122 results on '"Kedmi M"'
Search Results
2. Multi-resolution deconvolution of spatial transcriptomics data reveals continuous patterns of inflammation
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Michael I. Jordan, Baoguo Li, Nir Yosef, Hadas Keren-Shaul, Kedmi M, Addad Y, Romain Lopez, Ido Amit, Pierre Boyeau, Eyal David, Allon Wagner, Adam Jelinski, and David Pilzer
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Crosstalk (biology) ,Cell type ,Probabilistic method ,Computer science ,Deconvolution ,Function (mathematics) ,Biological system ,Pipeline (software) ,Spatial organization ,Codebase - Abstract
The function of mammalian cells is largely influenced by their tissue microenvironment. Advances in spatial transcriptomics open the way for studying these important determinants of cellular function by enabling a transcriptome-wide evaluation of gene expression in situ. A critical limitation of the current technologies, however, is that their resolution is limited to niches (spots) of sizes well beyond that of a single cell, thus providing measurements for cell aggregates which may mask critical interactions between neighboring cells of different types. While joint analysis with single-cell RNA-sequencing (scRNA-seq) can be leveraged to alleviate this problem, current analyses are limited to a discrete view of cell type proportion inside every spot. This limitation becomes critical in the common case where, even within a cell type, there is a continuum of cell states that cannot be clearly demarcated but reflects important differences in the way cells function and interact with their surroundings. To address this, we developed Deconvolution of Spatial Transcriptomics profiles using Variational Inference (DestVI), a probabilistic method for multi-resolution analysis for spatial transcriptomics that explicitly models continuous variation within cell types. Using simulations, we demonstrate that DestVI is capable of providing higher resolution compared to the existing methods and that it can estimate gene expression by every cell type inside every spot. We then introduce an automated pipeline that uses DestVI for analysis of single tissue slices and comparison between tissues. We apply this pipeline to study the immune crosstalk within lymph nodes to infection and explore the spatial organization of a mouse tumor model. In both cases, we demonstrate that DestVI can provide a high resolution and accurate spatial characterization of the cellular organization of these tissues, and that it is capable of identifying important cell-type-specific changes in gene expression - between different tissue regions or between conditions. DestVI is available as an open-source software package in the scvi-tools codebase (https://scvi-tools.org).
- Published
- 2021
3. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease
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Gan-Or, Z., Bar-Shira, A., Mirelman, A., Gurevich, T., Kedmi, M., Giladi, N., and Orr-Urtreger, A.
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- 2010
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4. Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients
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Rund, D, Krichevsky, S, Bar-Cohen, S, Goldschmidt, N, Kedmi, M, Malik, E, Gural, A, Shafran-Tikva, S, Ben-Neriah, S, and Ben-Yehuda, D
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- 2005
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5. Bluetongue-associated clinical signs in Israel
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Klement, E. and Kedmi, M.
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- 2011
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6. What to do when the first allogeneic stem cell transplantation fails?
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Kedmi, M., Resnick, I. B., Gesundeheidt, B., Drey, L., Samuel, S., Or, R., and Shapira, M. Y.
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- 2008
7. Indole-3-carbinol and 3,3′-diindolylmethane induce apoptosis in human prostate cancer cells
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Nachshon-Kedmi, M., Yannai, S., Haj, A., and Fares, F.A.
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- 2003
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8. PB1787 OUTCOMES OF PATIENTS WITH PRIMARY MEDIASTINAL B-CELL LYMPHOMA AFTER UPFRONT R-DAEPOCH ARE COMPARABLE TO R-VACOPB REGIMEN: A SINGLE CENTER EXPERIENCE WITH RETROSPECTIVE HISTORICAL COHORT COMPARISON.
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Zlotnick, M., primary, Kedmi, M., additional, Ribakovsky, E., additional, Benjamini, O., additional, Volcheck, Y., additional, Merckel, D., additional, Nagler, A., additional, and Avigdor, A., additional
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- 2019
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9. The severity of experimental colitis in mice is dependent on the presence of the [Alpha]5 neuronal nicotinic acetylcholine receptor (nAChR) subunit
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Kedmi, M., Karmeli, F., Yaron, Y., and Rachmilewitz, D.
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Genetic research -- Analysis ,Human genetics -- Research ,Inflammatory bowel diseases -- Genetic aspects ,Colitis -- Genetic aspects ,Biological sciences - Published
- 2000
10. Associations between B-cell non-Hodgkin lymphoma and exposure, persistence and immune response to hepatitis B
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Kleinstern, G., primary, Seir, R. A., additional, Perlman, R., additional, Abdeen, Z., additional, Khatib, A., additional, Elyan, H., additional, Dann, E. J., additional, Kedmi, M., additional, Ellis, M., additional, Nagler, A., additional, Amir, G., additional, Ben Yehuda, D., additional, Safadi, R., additional, and Paltiel, O., additional
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- 2016
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11. No evidence for involvement of sheep in the epidemiology of cattle virulent epizootic hemorrhagic disease virus
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Kedmi, M., Levi, S., Galon, N., Bomborov, V., Yadin, H., Batten, C., and Klement, E.
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- 2011
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12. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes
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Vacic, V., primary, Ozelius, L. J., additional, Clark, L. N., additional, Bar-Shira, A., additional, Gana-Weisz, M., additional, Gurevich, T., additional, Gusev, A., additional, Kedmi, M., additional, Kenny, E. E., additional, Liu, X., additional, Mejia-Santana, H., additional, Mirelman, A., additional, Raymond, D., additional, Saunders-Pullman, R., additional, Desnick, R. J., additional, Atzmon, G., additional, Burns, E. R., additional, Ostrer, H., additional, Hakonarson, H., additional, Bergman, A., additional, Barzilai, N., additional, Darvasi, A., additional, Peter, I., additional, Guha, S., additional, Lencz, T., additional, Giladi, N., additional, Marder, K., additional, Pe'er, I., additional, Bressman, S. B., additional, and Orr-Urtreger, A., additional
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- 2014
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13. Assessment of the productivity effects associated with epizootic hemorrhagic disease in dairy herds
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Kedmi, M., primary, Van Straten, M., additional, Ezra, E., additional, Galon, N., additional, and Klement, E., additional
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- 2010
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14. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease
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Gan-Or, Z., primary, Bar-Shira, A., additional, Mirelman, A., additional, Gurevich, T., additional, Kedmi, M., additional, Giladi, N., additional, and Orr-Urtreger, A., additional
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- 2009
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15. Induction of apoptosis in human prostate cancer cell line, PC3, by 3,3′-diindolylmethane through the mitochondrial pathway
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Nachshon-Kedmi, M, primary, Yannai, S, additional, and Fares, F A, additional
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- 2004
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16. The role of nicotine in IBD: The severity of experimental colitis in mice is dependent on the presence of the α5 neuronal nicotinic acetylcholine receptor subunit (nAChR)
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Rachmilewitz, D., primary, Karmeli, F., additional, Kedmi, M., additional, and Orr-Urtreger, A., additional
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- 2000
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17. The role of nicotine in IBD: The severity of experimental colitis in mice is dependent on the presence of the A5 neuronal nicotinic acetylcholine receptor subunit (nAChR)
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Rachmilewitz, Daniel, primary, Karmeli, Fanny, additional, and Kedmi, M., additional
- Published
- 2000
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18. Nicotine ameliorates experimental colitis in mice deficient for the A5 neuronal nicotinic acetylcholine receptor subunit
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Orr-Urtreger, Avi, primary, Karmeli, Fanny, additional, Kedmi, M., additional, and Rachmilewitz, Daniel, additional
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- 2000
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19. Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease
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Giladi Nir, Gurevich Tanya, Bar-Shira Anat, Kedmi Merav, and Orr-Urtreger Avi
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Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Results Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Conclusions Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.
