tbuckley/cabot-search huggingface dataset:
Machine learning to detect the SINEs of cancer
Authors: Christopher Douville, Kamel Lahouel, Albert Kuo, Haley Grant, Bracha Erlanger Avigdor, Samuel D. Curtis, Mahmoud Summers, Joshua D. Cohen, Yuxuan Wang, Austin Mattox, Jonathan Dudley, Lisa Dobbyn, Maria Popoli, Janine Ptak, Nadine Nehme, Natalie Silliman, Cherie Blair, Katharine Romans, Christopher Thoburn, Jennifer Gizzi, Robert E. Schoen, Jeanne Tie, Peter Gibbs, Lan T. Ho-Pham, Bich N. H. Tran, Thach S. Tran, Tuan V. Nguyen, Michael Goggins, Christopher L. Wolfgang, Tian-Li Wang, Ie-Ming Shih, Anne Marie Lennon, Ralph H. Hruban, Chetan Bettegowda, Kenneth W. Kinzler, Nickolas Papadopoulos, Bert Vogelstein, Cristian Tomasetti
Journal: Science Translational Medicine (2024)

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature—the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.
Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health
Authors: Seyedeh Maryam Zekavat, Saman Doroodgar Jorshery, Franziska G. Rauscher, Katrin Horn, Sayuri Sekimitsu, Satoshi Koyama, Trang T. Nguyen, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Andreas Kühnapfel, Yusrah Shweikh, Yixuan Ye, Vineet Raghu, Hongyu Zhao, Marzyeh Ghassemi, Tobias Elze, Ayellet V. Segrè, Janey L. Wiggs, Lucian Del Priore, Markus Scholz, Jay C. Wang, Pradeep Natarajan, Nazlee Zebardast
Journal: Science Translational Medicine (2024)

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study ( N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.
SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency
Authors: Yijia Li, Manish C. Choudhary, James Regan, Julie Boucau, Anusha Nathan, Tessa Speidel, May Yee Liew, Gregory E. Edelstein, Yumeko Kawano, Rockib Uddin, Rinki Deo, Caitlin Marino, Matthew A. Getz, Zahra Reynolds, Mamadou Barry, Rebecca F. Gilbert, Dessie Tien, Shruti Sagar, Tammy D. Vyas, James P. Flynn, Sarah P. Hammond, Lewis A. Novack, Bina Choi, Manuela Cernadas, Zachary S. Wallace, Jeffrey A. Sparks, Jatin M. Vyas, Michael S. Seaman, Gaurav D. Gaiha, Mark J. Siedner, Amy K. Barczak, Jacob E. Lemieux, Jonathan Z. Li
Journal: Science Translational Medicine (2024)

Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median times to nasal viral RNA and culture clearance in individuals with severe immunosuppression due to hematologic malignancy or transplant (S-HT) were 72 and 40 days, respectively, both of which were significantly longer than clearance rates in individuals with severe immunosuppression due to autoimmunity or B cell deficiency (S-A), individuals with nonsevere immunodeficiency, and nonimmunocompromised groups ( P &lt; 0.01). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing resistance against therapeutic monoclonal antibodies. Both S-HT and S-A participants had diminished SARS-CoV-2–specific humoral responses, whereas only the S-HT group had reduced T cell–mediated responses. This highlights the varied risk of persistent COVID-19 across distinct immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.
The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers
Authors: Aurélien Voissière, Carlos Gomez-Roca, Sylvie Chabaud, Céline Rodriguez, Axelle Nkodia, Justine Berthet, Laure Montane, Anne-Sophie Bidaux, Isabelle Treilleux, Lauriane Eberst, Catherine Terret, Iphigénie Korakis, Gwenaelle Garin, David Pérol, Jean-Pierre Delord, Christophe Caux, Bertrand Dubois, Christine Ménétrier-Caux, Nathalie Bendriss-Vermare, Philippe A. Cassier
Journal: Science Translational Medicine (2024)

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R–directed tyrosine kinase inhibitor (TKI), and durvalumab (anti–PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1–dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14 low CD16 high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L– but not GM-CSF–dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.
Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology
Authors: Su’an Tang, Lutian Yao, Jianzhao Ruan, Jingliang Kang, Yumei Cao, Xiaoyu Nie, Weiren Lan, Zhaohua Zhu, Weiyu Han, Yongguang Liu, Jing Tian, Patrick Seale, Ling Qin, Changhai Ding
Journal: Science Translational Medicine (2024)

