1,063 results on '"Yaron, Y."'
Search Results
2. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma
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Schlumberger, M, Elisei, R, Müller, S, Schöffski, P, Brose, M, Shah, M, Licitra, L, Krajewska, J, Kreissl, MC, Niederle, B, Cohen, EEW, Wirth, L, Ali, H, Clary, DO, Yaron, Y, Mangeshkar, M, Ball, D, Nelkin, B, and Sherman, S
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Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Anilides ,Carcinoma ,Medullary ,Diagnostic Imaging ,Double-Blind Method ,Female ,Follow-Up Studies ,Humans ,International Agencies ,Male ,Prognosis ,Pyridines ,Survival Rate ,Thyroid Neoplasms ,cabozantinib ,medullary thyroid cancer ,progression-free survival ,overall survival ,RET M918T ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.Trial registration numberNCT00704730.
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- 2017
3. Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.
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Brabbing‐Goldstein, D., Kozlova, D., Bazak, L., Basel‐Salmon, L., Gilboa, Y., Marciano‐Levi, I., Zahra, J., Kanengisser‐Pines, B., Botvinik, A., Kurolap, A., Birnbaum, R., and Yaron, Y.
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HYDROPS fetalis ,IODINE deficiency ,FETAL growth retardation ,FETAL tissues ,HUMAN abnormalities ,FETAL development ,MITOCHONDRIAL pathology - Abstract
Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Diagnostic yield of exome sequencing in prenatal agenesis of corpus callosum: systematic review and meta‐analysis.
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Mustafa, H. J., Barbera, J. P., Sambatur, E. V., Pagani, G., Yaron, Y., Baptiste, C. D., Wapner, R. J., Brewer, C. J., and Khalil, A.
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AGENESIS of corpus callosum ,CENTRAL nervous system ,GENETIC variation - Abstract
Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants. Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta‐analysis, only studies with ≥ three ACC cases were included. Meta‐analysis of proportions was employed using a random‐effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria. Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta‐analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35–73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30–57%)) and isolated ACC (32% (95% CI, 18–51%)). Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]
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- 2024
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5. EP06.25: Malformations of cortical development revisited: can we improve prenatal sonographic diagnostic rates?
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Reddy, M., primary, Gupta, R., additional, Birnbaum, R., additional, Brusilov, M., additional, Har‐Toov, J., additional, Tourani, A., additional, Izhar, E., additional, Kidron, D., additional, Yaron, Y., additional, Ben‐Sira, L., additional, Malinger, G., additional, and Haratz, K. Krajden, additional
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- 2023
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6. Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of the phenotype
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Brabbing‐Goldstein, D., primary, Kozlova, D., additional, Bazak, L., additional, Basel‐Salmon, L., additional, Gilboa, Y., additional, Marciano‐Levi, I., additional, Zahra, J., additional, Kanengisser‐Pines, B., additional, Botvinik, A., additional, Kurolap, A., additional, Birnbaum, R., additional, and Yaron, Y., additional
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- 2023
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7. Diagnostic Yield of Exome Sequencing in Prenatal Agenesis of Corpus Callosum: A Systematic Review and Meta‐analysis
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Mustafa, H. J., primary, Barbera, J. P., additional, Sambatur, E. V., additional, Pagani, G., additional, Yaron, Y., additional, Baptiste, C. D., additional, Wapner, R. J., additional, Brewer, C. J., additional, and Khalil, A., additional
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- 2023
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8. Reply
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Yaron, Y., primary and Krajden Haratz, K., additional
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- 2023
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9. Exome sequencing as first‐tier test for fetuses with severe central nervous system structural anomalies
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Yaron, Y., primary, Ofen Glassner, V., additional, Mory, A., additional, Zunz Henig, N., additional, Kurolap, A., additional, Bar Shira, A., additional, Brabbing Goldstein, D., additional, Marom, D., additional, Ben Sira, L., additional, Baris Feldman, H., additional, Malinger, G., additional, Krajden Haratz, K., additional, and Reches, A., additional
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- 2022
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10. OC01.02: Genotype‐phenotype correlation in fetuses with major brain malformations using whole‐exome sequencing
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Haratz, K.K., primary, Reches, A., additional, Glassner, V. Offen, additional, Har‐Toov, J., additional, Ben‐Sira, L., additional, Birnbaum, R., additional, Brusilov, M., additional, Erez, I., additional, Gull, I., additional, Malinger, G., additional, and Yaron, Y., additional
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- 2021
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11. OC01.05: Variants of unknown significance in the setting of severe brain malformations: are the dedicated imaging studies of any help?
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Haratz, K.K., primary, Reches, A., additional, Glassner, V. Offen, additional, Har‐Toov, J., additional, Ben‐Sira, L., additional, Birnbaum, R., additional, Brusilov, M., additional, Erez, I., additional, Gull, I., additional, Malinger, G., additional, and Yaron, Y., additional
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- 2021
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12. Benefits of contingent screening vs primary screening by cell-free DNA testing: think again
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Oepkes, D., Bartha, J. L., Schmid, M., and Yaron, Y.
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- 2016
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13. Counseling for non-invasive prenatal testing (NIPT): what pregnant women may want to know
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Oepkes, D., Yaron, Y., Kozlowski, P., Rego de Sousa, M. J., Bartha, J. L., van den Akker, E. S., Dornan, S. M., Krampl-Bettelheim, E., Schmid, M., Wielgos, M., Cirigliano, V., Di Renzo, G. C., Cameron, A., Calda, P., and Tabor, A.
