, Silvio, Cordon-Cardo, Carlos, Rahman, Adeeb, Schwartz, Robert E., Kumta, Nikhil A., Aghemo, Alessio, Bjorkman, Pamela J., Petralia, Francesca, van Bakel, Harm, Garcia-Sastre, Adolfo, and Mehandru, Saurabh

Published
2021
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13. Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin

Author

Marcellino, Bridget K., Farnoud, Noushin, Cassinat, Bruno, Lu, Min, Verger, Emanuelle, McGovern, Erin, Patel, Minal, Medina-Martinez, Juan, Levine, Max Fine, Arango Ossa, Juanes E., Zhou, Yangyu, Kosiorek, Heidi, Mehrotra, Meenakshi, Houldsworth, Jane, Dueck, Amylou, Rossi, Michael, Mascarenhas, John, Kiladjian, Jean-Jacques, Rampal, Raajit K., and Hoffman, Ronald

Published
2020
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14. Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study

Author

Wajnberg, Ania, Mansour, Mayce, Leven, Emily, Bouvier, Nicole M, Patel, Gopi, Firpo-Betancourt, Adolfo, Mendu, Rao, Jhang, Jeffrey, Arinsburg, Suzanne, Gitman, Melissa, Houldsworth, Jane, Sordillo, Emilia, Paniz-Mondolfi, Alberto, Baine, Ian, Simon, Viviana, Aberg, Judith, Krammer, Florian, Reich, David, and Cordon-Cardo, Carlos

Published
2020
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17. Development and Validation of a Gene-Based Model for Outcome Prediction in Germ Cell Tumors Using a Combined Genomic and Expression Profiling Approach.

Author

Korkola, James E, Heck, Sandy, Olshen, Adam B, Feldman, Darren R, Reuter, Victor E, Houldsworth, Jane, Bosl, George J, and Chaganti, RSK

Subjects
Humans, Neoplasms, Germ Cell and Embryonal, Disease-Free Survival, Models, Statistical, Gene Expression Profiling, Genomics, Comparative Genomic Hybridization, DNA Copy Number Variations, Models, Statistical, Neoplasms, Germ Cell and Embryonal, General Science & Technology
Abstract

Germ Cell Tumors (GCT) have a high cure rate, but we currently lack the ability to accurately identify the small subset of patients who will die from their disease. We used a combined genomic and expression profiling approach to identify genomic regions and underlying genes that are predictive of outcome in GCT patients. We performed array-based comparative genomic hybridization (CGH) on 53 non-seminomatous GCTs (NSGCTs) treated with cisplatin based chemotherapy and defined altered genomic regions using Circular Binary Segmentation. We identified 14 regions associated with two year disease-free survival (2yDFS) and 16 regions associated with five year disease-specific survival (5yDSS). From corresponding expression data, we identified 101 probe sets that showed significant changes in expression. We built several models based on these differentially expressed genes, then tested them in an independent validation set of 54 NSGCTs. These predictive models correctly classified outcome in 64-79.6% of patients in the validation set, depending on the endpoint utilized. Survival analysis demonstrated a significant separation of patients with good versus poor predicted outcome when using a combined gene set model. Multivariate analysis using clinical risk classification with the combined gene model indicated that they were independent prognostic markers. This novel set of predictive genes from altered genomic regions is almost entirely independent of our previously identified set of predictive genes for patients with NSGCTs. These genes may aid in the identification of the small subset of patients who are at high risk of poor outcome.

Published
2015

24. Supplementary Figures from NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Author

Su, Xiaoping, primary, Zhang, Jianping, primary, Mouawad, Roger, primary, Compérat, Eva, primary, Rouprêt, Morgan, primary, Allanic, Frederick, primary, Parra, Jérôme, primary, Bitker, Marc-Olivier, primary, Thompson, Erika J., primary, Gowrishankar, Banumathy, primary, Houldsworth, Jane, primary, Weinstein, John N., primary, Tost, Jorg, primary, Broom, Bradley M., primary, Khayat, David, primary, Spano, Jean-Philippe, primary, Tannir, Nizar M., primary, and Malouf, Gabriel G., primary

Published
2023
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25. Supplementary Table S1 from NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Author

Su, Xiaoping, primary, Zhang, Jianping, primary, Mouawad, Roger, primary, Compérat, Eva, primary, Rouprêt, Morgan, primary, Allanic, Frederick, primary, Parra, Jérôme, primary, Bitker, Marc-Olivier, primary, Thompson, Erika J., primary, Gowrishankar, Banumathy, primary, Houldsworth, Jane, primary, Weinstein, John N., primary, Tost, Jorg, primary, Broom, Bradley M., primary, Khayat, David, primary, Spano, Jean-Philippe, primary, Tannir, Nizar M., primary, and Malouf, Gabriel G., primary

Published
2023
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26. Data from NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Author

Su, Xiaoping, primary, Zhang, Jianping, primary, Mouawad, Roger, primary, Compérat, Eva, primary, Rouprêt, Morgan, primary, Allanic, Frederick, primary, Parra, Jérôme, primary, Bitker, Marc-Olivier, primary, Thompson, Erika J., primary, Gowrishankar, Banumathy, primary, Houldsworth, Jane, primary, Weinstein, John N., primary, Tost, Jorg, primary, Broom, Bradley M., primary, Khayat, David, primary, Spano, Jean-Philippe, primary, Tannir, Nizar M., primary, and Malouf, Gabriel G., primary

Published
2023
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31. 61. Clinical whole exome/whole transcriptome analysis detects clinically relevant structural alterations in Multiple Myeloma

Author

Calvo, Maria Nieves, primary, Caruthers, Sean, additional, Tripodi, Joseph, additional, Houldsworth, Jane, additional, Fink, Marc, additional, Newman, Scott, additional, Chen, Rong, additional, Zhang, Wanying, additional, Liu, Liu, additional, Shi, Yong, additional, Jun, Tomi, additional, Onel, Ken, additional, Oh, William, additional, Edelmann, Lisa, additional, Schadt, Eric, additional, Rossi, Michael, additional, Hantash, Feras, additional, and Al-Kateb, Hussam, additional

Published
2022
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32. Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All "BRCAness" Is Created Equal.

