The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index; 23 of the 51 sources its claims cite were checked for support.
Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells
Open accessAbstract
Adoptive transfer of dendritic cells (DCs) transfected with in vitro–transcribed, RNA-encoding, tumor-associated antigens has recently entered clinical testing as a promising approach for cancer immunotherapy. However, pharmacokinetic exploration of RNA as a potential drug compound and a key aspect of clinical development is still pending. While investigating the impact of different structural modifications of RNA molecules on the kinetics of the encoded protein in DCs, we identified components located 3′ of the coding region that contributed to a higher transcript stability and translational efficiency. With the use of quantitative reverse transcription–polymerase chain reaction (RT-PCR) and eGFP variants to measure transcript amounts and protein yield, we showed that a poly(A) tail measuring 120 nucleotides compared with a shorter one, an unmasked poly(A) tail with a free 3′ end rather than one extended with unrelated nucleotides, and 2 sequential β-globin 3′ untranslated regions cloned head to tail between the coding region and the poly(A) tail each independently enhanced RNA stability and translational efficiency. Consecutively, the density of antigen-specific peptide/MHC complexes on the transfected cells and their potency to stimulate and expand antigen-specific CD4+ and CD8+ T cells were also increased. In summary, our data provide a strategy for optimizing RNA-transfected DC vaccines and a basis for defining release criteria for such vaccine preparations.
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Claims the paper makes
26 Own result · 14 Own interpretation · 12 Partly supported · 5 No full text of the sources · 5 No basis given · 3 Supported so far · 1 Supported · 1 Couldn’t confirm · 1 Sources not found · 1 Own method · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Protein decay kinetics is regarded as a state-of-the-art tool favored over RNA kinetics because it allows integrated recording of all relevant translational characteristics in the function-oriented manner required for the objective of our investigations.20”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Overhang at the 3 end of the poly(A) tail hampers translational efficiency of IVT RNA
What the sources say
- Not checked — no full text of the sourcecites [19] Kren BT, Trembley JH, Steer CJ. Alterations in mRNA stability during rat liver regeneration. Am J Physiol. 1996;270: G763-G777. source
- Partly supportedcites [20] Tanguay RL, Gallie DR. Translational efficiency is regulated by the length of the 3' untranslated region. Mol Cell Biol. 1996;16: 146-156. sourceExperimental — accuracy not yet measured
The Results (page not available in our copy) use luciferase protein accumulation over time to measure translational efficiency and functional mRNA stability, and explain why functional half-life better reflects actively translated mRNA than physical half-life. They do not study protein decay kinetics or call the method state-of-the-art or generally favored over RNA kinetics; the two measures are quantified separately, not as a recording of all translational characteristics. (LLM, conf=0.85)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similar time kinetics have been reported for intradermally injected DCs in melanoma patients.52,53”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Supportedcites [52] de Vries IJ, Krooshoop DJ, Scharenborg NM, et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res. 2003;63: 12-17.
The section “Migratory Capacity of DCs after Injection into Melanoma Patients” (page not supplied) reports migration over time after intradermal injection in melanoma patients: mature DC migration was somewhat greater at 48 than at 24 hours, with no further increase observed through 144 hours in one patient. This supports the attribution that time kinetics were reported, though the unspecified comparison behind “similar” cannot be assessed from this claim. (LLM, conf=0.88)
- Partly supportedcites [53] Adema GJ, de Vries IJ, Punt CJ, Figdor CG. Migration of dendritic cell based cancer vaccines: in vivo veritas? Curr Opin Immunol. 2005;17: 170-174. sourceExperimental — accuracy not yet measured
The ‘Migration of ex vivo generated DC vaccines’ section reports that intradermally administered DCs reach draining lymph nodes, and the reference annotation for de Vries et al. identifies melanoma patients. Neither passage gives the time course of that migration, so the claimed similarity in time kinetics is unsupported by this copy. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“This variant has a half-life of 2 hours because of a C-terminal PEST region that promotes protein degradation.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Poly(A) tail length has an impact on translational efficiency
What the sources say
- Supportedcites [22] Li X, Zhao X, Fang Y, et al. Generation of destabilized green fluorescent protein as a transcription reporter. J Biol Chem. 1998;273: 34970-34975. source
The Discussion (page not provided) reports a 2-hour fluorescence half-life for the destabilized EGFP fusion and says it was made by appending the degradation domain of mouse ornithine decarboxylase to EGFP’s C terminus. It also identifies a PEST sequence in that domain and links it to degradation. The paper calls the variant dEGFP rather than d2eGFP. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
In the paper
