bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S7 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Hi-C interaction and TAD map of TI2 and G8 regions. A comparison of the chromatin conformation of the region which encompasses TI2 and G8 across the 3 HMCLs (U266, RPMI8226, and KMS11) and PC. We note that there are noticeable loss of TAD boundary within the G8 region between PC and U266 and RPMI8226 that may allow accessibility to distal super-enhancers and result in overexpression. A similar change is seen in KMS11 at the ELF3 locus.
Supplementary Figure S4 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Chromatin state of varying deleted regions. There is a greater variability in terms of chromatin composition of the lost regions in comparision to the region of gain. The D1 region had identical an A-compartment percentage (56%) across all samples and reflected loss of significant subtelomeric region, including TNFRSF4. The D2 region was consistent across all samples (range 96-100% A-compartment) with the exception of KMS11 (47%), however this switch to a B-compartment occurred in a gene-sparse region. The D3 region encompasses the tumour suppressor genes CDKN2C and FAF1 and had similar active chromatin profiles (range 44-77%) except in RPMI8226 (0%). The D4 and D5 regions lie completely (100%) and near completely (>87%) in inactive compartments. Interestingly, the small A-compartments in D5 across U266 and RPMI8226 correspond to the tumour suppressor FUBP1. The D6 region showed conserved A-compartment across the samples specifically at the RPL5 and MTF2 loci while EVI5 and GFI1 showed switching from B-A across the differentiation stages. The D7 region, focused on TENT5C lies within an A-compartment across all samples except for KMS11, NBC=Naïve B-cell, MBC=Memory B-cell, GCBC=Germinal Center B-cell, PC=plasma cell.
Supplementary Figure S3 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Hi-C interaction and TAD map of G7 region. The chromatin confirmation of the G7 region across the 3 HMCLs (U266, RPMI8226, and KMS11) and PC for comparison. The local TAD structure around the ABL2 locus appears conserved across the samples suggesting the additional gene dosage as a result of the CNV gain is likely the cause of the overexpression.
Supplementary Figure 1 from Development and Multicenter Case–Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction
Authors: Salari Keyan , Sundi Debasish , Lee Jason J. , Wu Shulin , Wu Chin-Lee , DiFiore Gabrielle , Yan Q. Robert , Pienkny Andrew , Lee Chi K. , Oberlin Daniel , Barme Greg , Piser Joel , Kahn Robert , Collins Edward , Phillips Kevin G. , Caruso Vincent M. , Goudarzi Mahdi , Garcia-Ransom Monica , Lentz Peter S. , Evans-Holm Martha E. , MacBride Andrew R. , Fischer Daniel S. , Haddadzadeh Iden J. , Mazzarella Brian C. , Gray Joe W. , Koppie Theresa M. , Bicocca Vincent T. , Levin Trevor G. , Lotan Yair , Feldman Adam S.
Published: August 2023

Supplementary Figure 1. Genomic profiles of the validation cohort.
Supplementary Figure S17 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Differential methylation of MM relevent genes. Volcano plots of the CpG probes (probes=2498) across chromosome 1 between MM (n=161) and normal PC (n=3), as a result there are 378 probes (genes=360) that are significantly hypomethylated in MM on in comparison to the normal phenotype and 5 probes (genes=7) are significantly hypermethylated. The plot is further annotated to show the probe associated with A. the GEP70 genes located on chromosome 1 (n=20, p-arm=12, q-arm=8), and B. genes that have been previously implicated as driver genes of the gain/1amp(1q) phenotype in MM (n=20, p-arm=7, q-arm=13).
Supplementary Tables S1-S9 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: August 2023

Supplementary Tables S1-S9
Supplementary Figure S15 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Genes with increased dependency in cell lines with del(1p) [part A] Genes with increased dependency in cell lines with del(1p) [part B]
Supplementary Figure S13 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

CRISPR dependencies on chromosome 1. Nineteen myeloma cell lines and 15 random non-myeloma cell lines were identified and CERES dependencies for genes located on chr1 recorded. A total of 1701 genes were analyzed. Cell lines did not cluster according to their copy number profile but tended to clutter according to disease type. Common dependencies genes with gene dependencies< -1 clustered together and comprised proteasome subunit coding genes (PSMA5, PSMB2, PSMB4), three regulators of ubiquitin-protein transferase activity (RPL5, RPL11, CDC20), splicing factors (SF3B4, SF3A3, SFPQ, RNPC3, SRNPE, PRPF38A, PRPF38B) and DTL. The second clade could be further subdivided into two clades (n2.1=125 and n2.2=1594). The second of these two clades could further be divided into two clades (n2.2.1=105 and n2.2.2=1489). Clades 2.1 and 2.2.0 included genes with significant dependencies in some cell lines but not the others. Genes in these clusters include suspected drivers such as ADAR alongside more unexpected genes such as CD30. The tumor suppressor genes commonly found in deleted regions on 1p such as CDKN2C, or FAF1 were commonly found in clade with no dependency.
Supplementary Figure S4 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: August 2023

