Machine learning to detect the SINEs of cancer
Science Translational Medicine
Published On 2024/1/24
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 …
Journal
Science Translational Medicine
Published On
2024/1/24
Volume
16
Issue
731
Page
eadi3883
Authors
Bert Vogelstein
Johns Hopkins University
Position
H-Index(all)
289
H-Index(since 2020)
144
I-10 Index(all)
0
I-10 Index(since 2020)
0
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0
Citation(since 2020)
0
Cited By
0
Research Interests
Cancer
Biology
University Profile Page
Kenneth Kinzler
Johns Hopkins University
Position
H-Index(all)
248
H-Index(since 2020)
136
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0
I-10 Index(since 2020)
0
Citation(all)
0
Citation(since 2020)
0
Cited By
0
Research Interests
Cancer
Genetics
Genomics
University Profile Page
Ralph Hruban
Johns Hopkins University
Position
H-Index(all)
228
H-Index(since 2020)
116
I-10 Index(all)
0
I-10 Index(since 2020)
0
Citation(all)
0
Citation(since 2020)
0
Cited By
0
Research Interests
Pancreatic cancer
pancreas cancer
pathology
University Profile Page
Michael Goggins
Johns Hopkins University
Position
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143
H-Index(since 2020)
81
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0
I-10 Index(since 2020)
0
Citation(all)
0
Citation(since 2020)
0
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0
Research Interests
Pancreatic cancer
University Profile Page
Ie-Ming Shih
Johns Hopkins University
Position
Department of Gynecology and Obstetrics
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119
H-Index(since 2020)
68
I-10 Index(all)
0
I-10 Index(since 2020)
0
Citation(all)
0
Citation(since 2020)
0
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0
Research Interests
Gynecologic pathology
surgical pathology
gynecology
ovarian cancer
anatomic pathology
University Profile Page
Tian-Li Wang
Johns Hopkins University
Position
Professor of Pathology Oncology and Gynecology/Obstetrics
H-Index(all)
92
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54
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0
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0
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0
Citation(since 2020)
0
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0
Research Interests
Cancer genomics
Epigenomics
Notch signaling
Chemoresistance
University Profile Page
Chetan Bettegowda
Johns Hopkins University
Position
Jennison and Novak Families Professor Department of Neurosurgery
H-Index(all)
59
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50
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0
I-10 Index(since 2020)
0
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0
Citation(since 2020)
0
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0
Research Interests
Cancer genetics
Neurosurgery
Neuro-oncology
University Profile Page
Anne Marie Lennon
Johns Hopkins University
Position
H-Index(all)
57
H-Index(since 2020)
46
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0
I-10 Index(since 2020)
0
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0
Citation(since 2020)
0
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0
Research Interests
pancreatic cancer
endoscopy
EUS
pancreatic cysts
University Profile Page
Cristian Tomasetti
Johns Hopkins University
Position
H-Index(all)
33
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31
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0
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0
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0
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0
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0
Research Interests
Cancer Etiology
Cancer Evolution
Early Cancer Detection
Cancer Risk Prediction
University Profile Page
Other Articles from authors
Christopher Douville
Johns Hopkins University
Methods of detecting high risk barrett's esophagus with dysplasia, and esophageal adenocarcinoma
AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O ([C@ H] 1C [C@@](O)(CC= 2C (O)= C3C (= O) C= 4C= CC= C (C= 4C (= O) C3= C (O) C= 21) OC) C (= O) CO)[C@ H] 1C [C@ H](N)[C@@ H](O)[C@ H](C) O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1= C (F) C (NC (= O) OCCCCC)= NC (= O) N1 [C@ H] 1 [C@ H](O)[C@ H](O)[C@@ H](C) O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 6
2024/2/29
Article DetailsChetan Bettegowda
Johns Hopkins University
Nature
TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers
Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1, 2, 3, 4, 5, 6, 7, 8, 9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10, 11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells 13, 14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T …
2024/4
Article DetailsChetan Bettegowda
Johns Hopkins University
World neurosurgery
Impact of Antithrombotic Medications and Reversal Strategies on the Surgical Management and Outcomes of Traumatic Acute Subdural Hematoma
