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Simulated clinical trial work flow and shared neoantigen analysis. Using ca...
Published: 30 November 2021
FIGURE 1 Simulated clinical trial work flow and shared neoantigen analysis. Using cancer-type matched cohorts from the TCGA, 33 samples were selected randomly and designated as either “vaccine” (n = 3) or “patient” (n = 30). Analysis was then performed to determine the number of shared tumor-specific neoantigens between the pooled vaccine and each patient individually. Right, a neoantigen analysis workflow is depicted. Tumor-specific neoantigens were determined for each sample individually in the following order. All somatic variants in the tumor were first identified. Non–protein-altering variants were excluded. The total pool of possible peptides was then calculated, and those that did not result in a predicted neoantigen with an IC50 < 500 nm were excluded for the lysate-based analysis. In addition, predicted neoantigens not presented on both the vaccine and patient's MHC haplotype were excluded for the cell-based analysis (Materials and Methods). More
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TAA expression analysis.  A,  TAA expression in a single simulation of a pa...
Published: 30 November 2021
FIGURE 2 TAA expression analysis. A, TAA expression in a single simulation of a pancreatic adenocarcinoma clinical trial. Tumor associated antigen counts (MUC1 and Mesothelin for PAAD) are summarized for an example trial simulation in pancreatic adenocarcinoma. TAAs were assessed for each patien... More
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Shared neoantigen analysis in melanoma.  A,  Single Iteration of a simulate...
Published: 30 November 2021
FIGURE 3 Shared neoantigen analysis in melanoma. A, Single Iteration of a simulated clinical trial using TCGA's melanoma (SKCM) cohort. The count of each patient's (n = 30) protein-altering somatic variants and predicted neoantigens are shown in the top left panel. Quantification of each designated “vaccine” sample, both individually (n = 3) and as a pooled “Vaccine” are provided in the top right panel. Shared variants and predicted neoantigens by cell-based and lysate-based analysis are shown in the bottom panel. B, Lysate-based neoantigen analysis of melanoma simulated clinical trial. Ten clinical trials in melanoma were simulated analyzing a total of 300 patients. The total number of shared neoantigens that each patient shared with the vaccine, by lysate-based analysis, is shown in the left. In patients who had one or more shared neoantigens with the vaccine, the identity and frequency of each neoantigen is shown in the right. C, Cell-based neoantigen analysis of melanoma simulated clinical trial. Ten clinical trials in melanoma were simulated analyzing a total of 300 patients. The total number of shared neoantigens that each patient shared with the vaccine, by cell-based analysis, is shown in the left. In patients who had one or more shared neoantigens with the vaccine, the identity and frequency of each neoantigen is shown in the right. More
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Shared neoantigen analysis in common allogeneic vaccine cancer types.  A,  ...
Published: 30 November 2021
FIGURE 4 Shared neoantigen analysis in common allogeneic vaccine cancer types. A, Lysate-based overlap analysis. Counts of shared neoantigens per patient for each cancer type based on a lysate-based vaccine administration are shown on the left. Counts summarize 10 complete trial simulations (300... More
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Genome-wide germline variant and alloantigen analysis.  A,  Alloantigen ana...
Published: 30 November 2021
FIGURE 5 Genome-wide germline variant and alloantigen analysis. A, Alloantigen analysis in a single simulation of a melanoma clinical trial. Nonspecific alloantigen presentation provided by allogeneic vaccines are quantified for each of 30 patients. Unique protein altering variants (teal) are shown along with those predicted to be strong binding (IC50 < 500 nm) by cell based (tan) and lysate-based (green) analysis. B, Alloantigen analysis for five common cancer types, lysate and cell-based. The counts of predicted alloantigens corresponding to 10 simulated vaccine trials for five cancer types (300 simulated patients per cancer type) are depicted as violin plots for both a lysate-based (top) and cell-based (bottom) analysis. More
Journal Articles
Cancer Research Communications (2021) 1 (2): 115–126.
Published: 30 November 2021
Includes: Supplementary data
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A,  DFS after surgery in patients treated (<em>n</em> = 135) or not...