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- 2014
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14. OC06.07: Maternal plasma genome‐wide cell‐free DNA testing can detect fetal aneuploidy in pregnancy loss and can be used to guide further work‐up in recurrent losses
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Borrell, A., primary, Pauta, M., additional, Badenas, C., additional, Soler, A., additional, Borobio, V., additional, Illanes, C., additional, Paz, F., additional, Miño, Y., additional, and Yaron, Y., additional
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- 2019
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15. Immunohistochemical Performance of Estrogen and Progesterone Receptor Antibodies on the Dako Omnis Staining Platform: Evaluation in Multicenter Studies
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Leila Russo, David G. Hicks, Loralee McMahon, Mary Falzon, Kirsten D. Hoff, Patrizia Dell'Orto, Yaron Y. Levy, Keith W. Miller, and Giuseppe Viale
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Histology ,Clone (cell biology) ,Estrogen receptor ,Breast Neoplasms ,progesterone receptor ,Antibodies ,Pathology and Forensic Medicine ,Random Allocation ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,estrogen receptor-α ,Progesterone receptor ,Carcinoma ,medicine ,Humans ,Research Articles ,Staining and Labeling ,business.industry ,Gene Expression Profiling ,Reproducibility of Results ,medicine.disease ,Immunohistochemistry ,Staining ,Medical Laboratory Technology ,030104 developmental biology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,Receptors, Progesterone ,Breast carcinoma ,business ,in vitro diagnostic medical devices - Abstract
Supplemental Digital Content is available in the text., The analysis of estrogen receptor (ER) and progesterone receptor (PR) expression levels by immunohistochemistry is an important part of the initial evaluation of breast cancer and critically important in treatment planning. Anti-ERα (clone EP1) and anti-PR (clone PgR 1294) antibodies are in development for the Dako Omnis automated staining platform. These antibodies are not yet commercially available and are in performance evaluation, including the 4 international, multicenter studies reported here. For each antibody, a reproducibility study and a method comparison study was done in a randomized manner in order to test the antibodies under conditions closest to real-world user conditions. The reproducibility studies included 5 staining runs on the Dako Omnis with 20 formalin-fixed and paraffin-embedded human breast carcinoma specimens in 3 independent laboratories, and the method comparison studies included several hundred specimens stained on the Dako Omnis and on the Autostainer Link 48 platforms. Stained slides were evaluated for nuclear ER or PR expression according to American Society of Clinical Oncology/College of American Pathologists guidelines (≥1% cut-off for positive) by pathologists who were blinded from the staining method and specimen ID. For both anti-ERα (clone EP1) and anti-PR (clone PgR 1294) on the Dako Omnis, high reproducibility agreement rates were obtained on the interrun, interlaboratory, and interobserver endpoints. High concordance rates were observed between the specimens stained on the Dako Omnis platform and the Autostainer Link 48 platform. Staining quality was excellent for both anti-ERα (clone EP1) and anti-PR (clone PgR 1294) on the Dako Omnis. These results suggest that these antibodies are reliable and reproducible tools for immunohistochemistry analysis of ER and PR expression levels in formalin-fixed and paraffin-embedded breast carcinoma tissues on the Dako Omnis platform.
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- 2017
16. Assessment of HER2 amplification status in breast cancer using a new automated HER2 IQFISH pharmDx™ (Dako Omnis) assay
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Miriam Bloch, Patrizia Dell'Orto, Jennifer C. Paterson, Giuseppe Viale, Yaron Y. Levy, David Allen, Jan Trøst Jørgensen, Gitte Kjærsgaard, and George Csathy
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Receptor, ErbB-2 ,Breast Neoplasms ,In situ hybridization ,Biology ,Pathology and Forensic Medicine ,Automation ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,HER2 ,medicine ,Humans ,HER2 Amplification ,030212 general & internal medicine ,skin and connective tissue diseases ,Human Epidermal Growth Factor Receptor 2 ,In Situ Hybridization, Fluorescence ,medicine.diagnostic_test ,Hybridization probe ,Companion diagnostic ,Gene Amplification ,Reproducibility of Results ,Cell Biology ,medicine.disease ,Molecular biology ,Method comparison ,030220 oncology & carcinogenesis ,IQFISH ,%22">Fish ,Female ,Fluorescence in situ hybridization - Abstract
In breast cancer the human epidermal growth factor receptor 2 (HER2) is an important target for a number of different HER2 inhibitors. Different slide-based assays are available for assessment of treatment eligibility, which include fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods for assessment of the HER2 gene status. Here we report a summary of the validation data on HER2 IQFISH pharmDx™ (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. The assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of 3½ to 4h from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary covers method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay with a high precision that is at least comparable to the manual HER2 IQFISH pharmDx™ assay and the PathVysion® HER-2 DNA Probe Kit.
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- 2016
17. Parental Origin of the Retained X Chromosome in Monosomy X Miscarriages and Ongoing Pregnancies
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Grande M, Stergiotou I, Pauta M, Marquès B, Badenas C, Soler A, Yaron Y, and Borrell A
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45,X, Karyotype, Miscarriages, Ongoing pregnancies, Parental origin, Retained X chromosome, Turner syndrome - Abstract
To assess the distribution of the parental origin of the retained X chromosome in monosomy X, either in miscarriages or in ongoing pregnancies.
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- 2017
18. OP08.06: Is aberrant right subclavian artery in fetuses a risk factor for microscopic and submicroscopic chromosomal aberrations?
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Ran, S., primary, Reches, A., additional, Brabbing, D., additional, Bar Shira, A., additional, and Yaron, Y., additional
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- 2017
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19. Analysis of HER2 status in gastroesophageal tumor specimens using a new automated HER2 IQFISH pharmDx™ (Dako Omnis) assay
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Viale, Giuseppe, Paterson, Jennifer, Bloch, Miriam, Csathy, George, Allen, David, Dell’Orto, Patrizia, Kjærsgaard, Gitte, Levy, Yaron Y., and Trøst Jørgensen, Jan
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Automation ,HER2 ,IQFISH ,Companion diagnostic ,6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología [CDU] ,skin and connective tissue diseases ,Gastric cancer ,neoplasms - Abstract
The human epidermal growth factor receptor 2 (HER2) is an important target for treatment of gastroesophageal cancer. Different slide-based assays are available for assessment of HER2 status. Overexpression of the HER2 protein is assessed by immunohistochemistry (IHC) whereas amplification of the HER2 gene is assessed by fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods. Here we report a summary of the validation data on HER2 IQFISH pharmDx™ (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. This assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of less than 4 hours from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary cover method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay, with high precision and at least comparable to the manual HER2 IQFISH pharmDx™ assay. The HER2 IQFISH pharmDx (Dako Omnis) assay is currently not commercially available outside the European Union.