The infrapatellar fat pad (IPFP) and synovium play essential roles in maintaining knee joint homeostasis and in the progression of osteoarthritis (OA). The cellular and transcriptional mechanisms regulating the function of these specialized tissues under healthy and diseased conditions are largely unknown. Here, single-cell and single-nuclei RNA sequencing of human IPFP and synovial tissues were performed to elucidate the cellular composition and transcriptional profile. Computational trajectory analysis revealed that dipeptidyl peptidase 4 + mesenchymal cells function as a common progenitor for IPFP adipocytes and synovial lining layer fibroblasts, suggesting that IPFP and synovium represent an integrated tissue unit. OA induced a profibrotic and inflammatory phenotype in mesenchymal lineage cells with biglycan + intermediate fibroblasts as a major contributor to OA fibrosis. Apolipoprotein E (APOE) signaling from intermediate fibroblasts and macrophages was identified as a critical regulatory factor. Ex vivo incubation of human cartilage with soluble APOE accelerated proteoglycan degeneration. Inhibition of APOE signaling by intra-articular injection of an anti-APOE neutralizing antibody attenuated the progression of collagenase-induced OA in mice, demonstrating a detrimental effect of APOE on cartilage. Our studies provide a framework for designing further therapeutic strategies for OA by describing the cellular and transcriptional landscape of human IPFP and synovium in healthy versus OA joints.
The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia
Authors: Yongwei Su, Jenna L. Carter, Xinyu Li, Yu Fukuda, Ashley Gray, John Lynch, Holly Edwards, Jun Ma, Patrick Schreiner, Lisa Polin, Juiwanna Kushner, Sijana H. Dzinic, Steven A. Buck, Shondra M. Pruett-Miller, Katie Hege-Hurrish, Camenzind Robinson, Xinan Qiao, Shuang Liu, Shuangshuang Wu, Guan Wang, Jing Li, Joshua E. Allen, Varun V. Prabhu, Aaron D. Schimmer, Dhananjay Joshi, Shiva Kalhor-Monfared, Iain D. G. Watson, Richard Marcellus, Methvin B. Isaac, Rima Al-awar, Jeffrey W. Taub, Hai Lin, John D. Schuetz, Yubin Ge
Journal: Cancer Research (2024)

Abstract Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity. Deletion of OGDH, which encodes αKGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for αKGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced the translation of MCL1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitive to ONC213 in vivo. Collectively, these findings support further development of ONC213 for treating AML. Significance: In AML cells, ONC213 suppresses αKGDH, which induces a unique mitochondrial stress response, and reduces MCL1 to decrease oxidative phosphorylation and elicit potent antileukemia activity. See related commentary by Boët and Sarry, p. 950
Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment
Authors: Apoorvi Chaudhri, Gregory Lizee, Patrick Hwu, Kunal Rai
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification of alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators of tumor-intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations with immune checkpoint inhibitors. Some success has been observed in early clinical studies that combined immunotherapy with agents targeting DNA methylation and histone modification; however, less is known about chromatin remodeler-targeted therapies. Here, we provide a discussion on the regulation of tumor immunogenicity by the chromatin remodeling SWI/SNF complex through multiple mechanisms associated with immunotherapy response that broadly include IFN signaling, DNA damage, mismatch repair, regulation of oncogenic programs, and polycomb-repressive complex antagonism. Context-dependent targeting of SWI/SNF subunits can elicit opportunities for synthetic lethality and reduce T-cell exhaustion. In summary, alongside the significance of SWI/SNF subunits in predicting immunotherapy outcomes, their ability to modulate the tumor immune landscape offers opportunities for therapeutic intervention.
Deep Learning in Breast Cancer Imaging: A Decade of Progress and Future Directions
Authors: Luyang Luo, Xi Wang, Yi Lin, Xiaoqi Ma, Andong Tan, Ronald Chan, Varut Vardhanabhuti, Winnie CW Chu, Kwang-Ting Cheng, Hao Chen
Journal: IEEE Reviews in Biomedical Engineering (2024)