Supplementary Figure S4. Kaplan–Meier estimates of time to progression and overall survival according to etiology in the intent-to-treat population. (A) Time to progression. (B) Overall survival. (C) Progression-free survival.
Supplementary Figure S11 from Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzsky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Differential expression between patients with no 1q gain and those with a gain(1q:CKS1B). A. All genes that are differentially expressed
Supplementary Figure S2 from A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma
Authors: Lee Yun Bin , Nam Joon Yeul , Cho Eun Ju , Lee Jeong-Hoon , Yu Su Jong , Kim Hyo-Cheol , Paeng Jin Chul , Yoon Jung-Hwan , Kim Yoon Jun
Published: August 2023

Supplementary Figure S2. Kaplan–Meier estimates of time to progression and overall survival according to BCLC stage in the intent-to-treat population. (A) Time to progression. (B) Overall survival. (C) Progression-free survival.
Supplementary Table S8 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

List Of TSGs On Chromosome 3q, 10q, and 11q
Supplementary Table S5 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

TP53 hotspot variant distribution
Suppl. Figure 5 from Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis
Authors: González-Muñoz Teresa , Di Giannatale Angela , García-Silva Susana , Santos Vanesa , Sánchez-Redondo Sara , Savini Claudia , Graña-Castro Osvaldo , Blanco-Aparicio Carmen , Fischer Suzanne , De Wever Olivier , Creus-Bachiller Edgar , Ortega-Bertran Sara , Pisapia David J. , Rodríguez-Peralto Jose L. , Fernández-Rodríguez Juana , Pérez-Portabella Cleofé Romagosa , Alaggio Rita , Benassi Maria Serena , Pazzaglia Laura , Scotlandi Katia , Ratner Nancy , Yohay Kaleb , Theuer Charles P. , Peinado Héctor
Published: August 2023

Combined anti-ENG/anti-MEK therapy inhibits MPNST growth without toxicity in vivo.
Supplementary Table S2 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

Pathway Gene Lists
Supplementary Table S16 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

Mutational Profile of BRAF in frame deleted organoid cases
Supplementary Table S10 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

BRAF alteration clonality assessment
Supplementary Figure S7 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

Copy number gains in MAPK genes are infrequent in KRAS WT, MAPK Negative pancreatic cancer
Supplementary Figure S4 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

RTK fusions detected in the pancreatic cancer cohort via both DNA-based and RNA-based analyses
Supplementary Figure S2 from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

Global survey of pancreatic cancer genomics captures known features of disease
Data from Multiomic mapping of acquired chromosome 1 copy number and structural variants to identify therapeutic vulnerabilities in multiple myeloma.
Authors: Boyle Eileen M. , Blaney Patrick , Stoeckle James H. , Wang Yubao , Ghamlouch Hussein , Gagler Dylan , Braunstein Marc , Williams Louis , Tenenbaum Avital , Siegel Ariel , Chen Xiaoyi , Varma Gaurav , Avigan Jason , Li Alexander , Jinsi Monica , Kaminetzky David , Arbini Arnaldo , Montes Lydia , Corre Jill , Rustad Even H. , Landgren Ola , Maura Francesco , Walker Brian A. , Bauer Michael , Bruno Benedetto , Tsirigos Aristotelis , Davies Faith E. , Morgan Gareth J.
Published: August 2023

Abstract
Purpose: Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the drivers of which are largely unknown. Experimental Design: A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilisation. Results: We identified two distinct groups of gain(1q): focal gains associated with limited gene expression changes and a neutral prognosis, and whole-arm gains, which associate with substantial gene expression changes, complex genetics and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT) and two of templated-insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. Conclusions: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
Data from Poor Outcome in Postpartum Breast Cancer Patients Is Associated with Distinct Molecular and Immunologic Features
Authors: Lefrère Hanne , Moore Kat , Floris Giuseppe , Sanders Joyce , Seignette Iris M. , Bismeijer Tycho , Peters Dennis , Broeks Annegien , Hooijberg Erik , Van Calsteren Kristel , Neven Patrick , Warner Ellen , Peccatori Fedro Alessandro , Loibl Sibylle , Maggen Charlotte , Han Sileny N. , Jerzak Katarzyna J. , Annibali Daniela , Lambrechts Diether , de Visser Karin E. , Wessels Lodewyk , Lenaerts Liesbeth , Amant Frédéric
Published: August 2023