“Notably, by revisiting our database of genomewide expression profiles of immature and mature human DCs obtained with microarrays, 46 we found that factors involved in RNA stability are induced in the course of maturation (data not shown).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [46] Tureci O, Bian H, Nestle FO, et al. Cascades of transcriptional induction during dendritic cell maturation revealed by genome-wide expression analysis. FASEB J. 2003;17: 836-847. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, for this structural modification, the translational characteristics influenced in immature DCs (primarily message stability and functional half-life) differed from those in mature DCs (primarily translation efficiency).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Two 3 UTRs of the human -globin gene cloned in tandem improve protein level
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Antigen titration shows a higher impact of stabilized IVT RNA constructs on CD4 ϩ compared with CD8 ϩ immune responses, most likely because of the preexistence of highaffinity CD8 ϩ T cells against immunodominant epitopes in the respective donor repertoires.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Density and persistence of peptide/MHC complexes correlated with the amount of RNA transferred into the cells.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Density of peptide/MHC complexes on the cell surface correlates with the dose of antigen-encoding RNA electroporated into cells
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, the level and stability of d2eGFP RNA and the protein amounts were higher in immature than in mature DCs.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Poly(A) tail length has an impact on translational efficiency
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, inclusion of the human -globin 5Ј UTR did not have an additional beneficial effect on protein yield (data not shown).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Two 3 UTRs of the human -globin gene cloned in tandem improve protein level
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As we show, this can be achieved by encoding the poly(A) tract in the template vector rather than attaching it by enzymatic polyadenylation.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 20
- It may state two separate claims as one. 24
- The quote only partly states this claim. 2
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Antigen-encoding RNA constructs used currently for preclinical studies have poly(A) tails measuring 30 to 70 nucleotides in length, 4,5 whereas those administered in clinical trials measure 64 nucleotides in length.8,12”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Could not verifycites [4] van Tendeloo VF, Ponsaerts P, Lardon F, et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 2001;98: 49-56. sourceExperimental — accuracy not yet measured
The ‘Production of in vitro-transcribed mRNA’ section describes the RNA templates and transcription method but gives no poly(A)-tail length. Searches for 64-nucleotide and poly(A) tails found no passage addressing the length of RNA constructs administered in clinical trials. (LLM, conf=0.76)
- Supportedcites [5] Teufel R, Carralot JP, Scheel B, et al. Human peripheral blood mononuclear cells transfected with messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes in vitro. Cell Mol Life Sci. 2005;62: 1755-1762. source
The Messenger RNA section states that the antigen-encoding RNActive constructs used in this study have a poly(A) tail of 70 As. This supports the 70-nucleotide end of the preclinical range for which this paper is cited; the separate clinical-trial claim carries other citations. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [8] Su Z, Dannull J, Yang BK, et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol. 2005;174: 3798-3807. source
- Not checked — no full text of the sourcecites [12] Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002; 109: 409-417. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The poly(A) tail regulates the fate of mRNA by synergy with the 5Ј cap, with the internal ribosomal entry site, and with various RNA stability determinants.31,[38][39][40][41]”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [31] Gallie DR. A tale of two termini: a functional interaction between the termini of an mRNA is a pre-requisite for efficient translation initiation. Gene. 1998;216: 1-11. source
- Partly supportedcites [38] Grosset C, Chen CY, Xu N, et al. A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c-fos RNA coding determinant via a protein complex. Cell. 2000;103: 29-40. sourceExperimental — accuracy not yet measured
The passages labeled Abstract (page unavailable) describe an interaction between the poly(A) tail and 5′ cap that influences translation, and experiments linking the tail to an mRNA decay determinant, the mCRD. They also mention cap-independent initiation, but do not establish that the poly(A) tail acts synergistically with an internal ribosomal entry site. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [39] Wakiyama M, Imataka H, Sonenberg N. Interaction of eIF4G with poly(A)-binding protein stimulates translation and is critical for Xenopus oocyte maturation. Curr Biol. 2000;10: 1147-1150. source