Author

Doroshow, Deborah Blythe, Wei, Wei, Mehrotra, Meenakshi, Sia, Daniella, Eder, Joseph Paul, Bindra, Ranjit, Houldsworth, Jane, LoRusso, Patricia, and Walther, Zenta

Subjects
RESEARCH, GENETIC mutation, CHOLANGIOCARCINOMA, CANCER chemotherapy, BRCA genes, ACQUISITION of data, RETROSPECTIVE studies, PLATINUM, TREATMENT effectiveness, CANCER patients, COMPARATIVE studies, MEDICAL records, DESCRIPTIVE statistics, RESEARCH funding, DRUG allergy, HEPATOCELLULAR carcinoma, EVALUATION
Abstract

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context. [ABSTRACT FROM AUTHOR]

Published
2023
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34. P-078: Targeted sequencing in a diverse real-world cohort of multiple myeloma patients reveals pathogenic mutations of likely germline origin in BRCA2 and other DNA damage repair genes

Author

Thibaud, Santiago, primary, Brander, tehilla, additional, Balwani, Manisha, additional, Mouhieddine, Tarek, additional, Melnekoff, david, additional, Van Oekelen, Oliver, additional, Lagana, Alessandro, additional, Houldsworth, Jane, additional, Chari, Ajai, additional, Richter, Joshua, additional, Sanchez, Larysa, additional, Richard, Shambavi, additional, Rodriguez, Cesar, additional, Rossi, Adriana, additional, Cho, Hearn, additional, Jagannath, Sundar, additional, Onel, Kenan, additional, and Parekh, Samir, additional

Published
2022
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42. Anti-invasive efficacy and survival benefit of the YAP-TEAD inhibitor verteporfin in preclinical glioblastoma models

Author

Barrette, Anne Marie, primary, Ronk, Halle, additional, Joshi, Tanvi, additional, Mussa, Zarmeen, additional, Mehrotra, Meenakshi, additional, Bouras, Alexandros, additional, Nudelman, German, additional, Jesu Raj, Joe Gerald, additional, Bozec, Dominique, additional, Lam, William, additional, Houldsworth, Jane, additional, Yong, Raymund, additional, Zaslavsky, Elena, additional, Hadjipanayis, Constantinos G, additional, Birtwistle, Marc R, additional, and Tsankova, Nadejda M, additional

Published
2021
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47. Chromosomal copy number alterations in anal precancers from people with HIV

Author

Mutetwa, Tinaye, Karlić, Rosa, Houldsworth, Jane, Bowcock M., Anne, Gaisa M., Michael, Liu, Yuxin, Polak, Paz, and Sigel, Kieth

Subjects
Anal cancer, Copy number alteration, FISH, HPV, HIV
Abstract

Background: People living with HIV (PWH) are susceptible to high-risk human papillomavirus (HPV) infection of the anal canal owing to their immunocompromised status. The virus can transform anal squamous epithelia to low-grade squamous intraepithelial lesions (LSILs) and further to high-grade squamous intraepithelial lesions (HSILs). HSILs are well-defined cancer precursors that can progress to invasive cancer if left untreated. HPV-associated cancers commonly carry genomic abnormalities, specifically, a gain of chromosome 3q26 (PIK3CA), 20q13, 5p15 (TERT) and 7 centromere (cen7). We aimed to determine whether HPV-associated anal precancers carry similar genomic abnormalities and if so, to analyze their associations with histological severity and specific HPV types. Methods: Anal lesions from 63 unique patients (36 HSIL, 27 LSIL) were obtained via high-resolution anoscopy (HRA)-directed biopsy. Anal swabs were performed at the time of HRA to collect samples for cytological diagnosis and HPV DNA testing of HPV16, 18, and other (12) high-risk types. FISH-based HPV-associated Cancer Test (FHACT) was performed on the biopsy samples using four-color probes to detect any gain of chromosome 3q, 20q, 5p, and 7. The associations between genomic alterations, histological severity and HPV types were analyzed. Results: Our cohort had a median age of 50, was predominantly (70%) of Black and Hispanic race/ethnicity and 95% had suppressed HIV viral loads. Genomic abnormalities were detected in 47% of anal HSILs and 7% of LSILs (p=0.002). A gain of 3q, 20q, 5p, and cen7 was detected in 42%, 31%, 31%, and 19% of HSILs and 7%, 4%, 0%, and 0% of LSILs, respectively. Genomic abnormalities were more frequent in lesions associated with HPV16/18 infection, compared with those associated with non-16/18 types and negative HPV (42% vs. 24% vs. 9% ; p=0.06). 91% of lesions with 5p gain had gain in 20q. Cen7 gains were only detected in lesions with a gain of 20q13, suggesting a possible sequential order in development of chromosomal gains: 3q26 first, followed by 20q13 or 5p15, and then cen7. Conclusion: Anal precancers frequently demonstrate genomic abnormalities found in other HPV-associated cancers. The most common abnormality was the amplification of chromosome 3q, the location of PIK3CA gene. Our results suggest that PI3- kinase/AKT signaling pathway may play an important role in anal cancer development in PWH.

Published
2021

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