Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical grade tumor-redirected TSCM cells starting from nave precursors. CD8+CD62L+CD45RA+ nave T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3 inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions allowed for the generation of CD19-CAR modified TSCM cells that were phenotypically, functionally and transcriptomically equivalent to their naturally occurring counterpart. Compared with T cell products currently under clinical investigation, CD19-CAR modified TSCM cells exhibit enhanced metabolic fitness, persistence and anti-tumor activity against systemic acute lymphoblastic leukemia xenografts. Based on these findings, we have initiated a phase 1 clinical study to evaluate the activity of CD19-CAR modified TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation.
Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies.
Subject
View SamplesThe aim of this study was to minimize the number of candidate genes responsible for salt tolerance between a pair of rice varieties (CSR27 and MI48) with contrasting level of salt tolerance by bulked segregant analysis of their recombinant inbred lines. Microarray analysis of RNA extracted from the tolerant and susceptible parents without and with stress showed 798 and 2407 differentially expressed genes, respectively. The number of differentially expressed genes was drastically reduced to 70 and 30, by pooling the RNAs from ten extreme tolerant and ten extreme susceptible RILs due to normalization of irrelevant differentially expressed genes between the parents.
Combining QTL mapping and transcriptome profiling of bulked RILs for identification of functional polymorphism for salt tolerance genes in rice (Oryza sativa L.).
No sample metadata fields
View SamplesGoal was to detect differences in response to TLR7 versus TLR8 agonists in human monocytes from healthy donors
Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity.
Specimen part, Treatment, Subject
View SamplesAntisense long non-coding (aslnc)RNAs represent a substantial part of eukaryotic transcriptomes that are, in yeast, controlled by the Xrn1 exonuclease. Nonsense-Mediated Decay (NMD) destabilizes the Xrn1-sensitive aslncRNAs (XUT), but what determines their sensitivity remains unclear. We report that 3’ single-stranded (3’-ss) extension mediates XUTs degradation by NMD, assisted by the Mtr4 and Dbp2 helicases. Single-gene investigation, genome-wide RNA analyses and double-stranded (ds)RNA mapping revealed that 3''-ss extensions discriminate the NMD-targeted XUTs from stable lncRNAs. Ribosome profiling showed that XUT are translated locking them for NMD activity. Interestingly, mutants of the Mtr4 and Dbp2 helicases accumulated XUTs, suggesting that dsRNA unwinding is a critical step for degradation. Indeed, expression of anti-complementary transcripts protects cryptic intergenic lncRNAs from NMD. Our results indicate that aslncRNAs form dsRNA that are only translated and targeted to NMD if dissociated by Mtr4 and Dbp2. We propose that NMD buffers genome expression by discarding pervasive regulatory transcripts. Overall design: Strand-specific transcriptome analysis of biological replicates (1) of WT and xrn1-delta cells of the S288C, W303 and SK1 (n & 2n) genetic background of S. cerevisiae; (2) of WT, dcp2-7 and upf1-delta cells; (3) of WT, xrn1-delta and dcp2-7 cells upon treatment of total RNA with Terminator 5''-Phosphate-Dependent Exonuclease. This record also contains CAGE-Seq analysis in wild-type and decapping-deficient cells of the budding yeast S. cerevisiae.
Nonsense-Mediated Decay Restricts LncRNA Levels in Yeast Unless Blocked by Double-Stranded RNA Structure.
Subject
View SamplesGene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood
AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.
Specimen part
View SamplesNeural stem cells were sorted according to their activated or quiescent state by flow cytometry using a set of 3 markers (LeX, CD24 and EGFR)
Distinct Molecular Signatures of Quiescent and Activated Adult Neural Stem Cells Reveal Specific Interactions with Their Microenvironment.
Sex, Specimen part
View SamplesIn the current study, we used exon arrays and clinical samples from a previous trial (SAKK 19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response (EGFR, KRAS, VEGFA).