- Partly supportedcites [40] Wang Z, Day N, Trifillis P, Kiledjian M. An mRNA stability complex functions with poly(A)-binding protein to stabilize mRNA in vitro. Mol Cell Biol. 1999;19: 4552-4560. sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) describes an interaction between a stability complex on the α-globin mRNA 3′ UTR and poly(A)-binding protein that may slow deadenylation. The paper also discusses protective roles for the 5′ cap and poly(A) tail, but the passages do not establish synergy between them or address synergy with an internal ribosomal entry site. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [41] Preiss T, Muckenthaler M, Hentze MW. Poly(A)-tail-promoted translation in yeast: implications for translational control. RNA. 1998;4: 1321-1331. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The mechanisms underlying the steady state levels of naturally expressed mRNAs in the cytoplasm have received considerable attention recently because the regulation of mRNA turnover plays a major role in the overall control of gene expression.26,27”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Could not verifycites [26] Gebauer F, Hentze MW. Molecular mechanisms of translational control. Nat Rev Mol Cell Biol. 2004;5: 827-835. sourceExperimental — accuracy not yet measured
The Main section discusses translational control of gene expression, including whether cytoplasmic mRNAs are actively translated. It does not address mRNA turnover as a determinant of steady-state mRNA levels or say that those mechanisms have received considerable attention (searched: mRNA turnover, steady-state levels, stability, degradation and decay). (LLM, conf=0.72)
- Not checked — no full text of the sourcecites [27] Cleveland DW. Gene regulation through messenger RNA stability. Curr Opin Cell Biol. 1989;1: 1148-1153. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, it has also been reported that the production of MHC-associated epitopes and priming of cytotoxic T-lymphocytes is achieved even if the full-length protein encoded by the transferred RNA cannot be detected in DCs.42,48”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [42] Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med. 1996;184: 465-472. sourceExperimental — accuracy not yet measured
The Results (p. 468) show that RNA-pulsed dendritic cells induced OVA-specific cytotoxic T lymphocytes, and the Discussion (p. 470) links this to antigen presentation through the MHC class I pathway. Our copy does not report that full-length protein encoded by the transferred RNA was undetectable in the dendritic cells, so it does not support that condition of the claim. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [48] Grunebach F, Muller MR, Nencioni A, Brossart P. Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes. Gene Ther. 2003;10: 367-374. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Antigen-encoding RNA 1,2 has the advantages of a genetic vaccine (delivery of all epitopes of the whole antigen, easy manufacturing, standardized purification) and the added value of a safe pharmaceutical characterized by transient expression and lack of integration into the genome of the treated host.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] Hoerr I, Obst R, Rammensee HG, Jung G. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000;30: 1-7. source
- Partly supportedcites [2] Carralot JP, Probst J, Hoerr I, et al. Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines. Cell Mol Life Sci. 2004;61: 2418-2424. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“As previous reports show, the length of the 3Ј UTR as such has an effect on the stability and translational efficiency of poly(A)-negative RNA but not of poly(A)-positive RNA, for which a 27-bp 3Ј UTR appears to be optimal.20”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [20] Tanguay RL, Gallie DR. Translational efficiency is regulated by the length of the 3' untranslated region. Mol Cell Biol. 1996;16: 146-156. sourceExperimental — accuracy not yet measured
The Results report that increasing 3′ UTR length increased translational efficiency and half-life for poly(A)-negative mRNA, while these measures varied little for poly(A)-positive mRNA over most lengths tested. The claim's categorical 'not' misses a substantial exception: a 7-base UTR sharply reduced translation of poly(A)-positive mRNA. The reported 27-base optimum is specifically for poly(A)-tail-mediated stimulation of translation. Page numbers are not provided in the supplied passages. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Previous studies reported that the density of MHC epitopes presented on the cell surface correlates with the amount of intracellular protein detected at a defined time point.47”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [47] Princiotta MF, Finzi D, Qian SB, et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity. 2003;18: 343-354. sourceExperimental — accuracy not yet measured
The Results passage on quantitating peptide–class I complexes reports that, for KEKE-NP-GFP, the rate of complex formation increased as a cellular protein pool accumulated. That supports a relationship in this experimental condition, but it does not establish the claimed general correlation between surface epitope density and the amount of intracellular protein detected at a single time point; the paper also reports different complex-formation kinetics for its other substrates. Our copy provides no page number for the deciding passage. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“(having been reported as the amount required for induction of robust IFN-␥ secretion of specific T cells in this particular system 17 )”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [17] Porgador A, Yewdell JW, Deng Y, Bennink JR, Germain RN. Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. Immunity. 1997;6: 715-726. sourceExperimental — accuracy not yet measured