AbstractPurpose:
Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data.
Experimental Design:
We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC.
Results:
We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups.
Conclusion:
These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer.
Data from Development and Multicenter Case–Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction
Authors: Salari Keyan , Sundi Debasish , Lee Jason J. , Wu Shulin , Wu Chin-Lee , DiFiore Gabrielle , Yan Q. Robert , Pienkny Andrew , Lee Chi K. , Oberlin Daniel , Barme Greg , Piser Joel , Kahn Robert , Collins Edward , Phillips Kevin G. , Caruso Vincent M. , Goudarzi Mahdi , Garcia-Ransom Monica , Lentz Peter S. , Evans-Holm Martha E. , MacBride Andrew R. , Fischer Daniel S. , Haddadzadeh Iden J. , Mazzarella Brian C. , Gray Joe W. , Koppie Theresa M. , Bicocca Vincent T. , Levin Trevor G. , Lotan Yair , Feldman Adam S.
Published: August 2023

AbstractPurpose:
Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk.
Experimental Design:
This is a multicenter case–control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology.
Results:
uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%.
Conclusions:
uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.
Data from Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

AbstractPurpose:
Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents.
Experimental Design:
We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer.
Results:
Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases.
Conclusions:
This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.
Data from Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis
Authors: González-Muñoz Teresa , Di Giannatale Angela , García-Silva Susana , Santos Vanesa , Sánchez-Redondo Sara , Savini Claudia , Graña-Castro Osvaldo , Blanco-Aparicio Carmen , Fischer Suzanne , De Wever Olivier , Creus-Bachiller Edgar , Ortega-Bertran Sara , Pisapia David J. , Rodríguez-Peralto Jose L. , Fernández-Rodríguez Juana , Pérez-Portabella Cleofé Romagosa , Alaggio Rita , Benassi Maria Serena , Pazzaglia Laura , Scotlandi Katia , Ratner Nancy , Yohay Kaleb , Theuer Charles P. , Peinado Héctor
Published: August 2023

AbstractPurpose:
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFβ coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs.
Experimental Design:
ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell–specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models.
Results:
ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis.
Conclusions:
Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.
Data from Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages
Authors: Yuan Wei , Zhang Qian , Gu Danling , Lu Chenfei , Dixit Deobrat , Gimple Ryan C. , Gao Yisu , Gao Jiancheng , Li Daqi , Shan Danyang , Hu Lang , Li Lu , Li Yangqing , Ci Shusheng , You Hao , Yan Linping , Chen Kexin , Zhao Ningwei , Xu Chuanhai , Lan Jianyun , Liu Dong , Zhang Junxia , Shi Zhumei , Wu Qiulian , Yang Kailin , Zhao Linjie , Qiu Zhixin , Lv Deguang , Gao Wei , Yang Hui , Lin Fan , Wang Qianghu , Man Jianghong , Li Chaojun , Tao Weiwei , Agnihotri Sameer , Qian Xu , Mack Stephen C. , Zhang Nu , You Yongping , Rich Jeremy N. , Sun Guan , Wang Xiuxing
Published: August 2023

AbstractPurpose:
The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state.
Experimental Design:
We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization.
Results:
We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2–JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule–based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice.
Conclusions:
CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
MCR-21-0354_SM2 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supplementary figure legends are included in this document for supplementary figures 1-8.
MCR-21-0354_SM1 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Tables 1-2 and the corresponding table legends are included here. These include cDNA construct sequences and qPCR primer sequences.
MCR-21-0354_SF7 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 7 contains results of a pathway analysis performed on FET/ETS-regulated genes in Ewing sarcoma cells.
MCR-21-0354_SF6 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 6 demonstrates similar transcriptional regulatory patterns between FET/ETS proteins at Ewing sarcoma-specific genes.
MCR-21-0354_SF5 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 5 demonstrates similar DNA-binding patterns between FET/ETS proteins at EWS/FLI-specific regulatory elements.
MCR-21-0354_SF3 from Identification of a Novel FUS/ETV4 Fusion and Comparative Analysis with Other Ewing Sarcoma Fusion Proteins
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Watson Mike , Heppner Peter , Hamill James , Wood Andrew C. , Lessnick Stephen L. , Winstanley Mark
Published: August 2023