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- 2011
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20. Ethnic variation in medical and lifestyle risk factors for B cell non-Hodgkin lymphoma: A case-control study among Israelis and Palestinians
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Dina Ben Yehuda, Husein Elyan, Fouad Sabatin, Rania Abu Seir, Ora Paltiel, Ziad Abdeen, Arnon Nagler, Eldad J. Dann, Ronit Nirel, Riki Perlman, Gail Amir, Geffen Kleinstern, Paolo Boffetta, Martin Ellis, Asad Ramlawi, Meirav Kedmi, Areej Khatib, Kleinstern, G., Seir, R.A., Perlman, R., Khatib, A., Abdeen, Z., Elyan, H., Nirel, R., Amir, G., Ramlawi, A., Sabatin, F., Boffetta, P., Dann, E.J., Kedmi, M., Ellis, M., Nagler, A., Yehuda, D.B., and Paltiel, O.
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0301 basic medicine ,B Cells ,Blood transfusion ,Mononucleosis ,Epidemiology ,medicine.medical_treatment ,Hair Dyes ,Follicular lymphoma ,lcsh:Medicine ,Hematologic Cancers and Related Disorders ,White Blood Cells ,0302 clinical medicine ,Risk Factors ,Animal Cells ,hemic and lymphatic diseases ,Odds Ratio ,Medicine and Health Sciences ,Ethnicities ,Israel ,lcsh:Science ,Non-Hodgkin lymphoma ,Multidisciplinary ,Hematology ,Middle Aged ,Clinical Laboratory Sciences ,Arabs ,Oncology ,030220 oncology & carcinogenesis ,Sunlight ,B-Cell Non-Hodgkin Lymphoma ,Lymphomas ,Lymphoma, Large B-Cell, Diffuse ,Cellular Types ,Medical and lifestyle risk factors for B cell non-Hodgkin lymphoma ,Research Article ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Immune Cells ,Immunology ,Ethnic Epidemiology ,03 medical and health sciences ,Diagnostic Medicine ,Internal medicine ,Cancer Detection and Diagnosis ,medicine ,Humans ,Blood Transfusion ,Antibody-Producing Cells ,Life Style ,Aged ,Family Health ,Blood Cells ,Transfusion Medicine ,business.industry ,lcsh:R ,Case-control study ,Cancers and Neoplasms ,Biology and Life Sciences ,Cell Biology ,Odds ratio ,medicine.disease ,Confidence interval ,Lymphoma ,030104 developmental biology ,Case-Control Studies ,Jews ,People and Places ,lcsh:Q ,Population Groupings ,business - Abstract
Background: Risk factors for B-cell non-Hodgkin lymphoma (B-NHL) have not been assessed among Palestinian Arabs (PA) and Israeli Jews (IJ). Methods: In a case-control study we investigated self-reported medical and lifestyle exposures, reporting odds ratios (ORs) and 95% confidence intervals [CIs], by ethnicity, for overall B-NHL and subtypes. Results: We recruited 823 cases and 808 healthy controls. Among 307 PA/516 IJ B-NHL cases (mean age at diagnosis = 51 [±17] versus 60 [±15] years, respectively) subtype distributions differed, with diffuse large B-cell lymphoma (DLBCL) being prominent among PA (71%) compared to IJ (41%); follicular lymphoma (FL), was observed in 14% versus 28%, and marginal zone lymphoma, in 2% versus 14%, respectively. Overall B-NHL in both populations was associated with recreational sun exposure OR = 1.43 [CI:1.07-1.91], black hair-dye use OR = 1.70 [CI:1.00-2.87], hospitalization for infection OR = 1.68 [CI:1.34-2.11], and first-degree relative with hematopoietic cancer, OR = 1.69 [CI:1.16-2.48]. An inverse association was noted with alcohol use, OR = 0.46 [CI:0.34-0.62]. Subtype-specific exposures included smoking (FL, OR = 1.46 [CI:1.01-2.11]) and >monthly indoor pesticide use (DLBCL, OR = 2.01 [CI:1.35-3.00]). Associations observed for overall B-NHL in PA only included: gardening OR = 1.93 [CI:1.39-2.70]; history of herpes, mononucleosis, rubella, blood transfusion (OR>2.5, P
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- 2017
21. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment
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Morris E. Feldman, Lee Roth, Hadas Cohen-Dvashi, Moshit Lindzen, Fernando Schmitt, Rossella Solmi, Michal Sharon-Sevilla, Amit Zeisel, Stefan Wiemann, Yehoshua Enuka, Gabriele D'Uva, Mattia Lauriola, Nir Ben-Chetrit, Yosef Yarden, Nava Nevo, Eytan Domany, Silvia Carvalho, Alon Chen, Kirti Sharma, Merav Kedmi, Lauriola M, Enuka Y, Zeisel A, D'Uva G, Roth L, Sharon-Sevilla M, Lindzen M, Sharma K, Nevo N, Feldman M, Carvalho S, Cohen-Dvashi H, Kedmi M, Ben-Chetrit N, Chen A, Solmi R, Wiemann S, Schmitt F, Domany E, and Yarden Y.