Breast cancer has reached the highest incidence rate worldwide among all malignancies since 2020. Breast imaging plays a significant role in early diagnosis and intervention to improve the outcome of breast cancer patients. In the past decade, deep learning has shown remarkable progress in breast cancer imaging analysis, holding great promise in interpreting the rich information and complex context of breast imaging modalities. Considering the rapid improvement in deep learning technology and the increasing severity of breast cancer, it is critical to summarize past progress and identify future challenges to be addressed. This paper provides an extensive review of deep learning-based breast cancer imaging research, covering studies on mammograms, ultrasound, magnetic resonance imaging, and digital pathology images over the past decade. The major deep learning methods and applications on imaging-based screening, diagnosis, treatment response prediction, and prognosis are elaborated and discussed. Drawn from the findings of this survey, we present a comprehensive discussion of the challenges and potential avenues for future research in deep learning-based breast cancer imaging.
Incidence, Outcomes, and Opportunity for Left Ventricular Assist Device Weaning for Myocardial Recovery
Authors: Shinobu Itagaki, Noah Moss, Nana Toyoda, Donna Mancini, Natalia Egorova, Gregory Serrao, Anuradha Lala, Sean P. Pinney, Percy Boateng, David H. Adams, Anelechi C. Anyanwu
Journal: JACC Heart Failure (2024)
Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers
Authors: Jianfei Qian, Qiang Wang, Liuling Xiao, Wei Xiong, Miao Xian, Pan Su, Maojie Yang, Chuanchao Zhang, Yabo Li, Ling Zhong, Siddhartha Ganguly, Youli Zu, Qing Yi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development of mAbs with improved cytotoxicity, targeting new and known tumor-associated antigens, therefore continues to be an active research area. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo. The specificity and antibody-binding capacity of DKK1-A2 mAbs were determined using indirect ELISA, confocal imaging, QIFIKIT antibody-binding capacity and cell surface binding assays. The affinity of mAbs was determined using a surface plasmon resonance biosensor. A flow cytometry-based cell death was performed to detect tumor cell apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays were used to evaluate the ability of DKK1-A2 mAbs to mediate ADCC and CDC activities against tumor cells in vitro. Flow cytometry data were collected with an FACSymphony A3 cell analyzer and analyzed with FlowJo V.10.1 software. Human cancer xenograft mouse models were used to determine the in vivo therapeutic efficacy and the potential safety and toxicity of DKK1-A2 mAbs. In situ TUNEL assay was performed to detect apoptosis in tumors and mouse organs. We generated novel DKK1-A2 mAbs that recognize the DKK1 P20 peptide presented by human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+ cancer cells. These mAbs directly induced apoptosis in HLA-A2+DKK1+ hematologic and solid cancer cells by activating the caspase-9 cascade, effectively lysed the cancer cells in vitro by mediating CDC and ADCC and were therapeutic against established cancers in their xenograft mouse models. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs neither bound to or killed HLA-A2+ blood cells in vitro nor caused tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice. Our study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers.
Increasing Utilization of Extended Criteria Donor Hearts for Transplantation
Authors: Jacob N. Schroder, Chetan B. Patel, Adam D. DeVore, Sarah Casalinova, Kevin J. Koomalsingh, Ashish S. Shah, Anelechi C. Anyanwu, David A. D’Alessandro, Karol Mudy, Benjamin Sun, Martin Strueber, Asghar Khaghani, Yasuhiro Shudo, Fardad Esmailian, Kenneth Liao, Francis D. Pagani, Scott Silvestry, I-wen Wang, Christopher T. Salerno, Tarek S. Absi, Joren C. Madsen, Donna Mancini, Amy G. Fiedler, Carmelo A. Milano, Jason W. Smith
Journal: JACC Heart Failure (2024)
Acute Response of the Noninfarcted Myocardium and Surrounding Tissue Assessed by T2 Mapping After STEMI
Authors: Luca Bergamaschi, Antonio Landi, Niccolò Maurizi, Carmine Pizzi, Laura Anna Leo, Dimitri Arangalage, Juan F. Iglesias, Eric Eeckhout, Juerg Schwitter, Marco Valgimigli, Anna Giulia Pavon
Journal: JACC. Cardiovascular imaging (2024)
Effect of Donor Age and Liver Steatosis on Potential of Decellularized Liver Matrices to be used as a Platform for iPSC‐Hepatocyte Culture
Authors: Aylin Acun, Letao Fan, Ruben Oganesyan, Korkut M. Uygun, Heidi Yeh, Martin L. Yarmush, Basak E. Uygun
Journal: Advanced Healthcare Materials (2024)