Published: 22 November 2021
FIGURE 1 A, DFS after surgery in patients treated (n = 135) or not treated (n = 125) with DPP-4i was evaluated using the Kaplan–Meier method and P value was calculated using the log-rank test. B, DFS of 94 patients who were confirmed to have continued DPP-4i treatment after colectomy compared with DFS of patients not treated. More
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Representative images of multiplex immunostaining of Zeb1 and pan cytokerat...
Published: 22 November 2021
FIGURE 2 Representative images of multiplex immunostaining of Zeb1 and pan cytokeratin at the invasive front of colorectal cancer (CRC) from patients treated with DPP-4i ( A ). Images stained with hematoxylin (green), pan cytokeratin (blue), and Zeb1 (red) were merged. Arrow heads in A show Zeb1+ tumor cells. The average numbers of Zeb1+ tumor cells from patients treated with and without DPP-4i in square ROIs of 1.0×1.0 mm2 were compared ( B ). P values were calculated using Mann–Whitney U test. **, P < 0.01. More
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Representative images of multiplex immunostaining of TILs in colorectal can...
Published: 22 November 2021
FIGURE 3 Representative images of multiplex immunostaining of TILs in colorectal cancer (CRC) treated with DPP-4i ( A ). Images stained for CD3 (green) and CD8 (red) were merged. Arrow and arrowhead show a representative T cells of CD3+CD8 and CD3+CD8+ phenotypes, respectively. The average numbers of CD3+ TILs ( B ), CD3+CD8+ TILs ( C ) and the ratios of CD8+/CD3+ ( D ) in square ROIs of 0.5×0.5 mm2 were compared for colorectal cancer from patients treated with and without DPP-4i. P values were calculated using Mann–Whitney U test. ***, P < 0.001. More
Images
Representative images of immunostaining of TAMs in colorectal cancer (CRC) ...
Published: 22 November 2021
FIGURE 4 Representative images of immunostaining of TAMs in colorectal cancer (CRC) tumors from patients treated with DPP-4i ( A ). Images stained for CD68 (green) and CD163 (red) were merged. Arrow and arrowhead show representative macrophages with CD68+CD163 and CD68+CD163+ phenotype, respectively. The average numbers of CD68+ TAMs ( B ), CD68+CD163+ TAMs ( C ), and the ratios of CD163+/CD68+ ( D ) in square ROIs of 0.5×0.5 mm2 were compared for colorectal cancers from patients treated with and without DPP-4i. P values were calculated using the Mann–Whitney U test. **, P < 0.01; ***, P < 0.001. More
Images
A,  Representative image TLS with or without GC formation in colorectal can...
Published: 22 November 2021
FIGURE 5 A, Representative image TLS with or without GC formation in colorectal cancer (CRC) from patients without DPP-4i treatment. H&E staining and immunostaining of CD20+ B cells (purple) and CD3+ T cells (blue). Immunostaining of Ki-67 of the TLS was performed in continuous tissue section (right figures). B, Total numbers of TLS ( B ) and TLS with GC formation ( C ) in five randomly selected low power fields (LPF; 40×) of colorectal cancer from patients treated with or without DPP-4i. P values were calculated using the Mann–Whitney U test. **, P < 0.01; ***, P <0.001. More
Journal Articles
Cancer Research Communications (2021) 1 (2): 106–114.
Published: 22 November 2021
Includes: Supplementary data
Journal Articles
Cancer Research Communications (2021) 1 (2): 90–105.
Published: 12 November 2021
Includes: Supplementary data
Images
Evaluation of the HR activity and sensitivity to olaparib of 30 BRCA1 misse...
Published: 12 November 2021
FIGURE 1 Evaluation of the HR activity and sensitivity to olaparib of 30 BRCA1 missense variants. A, Schematic of ASHRA and the design of primers used in this study. B, HR activities of HeLa cells expressing BRCA1 missense variants were measured by ASHRA. The amount of the marker sequence was quantified by the ΔΔCt method using the positive control samples (transfected with gRNA against the ACTB gene and control siRNA) as a reference. Values were normalized to the samples rescued by BRCA1-WT as 1. Data are the mean of at least three independent experiments. Error bars show SEM. Variants presented in yellow or pale pink bars and blue or pale blue bars were categorized by the DR-GFP assay as HR proficient and HR deficient, respectively ( 20 ). The blue solid line and blue broken line indicate levels of 1.0 and 0.8, respectively. The red broken line indicates the level of samples with BRCA1 knockdown. scr: scramble gRNA was used as the negative control for ASHRA. * and **: versus WT, P < 0.05 and P < 0.01, respectively. ¶ and ¶¶: versus BRCA1-knockdown samples, P < 0.05 and P < 0.01, respectively. C, Relative survival of HeLa cells expressing BRCA1 missense variants. Cells were treated with 0.5 μmol/L olaparib for 5 days after transfection of siRNA and HA-BRCA1 expression vectors. Values were normalized to control sample (transfected with control siRNA) as 1. Data are expressed as the mean ± SEM of three independent experiments. The bar colors of variants are the same as in A. The blue solid line and red broken line indicate 1.0 and 0.24 (value of BRCA1-knockdown samples), respectively. More
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Correlation between HR activity and sensitivity to olaparib.  A,  Relative ...