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- 2016
20. OC12.10: Neurosonographic features of L1 syndrome: way beyond ventriculomegaly.
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Giorgione, V., Birnbaum, R., Yaron, Y., Reches, A., Brusilov, M., Jaffa, A., Salemnick, Y., Ben‐Sira, L., Malinger, G., and Haratz, K. Krajden
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In addition to ventriculomegaly, abnormal corpus callosum and adducted thumbs, fetal MRI has also detected diencephalic and midbrain-hindbrain malformations in most fetuses affected by the L1 syndrome. L1 syndrome includes a spectrum of X-linked disorders caused by pathogenic variants of L1CAM gene, which encodes a cell adhesion molecule involved in the central nervous system (CNS) development. In addition to the evaluation of lateral ventricles, corpus callosum and cortical development, thalami and midbrain-hindbrain were investigated. [Extracted from the article]
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- 2022
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21. OC12.05: Early second trimester diagnosis of fetal midbrain–hindbrain malformations: a transvaginal neurosonographic study.
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Birnbaum, R., Brusilov, M., Lerman‐Sagie, T., Leibovitz, Z., Gindes, L., Farajov, A.T., Krzeszowski, W., Arad, A., Kidron, D., Yaron, Y., Reches, A., Malinger, G., and Haratz, K.K.
- Abstract
OC12.05: Early second trimester diagnosis of fetal midbrain-hindbrain malformations: a transvaginal neurosonographic study To describe the clinical and neurosonographic features of fetal midbrain-hindbrain (MBHB malformation diagnosed at 14-18 weeks. The MBHB abnormalities include; kinking of the brainstem (KBS) (n = 3), Joubert syndrome (JS) (n = 2), aqueductal stenosis (AS) (n = 11), rhombencephalosynapsis (RES) (n = 3), "open" fourth ventricle (OFV) (n = 6), and Mobius syndrome (MS) (n = 1). [Extracted from the article]
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- 2022
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22. Benefits of contingent screeningvsprimary screening by cell-free DNA testing: think again
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Oepkes, D., primary, Bartha, J. L., additional, Schmid, M., additional, and Yaron, Y., additional
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- 2016
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23. Refusals of Requests and Offers in Iraqi Arabic And British English
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Jasim, Mohammed Taher, MATRAS, YARON Y, Matras, Yaron, and Hansen, Maj-Britt
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Refusals, Requests, Offers, (im)politeness, Cross Cultural Pragmatics - Abstract
This study investigates refusals of requests and offers utilised by speakers of Iraqi Arabic and British English, as well as by Iraqi learners of English. It aims to identify the strategies of refusal employed by these three groups of speakers, as well as any differences between them. 60 subjects participated in this study. 20 Iraqi Arabic Speakers (IAs), 20 Iraqi Learners of English (ILEs), and 20 British English Speakers (BEs). The elicitation method adopted for the data collection consisted of a discourse completion test (DCT) and a series of open-ended role plays. In both cases, the scenarios employed varied systematically along the following parameters: social status, social distance, rank of imposition and gender.The data obtained by both methods were categorised into a number of strategies. An attempt was made to provide a comprehensive description of the nature of refusal strategies used by the subjects. The strategies identified were categorised following the Beebe et al (1990) scheme of refusals. In addition, they were classified according to the (im)politeness superstrategies posited by Brown and Levinson (1987) and Culpeper (1996). The results indicate that the choice of refusal strategies reflects characteristics of Iraqi versus British English culture. These results are as follows: 1. Although both groups of subjects displayed sensitivity to the social factors referred to above, the relative influence of each factor differed from one group to another. Thus, Iraqi Arabic Speakers (IAs) and Iraqi Learners of English (ILEs) varied their refusal strategies mainly according to status and distance, while British English Speakers (BEs) did so mainly according to status and gender. Besides, the responses of the three groups were influenced by the degree of imposition.2. The application of refusals employed by the three groups differed according to the eliciting method, namely, the DCT and the Role-Play. Consequently, various refusal strategies collected via the Role Play did not appear in the data collected by the DCT and vice versa. 3. Certain strategies employed by Iraqi speakers of Arabic were nonexistent in the data of British English speakers and vice versa. 4. The study of the interlanguage of Iraqi learners of English as a foreign language also confirmed the hypothesis that there is evidence for pragmatic transfer in the order, the frequency and the content of semantic formulae used. A CD-Rom that contains the audio recordings of the Role Plays will be submitted to the Postgraduate office.
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- 2017
24. Selective enzymatic debridement and modified Meek technique in the treatment of extensive burns: Preliminary observations.
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Minic J, Vigato E, Shoham Y, Lavagnolo U, and Governa M
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Background: Selective bromelain-based enzymatic debridement (BED) has emerged as a valid alternative for the treatment of extensive burns, with Total Body Surface Area (TBSA) > 20%. Autologous skin grafting represents the procedure of choice but the scarcity of donor sites remains the main reconstructive challenge. The modified Meek micro-grafting technique may represent a valid strategy to optimize the final outcome., Methods: A single-cohort retrospective analysis was performed, involving nine burn patients (TBSA > 20%) who underwent both BED and subsequently modified Meek technique. Demographic and clinical data (mechanism of injury, surgical treatment, complications, necessity of re-grafting, further surgery and esthetic outcome) were collected., Results: All patients had large burns of mixed and deep dermal thickness (first, second, and third degree). All burns were enzymatically debrided postadmission and covered by the modified Meek technique. Local infection due to poor general conditions was the main complication for all patients. All but two patients survived. The selectiveness of the enzymatic debridement and dermal preservation seemed to improve the quality of scars resulting from micro-grafting. Evaluations performed at 12 ± 2 months postburn showed superior scar quality compared to areas treated with traditional (sheet/mesh) grafts., Conclusion: Combined BED and Meek techniques may provide an effective synergic combination for the treatment of extensive burns., Competing Interests: All authors declare that they have no conflict of interest., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)
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- 2024
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25. Expanded targeted preconception screening panel in Israel: findings and insights.