Decellularization of discarded whole livers and their recellularization with patient-specific induced pluripotent stem cells (iPSCs) to develop a functional organ is a promising approach to increasing the donor pool. The effect of extracellular matrix (ECM) of marginal livers on iPSC-hepatocyte differentiation and function has not been shown. To test the effect of donor liver ECM age and steatosis, young and old, as well as no, low, and high steatosis livers, are decellularized. All livers are decellularized successfully. High steatosis livers have fat remaining on the ECM after decellularization. Old donor liver ECM induces lower marker expression in early differentiation stages, compared to young liver ECM, while this difference is closed at later stages and do not affect iPSC-hepatocyte function significantly. High steatosis levels of liver ECM lead to higher albumin mRNA expression and secretion while at later stages of differentiation expression of major cytochrome (CYP) 450 enzymes is highest in low steatosis liver ECM. Both primary human hepatocytes and iPSC-hepatocytes show an increase in fat metabolism marker expression with increasing steatosis levels most likely induced by excess fat remaining on the ECM. Overall, removal of excess fat from liver ECM may be needed for inducing proper hepatic function after recellularization.
Effective Treatments for Opioid Use Disorder — Finding Recovery and Staying Safe
Authors: Sarah Bagley, Dylan Glover, Jennifer Foreman, Scott Hadland, L J Punch, Darren Taichman
Journal: New England Journal of Medicine (2024)

Substance use disorders don't discriminate.They affect the rich and the poor, all socioeconomic groups and ethnic groups.They affect people in urban areas and rural ones.Far more people than we realize are affected.It's important for us to bring people out from the shadows, and get them the help that they need."
Longitudinal trends in causes of death among adults with HIV on antiretroviral therapy in Europe and North America from 1996 to 2020: a collaboration of cohort studies
Authors: Adam Trickey, Kathleen McGinnis, M John Gill, Sophie Abgrall, Juan Berenguer, Christoph Wyen, Mojgan Hessamfar, Peter Reiss, Katharina Kusejko, Michael J Silverberg, Arkaitz Imaz, Ramon Teira, Antonella d'Arminio Monforte, Robert Zangerle, Jodie L Guest, Vasileios Papastamopoulos, Heidi Crane, Timothy R Sterling, Sophie Grabar, Suzanne M Ingle, Jonathan A C Sterne
Journal: The Lancet HIV (2024)

Mortality rates among people with HIV have fallen since 1996 following the widespread availability of effective antiretroviral therapy (ART). Patterns of cause-specific mortality are evolving as the population with HIV ages. We aimed to investigate longitudinal trends in cause-specific mortality among people with HIV starting ART in Europe and North America.
Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study
Authors: Ralf Reilmann, Karen E Anderson, Andrew Feigin, Sarah J Tabrizi, Blair R Leavitt, Julie C Stout, Paola Piccini, Robin Schubert, Pippa Loupe, Anna Wickenberg, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Thomas Li, Juha-Matti Savola, Michael Hayden, Mark Forrest Gordon, Mark Guttman, Lynn Raymond, Tilak Mendis, Oksana Suchowersky, Jody Corey-Bloom, Michael D Geschwind, Frederick J Marshall, Karen S Marder, Martha Nance, Brad Racette, Jee Bang, Victoria Segro, Katherine McDonell, John Kamholz, Mark S LeDoux, Juan Sanchez-Ramos, Giuseppe DeMichele, Caterina Mariotti, Ferdinando Squitieri, Paola Soliveri, Pietro Cortelli, José Esteban Muñoz García, Jaime Kulisevsky Bojarski, José Luis López-Sendón Moreno, Koldo Berganzo Corrales, Esther Cubo, José Manuel García Moreno, Michael Orth, Josef Priller, Carsten Saft, Adolf Weindl, Juergen Winkler, David Craufurd, Zofia Miedzybrodzka, Hugh Rickards, Rhys Richard Davies, Nayana Lahiri, Deborah Ruddy, Suresh K Komati, Oliver William John Quarrell, Leonor Correira Guedes, Raymund A C Roos, Zuleykha Zalyalova, Sergey Illarioshkin, Aleksandr Gustov, Jiri Klempir
Journal: The Lancet Neurology (2024)