EGFR exon-level biomarkers of the response to bevacizumab/erlotinib in non-small cell lung cancer.
Sex, Specimen part, Disease, Disease stage, Treatment
View SamplesHuman Whartons jelly stem cells (hWJSCs) are derived ethically in large amounts from the umbilical cord matrix. Besides their differentiation capabilities, WJSCs also display a notable lack of ability to form teratoma. hWJSCs have been shown to exert immunomodulatory effects and have recently been reported to kill or diminish cancer cell growth. These characteristics are important considerations for their use in cell therapy. In this transcriptome analysis, hWJSCs were profiled using Affymetrix DNA microarrays and compared to a panel of human stem cells and stromal cells. Although hWJSCs are multipotent, they expressed very low levels of the majority of stem cell markers, including POU5F1, NANOG, SOX2 and LIN28. BIRC5 has recently been shown to be required for teratoma formation in SCID mice. The lower levels of BIRC5 expression in hWJSCs compared to hESCs and the very low levels of stem cell markers might account for hWJSCs inability to form teratomas. IL12A which is known to be associated with the induction of apoptosis, was amongst the several cytokines identified to be significantly upregulated in hWJSCs. The ability of hWJSCs to compliment the host immune responses was further highlighted with the GO Biological Process analysis showing high association with immune system, chemotaxis and cell death. The ability to modulate immune responses confers hWJSCs an additional advantage in stem cell therapy and potentially allows hWJSCs as a form of treatment for cancer and immune disorders. In summary, the transcriptome profile of hWJSCs has provided indications on the genetic basis for their biological characteristics in immunomodulatory response, anti-cancer effects, and the lack of teratoma formation.
Human Wharton's jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells.
Specimen part
View SamplesPitx1, critical regulator of a limited hindlimb-specific gene network, targets the limb development program common to both fore- and hindlimbs in order to implement hindlimb-specific limb morphology. Overall design: The gene regulatory networks governing forelimb vs. hindlimb development in mouse were investigated using expressing profiling of morphologically stage-matched e10.5 forelimbs and e11.0 hindlimbs, ChIPseq of chromatin marks, and ChIPseq of limb-specific transcription factors Pitx1 and Tbx5. The makeup of the Pitx1-directed components of the hindlimb gene network were investigated using expression profiling of Pitx1 null hindlimbs at two stages (e11.0 and e11.5).
Regulatory integration of Hox factor activity with T-box factors in limb development.
Specimen part, Cell line, Subject
View SamplesHuman Whartons jelly stem cells (hWJSCs) are derived ethically in large amounts from the umbilical cord matrix. Besides their differentiation capabilities, WJSCs also display a notable lack of ability to form teratoma. hWJSCs have been shown to exert immunomodulatory effects and have recently been reported to kill or diminish cancer cell growth. These characteristics are important considerations for their use in cell therapy. In this transcriptome analysis, hWJSCs were profiled using Affymetrix DNA microarrays and compared to a panel of human stem cells and stromal cells. Although hWJSCs are multipotent, they expressed very low levels of the majority of stem cell markers, including POU5F1, NANOG, SOX2 and LIN28. BIRC5 has recently been shown to be required for teratoma formation in SCID mice. The lower levels of BIRC5 expression in hWJSCs compared to hESCs and the very low levels of stem cell markers might account for hWJSCs inability to form teratomas. IL12A which is known to be associated with the induction of apoptosis, was amongst the several cytokines identified to be significantly upregulated in hWJSCs. The ability of hWJSCs to compliment the host immune responses was further highlighted with the GO Biological Process analysis showing high association with immune system, chemotaxis and cell death. The ability to modulate immune responses confers hWJSCs an additional advantage in stem cell therapy and potentially allows hWJSCs as a form of treatment for cancer and immune disorders. In summary, the transcriptome profile of hWJSCs has provided indications on the genetic basis for their biological characteristics in immunomodulatory response, anti-cancer effects, and the lack of teratoma formation.
Human Wharton's jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells.
Specimen part
View Samples