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medicine.medical_specialty ,MAP Kinase Signaling System ,EGFR ,Circadian clock ,General Physics and Astronomy ,Biology ,Ligands ,Article ,General Biochemistry, Genetics and Molecular Biology ,Receptor tyrosine kinase ,Mice ,Receptors, Glucocorticoid ,Cell Movement ,Cell Line, Tumor ,Neoplasms ,Oscillometry ,Internal medicine ,Negative feedback ,medicine ,Animals ,Humans ,Receptor ,Glucocorticoids ,Mice, Knockout ,Multidisciplinary ,Kinase ,General Chemistry ,Circadian Rhythm ,ErbB Receptors ,Mice, Inbred C57BL ,Treatment Outcome ,Endocrinology ,Nuclear receptor ,Disease Progression ,Cancer research ,biology.protein ,Female ,Signal transduction ,Signal Transduction ,Hormone - Abstract
Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR’s feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy., Glucocorticoids are released in a diurnal pattern. Here, the authors show that EGF receptor (EGFR) signalling is negatively regulated by glucocorticoids, and that EGFR inhibitor has stronger antitumour effects when administered during the resting phase, when glucocorticoids are low, offering potential optimization of cancer therapy regimens.
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- 2014
22. A spatial expression atlas of the adult human proximal small intestine.
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Harnik Y, Yakubovsky O, Hoefflin R, Novoselsky R, Bahar Halpern K, Barkai T, Korem Kohanim Y, Egozi A, Golani O, Addadi Y, Kedmi M, Keidar Haran T, Levin Y, Savidor A, Keren-Shaul H, Mayer C, Pencovich N, Pery R, Shouval DS, Tirosh I, Nachmany I, and Itzkovitz S
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- Adult, Animals, Female, Humans, Male, Mice, Cell Movement, Chylomicrons biosynthesis, Enterocytes metabolism, Enterocytes cytology, Epithelial Cells, In Situ Hybridization, Fluorescence, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Iron metabolism, Lipid Droplets metabolism, Macrophages cytology, Macrophages immunology, Macrophages metabolism, Mesoderm cytology, Mesoderm metabolism, Proteomics, Single Molecule Imaging, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcriptome, Gene Expression Profiling, Intestine, Small cytology, Intestine, Small immunology, Intestine, Small metabolism, Cell Biology
- Abstract
The mouse small intestine shows profound variability in gene expression along the crypt-villus axis
1,2 . Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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23. Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues.
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Liu J, Stoler-Barak L, Hezroni-Bravyi H, Biram A, Lebon S, Davidzohn N, Kedmi M, Chemla M, Pilzer D, Cohen M, Brenner O, Biton M, and Shulman Z
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- Animals, Female, Male, Mice, Bacteria immunology, Cell Movement, Chemokines, CC immunology, Chemokines, CC metabolism, Germinal Center immunology, Germinal Center cytology, Mice, Inbred C57BL, Vaccination, Administration, Intranasal, Vaccines immunology, Symbiosis, Immunoglobulin A immunology, Immunoglobulin A metabolism, Lymphoid Tissue immunology, Lymphoid Tissue cytology, Nasal Mucosa cytology, Nasal Mucosa immunology, Plasma Cells immunology, Plasma Cells cytology, Plasma Cells metabolism, T-Lymphocytes immunology, T-Lymphocytes cytology, T-Lymphocytes metabolism, Turbinates cytology, Turbinates immunology
- Abstract
Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens
1 , yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear2 . Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs)3 . Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA+ B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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24. Bovine Ephemeral Fever Viruses in Israel 2014-2023: Genetic Characterization of Local and Emerging Strains.
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Golender N, Hoffmann B, Kenigswald G, Scheinin S, Kedmi M, Gleser D, and Klement E
- Abstract
Bovine ephemeral fever (BEF) is an arthropod-borne viral disease, which frequently causes significant epizootics in susceptible water buffalo and cattle in Africa, Australia, Asia and the Middle East. In the current study, a two-stage protocol for BEFV viral isolation was developed. Data on the clinical signs, geographic distribution and phylogenetic analysis of BEFV strains isolated in Israel in 2015, 2018, 2021 and 2023 were summarized. It was found that during 2015-2021, all BEF outbreaks were caused by local BEFV strains, whereas the epizootic of BEFV in 2023 was caused by a new "Mayotte-like" BEFV strain. A comparison of bluetongue (BT) and BEF outbreaks during 2023 in Israel demonstrated that the incidence of BEFV was 2.21 times higher and its pathogenicity was more serious for the cattle population compared to that caused by BTVs. A phylogenetic analysis of Israeli and global BEFV revealed the emergence of non-local strains in new areas. This finding suggests that BEFV can no longer be classified based only upon geographic distribution. Considering a phylogenetic, genetic and proteomic analysis of all available BEFV strains, we suggest classifying them as a single serotype, which includes four lineages.
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- 2024
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25. Integrative spatial analysis reveals a multi-layered organization of glioblastoma.
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Greenwald AC, Darnell NG, Hoefflin R, Simkin D, Mount CW, Gonzalez Castro LN, Harnik Y, Dumont S, Hirsch D, Nomura M, Talpir T, Kedmi M, Goliand I, Medici G, Laffy J, Li B, Mangena V, Keren-Shaul H, Weller M, Addadi Y, Neidert MC, Suvà ML, and Tirosh I
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- Humans, Spatial Analysis, Transcriptome genetics, Tumor Microenvironment, Proteomics, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Gene Expression Regulation, Neoplastic, Glioblastoma pathology, Glioblastoma genetics, Glioblastoma metabolism, Brain Neoplasms pathology, Brain Neoplasms genetics, Brain Neoplasms metabolism
- Abstract
Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer., Competing Interests: Declaration of interests I.T. is an advisory board member of Immunitas Therapeutics. M.L.S. is an equity holder, scientific co-founder, and advisory board member of Immunitas Therapeutics. Abcam provided carrier-free antibodies for CODEX experiments (to R.H.)., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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26. Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response.
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Nevo S, Frenkel N, Kadouri N, Gome T, Rosenthal N, Givony T, Avin A, Peligero Cruz C, Kedmi M, Lindzen M, Ben Dor S, Damari G, Porat Z, Haffner-Krausz R, Keren-Shaul H, Yarden Y, Munitz A, Leshkowitz D, Goldfarb Y, and Abramson J
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- Mice, Animals, Lymphocytes, Tuft Cells, Alarmins, Disease Models, Animal, Fibroblasts, Dexamethasone pharmacology, Immunity, Innate, Interleukin-33
- Abstract
The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response.