ObjectiveCareful hematologic management is required in surgical patients with traumatic acute subdural hematoma (aSDH) taking antithrombotic medications. We sought to compare outcomes between patients with aSDH taking antithrombotic medications at admission who received antithrombotic reversal with patients with aSDH not taking antithrombotics.MethodsRetrospective review identified patients with traumatic aSDH requiring surgical evacuation. The cohort was divided based on antithrombotic use and whether pharmacologic reversal agents or platelet transfusions were administered. A 3-way comparison of outcomes was performed between patients taking anticoagulants who received pharmacologic reversal, patients taking antiplatelets who received platelet transfusion, and patients not taking antithrombotics. Multivariable regressions, adjusted for injury severity, further investigated associations with …
2024/2/1
Article DetailsIe-Ming Shih
Johns Hopkins University
Clinical Cancer Research
Aneuploidy landscape in precursors of ovarian cancer
Purpose Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. Experimental Design We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We …
2024/2/1
Article DetailsChetan Bettegowda
Johns Hopkins University
Journal of Neuro-Oncology
Exploring the impact of primary care utilization and health information exchange upon treatment patterns and clinical outcomes of glioblastoma patients
PurposeThere is limited literature describing care coordination for patients with glioblastoma (GBM). We aimed to investigate the impact of primary care and electronic health information exchange (HIE) between neurosurgeons, oncologists, and primary care providers (PCP) on GBM treatment patterns, postoperative outcomes, and survival.MethodsWe identified adult GBM patients undergoing primary resection at our institution (2007–2020). HIE was defined as shared electronic medical information between PCPs, oncologists, and neurosurgeons. Multivariate logistic regression analyses were used to determine the effect of PCPs and HIE upon initiation and completion of adjuvant therapy. Kaplan-Meier and multivariate Cox regression models were used to evaluate overall survival (OS).ResultsAmong 374 patients (mean age±SD: 57.7±13.5, 39.0% female), 81.0% had a PCP and 62.4% had electronic HIE. In …
2024/4/25
Article DetailsMichael Goggins
Johns Hopkins University
The role of biomarkers in the early detection of pancreatic cancer
Pancreatic surveillance can detect early-stage pancreatic cancer and achieve long-term survival, but currently involves annual endoscopic ultrasound and MRI/MRCP, and is recommended only for individuals who meet familial/genetic risk criteria. To improve upon current approaches to pancreatic cancer early detection and to expand access, more accurate, inexpensive, and safe biomarkers are needed, but finding them has remained elusive. Newer approaches to early detection, such as using gene tests to personalize biomarker interpretation, and the increasing application of artificial intelligence approaches to integrate complex biomarker data, offer promise that clinically useful biomarkers for early pancreatic cancer detection are on the horizon.
2024/4/25
Article DetailsIe-Ming Shih
Johns Hopkins University
npj Women's Health
Deep learning detects premalignant lesions in the Fallopian tube
Tubo-ovarian high-grade serous carcinoma is believed to originate in the fallopian tubes, arising from precursor lesions like serous tubal intraepithelial carcinoma (STIC) and serous tubal intraepithelial lesion (STIL). Adequate diagnosis of these precursors is important, but can be challenging for pathologists. Here we present a deep-learning algorithm that could assist pathologists in detecting STIC/STIL. A dataset of STIC/STIL (n = 323) and controls (n = 359) was collected and split into three groups; training (n = 169), internal test set (n = 327), and external test set (n = 186). A reference standard was set for the training and internal test sets, by a panel review amongst 15 gynecologic pathologists. The training set was used to train and validate a deep-learning algorithm (U-Net with resnet50 backbone) to differentiate STIC/STIL from benign tubal epithelium. The model’s performance was evaluated on the …
2024/4/29
Article DetailsCristian Tomasetti
Johns Hopkins University
Signal
A method for classifying data using non-negative matrix factorization can include receiving a population of sample data, generating a first matrix of the amplicon counts per sample data, dividing the first matrix into a product of a second matrix and a third matrix, in the second matrix, determining whether each signature is a long or short fragment per each amplicon count, in the third matrix, determining intensities of each signature per the sample data, and classifying the sample data based on the intensities of each signature. The population can include amplicon counts per sample data. The second matrix can include signatures of short and long DNA fragments and the third matrix can include intensities of each signature of the short and long DNA fragments.