Supp Figure 3 depicts knock-down of endogenous EWS/FLI RNA and expression of the rescue FET/ETS fusion RNA via RNA-sequencing peak tracks.
TABLE 1A from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

Prostaglandin pathway inhibitor drugs
Supplementary Figures S1-S8 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

Supplementary Figures S1-S8
FIGURE 6 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

TPST-1495 effectively increases survival and modulates the TME in APCmin/+ mice. A, Tumor counts in the small intestine of APCmin/+ mice. Mice were treated starting at 13 weeks of age for 3 weeks with TPST-1495 (100 mg/kg twice a day, orally), E7046 (150 mg/kg every day, orally), PF04418948 (100 mg/kg every day, orally), or Celecoxib (60 mg/kg every day, orally). Results are representative of multiple experiments with 7–10 mice. B, Kaplan–Meier curve of survival of APCmin/+ mice and log-rank Mantel–Cox P values of listed comparisons. Mice were ages to 13 weeks, then treated with as in A or with the combination of E7046 and PF04418948 at monotherapy doses, for 6 weeks. Survival was monitored longitudinally and mice were sacrificed as they became moribund. Results are representative of two similar experiments with 8 mice per group. C, IHC of tumor or hyperplasia excised from small intestines of mice from experiment in A. Quantification displays values from one tumor in each biological replicate. TPST-1495 every day and twice a day groups are concatenated because of limited tumor tissue in these groups. Mean and SD are depicted in all graphs and the Student two-sided t test was used to assess significance between individual groups. ****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05. BID, twice a day; QD, every day.
FIGURE 5 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

TPST-1495 exhibits immune-independent antitumor activity. CT26 tumor longitudinal outgrowth of WT and RAG2−/− mice treated with 100 mg/kg TPST-1495 BID for 2 weeks (A) and day 14 volumetric comparisons between mouse groups (B). Results are representative of three experiments with at least 8 mice per experiment. CT26 tumor longitudinal outgrowth (C) and day 14 volumetric comparisons (D and E) in WT and RAG2−/− mice treated with 100 mg/kg TPST-1495 twice a day for 2 weeks and 10 μL anti-asialo-GM1 antibody. F, Experimental schematic of LS174T colorectal xenograft model and tumor growth results. G, Enumeration of tumor burden by primary tumor weight, metastatic organ weight, or count of metastatic nodules. Results are representative of two experiments with at least 8 mice per experiment. Mean and SD are depicted in all graphs and the Student two-sided t test was used to assess significance between individual groups. ns, not significant; ***, P < 0.001; **, P < 0.01; *, P < 0.05.
FIGURE 2 from Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
Authors: Francica Brian J. , Holtz Anja , Lopez Justine , Freund David , Chen Austin , Wang Dingzhi , Powell David , Kipper Franciele , Panigrahy Dipak , Dubois Raymond N. , Whiting Chan C. , Prasit Peppi , Dubensky Thomas W.
Published: August 2023

TPST-1495 is more effective than a single EP4 or EP2 antagonists in overcoming PGE2-mediated immune suppression of recovery of cytokine production from murine monocytes and T cells. A, Schematic of PGE2 blockade assay. Murine whole blood (B–F) or splenic and lymph node T cells (G, H) were collected and incubated with inhibitors for 30 minutes at 37°C, followed by incubation with PGE2 at labeled concentrations for 30 minutes at 37°C, followed by stimulation with LPS (0.5 μg/mL, overnight) or SIINFEKL peptide (2 μmol/L, 5 hours). Detection of TNFα production by ELISA (B–D) and maximum percent recovery (E, F) after blockade assay was performed on murine whole blood. Representative data shown from one of three experiments performed with N = 3 technical replicates per experiment. Some technical replicates failed to meet threshold TNFα values in low Stim groups. Percent recovery as calculated Percent recovery = 100*(“Experimental group” − “LPS+PGE2”)/(“LPS” − “LPS+PGE2”). G and H, IFNγ production detected by Luminex in culture supernatants after treatment with TPST-1495 across a PGE2 concentration gradient (F), or with 333 nmol/L PGE2 comparing multiple PGE2 receptor inhibitors (G) in the PGE2 blockade assay performed with a single-cell suspension of OT-1 splenic and lymph node isolates stimulated with SIINFEKL peptide. Data are representative of three experiments with N = 3 technical replicates per experiment. H, IFNγ production levels in OT-1 T cell cultures containing 333 nmol/L PGE2 and incubated with TPST-1495 EP2/EP4 dual antagonist, or EP2 (PF04418948) or EP4 (E7046) single antagonists. Mean and SD are depicted in all graphs and the ordinary one-way ANOVA with Tukey multiple comparisons test was used to assess significance between individual groups. ****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05.
Quality of Life Measures in Aortic Stenosis Research: A Narrative Review
Authors: Frank Derk , Kennon Simon , Bonaros Nikolaos , Romano Mauro , Di Mario Carlo , van Ginkel Dirk-Jan , Bor Wilbert , Kasel Markus , Backer Ole De , Hachaturyan Violetta , Lüske Claudia M. , Kurucova Jana , Bramlage Peter , Styra Rima
Published: August 2023