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- 2024
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27. Point-of-care anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory follicular lymphoma.
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Fried S, Shkury E, Itzhaki O, Sdayoor I, Yerushalmi R, Shem-Tov N, Danylesko I, Jacoby E, Shouval R, Kedmi M, Marcus R, Nagler A, Shimoni A, and Avigdor A
- Subjects
- Humans, Point-of-Care Systems, Immunotherapy, Adoptive adverse effects, Cell- and Tissue-Based Therapy, Antigens, CD19, Receptors, Chimeric Antigen, Lymphoma, Follicular therapy, Lymphoma, Follicular drug therapy
- Abstract
Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.
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- 2023
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28. Author Correction: Thymic mimetic cells function beyond self-tolerance.
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Givony T, Leshkowitz D, Del Castillo D, Nevo S, Kadouri N, Dassa B, Gruper Y, Khalaila R, Ben-Nun O, Gome T, Dobeš J, Ben-Dor S, Kedmi M, Keren-Shaul H, Heffner-Krausz R, Porat Z, Golani O, Addadi Y, Brenner O, Lo DD, Goldfarb Y, and Abramson J
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- 2023
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29. Thymic mimetic cells function beyond self-tolerance.
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Givony T, Leshkowitz D, Del Castillo D, Nevo S, Kadouri N, Dassa B, Gruper Y, Khalaila R, Ben-Nun O, Gome T, Dobeš J, Ben-Dor S, Kedmi M, Keren-Shaul H, Heffner-Krausz R, Porat Z, Golani O, Addadi Y, Brenner O, Lo DD, Goldfarb Y, and Abramson J
- Subjects
- Animals, Mice, Cell Differentiation, Chromatin, Endocrine Cells, Epithelial Cells cytology, Epithelial Cells metabolism, Ghrelin, Muscle Cells, Parenchymal Tissue, Transcription, Genetic, DNA-Binding Proteins metabolism, Transcription Factors, Self Tolerance immunology, Self Tolerance physiology, T-Lymphocytes classification, T-Lymphocytes cytology, T-Lymphocytes immunology, Thymus Gland cytology, Thymus Gland immunology
- Abstract
Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection
1 .Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2-7 . Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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30. Complete human day 14 post-implantation embryo models from naive ES cells.
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Oldak B, Wildschutz E, Bondarenko V, Comar MY, Zhao C, Aguilera-Castrejon A, Tarazi S, Viukov S, Pham TXA, Ashouokhi S, Lokshtanov D, Roncato F, Ariel E, Rose M, Livnat N, Shani T, Joubran C, Cohen R, Addadi Y, Chemla M, Kedmi M, Keren-Shaul H, Pasque V, Petropoulos S, Lanner F, Novershtern N, and Hanna JH
- Subjects
- Humans, Fertilization, Gastrulation, Germ Layers cytology, Germ Layers embryology, Trophoblasts cytology, Yolk Sac cytology, Yolk Sac embryology, Giant Cells cytology, Embryo Implantation, Embryo, Mammalian cytology, Embryo, Mammalian embryology, Embryonic Development, Human Embryonic Stem Cells cytology
- Abstract
The ability to study human post-implantation development remains limited owing to ethical and technical challenges associated with intrauterine development after implantation
1 . Embryo-like models with spatially organized morphogenesis and structure of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (that is, the embryonic disc, the bilaminar disc, the yolk sac, the chorionic sac and the surrounding trophoblast layer) remain lacking1,2 . Mouse naive embryonic stem cells have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation structured stem-cell-based embryo models with spatially organized morphogenesis (called SEMs)3 . Here we extend those findings to humans using only genetically unmodified human naive embryonic stem cells (cultured in human enhanced naive stem cell medium conditions)4 . Such human fully integrated and complete SEMs recapitulate the organization of nearly all known lineages and compartments of post-implantation human embryos, including the epiblast, the hypoblast, the extra-embryonic mesoderm and the trophoblast layer surrounding the latter compartments. These human complete SEMs demonstrated developmental growth dynamics that resemble key hallmarks of post-implantation stage embryogenesis up to 13-14 days after fertilization (Carnegie stage 6a). These include embryonic disc and bilaminar disc formation, epiblast lumenogenesis, polarized amniogenesis, anterior-posterior symmetry breaking, primordial germ-cell specification, polarized yolk sac with visceral and parietal endoderm formation, extra-embryonic mesoderm expansion that defines a chorionic cavity and a connecting stalk, and a trophoblast-surrounding compartment demonstrating syncytium and lacunae formation. This SEM platform will probably enable the experimental investigation of previously inaccessible windows of human early post implantation up to peri-gastrulation development., (© 2023. The Author(s).)- Published
- 2023
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31. IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data.
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Peres A, Lees WD, Rodriguez OL, Lee NY, Polak P, Hope R, Kedmi M, Collins AM, Ohlin M, Kleinstein SH, Watson CT, and Yaari G
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- Alleles, Genotype, Genomics, Receptors, Antigen, B-Cell genetics, Immunoglobulin Heavy Chains genetics
- Abstract
In adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step. This process is highly impacted by allele annotations. Aligning sequences, assigning them to specific germline alleles, and inferring individual genotypes are challenging when the repertoire is highly mutated, or sequence reads do not cover the whole V region. Here, we propose an alternative naming scheme for the V alleles, as well as a novel method to infer individual genotypes. We demonstrate the strengths of the two by comparing their outcomes to other genotype inference methods. We validate the genotype approach with independent genomic long-read data. The naming scheme is compatible with current annotation tools and pipelines. Analysis results can be converted from the proposed naming scheme to the nomenclature determined by the International Union of Immunological Societies (IUIS). Both the naming scheme and the genotype procedure are implemented in a freely available R package (PIgLET https://bitbucket.org/yaarilab/piglet). To allow researchers to further explore the approach on real data and to adapt it for their uses, we also created an interactive website (https://yaarilab.github.io/IGHV_reference_book)., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2023
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32. The transcriptional and regulatory identity of erythropoietin producing cells.