2024/2/8
Article DetailsKenneth Kinzler
Johns Hopkins University
Nature
TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers
Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1, 2, 3, 4, 5, 6, 7, 8, 9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10, 11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells 13, 14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T …
2024/4
Article DetailsBert Vogelstein
Johns Hopkins University
Circulating mutant dna to assess tumor dynamics
DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. We apply a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in body samples of patients. Measurements of ctDNA can be used to reliably monitor tumor dynamics in subjects with cancer, especially those who are undergoing surgery or chemotherapy. This personalized genetic approach can be generally applied.
2024/1/4
Article DetailsRalph Hruban
Johns Hopkins University
Advanced Materials Technologies
High‐Resolution 3D Printing of Pancreatic Ductal Microanatomy Enabled by Serial Histology
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that can develop from pancreatic intraepithelial neoplasia (PanIN), a microscopic lesion in the pancreatic ductal system. PanIN and PDAC are conventionally studied in 2D via histological tissue sections. As such, their true structure is poorly understood due to the inability to image them in 3D. CODA, a recently developed technique for reconstruction of tissues at cellular resolution, is used to study the 3D morphology of the pancreas. Here, CODA is extended through 3D printing of normal pancreatic ducts, PanIN, and PDAC at cm‐scale and µm resolution. A methodology is presented to create 3D printable files from anatomical maps generated from serial histological images and to show detailed validation of the accuracy of this method. Existing 3D printing workflows utilizing medical images derived from computerized tomography (CT), X‐ray, and …
2024/1/20
Article DetailsChetan Bettegowda
Johns Hopkins University
World neurosurgery
The Ribbon Sign as a Radiological Indicator of Intramedullary Spinal Cord Subependymomas
ObjectiveIntramedullary spinal cord (IMSC) subependymomas are rare World Health Organization grade 1 ependymal tumors. The potential presence of functional neural tissue within the tumor and poorly demarcated planes presents a risk to resection. Anticipating a subependymoma on preoperative imaging can inform surgical decision-making and improve patient counseling. Here, we present our experience recognizing IMSC subependymomas on preoperative magnetic resonance imaging (MRI) based on a distinctive characteristic termed the “ribbon sign.”MethodsWe retrospectively reviewed preoperative MRIs of patients presenting with IMSC tumors at a large tertiary academic institution between April 2005 and January 2022. The diagnosis was confirmed histologically. The “ribbon sign” was defined as a ribbon-like structure of T2 isointense spinal cord tissue interwoven between regions of T2 hyperintense …
2023/7/1
Article DetailsTian-Li Wang
Johns Hopkins University
Angewandte Chemie
Novel Stereo‐Induction Pattern in Pudovik Addition/Phospha‐Brook Rearrangement towards Chiral Trisubstituted Allenes
Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities, facilitated by peptide‐mimic phosphonium salt (PPS) catalysis. Additionally, a comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha‐Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central‐to‐axial chirality transfer in a cascade …
2024/3/23
Article DetailsAnne Marie Lennon
Johns Hopkins University
Pancreatology
Impact of preoperative endoscopic procedures on adverse event rates after surgical resection for main-duct and mixed-type intraductal papillary mucinous neoplasms (IPMNs)
BackgroundMain-duct (MD-) and mixed-type (MT-) IPMNs harbor an increased risk of pancreatic cancer and warrant surgical resection. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are important in the diagnosis of IPMNs. The aim of this study was to investigate whether endoscopic procedures manipulating the MD impact postoperative adverse events in patients with MD- and MT-IPMNs.MethodsWe performed a retrospective study of 369 patients who underwent resections for MD- or MT-IPMN at two tertiary centers (2000–2019). Multivariable logistic regression analyses were performed for postoperative adverse events to compare the risks between intervention (ERCP, EUS-FNA with branch duct (BD) aspirated, EUS-FNA with MD aspirated from the duct directly or cyst/mass arising from MD) versus no-intervention …
2024/2/1
Article DetailsRalph Hruban
Johns Hopkins University