Background: Elderly patients with aortic stenosis (AS) not only have a reduced life expectancy but also a reduced quality of life (QoL). The benefits of an AS intervention may be considered a balance between a good QoL and a reasonably extended life. However, the different questionnaires being used to determine the QoL were generally not developed for the specific situation of patients with AS and come with strengths and considerable weaknesses. The objective of this article was to provide an overview of the available QoL instruments in AS research, describe their strengths and weaknesses, and provide our assessment of the utility of the available scoring instruments for QoL measurements in AS. Summary: We identified and reviewed the following instruments that are used in AS research: Short Form Health Survey (SF-36/SF-12), EuroQol-5D (EQ-5D), the Illness Intrusiveness Rating Scale (IIRS), the HeartQoL, the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure Questionnaire (MLHF), the MacNew Questionnaire, and the Toronto Aortic Stenosis Quality of Life Questionnaire (TASQ). Key Messages: There is no standardized assessment of QoL in patients with AS. Many different questionnaires are being used, but they are rarely specific for AS. There is a need for AS-specific research into the QoL of patients as life prolongation may compete for an improved QoL in this elderly patient group.
Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study
Authors: Uekusa Shusuke , Hanai Yuki , Hirayama Shinobu , Yokoo Takuya , Hasegawa Tetsuya , Shimoyama Kohei , Kusano Ayumu , Nishizawa Kenji , Matsumoto Takahiro , Matsuo Kazuhiro
Published: August 2023

Introduction: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5–43%. VCM-induced AKI was reported to be more likely to occur 4–17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. Methods: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. Results: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 μg/mL within the 48 h threshold (AKI2days) and 19.03 μg/mL within the 7-day threshold (AKI7days). Conclusion: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.
Usefulness of Serum Leucine-Rich Alpha-2 Glycoprotein as a Surrogate Marker of Small Bowel Mucosal Injury in Crohn’s Disease
Authors: Saiki Takuto , Torisu Takehiro , Harada Akira , Kajiya Yu , Taniguchi Yoshiaki , Morisaki Shinji , Umeno Junji , Suekane Hiroshi , Kitazono Takanari
Published: August 2023

Introduction: Although the importance of mucosal healing has been suggested in Crohn’s disease, it is difficult to repeat endoscopy, especially for the entire small bowel. Recently, serum leucine-rich alpha-2 glycoprotein (LRG) has been used as a surrogate marker of endoscopy. However, few studies have investigated a correlation between LRG and mucosal injury of the entire small bowel. Methods: We retrospectively analyzed the clinical data of 30 patients with Crohn’s disease from June 2020 to August 2022 at Yamaguchi Red Cross Hospital. All the patients were surveyed through the gastrointestinal tract by esophagogastroduodenoscopy, total colonoscopy, and capsule endoscopy (CE). Subjects with mucosal injury only in the small bowel were selected. Then, we assessed the relationship between serum biomarkers (LRG, C-reactive protein [CRP], hemoglobin, albumin) and small bowel mucosal injury scores (Lewis score [LS], Capsule Endoscopy Crohn’s Disease Activity Index [CECDAI], and Crohn’s Disease Activity in Capsule Endoscopy [CDACE]) calculated by CE. Results: LRG and CRP were significantly correlated with small bowel mucosal injury scores (LS, CECDAI, CDACE) (p < 0.05, Spearman’s rank correlation coefficient). The degree of correlation was greater for LRG than for CRP. Conclusions: LRG is a useful surrogate marker that closely reflects small bowel mucosal injury in the entire small bowel.