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Kragesteen BK, Giladi A, David E, Halevi S, Geirsdóttir L, Lempke OM, Li B, Bapst AM, Xie K, Katzenelenbogen Y, Dahl SL, Sheban F, Gurevich-Shapiro A, Zada M, Phan TS, Avellino R, Wang SY, Barboy O, Shlomi-Loubaton S, Winning S, Markwerth PP, Dekalo S, Keren-Shaul H, Kedmi M, Sikora M, Fandrey J, Korneliussen TS, Prchal JT, Rosenzweig B, Yutkin V, Racimo F, Willerslev E, Gur C, Wenger RH, and Amit I
- Subjects
- Animals, Humans, Mice, Erythropoiesis genetics, Kidney metabolism, RNA metabolism, Anemia genetics, Erythropoietin genetics
- Abstract
Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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33. B cell M-CLL clones retain selection against replacement mutations in their immunoglobulin gene framework regions.
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Neuman H, Arrouasse J, Benjamini O, Mehr R, and Kedmi M
- Abstract
Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, accounting for 30-40% of all adult leukemias. The dynamics of B-lymphocyte CLL clones with mutated immunoglobulin heavy chain variable region (IgHV) genes in their tumor (M-CLL) can be studied using mutational lineage trees., Methods: Here, we used lineage tree-based analyses of somatic hypermutation (SHM) and selection in M-CLL clones, comparing the dominant (presumably malignant) clones of 15 CLL patients to their non-dominant (presumably normal) B cell clones, and to those of healthy control repertoires. This type of analysis, which was never previously published in CLL, yielded the following novel insights., Results: CLL dominant clones undergo - or retain - more replacement mutations that alter amino acid properties such as charge or hydropathy. Although, as expected, CLL dominant clones undergo weaker selection for replacement mutations in the complementarity determining regions (CDRs) and against replacement mutations in the framework regions (FWRs) than non-dominant clones in the same patients or normal B cell clones in healthy controls, they surprisingly retain some of the latter selection in their FWRs. Finally, using machine learning, we show that even the non-dominant clones in CLL patients differ from healthy control clones in various features, most notably their expression of higher fractions of transition mutations., Discussion: Overall, CLL seems to be characterized by significant loosening - but not a complete loss - of the selection forces operating on B cell clones, and possibly also by changes in SHM mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neuman, Arrouasse, Benjamini, Mehr and Kedmi.)
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- 2023
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34. Allogeneic Hematopoietic Cell Transplantation after Chimeric Antigen Receptor T Cell Therapy in Large B Cell Lymphoma.
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Fried S, Shouval R, Walji M, Flynn JR, Yerushalmi R, Shem-Tov N, Danylesko I, Tomas AA, Fein JA, Devlin SM, Sauter CS, Shah GL, Kedmi M, Jacoby E, Shargian L, Raanani P, Yeshurun M, Perales MA, Nagler A, Avigdor A, and Shimoni A
- Subjects
- Adult, Humans, Young Adult, Middle Aged, Aged, Neoplasm Recurrence, Local complications, Receptors, Chimeric Antigen, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate., Competing Interests: Declaration of Competing Interest R.S. has served as a consultant for Medexus and MyBiotics. M.A.P. has received honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Celgene, Equilium, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, Takeda, VectivBio AG, and Vor Biopharma; has served on data safety and monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier and the scientific advisory board of NexImmune; has ownership interests in NexImmune and Omeros; has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; and serves in a volunteer capacity as a member of the Board of Directors of the American Society for Transplantation and Cellular Therapy and Be the Match (National Marrow Donor Program), as well as on the Center for International Blood and Marrow Transplant Research's Cellular Immunotherapy Data Resource executive committee. A.S. has served on scientific advisory boards for Jazz Pharmaceutical, Gilead, Novartis, AbbVie, Bristol-Myers Squibb, and Medac. A.A. reports honoraria from Gilead, Novartis, Takeda, Roche, Bristol-Myers Squibb, and Sanofi. C.S.S. has served as a paid consultant on advisory boards for Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite/Gilead, Celgene/BMS, Gamida Cell, Karyopharm, Ono Pharmaceuticals, and GSK and has received research funds for clinical trials from Juno Therapeutics, Celgene/BMS, Bristol-Myers Squibb, Precision Biosciences, Actinium Pharmaceuticals, and Sanofi-Genzyme. G.L.S. has received research funding from Janssen, Amgen, and Beyond Spring., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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35. Cellular and humoral response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL.
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Benjamini O, Gershon R, Bar-Haim E, Lustig Y, Cohen H, Doolman R, Kedmi M, Ribakovsky E, Kneller A, Hod T, Erez N, Levy I, Rahav G, and Avigdor A
- Subjects
- Humans, COVID-19 Vaccines, RNA, Messenger, BNT162 Vaccine, SARS-CoV-2, Antibodies, Viral, Leukemia, Lymphocytic, Chronic, B-Cell therapy, COVID-19 prevention & control
- Abstract
We assessed the humoral and cellular response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL. A total of 67 patients with CLL and 85 age matched controls tested for serologic response and pseudo-neutralization assay. We also tested the functional T-cell response by interferon gamma (IFNγ) to spike protein in 26 patients. Two weeks after the fourth vaccine antibody serologic response was evident in 37 (55.2%) patients with CLL, 20 /22 (91%) of treatment naïve, and 9/32 (28%) patients with ongoing therapy, compared with 100% serologic response in age matched controls. The antibody titer increased by 10-fold in patients with CLL, however, still 88-folds lower than age matched controls. Predictors of better chances of post fourth vaccination serologic response were previous positive serologies after second, third, and pre-fourth vaccination, neutralizing assay, and treatment naïve patients. T-cell response improved from 42.3% before the fourth vaccine to 84.6% 2 weeks afterwards. During the time period of 3 months after the fourth vaccination, 14 patients (21%) developed COVID-19 infection, all recovered uneventfully. Our data demonstrate that fourth SARS-CoV-2 vaccination improves serologic response in patients with CLL to a lesser extent than healthy controls and induces functional T-cell response., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2023
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36. Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma.
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Alarcon Tomas A, Fein JA, Fried S, Flynn JR, Devlin SM, Fingrut WB, Anagnostou T, Alperovich A, Shah N, Fraint E, Lin RJ, Scordo M, Batlevi CL, Besser MJ, Dahi PB, Danylesko I, Giralt S, Imber BS, Jacoby E, Kedmi M, Nagler A, Palomba ML, Roshal M, Salles GA, Sauter C, Shem-Tov N, Shimoni A, Yahalom J, Yerushalmi R, Shah GL, Avigdor A, Perales MA, and Shouval R
- Subjects
- Adult, Humans, Aged, Lenalidomide therapeutic use, Immunotherapy, Adoptive, Remission Induction, Antigens, CD19, Receptors, Chimeric Antigen therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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37. Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel.