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Reches A, Ofen Glassner V, Goldstein N, Yeshaya J, Delmar G, Portugali E, Hallas T, Weinstein A, Kurolap A, Berkenstadt M, Mantsour T, Abu-Gutstein L, Ries-Levavi L, Reznik-Wolf H, Behar DM, Yaron Y, Pras E, and Baris Feldman H
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- Humans, Israel epidemiology, Female, Male, Connexins genetics, Genetic Carrier Screening methods, Mutation, Preconception Care methods, Gene Frequency, Genetic Counseling, Heterozygote, Genes, Recessive, Adult, Genetic Testing methods, Connexin 26 genetics
- Abstract
Background: We aimed to analyse the efficacy and added value of a targeted Israeli expanded carrier screening panel (IL-ECSP), beyond the first-tier test covered by the Israeli Ministry of Health (IMOH) and the second-tier covered by the Health Maintenance Organisations (HMOs)., Methods: A curated variant-based IL-ECSP, tailored to the uniquely diverse Israeli population, was offered at two tertiary hospitals and a major genetics laboratory. The panel includes 1487 variants in 357 autosomal recessive and X-linked genes., Results: We analysed 10 115 Israeli samples during an 18-month period. Of these, 6036 (59.7%) were tested as couples and 4079 (40.3%) were singles. Carriers were most frequently identified with mutations in the following genes: GJB2/GJB6 (1:22 allele frequency), CFTR (1:28), GBA (1:34), TYR (1:39), PAH (1:50), SMN1 (1:52) and HEXA (1:56). Of 3018 couples tested, 753 (25%) had no findings, in 1464 (48.5%) only one partner was a carrier, and in 733 (24.3%) both were carriers of different diseases. We identified 79 (2.6%) at-risk couples, where both partners are carriers of the same autosomal recessive condition, or the female carries an X-linked disease. Importantly, 48.1% of these would not have been detected by ethnically-based screening tests currently provided by the IMOH and HMOs, for example, variants in GBA, TYR, PAH and GJB2/GJB6 ., Conclusion: This is the largest cohort of targeted ECSP testing, tailored to the diverse Israeli population. The IL-ECSP expands the identification of couples at risk and empowers their reproductive choices. We recommend endorsing an expanded targeted panel to the National Genetic Carrier Screening programme., Competing Interests: Competing interests: DMB was involved in the design of the CarrierScan array and is entitled to certain royalties., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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26. Generating, modeling and evaluating a large-scale set of CRISPR/Cas9 off-target sites with bulges.
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Yaish O and Orenstein Y
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- Humans, RNA, Guide, CRISPR-Cas Systems genetics, CRISPR-Cas Systems, Gene Editing methods, Machine Learning
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The CRISPR/Cas9 system is a highly accurate gene-editing technique, but it can also lead to unintended off-target sites (OTS). Consequently, many high-throughput assays have been developed to measure OTS in a genome-wide manner, and their data was used to train machine-learning models to predict OTS. However, these models are inaccurate when considering OTS with bulges due to limited data compared to OTS without bulges. Recently, CHANGE-seq, a new in vitro technique to detect OTS, was used to produce a dataset of unprecedented scale and quality. In addition, the same study produced in cellula GUIDE-seq experiments, but none of these GUIDE-seq experiments included bulges. Here, we generated the most comprehensive GUIDE-seq dataset with bulges, and trained and evaluated state-of-the-art machine-learning models that consider OTS with bulges. We first reprocessed the publicly available experimental raw data of the CHANGE-seq study to generate 20 new GUIDE-seq experiments, and hundreds of OTS with bulges among the original and new GUIDE-seq experiments. We then trained multiple machine-learning models, and demonstrated their state-of-the-art performance both in vitro and in cellula over all OTS and when focusing on OTS with bulges. Last, we visualized the key features learned by our models on OTS with bulges in a unique representation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2024
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27. Comparing Complication Rates, Costs, and Length of Stay between Unicompartmental and Total Knee Arthroplasty: Insights from a Big Data Analysis Using the National Inpatient Sample Dataset.
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Maman D, Mahamid A, Yonai Y, and Berkovich Y
- Abstract
Background: Unicompartmental knee arthroplasty (UKA) is increasingly used for knee osteoarthritis due to faster recovery, better range of motion, and lower costs compared to total knee arthroplasty (TKA). While TKA may offer longer-lasting results with lower revision rates, this study compares the relative benefits and limitations of UKA and TKA using the National Inpatient Sample (NIS) database. Methods: This retrospective analysis examined outcomes of elective UKA and TKA procedures from 2016 to 2019, identifying 2,606,925 patients via ICD-10 codes. Propensity score matching based on demographics, hospital characteristics, and comorbidities resulted in a balanced cohort of 136,890 patients. The present study compared in-hospital mortality, length of stay, postoperative complications, and hospitalization costs. Results: The results showed that UKA procedures increased significantly over the study period. Patients undergoing UKA were generally younger with fewer comorbidities. After matching, both groups had low in-hospital mortality (0.015%). UKA patients had shorter hospital stays (1.53 vs. 2.47 days) and lower costs (USD 55,976 vs. USD 61,513) compared to TKA patients. UKA patients had slightly higher rates of intraoperative fracture and pulmonary edema, while TKA patients had higher risks of blood transfusion, anemia, coronary artery disease, pulmonary embolism, pneumonia, and acute kidney injury. Conclusions: UKA appears to be a less-invasive, cost-effective option for younger patients with localized knee osteoarthritis.
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- 2024
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28. Correction: Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity.
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Farhat-Younis L, Na M, Zarfin A, Khateeb A, Santana-Magal N, Richter A, Gutwillig A, Rasoulouniriana D, Gleiberman A, Beck L, Giger T, Ashkenazi A, Barzel A, Rider P, and Carmi Y
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- 2024
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29. Spermatocytes have the capacity to segregate chromosomes despite centriole duplication failure.
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Skinner MW, Simington CJ, López-Jiménez P, Baran KA, Xu J, Dayani Y, Pryzhkova MV, Page J, Gómez R, Holland AJ, and Jordan PW
- Abstract
Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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30. Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer.