Published: 12 November 2021
FIGURE 2 Correlation between HR activity and sensitivity to olaparib. A, Relative HR activities by ASHRA and relative survival under 0.5 μmol/L olaparib in HeLa cells were plotted. Error bars show SEM. Correlation coefficient (R2) = 0.88. The broken line indicates a regression line. The arrow indicates BRCA1-C61G. To test for outliers, studentized residuals from values predicted by the regression formula were calculated. B, Relative HR activities by ASHRA in HeLa and MCF7 cells were plotted. Error bars show SEM. R2 = 0.84. The broken line indicates a regression line. The arrow indicates BRCA1-C61G. C, Relative survival in response to 0.5 μmol/L olaparib in HeLa and MCF7 cells was plotted. Error bars show SEM. R2 = 0.81. The broken line indicates a regression line. The arrow indicates BRCA1-C61G. D, HeLa cells were transfected as indicated, and whole-cell lysates were analyzed by Western blotting. E, HeLa cells were transfected as indicated and HR activity was measured by ASHRA. Data are expressed as the mean ± SEM of three independent experiments. *: versus WT, P < 0.05. ¶¶: versus BRCA1-knockdown samples, P < 0.01. F, HeLa cells were transfected as indicated and treated with 0.5 μmol/L olaparib for 5 days. Data represent the mean ± SEM of three independent experiments. **: versus WT, P < 0.01. ¶¶: vs. BRCA1-knockdown samples, P < 0.01. G, The HR activity by ASHRA and sensitivity to olaparib of BRCA1-R1699Q and BRCA1-V1736A are plotted on the graph of A . The black dots represent R1699Q and V1736A. The arrowhead and arrow indicate BRCA1-R1699Q and BRCA1-V1736A, respectively. Error bars represent SEM. Error bars of variants shown in A are omitted. More
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Resistance to olaparib induced by ATF1 overexpression in ATF1-low cells.  A...
Published: 12 November 2021
FIGURE 3 Resistance to olaparib induced by ATF1 overexpression in ATF1-low cells. A, HeLa cells were transfected with FLAG-ATF1 and lysed 48 hours after transfection. The lysate containing the FLAG-ATF1 protein was incubated with MBP, MBP-BRCA1-1-304-WT, BRCA1-C61G, or BRCA1-C64G and pulled down using amylose resin. Aliquots containing 1/100 of the lysate used for pulldown were loaded on the input lane. B, Whole-cell lysates of HeLa, MCF7, MCF10A, and BT-549 cells were analyzed by Western blotting. C, MCF7 cells were transfected as indicated and treated with 0.5 μmol/L olaparib for 5 days. WT, 61, and 64 indicate BRCA1-wild type, BRCA1-C61G, and BRCA1-C64G, respectively. Data represent the mean ± SEM of three independent experiments. *, P < 0.05; n.s., not significant. D, Whole-cell lysates of the samples in C were analyzed by Western blotting. Arrowhead: endogenous ATF1; Arrow: FLAG-ATF1. E and F, Experiments were performed as described in C and D using MCF10A cells. **, P < 0.01; n.s., not significant. Arrowhead: endogenous ATF1; Arrow: FLAG-ATF1. G, MCF7 cells were transfected as indicated and treated with 0.5 μmol/L olaparib for 5 days. WT and 61 mean BRCA1-wild type and BRCA1-C61G, respectively. Data represent the mean ± SEM of three independent experiments. **, P < 0.01; ***, P < 0.001. H, Whole-cell lysates of the samples in G were analyzed by Western blotting. Arrowhead: endogenous ATF1; Arrow: FLAG-ATF1. More
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Contribution of endogenous ATF1 to olaparib resistance in ATF1-high cells. ...