In “Sensitivity of Ligand Detection” (page unavailable), the paper compares SIINFEKL concentrations with IFN-γ secretion by a specific CD8+ T-cell line. Our copy discusses minimal concentrations for measurable secretion, but does not establish 56 pmol as an amount required for robust secretion; it reports peptide concentrations in pM, not amounts in pmol. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In principle, the improvement of RNA kinetics by these modifications is not restricted to DCs but is similar in K562 cells and may also be of interest for other cellular settings, such as T cells, 43 B cells, 44 and muscle cells, 45 which are attractive host cells for the expression of IVT RNA-encoded proteins.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Supportedcites [43] Zhao Y, Zheng Z, Cohen CJ, et al. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol Ther. 2006;13: 151-159. source
The citation is attached to T cells as a possible setting for expression of IVT RNA-encoded proteins, not to a claim that this paper tested the citing authors’ RNA modifications. The Discussion reports efficient mRNA electroporation of human and murine T cells and rapid protein expression after electroporation. The supplied passages have section labels but no page numbers. (LLM, conf=0.90)
- Supportedcites [44] Van den Bosch GA, Ponsaerts P, Nijs G, et al. Ex vivo induction of viral antigen-specific CD8 T cell responses using mRNA-electroporated CD40-activated B cells. Clin Exp Immunol. 2005;139: 458-467. source
The citation is attached specifically to B cells. In the Results section, the paper reports efficient expression of electroporated EGFP mRNA in CD40-activated B cells, supporting their identification as a cellular setting for IVT RNA-encoded protein expression. The proposed benefit of the citing paper’s RNA modifications is its own projection, not a result attributed to this source. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [45] Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247: 1465-1468. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Early clinical trials showed feasibility, lack of toxicity, and promising efficacy based on immunologic and clinical read-outs.[8][9][10][11][12]”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [8] Su Z, Dannull J, Yang BK, et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol. 2005;174: 3798-3807. source
- Supportedcites [9] Caruso DA, Orme LM, Neale AM, et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro-oncol. 2004;6: 236-246. source
The Feasibility and Toxicity sections report that vaccine production was feasible and vaccinations had no measurable toxicity. The Tumor Responses section reports clinical responses in 3 of 7 treated patients and modest increases in antitumor antibodies in 2 patients, supporting the cautious description of promising read-outs; it also notes that no statistically significant cell-mediated antitumor response was detected. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [10] Caruso DA, Orme LM, Amor GM, et al. Results of a phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with stage 4 neuroblastoma. Cancer. 2005;103: 1280-1291. source
- Not checked — no full text of the sourcecites [11] Morse MA, Nair SK, Mosca PJ, et al. Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest. 2003;21: 341-349. source
- Not checked — no full text of the sourcecites [12] Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002; 109: 409-417. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In vitro-transcribed RNA generated from plasmid templates and used in such studies typically consists of a 5Ј cap structure followed by the sequence encoding the antigen of interest and a poly(A) tail 30 to 70 nucleotides in length.4,5”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Introduction
What the sources say
- Partly supportedcites [4] van Tendeloo VF, Ponsaerts P, Lardon F, et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 2001;98: 49-56. sourceExperimental — accuracy not yet measured
The “Production of in vitro-transcribed mRNA” section (page unavailable) describes plasmid templates used to produce capped RNA, including RNA encoding the Melan-A antigen. Our copy does not specify a poly(A) tail or its claimed length of 30–70 nucleotides, so that part of the sentence is unsupported. (LLM, conf=0.86)
- Partly supportedcites [5] Teufel R, Carralot JP, Scheel B, et al. Human peripheral blood mononuclear cells transfected with messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes in vitro. Cell Mol Life Sci. 2005;62: 1755-1762. sourceExperimental — accuracy not yet measured
The “Messenger RNA” section (page unavailable) describes the study’s RNActive mRNAs as having a 5′ cap, an antigen-encoding open reading frame, and a poly(A) tail of 70 adenosines. It does not establish that a 30–70-nucleotide tail is typical across such studies or state that these mRNAs were generated from plasmid templates. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Vectors used currently for preclinical and clinical studies resort either to UTRs of -globin 5,14,23 or to autochthonous UTRs of the antigen they want to deliver, 12 which are not further characterized in terms of their impact on RNA stability.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [5] Teufel R, Carralot JP, Scheel B, et al. Human peripheral blood mononuclear cells transfected with messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes in vitro. Cell Mol Life Sci. 2005;62: 1755-1762. sourceExperimental — accuracy not yet measured
The Messenger RNA section (page unavailable) says the constructs used in this study contain UTRs from globin mRNAs, supporting this paper as an example of globin-UTR use. It does not specify β-globin or characterize the UTRs’ impact on RNA stability. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [14] Michiels A, Tuyaerts S, Bonehill A, et al. Electroporation of immature and mature dendritic cells: implications for dendritic cell-based vaccines. Gene Ther. 2005;12: 772-782. source
- Not checked — no full text of the sourcecites [23] Conry RM, LoBuglio AF, Wright M, et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 1995;55: 1397-1400.