- Author
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Fried S, Shouval R, Varda-Bloom N, Besser MJ, Yerushalmi R, Shem-Tov N, Danylesko I, Jacoby E, Teihman S, Itzhaki O, Fein JA, Kedmi M, Shimoni A, Nagler A, and Avigdor A
- Subjects
- Adult, Humans, Antigens, CD19, Neoplasm Recurrence, Local etiology, Point-of-Care Systems, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.
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- 2022
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38. IgTreeZ, A Toolkit for Immunoglobulin Gene Lineage Tree-Based Analysis, Reveals CDR3s Are Crucial for Selection Analysis.
- Author
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Neuman H, Arrouasse J, Kedmi M, Cerutti A, Magri G, and Mehr R
- Subjects
- Humans, Immunoglobulin Variable Region genetics, B-Lymphocytes, Clone Cells, Genes, Immunoglobulin, COVID-19
- Abstract
Somatic hypermutation (SHM) is an important diversification mechanism that plays a part in the creation of immune memory. Immunoglobulin (Ig) variable region gene lineage trees were used over the last four decades to model SHM and the selection mechanisms operating on B cell clones. We hereby present IgTreeZ (Immunoglobulin Tree analyZer), a python-based tool that analyses many aspects of Ig gene lineage trees and their repertoires. Using simulations, we show that IgTreeZ can be reliably used for mutation and selection analyses. We used IgTreeZ on empirical data, found evidence for different mutation patterns in different B cell subpopulations, and gained insights into antigen-driven selection in corona virus disease 19 (COVID-19) patients. Most importantly, we show that including the CDR3 regions in selection analyses - which is only possible if these analyses are lineage tree-based - is crucial for obtaining correct results. Overall, we present a comprehensive lineage tree analysis tool that can reveal new biological insights into B cell repertoire dynamics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Neuman, Arrouasse, Kedmi, Cerutti, Magri and Mehr.)
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- 2022
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39. Identifying a malignant B-cell lymphoma clone in peripheral blood using immunoglobulin high-throughput sequencing and lineage tree analysis.
- Author
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Kedmi M, Neuman H, Bitansky G, Nagar M, Scheinert-Shenhav G, Barshack I, Schiby G, Tabibian-Keissar H, Avigdor A, and Mehr R
- Subjects
- Clone Cells, High-Throughput Nucleotide Sequencing, Humans, Immunoglobulins, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics
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- 2022
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40. Exploring differential exon usage via short- and long-read RNA sequencing strategies.
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Leshkowitz D, Kedmi M, Fried Y, Pilzer D, Keren-Shaul H, Ainbinder E, and Dassa B
- Subjects
- Animals, DNA, Complementary genetics, Exons, Gene Expression Profiling, Mice, Protein Isoforms genetics, RNA genetics, Sequence Analysis, RNA, Transcriptome, Untranslated Regions, Alternative Splicing, High-Throughput Nucleotide Sequencing
- Abstract
Alternative splicing produces various mRNAs, and thereby various protein products, from one gene, impacting a wide range of cellular activities. However, accurate reconstruction and quantification of full-length transcripts using short-reads is limited, due to their length. Long-reads sequencing technologies may provide a solution by sequencing full-length transcripts. We explored the use of both Illumina short-reads and two long Oxford Nanopore Technology (cDNA and Direct RNA) RNA-Seq reads for detecting global differential splicing during mouse embryonic stem cell differentiation, applying several bioinformatics strategies: gene-based, isoform-based and exon-based. We detected the strongest similarity among the sequencing platforms at the gene level compared to exon-based and isoform-based. Furthermore, the exon-based strategy discovered many differential exon usage (DEU) events, mostly in a platform-dependent manner and in non-differentially expressed genes. Thus, the platforms complemented each other in the ability to detect DEUs (i.e. long-reads exhibited an advantage in detecting DEUs at the UTRs, and short-reads detected more DEUs). Exons within 20 genes, detected in one or more platforms, were here validated by PCR, including key differentiation genes, such as Mdb3 and Aplp1. We provide an important analysis resource for discovering transcriptome changes during stem cell differentiation and insights for analysing such data.
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- 2022
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41. Post-gastrulation synthetic embryos generated ex utero from mouse naive ESCs.
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Tarazi S, Aguilera-Castrejon A, Joubran C, Ghanem N, Ashouokhi S, Roncato F, Wildschutz E, Haddad M, Oldak B, Gomez-Cesar E, Livnat N, Viukov S, Lokshtanov D, Naveh-Tassa S, Rose M, Hanna S, Raanan C, Brenner O, Kedmi M, Keren-Shaul H, Lapidot T, Maza I, Novershtern N, and Hanna JH
- Subjects
- Animals, Cell Differentiation physiology, Embryo, Mammalian physiology, Embryonic Development, Endoderm, Mammals, Mice, Embryonic Stem Cells, Gastrulation
- Abstract
In vitro cultured stem cells with distinct developmental capacities can contribute to embryonic or extraembryonic tissues after microinjection into pre-implantation mammalian embryos. However, whether cultured stem cells can independently give rise to entire gastrulating embryo-like structures with embryonic and extraembryonic compartments remains unknown. Here, we adapt a recently established platform for prolonged ex utero growth of natural embryos to generate mouse post-gastrulation synthetic whole embryo models (sEmbryos), with both embryonic and extraembryonic compartments, starting solely from naive ESCs. This was achieved by co-aggregating non-transduced ESCs, with naive ESCs transiently expressing Cdx2 or Gata4 to promote their priming toward trophectoderm and primitive endoderm lineages, respectively. sEmbryos adequately accomplish gastrulation, advance through key developmental milestones, and develop organ progenitors within complex extraembryonic compartments similar to E8.5 stage mouse embryos. Our findings highlight the plastic potential of naive pluripotent cells to self-organize and functionally reconstitute and model the entire mammalian embryo beyond gastrulation., Competing Interests: Declaration of interests J.H.H. has submitted patent applications relevant to the findings reported herein and is a chief scientific advisor of Renewal Bio Inc., which has licensed technologies described herein., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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42. DestVI identifies continuums of cell types in spatial transcriptomics data.