Precursor lesions in familial and hereditary pancreatic cancer
Infiltrating ductal adenocarcinoma of the pancreas, referred to here as “pancreatic cancer,” is one of the deadliest of all of the solid malignancies. The five-year survival rate in the United States for individuals diagnosed today with pancreatic cancer is a dismal 12%. Many invasive cancers, including pancreatic cancer, however, arise from histologically and genetically well-characterized precursor lesions, and these precancers are curable. Precursor lesions therefore are an attractive target for early detection and treatment. This is particularly true for individuals with an increased risk of developing invasive cancer, such as individuals with a strong family history of pancreatic cancer, and individuals with a germline variant known to increase the risk of developing pancreatic cancer. There is therefore a need to understand the precursor lesions that can give rise to invasive pancreatic cancer in these individuals.
2024/2/6
Article DetailsBert Vogelstein
Johns Hopkins University
Methods of detecting high risk barrett's esophagus with dysplasia, and esophageal adenocarcinoma
AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O ([C@ H] 1C [C@@](O)(CC= 2C (O)= C3C (= O) C= 4C= CC= C (C= 4C (= O) C3= C (O) C= 21) OC) C (= O) CO)[C@ H] 1C [C@ H](N)[C@@ H](O)[C@ H](C) O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1= C (F) C (NC (= O) OCCCCC)= NC (= O) N1 [C@ H] 1 [C@ H](O)[C@ H](O)[C@@ H](C) O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 6
2024/2/29
Article DetailsMichael Goggins
Johns Hopkins University
Annals of surgical oncology
ASO Author Reflections: Using a CA19-9 Tumor Marker Gene Test to Assess Outcome after Pancreatic Cancer Surgery
Traditionally, carbohydrate antigen 19-9 (CA19-9) levels have been the most widely used marker for assessing tumor burden and therapy response in pancreatic ductal adenocarcinoma (PDAC). However, the interpretability of CA19-9 is complicated by significant differences in an individual’s capacity to synthesize CA19-9, influenced by common variants in the FUT2 and FUT3 genes. 1 Individuals can be classified into four functional FUT groups, each with distinct CA19-9 normal reference ranges that provide a more personalized approach to evaluating CA19-9 levels in patients undergoing pancreatic surveillance. 2 These four groups are:(i) FUT3-null individuals (homozygous or compound heterozygous for non-functional FUT3 alleles) who comprise~ 10% of the population;(ii) FUT-low individuals (one FUT3 null allele and at least one functional FUT2 allele, ie, FUT2 intact) who comprise~ 1/3 of the population;(iii …
2024/1/27
Article DetailsOther articles from Science Translational Medicine journal
Stefanie Menzies
Washington University in St. Louis
Science Translational Medicine
Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins
Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes. Our antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge. Structural analysis of the antibody-toxin complex revealed a binding mode that mimics the receptor-toxin interaction. The overall workflow presented is generalizable for the development of antibodies that target conserved epitopes among antigenically diverse targets, and it offers a …
2024/2/21
Article DetailsJohn Asara
Harvard University
Science translational medicine
Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice
Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury–induced CNV or mice with a deficiency in the very low–density lipoprotein receptor), we found that deletion of Adora2a either globally or specifically in endothelial cells reduced subretinal fibrosis independently of angiogenesis. We showed that Adora2a …
2024/3/6
Article DetailsANDREA MAYADO
Universidad de Salamanca
Science Translational Medicine
Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo
Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting …
2024/2/14
Article DetailsEllen Gravallese
Harvard University
Science Translational Medicine
Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis
It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion …
2024/4/10
Article DetailsZachary S. Wallace
Harvard University
Science Translational Medicine
SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency
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 < 0.01). Participants who were severely …
2024/1/24
Article DetailsEzra Cohen
University of California, San Diego
Science Translational Medicine
A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer
The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)–agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample …
2024/2/28
Article DetailsGaurav D Gaiha
Harvard University
Science Translational Medicine
SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency
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 < 0.01). Participants who were severely …
2024/1/24
Article DetailsSridevi Sarma
Johns Hopkins University
Science Translational Medicine
Nociceptor spontaneous activity is responsible for fragmenting non–rapid eye movement sleep in mouse models of neuropathic pain
Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund’s complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non–rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient …
2024/4/17
Article DetailsKevin Pethe
Nanyang Technological University
Science Translational Medicine
An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects. We report here a potent anti-Mab compound from the flexible molecular framework afforded by conjugated oligoelectrolytes (COEs). A screen of structurally diverse, noncytotoxic COEs identified a lead compound, COE-PNH2, which was bactericidal against replicating, nonreplicating persisters and intracellular Mab.COE-PNH2 had low propensity for resistance development, with a frequency of resistance below 1.25 × 10−9 and showed no detectable resistance upon serial passaging. Mechanism of action studies …
2024/2/21
Article DetailsDimitris Mathios
Johns Hopkins University
Science translational medicine
Genome-wide repeat landscapes in cancer and cell-free DNA
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver …
2024/3/13
Article DetailsRobert Zeiser
Albert-Ludwigs-Universität Freiburg
Science Translational Medicine
Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease
Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2 …
2024/2/21
Article DetailsSavita Rangarajan
University of Southampton
Science Translational Medicine
The translational gap for gene therapies in low-and middle-income countries
Gene therapy is at the forefront of modern medicine. Operating at the genomic level, these sophisticated technologies are designed to address the root cause of disease. This class of medicines is made possible by advances in genetic engineering and cellular delivery technologies. As scientific understanding behind disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies will hopefully become safe and effective treatment options for a wide range of genetic and non-genetic diseases. However, as the medicinal scope of gene therapies expands, consideration must be given to who will benefit and what proactive steps must be taken to widen development and access potential, particularly in areas carrying high burden diseases likely to benefit from their introduction.
2024/4/19
Article DetailsZahra Reynolds
Harvard University
Science Translational Medicine
SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency
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 < 0.01). Participants who were severely …
2024/1/24
Article DetailsOscar G. Wilkins
University College London
Science Translational Medicine
Mis-spliced transcripts generate de novo proteins in TDP-43–related ALS/FTD
Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons …
2024/1/26
Article DetailsJonathan C. Dudley
Johns Hopkins University
Science Translational Medicine
Machine learning to detect the SINEs of cancer
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 …
2024/1/24
Article DetailsAlessandro Aiuti
Università Vita-Salute San Raffaele
Science Translational Medicine
Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome
Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell–gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures …
2024/5/1
Article DetailsPeng Xia
Harvard University
Science Translational Medicine
Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human
Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was …
2024/4/17
Article DetailsSupriya Prakash
Harvard University
Science Translational Medicine
Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs
The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]–loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a …
2024/1/3
Article DetailsKenneth Kinzler
Johns Hopkins University
Science Translational Medicine
Machine learning to detect the SINEs of cancer
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 …
2024/1/24
Article DetailsRebekah Mannix
Harvard University
Science Translational Medicine
Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs
The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]–loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a …
2024/1/3
Article Details