- Not checked — no full text of the sourcecites [12] Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002; 109: 409-417. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Sequence elements within the 3Ј and 5Ј noncoding regions of the RNA molecule have been characterized as important factors in regulating the stability of a transcript in ways that are not completely understood.32,33”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Supportedcites [32] Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. Genome Biol. 2002;3: Reviews0004. source
The Regulation of mRNA stability section describes sequence elements in both UTRs that affect transcript stability: 3′ UTR elements regulate turnover, while upstream open reading frames in a 5′ UTR promote decay. It describes several proposed mechanisms of degradation, consistent with the claim’s qualification that the processes are not completely understood. No page numbers are available in our copy. (LLM, conf=0.88)
- Partly supportedcites [33] Yu J, Russell JE. Structural and functional analysis of an mRNP complex that mediates the high stability of human beta-globin mRNA. Mol Cell Biol. 2001;21: 5879-5888. sourceExperimental — accuracy not yet measured
The paper’s introductory discussion says that cis-acting elements, usually in the 3′ UTR, regulate mRNA stability; the Discussion identifies a stability element in the β-globin 3′ UTR. It also describes the 5′ cap as a general stabilizing feature, but does not characterize sequence elements within the 5′ noncoding region as stability regulators. Page numbers are not provided in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Mouse DCs start to enter the regional lymph node 18 hours after inoculation in the skin, reaching a maximum within 72 hours.50,51”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Partly supportedcites [50] Martin-Fontecha A, Sebastiani S, Hopken UE, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med. 2003;198: 615-621. sourceExperimental — accuracy not yet measured
In Results and Discussion, the authors report recovering injected mouse DCs from draining lymph nodes on day 2. They do not establish that entry begins at 18 hours or that DC numbers peak within 72 hours. The plateau by days 3–4 refers to total lymph-node cellularity, not DC migration. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [51] Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005;5: 617-628. source
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Expansion of T cells measured on day 7 in an IFN-␥ ELISpot using autologous DCs pulsed with a pool of overlapping peptides covering either the entire pp65 protein sequence or a control protein showed superiority of Sec-pp65-2-globinUTR-A(120), with effects most prominent for the expansion of CD4 ϩ T cells.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Stabilized IVT RNA increases the number of antigen-specific peptide/MHC complexes on the cell surface and improves the expansion of antigen-specific T cells in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Even after electroporation of RNA amounts as low as 10 pmol, surface expression of peptide/MHC molecules was easily detected 12 hours after transfection, declined over time, and was below the detection level 24 hours after RNA transfer (Figure 2).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Density of peptide/MHC complexes on the cell surface correlates with the dose of antigen-encoding RNA electroporated into cells
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, visual inspection of the curves showed that the message stability (eg, the length of time over which protein continued to accumulate) of both eGFP-A(67) and eGFP-A(67)ACUAG RNAs appeared to be comparable (Figure 4B).”
- Also stated in: § Overhang at the 3 end of the poly(A) tail hampers translational efficiency of IVT RNA · plain
“In addition, functional RNA half-life (eg, time needed to complete a 50% decay in the capacity of an RNA to synthesize protein, 21 which is a more accurate parameter than physical half-life because it also considers translational competence of an RNA species) is comparable for eGFP-A(67) and eGFP-A(67)ACUAG RNAs.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Overhang at the 3 end of the poly(A) tail hampers translational efficiency of IVT RNA
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Overhang at the 3 end of the poly(A) tail hampers translational efficiency of IVT RNA · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Again, protein levels were higher and decay was protracted in immature DCs compared with mature ones, with maximum protein levels sustained in steady state until 120 hours after electroporation (Figure 5C).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Poly(A) tail length has an impact on translational efficiency
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, 2 reiterated -globin 3Ј UTRs between the coding sequence and the poly(A) tail resulted in significantly higher maximum protein levels and prolonged persistence of the protein.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Two 3 UTRs of the human -globin gene cloned in tandem improve protein level
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“By combining these structural components, we achieved not only a more than 5-fold increase of maximum protein concentration but also persistence of protein expression over a longer time.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consecutively, the density of antigen-specific peptide/MHC complexes on the transfected cells and their potency to stimulate and expand antigen-specific CD4 ؉ and CD8 ؉ T cells were also increased.”