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Bojmar L, Zambirinis CP, Hernandez JM, Chakraborty J, Shaashua L, Kim J, Johnson KE, Hanna S, Askan G, Burman J, Ravichandran H, Zheng J, Jolissaint JS, Srouji R, Song Y, Choubey A, Kim HS, Cioffi M, van Beek E, Sigel C, Jessurun J, Velasco Riestra P, Blomstrand H, Jönsson C, Jönsson A, Lauritzen P, Buehring W, Ararso Y, Hernandez D, Vinagolu-Baur JP, Friedman M, Glidden C, Firmenich L, Lieberman G, Mejia DL, Nasar N, Mutvei AP, Paul DM, Bram Y, Costa-Silva B, Basturk O, Boudreau N, Zhang H, Matei IR, Hoshino A, Kelsen D, Sagi I, Scherz A, Scherz-Shouval R, Yarden Y, Oren M, Egeblad M, Lewis JS, Keshari K, Grandgenett PM, Hollingsworth MA, Rajasekhar VK, Healey JH, Björnsson B, Simeone DM, Tuveson DA, Iacobuzio-Donahue CA, Bromberg J, Vincent CT, O'Reilly EM, DeMatteo RP, Balachandran VP, D'Angelica MI, Kingham TP, Allen PJ, Simpson AL, Elemento O, Sandström P, Schwartz RE, Jarnagin WR, and Lyden D
- Abstract
Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B
+ natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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31. Impact of cannabidiol on myocardial recovery in patients with acute myocarditis: Rationale & design of the ARCHER trial.
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McNamara DM, Cooper LT, Arbel Y, Bhimaraj A, Bocchi E, Friedrich MG, Kerneis M, Liu P, Parker AB, Smith ER, Tang WHW, Torre-Amione G, and Tschöpe C
- Abstract
Aims: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF)., Methods and Results: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper., Conclusions: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
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- 2024
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32. Telling the truth to patients before hip fracture surgery.
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Masarwa R, Ben Natan M, and Berkovich Y
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- Humans, Cross-Sectional Studies, Female, Male, Surveys and Questionnaires, Self Efficacy, Middle Aged, Aged, Communication, Adult, Attitude of Health Personnel, Hip Fractures surgery, Hip Fractures mortality, Truth Disclosure, Orthopedic Surgeons, Physician-Patient Relations
- Abstract
Background: Hip fracture repair surgery carries a certain mortality risk, yet evidence suggests that orthopedic surgeons often refrain from discussing this issue with patients prior to surgery., Aim: This study aims to examine whether orthopedic surgeons raise the issue of one-year post-surgery mortality before hip fracture repair surgery and to explore factors influencing this decision., Method: The study employs a cross-sectional design, administering validated digital questionnaires to 150 orthopedic surgeons., Results: A minority of orthopedic surgeons reported always informing patients about the risk of mortality in the year following hip fracture surgery. The main reasons for not discussing this risk were a desire to avoid frightening patients, time constraints, and concerns about undermining patient hope. Orthopedic surgeons reported a medium-high level of perceived self-efficacy, with higher self-efficacy associated with a reduced likelihood of discussing one-year mortality risk. Conversely, older age and holding a specialist status in orthopedic surgery were associated with an increased likelihood of discussing this risk with patients., Conclusions: These findings suggest a need for interventions to address communication barriers and ensure consistent provision of essential information to patients undergoing hip fracture surgery. Additionally, they highlight the importance of considering individual factors such as self-efficacy, age, and expertise in designing strategies to improve patient-provider communication in orthopedic care settings., Trial Registration: The study doesn`t report the results of a health care intervention., (© 2024. The Author(s).)
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- 2024
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33. Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity.
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Farhat-Younis L, Na M, Zarfin A, Khateeb A, Santana-Magal N, Richter A, Gutwillig A, Rasoulouniriana D, Gleiberman A, Beck L, Giger T, Ashkenazi A, Barzel A, Rider P, and Carmi Y
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Cell Line, Tumor, Cytotoxicity, Immunologic, Immunoglobulin M metabolism, Immunoglobulin M immunology, Signal Transduction, Macrophages immunology, Macrophages metabolism, Neoplasms immunology, Receptors, IgG metabolism, Receptors, IgG immunology, Myeloid Cells immunology, Myeloid Cells metabolism
- Abstract
Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity., Competing Interests: LF, MN, AZ, AK, NS, AR, AG, AG, LB, TG, AA, AB No competing interests declared, DR This paper was funded by Gilboa Therapeutics where Diana Rasoulouniriana is a shareholder, PR This paper was funded by Gilboa Therapeutics where Peleg Rider is a shareholder, YC This paper was funded by Gilboa Therapeutics where Yaron Carmi is a shareholder, (© 2023, Farhat-Younis et al.)
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- 2024
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34. Expanding and Enriching the LncRNA Gene-Disease Landscape Using the GeneCaRNA Database.
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Aggarwal S, Rosenblum C, Gould M, Ziman S, Barshir R, Zelig O, Guan-Golan Y, Iny-Stein T, Safran M, Pietrokovski S, and Lancet D
- Abstract
The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ~280,000 human non-coding RNA genes, identified algorithmically from ~690,000 RNAcentral transcripts. This expands by ~tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains ~120,000 long non-coding RNAs (LncRNAs, >200 bases long), including ~100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1547 genes associated with 1 to 50 diseases. About 15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of lncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 lncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for ~110,000 lncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further lncRNA research in disease decipherment.
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- 2024
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35. Space radiation damage rescued by inhibition of key spaceflight associated miRNAs.
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McDonald JT, Kim J, Farmerie L, Johnson ML, Trovao NS, Arif S, Siew K, Tsoy S, Bram Y, Park J, Overbey E, Ryon K, Haltom J, Singh U, Enguita FJ, Zaksas V, Guarnieri JW, Topper M, Wallace DC, Meydan C, Baylin S, Meller R, Muratani M, Porterfield DM, Kaufman B, Mori MA, Walsh SB, Sigaudo-Roussel D, Mebarek S, Bottini M, Marquette CA, Wurtele ES, Schwartz RE, Galeano D, Mason CE, Grabham P, and Beheshti A
- Subjects
- Humans, DNA Breaks, Double-Stranded radiation effects, Radiation Injuries genetics, Radiation Injuries prevention & control, Male, Mitochondria radiation effects, Mitochondria metabolism, Mitochondria genetics, Female, Adult, MicroRNAs genetics, MicroRNAs metabolism, Space Flight, Cosmic Radiation adverse effects, Astronauts
- Abstract
Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage., (© 2024. The Author(s).)