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Lopez R, Li B, Keren-Shaul H, Boyeau P, Kedmi M, Pilzer D, Jelinski A, Yofe I, David E, Wagner A, Ergen C, Addadi Y, Golani O, Ronchese F, Jordan MI, Amit I, and Yosef N
- Subjects
- Animals, Gene Expression Profiling methods, Mice, Single-Cell Analysis methods, Software, Exome Sequencing, Neoplasms genetics, Transcriptome genetics
- Abstract
Most spatial transcriptomics technologies are limited by their resolution, with spot sizes larger than that of a single cell. Although joint analysis with single-cell RNA sequencing can alleviate this problem, current methods are limited to assessing discrete cell types, revealing the proportion of cell types inside each spot. To identify continuous variation of the transcriptome within cells of the same type, we developed Deconvolution of Spatial Transcriptomics profiles using Variational Inference (DestVI). Using simulations, we demonstrate that DestVI outperforms existing methods for estimating gene expression for every cell type inside every spot. Applied to a study of infected lymph nodes and of a mouse tumor model, DestVI provides high-resolution, accurate spatial characterization of the cellular organization of these tissues and identifies cell-type-specific changes in gene expression between different tissue regions or between conditions. DestVI is available as part of the open-source software package scvi-tools ( https://scvi-tools.org )., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2022
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43. FUS-P525L Juvenile Amyotrophic Lateral Sclerosis and Intellectual Disability: Evidence for Association and Oligogenic Inheritance.
- Author
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Goldstein O, Inbar T, Kedmi M, Gana-Weisz M, Abramovich B, Orr-Urtreger A, and Drory VE
- Abstract
Background and Objectives: Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature., Methods: Exome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma ( FUS )-ALS associated with ID., Results: A de novo mutation FUS -P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities ( p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS -related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities., Discussion: FUS -P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients ( GPT2 , DNAH10 , and SCUBE2 ) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2022
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44. Point-of-care anti-CD19 CAR T-cells for treatment of relapsed and refractory aggressive B-cell lymphoma.
- Author
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Kedmi M, Shouval R, Fried S, Bomze D, Fein J, Cohen Z, Danilesko I, Shem-Tov N, Yerushalmi R, Jacoby E, Besser M, Shimoni A, Nagler A, and Avigdor A
- Subjects
- Adult, Antigens, CD19, Cytokine Release Syndrome etiology, Humans, Middle Aged, Point-of-Care Systems, T-Lymphocytes, Lymphoma, B-Cell therapy, Receptors, Chimeric Antigen therapeutic use
- Abstract
Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed and refractory aggressive B-cell lymphoma. However, financial toxicity and manufacturing time represent barriers to its widespread implementation. Study applicability, toxicity, and efficacy of a locally produced autologous CD19-directed CAR T-cell product were studied. We performed a phase 1b/2 clinical trial with a point-of-care (POC) CAR T-cell product that contains a CD28 costimulatory domain. Adult patients with aggressive B-cell lymphoma or transformed low-grade lymphoma who received at least 2 prior regimens were eligible. A total of 73 patients, with a median age of 49 years, met inclusion criteria. CAR T-cell production time from apheresis was 10 days (interquartile range 10-11), negating the need for bridging chemotherapy. Overall and complete response rates were 62.5% and 37.5%. Median progression-free and overall survival were 3.7 and 12.1 months, respectively. Overall and progression-free survival at 12 months were 52.1% (confidence interval [CI]: 40.8%-66.5%) and 40% (CI: 30%-53.7%), respectively. Patients who achieved response had longer progression-free and overall survival. Grade 3-4 cytokine release syndrome was observed in 9.5% of the patients, and immune effector cell-associated neurotoxicity syndrome grade 3-4 in 21.9%. No deaths occurred due to CAR T-cell toxicity. Fifteen patients (20%) underwent allogeneic stem cell transplantation at a median time of 60 days after CAR T-cell therapy; 8 were alive at last follow-up. Of the 6 patients who underwent the transplantation in complete response 2 deceased because of toxicity. POC CAR T-cells are a feasible therapeutic option in aggressive B-cell lymphoma. They provide good efficacy while minimizing production time and the need for bridging therapy., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2022
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45. Cytological endometritis diagnosis in primiparous versus multiparous dairy cows.
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Druker SA, Sicsic R, van Straten M, Goshen T, Kedmi M, and Raz T
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- Animals, Cattle, Endometrium, Female, Milk, Parity, Pregnancy, Cattle Diseases diagnosis, Endometritis diagnosis, Endometritis veterinary
- Abstract
Endometritis is a uterine disease of dairy cows causing substantial negative effects on reproductive performance and inflicting considerable economic losses. It is typically diagnosed by endometrial cytology evaluation and commonly named cytological endometritis (CEM). In most previous studies, cows were defined as CEM positive if the proportion of polymorphonuclear cells (%PMN) in their endometrial cytology was above a pre-set threshold. Thresholds were established based on CEM diagnosis in association with reproductive performance, typically analyzed by a single reproductive parameter and calculated for all cows together. Our objective was to examine whether primiparous and multiparous cows should optimally be diagnosed for CEM by different %PMN thresholds and sampling timings, using a combination of several reproductive performance parameters. Two endometrial cytobrush cytology samples were collected from Holstein-Friesian dairy cows (n = 415; 269 multiparous; 146 primiparous), at 30-40 d in milk (DIM) and 60-70 DIM, and %PMN were evaluated microscopically (blindly; Diff-Quick stain, Medi-Market). The %PMN thresholds were set at ≥1% to ≥10%, ≥15%, and ≥20%, and accordingly, for each of the thresholds, several reproductive performance parameters were compared between CEM-positive versus CEM-negative cows. Upon application of several analytic approaches, our results indicated that optimal CEM diagnosis should be performed by different criteria in primiparous and multiparous cows: in primiparous cows at 30-40 DIM, using a threshold of ≥7%PMN, and in multiparous cows at 60-70 DIM, using a threshold of ≥4%PMN. Such a diagnostic approach provides a comprehensive view of the reproductive prognosis of CEM-positive primiparous and multiparous cows, which is pertinent information for researchers, veterinarians, and farmers., (© 2022, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)
- Published
- 2022
- Full Text
- View/download PDF
46. Imaging of Hematological Patients in the Era of COVID-19.
- Author
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Eshet Y, Avigdor A, Kedmi M, and Tau N
- Subjects
- Humans, Pandemics, SARS-CoV-2, COVID-19, Hematologic Diseases complications, Hematologic Diseases epidemiology, Hematologic Neoplasms complications
- Abstract
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in changes in management and imaging routines for patients with hematological malignancies. Treating physicians had to familiarize themselves with a new disease, with distinct imaging manifestations, sometimes overlapping with other infections prevalent in this patient population. In some aspects, infected hematological patients might exhibit a different disease course, and routine imaging in asymptomatic hematological patients may result in unexpected COVID-19 findings, implying covert infection, that should be further explored. Furthermore, some complications of hematological diseases and treatments may present with findings similar to COVID-19 manifestations, and treating physicians must consider both possibilities in the differential diagnosis. In this review, we aimed to present the influence the COVID-19 pandemic had on hematological malignancy imaging., (© 2022 S. Karger AG, Basel.)