Published: 12 November 2021
FIGURE 4 Contribution of endogenous ATF1 to olaparib resistance in ATF1-high cells. A, HeLa cells were transfected as indicated, and whole-cell lysates were analyzed by Western blotting. Arrowhead: endogenous ATF1; Arrow: FLAG-ATF1. B, HeLa cells were transfected as indicated and treated with 0.5 μmol/L olaparib for 5 days. WT, 61, and 64 indicate BRCA1-wild type, BRCA1-C61G, and BRCA1-C64G, respectively. Data are expressed as the mean ± SEM of three independent experiments. *, P < 0.05; **, P < 0.01; n.s., not significant. C, HeLa cells were transfected as indicated, and HR activity was measured by ASHRA. Data are expressed as the mean ± SEM of three independent experiments. n.s.: not significant. More
Images
BRCA1-wild-type and BRCA1-C61G activates ATF1-regulated transcription.  A, ...
Published: 12 November 2021
FIGURE 5 BRCA1-wild-type and BRCA1-C61G activates ATF1-regulated transcription. A, HeLa cells were transfected as indicated. Cells were harvested 72 hours after transfection, and total mRNA was extracted for qRT-PCR. Data are expressed as the mean ± SEM of four independent experiments. B, mRNA levels of NRAS and BIRC2 were quantified by qRT-PCR in HeLa cells transfected as indicated. Samples were prepared as in A . Data represent the mean ± SEM of four independent experiments. C, HeLa cells were transfected as indicated and treated with or without 0.5 μmol/L olaparib for 72 hours. Experiments were repeated as well as A . Data represent the mean ± SEM of four independent experiments. More
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High ATF1 expression confers resistance to olaparib in non-BRCA1 HR factor–...
Published: 12 November 2021
FIGURE 6 High ATF1 expression confers resistance to olaparib in non-BRCA1 HR factor–depleted cells. A, MCF7 cells were transfected as indicated and treated with olaparib for 5 days. Data are presented in three divided graphs for knockdown samples of BRCA1, BRCA2, or RAD51 for clarity, and they share the same data of siCtrl and siATF1 samples. Data represent the mean ± SEM of four independent experiments. **, P < 0.01 between knockdown of BRCA2 or RAD51 and knockdown of BRCA2 or RAD51 with FLAG-ATF1 overexpression. B, HeLa cells were transfected as indicated and treated with olaparib for 5 days. Data represent presented as in A . Data represent the mean ± SEM of four independent experiments. *, P < 0.05 between single knockdown of BRCA2 or RAD51 and double knockdown of BRCA2 or RAD51 and ATF1. C, HeLa cells were transfected as indicated, and HR activity was measured by ASHRA. Data represent the mean ± SEM of three independent experiments. n.s.: not significant. More
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High ATF1 expression confers resistance to PARP inhibitors and platinum age...
Published: 12 November 2021
FIGURE 7 High ATF1 expression confers resistance to PARP inhibitors and platinum agents in non-BRCA1 HR factor–depleted cells. A, MCF7 cells were transfected as indicated and treated with cisplatin for 4 days. Data are presented as in Fig. 6A . Data represent the mean ± SEM of four independent experiments. **, P < 0.01; *, P < 0.05 between knockdown of BRCA2 or RAD51 and knockdown of BRCA2 or RAD51 with FLAG-ATF1 overexpression. B, Schematic of ATF1-dependent survival and cell death in HR-deficient cells. When treated with olaparib, HR-proficient cells can repair DNA damage induced by olaparib and cells survive. Cells with the C61G variant cannot efficiently repair DNA damage by HR; however, in cells with high ATF1 expression, the C61G variant activates ATF1-mediated transcription and promotes cell proliferation and survival. HR-deficient cells (BRCAness), which show altered non-BRCA1 HR factors, such as BRCA2 or RAD51, but possess wild-type BRCA1, activate ATF1-mediated transcription to support cell survival under conditions of high ATF1 expression. Cells with the HR-deficient BRCA1 variants except C61G, such as the C64G variant, cannot repair DNA damage and activate transcription with ATF1, resulting in cell death. More