- Also stated in: § Introduction · boosted
“We show that this optimization improves the surface presentation of epitopes and the induction of T-cell responses.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Linearization with Sap1 improved expression significantly compared with restriction with Spe1 because the RNA with free-ending poly(A) tail resulted in 1.5-fold higher maximum protein levels and prolonged detectability of the protein.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Overhang at the 3 end of the poly(A) tail hampers translational efficiency of IVT RNA
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In principle, the improvement of RNA kinetics by these modifications is not restricted to DCs but is similar in K562 cells and may also be of interest for other cellular settings, such as T cells, 43 B cells, 44 and muscle cells, 45 which are attractive host cells for the expression of IVT RNA-encoded proteins.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As exemplified for immature and mature DCs by real-time RT PCR analysis, intracellular IVT RNA levels of d2eGFP variants at different time points after transfection were highest for poly(A) 120tailed RNA, suggesting that RNAs with shorter poly(A) tails undergo faster degradation (Figure 5A).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Poly(A) tail length has an impact on translational efficiency
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We detected significantly higher numbers of OVA peptide/K b complexes on the cell surface sustained over a longer time course upon electroporation of the genetically improved RNA Sec-SIINFEKL-2-globinUTR-A(120) (Figure 7A).”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Stabilized IVT RNA increases the number of antigen-specific peptide/MHC complexes on the cell surface and improves the expansion of antigen-specific T cells in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because many parameters influenced poly(A) tail length during the polyadenylation reaction, the number of attached ATP nucleotides could not be precisely controlled even if the same reaction conditions were applied.”
- Also stated in: § Enzymatic polyadenylation of RNA results in a mixture of transcripts varying in length · hedged
“In addition to this variability between different preparations, each individual preparation appeared to contain a mixture of RNA species differing in poly(A) tail length.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Enzymatic polyadenylation of RNA results in a mixture of transcripts varying in length
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Enzymatic polyadenylation of RNA results in a mixture of transcripts varying in length · hedged
In the paper
“These observations are not contradictory but may be explained by the fact that in addition to steady state protein levels, defective ribosomal products (DriPs) such as unfinished or misfolded proteins are quickly processed into peptides and contribute significantly to MHC-associated epitopes.49”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [49] Yewdell JW, Anton LC, Bennink JR. Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? J Immunol. 1996;157: 1823-1826. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, our report underscores that one of the many advantages of formulating the antigen as IVT RNA is the added value provided by recombinant DNA technology of easily engineering elements into vaccine constructs that enhance their potency.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Antigen titration shows a higher impact of stabilized IVT RNA constructs on CD4 ϩ compared with CD8 ϩ immune responses, most likely because of the preexistence of highaffinity CD8 ϩ T cells against immunodominant epitopes in the respective donor repertoires.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, templateencoded poly(A) tails were clearly superior because they reproducibly provided a well-defined product of sufficient purity.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Enzymatic polyadenylation of RNA results in a mixture of transcripts varying in length
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In some reports, the poly(A) tail is attached enzymatically by terminal polyadenylation instead of being encoded in the template.13”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [13] Steitz J, Britten CM, Wolfel T, Tuting T. Effective induction of anti-melanoma immunity following genetic vaccination with synthetic mRNA coding for the fusion protein EGFP.TRP2. Cancer Immunol Immunother. 2006;55: 246-253. source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“mRNA stability and translation are controlled by a complex network of RNA/protein interactions and depend on the primary and secondary structures of mRNAs, their rates of translation, and the initiation of one of the various degradation mechanisms.[28][29][30][31]”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [28] Guhaniyogi J, Brewer G. Regulation of mRNA stability in mammalian cells. Gene. 2001;265: 11-23. source
- Not checked — no full text of the sourcecites [29] Preiss T, Hentze W. Starting the protein synthesis machine: eukaryotic translation initiation. Bioessays. 2003;25: 1201-1211. source
- Not checked — no full text of the sourcecites [30] Meyer S, Temme C, Wahle E. Messenger RNA turnover in eukaryotes: pathways and enzymes. Crit Rev Biochem Mol Biol. 2004;39: 197-216. source