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- 2024
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36. A Feasibility Open-Labeled Clinical Trial Using a Second-Generation Artificial-Intelligence-Based Therapeutic Regimen in Patients with Gaucher Disease Treated with Enzyme Replacement Therapy.
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Hurvitz N, Dinur T, Revel-Vilk S, Agus S, Berg M, Zimran A, and Ilan Y
- Abstract
Background/Objectives: Gaucher Disease type 1 (GD1) is a recessively inherited lysosomal storage disorder caused by a deficiency in the enzyme β-glucocerebrosidase. Enzyme replacement therapy (ERT) has become the standard of care for patients with GD. However, over 10% of patients experience an incomplete response or partial loss of response to ERT, necessitating the exploration of alternative approaches to enhance treatment outcomes. The present feasibility study aimed to determine the feasibility of using a second-generation artificial intelligence (AI) system that introduces variability into dosing regimens for ERT to improve the response to treatment and potentially overcome the partial loss of response to the enzyme. Methods: This was an open-label, prospective, single-center proof-of-concept study. Five patients with GD1 who received ERT were enrolled. The study used the Altus Care™ cellular-phone-based application, which incorporated an algorithm-based approach to offer random dosing regimens within a pre-defined range set by the physician. The app enabled personalized therapeutic regimens with variations in dosages and administration times. Results: The second-generation AI-based personalized regimen was associated with stable responses to ERT in patients with GD1. The SF-36 quality of life scores improved in one patient, and the sense of change in health improved in two; platelet levels increased in two patients, and hemoglobin remained stable. The system demonstrated a high engagement rate among patients and caregivers, showing compliance with the treatment regimen. Conclusions: This feasibility study highlights the potential of using variability-based regimens to enhance ERT effectiveness in GD and calls for further and longer trials to validate these findings.
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- 2024
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37. Patient perspectives on the role of orthopedic nurse practitioners: a cross-sectional study.
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Ben Natan M, Revach M, Sade O, Yonay Y, and Berkovich Y
- Abstract
Background: The inclusion of nurse practitioners (NPs) specializing in orthopedics shows potential for improving the quality of care for orthopedic patients. A critical aspect of assessing the feasibility and acceptance of introducing NPs into orthopedic settings involves understanding patients' perspectives on this role. This study aims to explore the receptiveness of orthopedic patients to treatment by orthopedic Nurse Practitioners (NPs). Additionally, it investigates potential associations between patients' willingness to engage with NPs, their familiarity with the NPs role, perceptions of nursing, and satisfaction with orthopedic nursing care., Methods: This cross-sectional study involved patients admitted to an orthopedic department in a central Israeli hospital between January and February 2023. Data was collected using a questionnaire consisting of five sections, validated by content experts. Statistical analyses, performed using SPSS, included descriptive statistics, independent samples t-tests, Pearson correlations, and linear regression., Results: Orthopedic patient participants demonstrated a moderate willingness to undergo treatment by orthopedic NPs, with over two-thirds expressing strong openness. Patients displayed a high willingness for NPs to engage in various clinical tasks, albeit showing lesser enthusiasm for medication management and preoperative evaluation. Positive attitudes towards nurses and familiarity with the NP's role emerged as significant predictors of patient receptiveness to NPs' treatment., Conclusion: Patient acceptance of orthopedic NPs varies across different aspects of care. While there is overall willingness to receive care from NPs, these nuanced preferences should be considered when implementing NPs in orthopedic settings. Awareness and positive perceptions play crucial roles in shaping patients' willingness to receive care from these NPs., Trial Registration: The research doesn't report the results of a health care intervention., (© 2024. The Author(s).)
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- 2024
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38. Hydrothermal Hot Isostatic Pressing (HHIP)-Experimental Proof of Concept.
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Aviezer Y, Ariely S, Bamberger M, Zolotaryov D, Essel S, and Lahav O
- Abstract
A new hydrothermal hot isostatic pressing (HHIP) approach, involving hydrothermal water conditions and no usage of inert gas, was hypothesized and tested on 3D-printed Al-10%Si-0.3%Mg (%Wt) parts. The aluminum-based metal was practically inert at the applied HHIPing conditions of 300-350 MPa and 250-350 °C, which enabled the employment of a long (6-24 h) HHIP treatment with hardly any loss of material (the overall loss due to corrosion was mostly <0.5% w / w ). Applying the new approach on the above-mentioned samples resulted in an 85.7% reduction in the AM micro-pores, along with a 90.8% reduction in the pores' surface area at a temperature of 350 °C, which is much lower than the 500-520 °C applied in common argon-based aluminum HIPing treatments, while practically maintaining the as-recieved microstructure. These results show that better mechanical properties can be expected when using the suggested treatment without affecting the material fatigue resistance due to grain growth. The proof of concept presented in this work can pave the way to applying the new HHIPing approach to other AM metal parts.
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- 2024
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39. Towards precision medicine in vascular anomalies: Could protein kinase C inhibitors be repurposed for GNAQ/11-related phakomatoses?
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Gu Y, Pham JP, and Sebaratnam DF
- Subjects
- Humans, Protein Kinase C genetics, Protein Kinase C antagonists & inhibitors, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, Drug Repositioning, Vascular Malformations drug therapy, Vascular Malformations genetics, Vascular Malformations pathology, Precision Medicine, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology
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- 2024
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40. Author Correction: Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.
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Han Y, Duan X, Yang L, Nilsson-Payant BE, Wang P, Duan F, Tang X, Yaron TM, Zhang T, Uhl S, Bram Y, Richardson C, Zhu J, Zhao Z, Redmond D, Houghton S, Nguyen DT, Xu D, Wang X, Jessurun J, Borczuk A, Huang Y, Johnson JL, Liu Y, Xiang J, Wang H, Cantley LC, tenOever BR, Ho DD, Pan FC, Evans T, Chen HJ, Schwartz RE, and Chen S
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- 2024
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41. A snapshot into the transcriptomic landscape of apoptosis and ferroptosis in cancer.
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Vinik Y and Lev S
- Subjects
- Humans, Ferroptosis genetics, Neoplasms genetics, Neoplasms pathology, Neoplasms metabolism, Apoptosis genetics, Transcriptome genetics
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- 2024
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42. Nuclear RNA-related processes modulate the assembly of cytoplasmic RNA granules.