- Published
- 2022
- Full Text
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47. Outcomes Related to FDG-PET-CT Response in Patients With Hodgkin Lymphoma Treated With Brentuximab-Vedotin at Relapse or Consolidation.
- Author
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Kedmi M, Khaustov P, Ribakovsy E, Benjamini O, and Avigdor A
- Subjects
- Adult, Brentuximab Vedotin therapeutic use, Female, Fluorodeoxyglucose F18 therapeutic use, Humans, Male, Neoplasm Recurrence, Local drug therapy, Positron Emission Tomography Computed Tomography, Retrospective Studies, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Hodgkin Disease diagnostic imaging, Hodgkin Disease drug therapy, Hodgkin Disease pathology, Immunoconjugates adverse effects
- Abstract
Background: Brentuximab-vedotin (BV) monotherapy has shown high efficacy in heavily pre-treated patients with relapsed or refractory Hodgkin lymphoma (HL) after high-dose chemotherapy or autologous stem cell transplantation (ASCT). We retrospectively analyzed the outcomes of treatment with BV of HL patients and examined the predictive ability of PET-CT for response in this setting., Patients and Methods: Records of 49 HL patients (median age, 39 years, 55% male) treated with BV for relapse (71.4%) or consolidation (28.6%) post-ASCT were analyzed. Patients who did not reach complete response (CR) on PET/CT after 4 cycles (non-responders) discontinued BV and received the next treatment line. Overall survival (OS) and progression-free survival (PFS) were compared between responders and non-responders., Results: After a median follow-up of 19.1 months, all consolidation patients were alive and none progressed. Median OS in 23 relapsed patients that did not achieve CR after 4 cycles and continued to the next treatment was 55.0 months, while all those in CR (n = 24) were alive (P = .0120). No statistically significant differences in OS were observed between responders and non-responders with relapsed HL (P = .1072). Median PFS evaluated after 4 BV cycles was significantly longer in responders compared to non-responders (47.9 vs. 1.5 months, P < .0001). Neuropathy and neutropenia were the main toxicities observed., Conclusions: HL patients treated with BV for relapse or consolidation who achieved CR by PET-CT after 4 cycles showed improved PFS and OS compared to non-responders. Non-responders treated for relapsed HL who proceeded to the next treatment line demonstrated comparable OS to responders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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48. Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies.
- Author
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Biber G, Ben-Shmuel A, Noy E, Joseph N, Puthenveetil A, Reiss N, Levy O, Lazar I, Feiglin A, Ofran Y, Kedmi M, Avigdor A, Fried S, and Barda-Saad M
- Subjects
- Actins metabolism, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Movement drug effects, Cell Proliferation drug effects, Cytoskeletal Proteins metabolism, Hematologic Neoplasms metabolism, Hematologic Neoplasms pathology, Humans, Integrins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Mice, Neoplasm Invasiveness, Protein Binding drug effects, Small Molecule Libraries metabolism, Small Molecule Libraries pharmacokinetics, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Ubiquitination drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents metabolism, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Wiskott-Aldrich Syndrome Protein metabolism
- Abstract
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott-Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
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49. Progression of disease within 24 months of initial therapy (POD24) detected incidentally in imaging does not necessarily indicate worse outcome.
- Author
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Bitansky G, Avigdor A, Vasilev E, Zlotnick M, Ribakovsky E, Benjamini O, Nagler A, and Kedmi M
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Cohort Studies, Disease Progression, Humans, Prognosis, Retrospective Studies, Lymphoma, Follicular drug therapy
- Abstract
Progression of disease within 24 months of initial therapy (POD24) has previously been identified as a predictor of reduced overall survival (OS) for patients with follicular lymphoma (FL). Here we attempt to validate this finding in a retrospective cohort and understand whether the method by which progression is determined, clinically or radiographically, influences POD24 robustness. We reviewed records of 635 patients with FL and included 317 patients in our analysis. POD24 occurred in 21.5% of patients and it was evident that OS was significantly lower in the POD24 group. In multivariate analysis both POD24 and FLIPI were independently associated with inferior OS. POD24 that was detected by incidental routine imaging did not predict reduced OS as opposed to progression that was detected clinically. Although surveillance imaging is generally discouraged in FL, it still is a routine practice by many physicians, and therefore our findings are of significant clinical implications.
- Published
- 2020
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50. A novel mutation in TARDBP segregates with amyotrophic lateral sclerosis in a large family with early onset and fast progression.
- Author
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Goldstein O, Kedmi M, Gana-Weisz M, Nefussy B, Vainer B, Fainmesser Y, Drory VE, and Orr-Urtreger A
- Subjects
- Adult, Age of Onset, Female, Genetic Variation genetics, Humans, Male, Middle Aged, Pedigree, Time Factors, Young Adult, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis genetics, Arabs genetics, DNA-Binding Proteins genetics, Disease Progression, Mutation genetics
- Abstract
Objective: To identify the genetic background of ALS segregating in a large Bedouin family in Israel. Methods: Exome sequencing was carried out on three siblings in a family segregating ALS, two affected and one without neurological symptoms. Filtering for causative variants and for modifiers was carried out. Eight variants were confirmed by Sanger sequencing and genotyped on nine available members of the family (three affected and six unaffected). Results: We report the identification of a novel mutation in TARDBP , p.Ala321Asp, segregating in the family. The patients are affected with early onset (average age 34.5, 21-43 years old) and fast progressive disease. The mutation is in exon 6, in the glycin-rich domain, and is predicted to be deleterious. Additional rare, potentially deleterious variants were observed in the three patients, only one of them, PLEKHG5- Phe538Leu, which is located 4.5 Mb upstream to the TARDBP , was also fully segregating in the family. Conclusion: We identified a novel mutation in TARDBP which segregates with the disease in a large family. Additional rare variants were identified, and the combination of next-generation-sequencing together with linkage analysis was optimal to identify causality and modification, emphasizing the importance of combining the two analyses. Burden of deleterious variants may be associated with early age at onset.
- Published
- 2020
- Full Text
- View/download PDF
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