- Not checked — no full text of the sourcecites [31] Gallie DR. A tale of two termini: a functional interaction between the termini of an mRNA is a pre-requisite for efficient translation initiation. Gene. 1998;216: 1-11. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Flow cytometric data presented in Figure 6C feature results of 3 independent experiments conducted in parallel, showing nearly no SD and proving the high reproducibility of this procedure.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > The combination of the optimal poly(A) length, a free-ending poly(A) tail, and an optimized 3 UTR act synergistically on RNA stability and translational efficiency
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, we observed that stability and decay kinetics of the RNAs differ in immature and mature human DCs, most likely because of differences in the complex network of RNA/protein interactions in both cell types.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For human DCs, this is the only study systematically investigating the influence of several 3Ј elements on translational characteristics of transiently expressed RNA.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, our data provide a strategy for optimizing RNA-transfected DC vaccines and a basis for defining release criteria for such vaccine preparations.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“The gene of interest is used with its autochthonous noncoding regions 12 or is flanked by the untranslated region (UTR) of the human or Xenopus laevis -globin gene.14”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [12] Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002; 109: 409-417. source
- Not checked — no full text of the sourcecites [14] Michiels A, Tuyaerts S, Bonehill A, et al. Electroporation of immature and mature dendritic cells: implications for dendritic cell-based vaccines. Gene Ther. 2005;12: 772-782. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we confirm our starting assumption that the optimization of structural features of antigen-encoding RNA increases the density and stability of peptide/MHC complexes on the cell surface and translates into improved stimulation of CD4 ϩ and CD8 ϩ T cells in murine and human systems.”
§ Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The capacity of an antigen-encoding IVT RNA vaccine to induce efficient T-cell responses depends on prolonged surface presentation of sufficient amounts of MHC-bound peptide epitopes derived from the RNA-encoded antigen.
The paper relies on this without support.
Neither the pharmacokinetics of antigen-encoding RNA within DCs nor the impact of structural features of the drug formulation on its pharmacologic properties has thus far been addressed for antigen-encoding RNA.
“Neither of these questions has thus far been addressed for antigen-encoding RNA.”
The paper relies on this without support.
The effects of each structural feature on the intracellular bioavailability of IVT RNA have not been systematically investigated.
“The effects of each of these structural features on the intracellular bioavailability of the RNA molecule have not been systematically investigated.”
The paper relies on this without support.
Little is known about the time-dose curve and the translational efficiency of IVT antigen-encoding RNA after its electroporation into DCs.
“In fact, surprisingly little is known about the time-dose curve and the translational efficiency of in vitro-transcribed (IVT) antigen-encoding RNA after its electroporation into DCs.”
The paper relies on this without support.
A dose-response relationship between the levels of antigen-encoding RNA within the cell and the peptide/MHC molecules on the cell surface has not been established.
“Similarly, a dose-response relationship between the levels of antigen-encoding RNA within the cell and the peptide/MHC molecules on the cell surface has not been established.”
The paper relies on this without support.
The extent to which the density of peptide/MHC complexes on the cell surface can be influenced by augmenting RNA stability remains unclear.
“Thus, the extent to which the density of peptide/ MHC complexes on the cell surface can be influenced by augmenting RNA stability remains unclear.”
The paper relies on this without support.
This is the first study to determine the structural modifications that increase the stability and translational efficiency of RNA molecules in DCs.
“To our knowledge, this is the first study to determine the structural modifications that increase the stability and translational efficiency of RNA molecules in DCs.”
The paper relies on this without support.
The capacity of an antigen-encoding IVT RNA vaccine to induce efficient T-cell responses depends on prolonged surface presentation of sufficient amounts of MHC-bound peptide epitopes derived from the RNA-encoded antigen.
“The mode of action of such a vaccine and its capacity to induce efficient T-cell responses depends on prolonged surface presentation of sufficient amounts of MHC-bound peptide epitopes derived from the RNA-encoded antigen.”
Claims other papers make about this one
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In the citing paper
“These strategies have yielded modest improvements in RNA stability10, 13–16, and thus alternative approaches to RNA stabilization, such as circularization, are desirable.”
From Engineering circular RNA for potent and stable translation in eukaryotic cells (2018) · cites this paper as [13]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source doesn’t support the claim as written.