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Angel M, Fleshler E, Atrash MK, Kinor N, Benichou JIC, and Shav-Tal Y
- Subjects
- Humans, Cytoplasm metabolism, Eukaryotic Initiation Factor-2 metabolism, HeLa Cells, Phosphorylation, RNA Splicing, Stress Granules metabolism, Transcription, Genetic, Active Transport, Cell Nucleus, Cell Nucleus metabolism, Cell Nucleus genetics, Cytoplasmic Granules metabolism, RNA, Messenger metabolism, RNA, Messenger genetics
- Abstract
Stress granules (SGs) are cytoplasmic assemblies formed under various stress conditions as a consequence of translation arrest. SGs contain RNA-binding proteins, ribosomal subunits and messenger RNAs (mRNAs). It is well known that mRNAs contribute to SG formation; however, the connection between SG assembly and nuclear processes that involve mRNAs is not well established. Here, we examine the effects of inhibiting mRNA transcription, splicing and export on the assembly of SGs and the related cytoplasmic P body (PB). We demonstrate that inhibition of mRNA transcription, splicing and export reduces the formation of canonical SGs in a eukaryotic initiation factor 2α phosphorylation-independent manner, and alters PB size and quantity. We find that the splicing inhibitor madrasin promotes the assembly of stress-like granules. We show that the addition of synthetic mRNAs directly to the cytoplasm is sufficient for SG assembly, and that the assembly of these SGs requires the activation of stress-associated protein synthesis pathways. Moreover, we show that adding an excess of mRNA to cells that do not have active splicing, and therefore have low levels of cytoplasmic mRNAs, promotes SG formation under stress conditions. These findings emphasize the importance of the cytoplasmic abundance of newly transcribed mRNAs in the assembly of SGs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2024
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43. Root-secreted nucleosides: signaling chemoattractants of rhizosphere bacteria.
- Author
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Keren G, Yehezkel G, Satish L, Adamov Z, Barak Z, Ben-Shabat S, Kagan-Zur V, and Sitrit Y
- Abstract
The rhizosphere is a complex ecosystem, consisting of a narrow soil zone influenced by plant roots and inhabited by soil-borne microorganisms. Plants actively shape the rhizosphere microbiome through root exudates. Some metabolites are signaling molecules specifically functioning as chemoattractants rather than nutrients. These elusive signaling molecules have been sought for several decades, and yet little progress has been made. Root-secreted nucleosides and deoxynucleosides were detected in exudates of various plants by targeted ultra-performance liquid chromatography-mass spectrometry/mass spectrometry. Rhizobacteria were isolated from the roots of Helianthemum sessiliflorum carrying the mycorrhizal desert truffle Terfezia boudieri . Chemotaxis was determined by a glass capillary assay or plate assays on semisolid agar and through a soil plate assay. Nucleosides were identified in root exudates of plants that inhabit diverse ecological niches. Nucleosides induced positive chemotaxis in plant beneficial bacteria Bacillus pumilus , Bacillus subtilis , Pseudomonas turukhanskensis spp., Serratia marcescens , and the pathogenic rhizobacterium Xanthomonas campestris and E coli . In a soil plate assay, nucleosides diffused to substantial distances and evoked chemotaxis under conditions as close as possible to natural environments. This study implies that root-secreted nucleosides are involved in the assembly of the rhizosphere bacterial community by inducing chemotaxis toward plant roots. In animals, nucleoside secretion known as "purinergic signaling" is involved in communication between cells, physiological processes, diseases, phagocytic cell migration, and bacterial activity. The coliform bacterium E. coli that inhabits the lower intestine of warm-blooded organisms also attracted to nucleosides, implying that nucleosides may serve as a common signal for bacterial species inhabiting distinct habitats. Taken together, all these may indicate that chemotaxis signaling by nucleosides is a conserved universal mechanism that encompasses living kingdoms and environments and should be given further attention in plant rhizosphere microbiome research., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Keren, Yehezkel, Satish, Adamov, Barak, Ben-Shabat, Kagan-Zur and Sitrit.)
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- 2024
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44. Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification.
- Author
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Parikh R, Parikh S, Berzin D, Vaknine H, Ovadia S, Likonen D, Greenberger S, Scope A, Elgavish S, Nevo Y, Plaschkes I, Nizri E, Kobiler O, Maliah A, Zaremba L, Mohan V, Sagi I, Ashery-Padan R, Carmi Y, Luxenburg C, Hoheisel JD, Khaled M, Levesque MP, and Levy C
- Abstract
Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression., (© 2024. The Author(s).)
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- 2024
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45. Interventricular septal thickness on cardiac computed tomography as a novel risk factor for conduction disturbances in patients undergoing transcatheter aortic valve replacement.
- Author
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Schamroth Pravda N, Shaleve Y, Plakht Y, Shafir G, Grinberg T, Wiessman M, Aviv Y, Vaknin Assa H, Codner P, Golovchiner G, Barsheshet A, Kornowski R, Shiyovich A, and Hamdan A
- Subjects
- Humans, Male, Female, Aged, 80 and over, Risk Factors, Aged, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac physiopathology, Arrhythmias, Cardiac diagnostic imaging, Heart Conduction System physiopathology, Heart Conduction System diagnostic imaging, Treatment Outcome, Predictive Value of Tests, Risk Assessment, Severity of Illness Index, Retrospective Studies, Aortic Valve surgery, Aortic Valve diagnostic imaging, Multidetector Computed Tomography, Tomography, X-Ray Computed, Action Potentials, Transcatheter Aortic Valve Replacement adverse effects, Aortic Valve Stenosis surgery, Aortic Valve Stenosis diagnostic imaging, Ventricular Septum diagnostic imaging
- Abstract
Aims: We examined whether thickness of the basal muscular interventricular septum (IVS), as measured by pre-procedural computed tomography (CT), could be used to identify the risk of conduction disturbances following transcatheter aortic valve replacement (TAVR). The IVS is a pivotal region of the electrical conduction system of the heart where the atrioventricular conduction axis is located., Methods and Results: Included were 78 patients with severe aortic stenosis who underwent CT imaging prior to TAVR. The thickness of muscular IVS was measured in the coronal view, in systolic phases, at 1, 2, 5, and 10 mm below the membranous septum (MS). The primary endpoint was a composite of conduction disturbance following TAVR. Conduction disturbances occurred in 24 out of 78 patients (30.8%). Those with conduction disturbances were significantly more likely to have a thinner IVS than those without conduction disturbances at every measured IVS level (2.98 ± 0.52 mm vs. 3.38 ± 0.52 mm, 4.10 ± 1.02 mm vs. 4.65 ± 0.78 mm, 6.11 ± 1.12 mm vs. 6.88 ± 1.03 mm, and 9.72 ± 1.95 mm vs. 10.70 ± 1.55 mm for 1, 2, 5 and 10 mm below MS, respectively, P < 0.05 for all). Multivariable logistic regression analysis showed that pre-procedural IVS thickness (<4 mm at 2 mm below the MS) was a significant independent predictor of post-procedural conduction disturbance (adjOR 7.387, 95% CI: 2.003-27.244, P = 0.003)., Conclusion: Pre-procedural CT assessment of basal IVS thickness is a novel predictive marker for the risk of conduction disturbances following TAVR. The IVS thickness potentially acts as an anatomical barrier protecting the underlying conduction system from mechanical compression during TAVR., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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46. Author Correction: Systemic dysfunction and plasticity of the immune macroenvironment in cancer models.