In the citing paper
“A poly(A) tail of 120 units is considered the standard size for mRNA vaccines.9,20,21”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [9]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source doesn’t support the claim as written.
In the citing paper
“Furthermore, Holtkamp et al., have shown that 2 copies of 3′ UTR from β-globin result in increased protein levels and mRNA stability only in immature dendritic cells, whereas in mature dendritic cells, no effect could be observed18.”
From Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts (2016) · cites this paper as [18]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Both of the candidates are pharmacologically optimized 15,16 , N 1 -methylpseudouridine nucleoside-modified mRNAs 17 that are administered intramuscularly in a prime-boost regimen 21”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“The antigen-encoding RNA contains sequence elements that increase RNA stability and translation efficiency in human dendritic cells 15,16 .”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“numerous works have developed specific UTRs to increase the translational efficiency of mRNAs, as the use of one or two copies of the 3′ UTR of the globin or other known stable mRNA8,9 or short 14-nucleotide 5′ UTR.27”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [9]
The cited source says what the claim attributes to it.
In the citing paper
“The steady effect of human β-globin 3ʹ-UTR sequences is enhanced when two human β-globin 3ʹ-UTRs are placed in a head-to-tail orientation (Holtkamp et al. 2006).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Holtkamp et al. 2006
The cited source says what the claim attributes to it.
In the citing paper
“The structural characteristics of mRNA such as the CAP, poly(A) tail, and untranslated regions (UTRs) directly impact mRNA stability and translation efficiency (Orlandini von Niessen et al. 2019; Holtkamp et al. 2006).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Holtkamp et al. 2006
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, they could show that insertion of one copy of the 3′-UTR from human β-globin serves to increase protein translation which was further increased when two copies of the same 3′-UTR were introduced back-to-back18.”
From Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts (2016) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“We had previously shown in hDCs that two head-to-tail-cloned hBg 3′ UTRs (2hBg) are superior to a single copy in improving mRNA stability.7”
From Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening (2019) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“The potency of the antigen-specific immune response correlates positively with the persistence of the synthetic mRNA in the hDCs and the amount of translated protein.7,8”
From Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening (2019) · cites this paper as [7]
In the citing paper
“The design of (non-coding) structural elements of the mRNA such as the CAP structure, poly(A) tail and untranslated regions (UTRs) all have a major impact on the mRNA stability and translation capacity [31,32]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [32]
In the citing paper
“Correlations were found between the elongation of the poly(A) tail of mRNA and the duration of expression, and specific modifications at the 3' UTR were reported that can slow-down the decay of the poly(A) tail by deadenylation [57,58].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [57]
In the citing paper
“The beneficial effect of two copies of the same UTR has been reported previously by Holtkamp et al.18.”
From Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts (2016) · cites this paper as [18]
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Metadata
- Authors
- Holtkamp, S., Kreiter, S., Selmi, A., Simon, P., Koslowski, M., Huber, C., Türeci, O., & Sahin, U.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- From the Department of Internal Medicine III, Division of Experimental and Translational Oncology, Johannes-Gutenberg University, Mainz, Germany.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-12-15
- Volume
- 108
- Issue
- 13
- Pages
- 4009-4017
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2039422212
- Semantic Scholar
- 48122d1dd006266c2abd2c302acdc4fe220181de
- Cited by
- 625
- References
- 54
- Citations by year
- 2026: 51 · 2025: 62 · 2024: 60 · 2023: 73 · 2022: 77 · 2021: 62 · 2020: 35 · 2019: 25 · 2018: 35 · 2017: 20 · 2016: 24 · 2015: 22 · 2014: 11 · 2013: 13 · 2012: 7
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- dendritic cell vaccine, RNA vaccines, tumor-associated antigens, poly(A) tail length, 3' untranslated region, transcript stability, translation efficiency, antigen presentation, peptide-MHC complex, T cell stimulation, adoptive cell transfer, cancer immunotherapy, pharmacokinetics
- MeSH terms
- Animals, Antigens, Neoplasm, Cells, Cultured, Dendritic Cells, Humans, Lymphocyte Activation, Male, Neoplasms, Poly A, RNA, Neoplasm, Transfection, CD4-Positive T-Lymphocytes, Immunotherapy, Adoptive, Antigen Presentation, CD8-Positive T-Lymphocytes, Coculture Techniques, Cancer Vaccines, RNA Stability, Mice
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