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Allen BM, Hiam KJ, Burnett CE, Venida A, DeBarge R, Tenvooren I, Marquez DM, Cho NW, Carmi Y, and Spitzer MH
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- 2024
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47. Programming a Ferroptosis-to-Apoptosis Transition Landscape Revealed Ferroptosis Biomarkers and Repressors for Cancer Therapy.
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Vinik Y, Maimon A, Dubey V, Raj H, Abramovitch I, Malitsky S, Itkin M, Ma'ayan A, Westermann F, Gottlieb E, Ruppin E, and Lev S
- Subjects
- Humans, Animals, Mice, Female, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Disease Models, Animal, Biomarkers metabolism, Ferroptosis genetics, Apoptosis genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism
- Abstract
Ferroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis-to-apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA-assaociated protein 1(PDAP1), is found to suppress basal-like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)-stress and phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
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- 2024
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48. Emulated Trial for Discharge Prescription of Guideline-Directed Medical Therapy and 15-Year Survival After Coronary Artery Bypass Graft Surgery.
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Moshkovitz Y, Orenstein L, Olmer L, Laufer K, Ziv A, and Dankner R
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- Humans, Male, Female, Prospective Studies, Aged, Middle Aged, Israel epidemiology, Adrenergic beta-Antagonists therapeutic use, Practice Guidelines as Topic, Coronary Artery Bypass mortality, Patient Discharge statistics & numerical data, Platelet Aggregation Inhibitors therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Objectives: To explore admission and discharge prescription rates of guideline-directed medical therapy (GDMT), defined as aggregate antiplatelet agents, statins, and β-blockers, after coronary artery bypass graft (CABG) surgery and to reveal its association with long-term survival., Patients and Methods: This is a prospective cohort study-based emulated trial of patients undergoing elective or semi-elective isolated CABG surgery in 7 cardiothoracic units in Israel from January 1, 2004, to December 31, 2007, and followed up until December 31, 2020, for all-cause mortality., Results: Only 59.2% of 968 patients (n=573) were discharged on GDMT after CABG surgery. Admission GDMT use conferred a 7 times greater likelihood of discharge GDMT prescription (odds ratio, 7.07; 95% CI, 5.04 to 9.91; P<.001), with no sex differences observed. After applying inverse probability of treatment weighting, baseline characteristics were well balanced between groups. During a median follow-up of 13.7 years, a Cox regression model with propensity score-adjusted inverse probability of treatment weighting revealed lower mortality in patients with discharge GDMT prescription who underwent CABG surgery than in their counterparts (hazard ratio, 0.75; 95% CI, 0.60 to 0.93; P=.008)., Conclusion: The use of aggregate GDMT before surgery conferred a greater likelihood of GDMT prescription upon discharge, which, in turn, is associated with better long-term survival. Educational efforts of pertinent medical professionals are needed to minimize preventive treatment gaps., Trial Registration: clinicaltrials.gov Identifier: NCT00356863., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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49. Author Correction: Continuous glucose monitoring and intrapersonal variability in fasting glucose.
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Shilo S, Keshet A, Rossman H, Godneva A, Talmor-Barkan Y, Aviv Y, and Segal E
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- 2024
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50. Continuous glucose monitoring and intrapersonal variability in fasting glucose.
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Shilo S, Keshet A, Rossman H, Godneva A, Talmor-Barkan Y, Aviv Y, and Segal E
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- Humans, Middle Aged, Adult, Male, Female, Aged, Diabetes Mellitus blood, Diabetes Mellitus diagnosis, Continuous Glucose Monitoring, Blood Glucose analysis, Fasting blood, Prediabetic State diagnosis, Prediabetic State blood, Blood Glucose Self-Monitoring methods
- Abstract
Plasma fasting glucose (FG) levels play a pivotal role in the diagnosis of prediabetes and diabetes worldwide. Here we investigated FG values using continuous glucose monitoring (CGM) devices in nondiabetic adults aged 40-70 years. FG was measured during 59,565 morning windows of 8,315 individuals (7.16 ± 3.17 days per participant). Mean FG was 96.2 ± 12.87 mg dl
-1 , rising by 0.234 mg dl-1 per year with age. Intraperson, day-to-day variability expressed as FG standard deviation was 7.52 ± 4.31 mg dl-1 . As there are currently no CGM-based criteria for diabetes diagnosis, we analyzed the potential implications of this variability on the classification of glycemic status based on current plasma FG-based diagnostic guidelines. Among 5,328 individuals who would have been considered to have normal FG based on the first FG measurement, 40% and 3% would have been reclassified as having glucose in the prediabetes and diabetes ranges, respectively, based on sequential measurements throughout the study. Finally, we revealed associations between mean FG and various clinical measures. Our findings suggest that careful consideration is necessary when interpreting FG as substantial intraperson variability exists and highlight the potential impact of using CGM data to refine glycemic status assessment., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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