bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2078: VALIS: Virtual Alignment of pathoLogy Image Series for multi-gigapixel whole slide images
Authors: Gatenbee Chandler Dean , Baker Ann-Marie , Prabhakaran Sandhya , Robertson-Tessi Mark , Graham Trevor , Anderson Alexander R. 
Published: April 2023

Abstract
Interest in spatial omics is on the rise, but generation of highly multiplexed images used in many spatial analyses remains challenging, due to cost, expertise, methodical constraints, and/or access to technology. An alternative to performing highly multiplexed staining is to register collections of whole slide images (WSI), creating a collection of aligned images that can undergo spatial analyses. However, registration of WSI is two part problem, with the first being the alignment itself, and the second being the application of the transformations to huge multi-gigapixel images. To address both challenges, we have developed the Virtual Alignment of pathoLogy Image Series (VALIS) software, which enables one to rapidly and easily generate highly multiplexed images by aligning (registering) any number of multi-gigapixel whole slide images (WSI) stained using immunohistochemistry (IHC) and/or immunofluorescence (IF). Benchmarking using the publicly available 2019 ANHIR and 2022 ACROBAT Grand Challenge datasets indicates that VALIS provides state of the art accuracy, being one of the most accurate publicly available methods in the ANHIR challenge, and the most accurate opensource method in the ACROBAT challenge. VALIS is able to read, register, and save multi-gigapixel images as ome.tiff, thereby addressing the second challenge. In addition to the benchmarking datasets, the generalizability of VALIS has been tested with 273 IHC samples and 340 IF samples, each of which contained between 2-69 images per sample. In total, VALIS has therefore been tested with 5,138 images. The registered WSI tend to have low error and are completed within a matter of minutes. VALIS is written in Python, requires only few lines of code for execution, is readily available and fully documented. VALIS therefore provides a free, opensource, flexible, scalable, robust, and easy to use pipeline for rigid and non-rigid registration of multi-gigapixel WSI, facilitating spatial analyses of prospective and existing datasets,breathing new life into the countless collections of brightfield and immunofluorescence images.
Citation Format: Chandler Dean Gatenbee, Ann-Marie Baker, Sandhya Prabhakaran, Mark Robertson-Tessi, Trevor Graham, Alexander R. Anderson. VALIS: Virtual Alignment of pathoLogy Image Series for multi-gigapixel whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2078.
Abstract 2128: Genomic alterations in DNA mismatch repair (dMMR)
Authors: Holla Vijaykumar , Ronaghy Arash , Yang Richard K. , Patel Keyur P. , Routbort Mark J. , Overman Michael J. , Dumbrava Ecaterina E. , Shaw Kenna R. , Karp Daniel D. , Meric-Bernstam Funda 
Published: April 2023

Abstract
Background PD-1 inhibitors have been shown to be effective in advanced cancer patients with mismatch repair deficient tumors (dMMR) in a tumor agnostic fashion. dMMR testing by immunohistochemistry (IHC) is infrequently performed outside of colorectal and endometrial cancer. In contrast, comprehensive genomic sequencing (CGS) for somatic genomic alterations, is frequently perfomed across tumor types. We hypothesized that CGS may identify alterations in dMMR genes (MLH1, MSH2, MSH6, PMS2), and that patients with genomic MMR alterations will have higher rates of dMMR loss by IHC.
Methods From Jan 2016 to Dec 2021, 15,701 patients were identified as receiving CGS. Sequencing results were analyzed for mutations in dMMR genes, tumor type distribution and concordance with IHC results.
Results 627 (4%) of 15,701 patients had mutations in one of the dMMR genes; mutations were found across tumor types. Majority of patients with mutations in MMR genes had single nucleotide variants (SNV, 430, 68.6%) followed by frameshift/truncating (155, 24.7%), splice site (31, 4.9%) and in frame deletions/indel (11, 1.6%) mutations. A subset of the MMR gene mutant patients (n=279) had IHC testing for dMMR proteins: 99 (35.5%) demonstrated dMMR loss, including 55 (53.4%) of 103 patients with colorectal cancer, 3 (25%) of 12 patients with endometrial cancer and 41 (25%) of 164 with other tumor types. dMMR loss on IHC was found in 70 (71%) of 99 patients with frameshift/truncation/splice site/indel mutations compared with 29 (29%) of patients with SNVs (x2=8.49; p=0.00038).
Conclusion Mutations in MMR genes are found in multiple tumor types. Reflex IHC testing of patients carrying dMMR mutations inferred to be inactivating may identify patients with dMMR, expanding the pool of patients eligible for immunotherapy.
Citation Format: Vijaykumar Holla, Arash Ronaghy, Richard K. Yang, Keyur P. Patel, Mark J. Routbort, Michael J. Overman, Ecaterina E. Dumbrava, Kenna R. Shaw, Daniel D. Karp, Funda Meric-Bernstam. Genomic alterations in DNA mismatch repair (dMMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2128.
Abstract 2146: LDH as a surrogate marker for both pCR and survival in breast cancer patient
Authors: Lee In Hee , Lee Soo Jung , Lee Jeeyeon , Park Ho Yong , Jung Jin Hyang , Park Nora Jee-Young , Park Ji-Young , Chae Yee Soo , Kang Byeongju 
Published: April 2023

Abstract
Background: Glucose metabolism in cancer cells produces various glycolytic metabolites, which can affect cancer progression and treatment outcome. Herein we evaluated the association of glucose transporters and enzymes involved in glucose metabolism with clinic-pathological factors and outcomes in breast cancer patients who underwent neoadjuvant chemotherapy(NAC).
Methods: We selected 7 target transporters and enzymes(GLUT1, hexokinase 2, lactate dehydrogenase, MCT1, MCT4, IGF1RA, and IGF1RB) involved in glucose metabolism. Their tumoral expressions were scored both quantitively and qualitatively based on tissue microarrays and immunohistochemistry as previously described (Pinheiro et al, 2010) and then evaluated in relationships with pretreatment clinical/pathological characteristics and treatment outcomes including findings of 18F-FDG PET/CT,pathologic complete response(pCR), and relapse in breast cancer(stage IIA-IIIC) patients who underwent anthracycline or taxane-based NAC.
Results: Of the 236 enrolled patients, 145(61.4%), 44(18.6%), and 47(19.9%) were luminal, HER2-enriched, and TNBC subtypes. Pathologic CR was determined 50(21.2%) and 57(24.2%) relapses, 42(17.8%) distant relapses, and 28 deaths were observed during median follow-up duration of 64.0 (32.3-114.9) months. The expression rates of the target molecules were 76.0, 31.1, 42.1, 54.9, 67.9, 78.4, and 49.8% for GLUT1, hexokinase 2 (HK2), lactate dehydrogenase(LD), MCT1, MCT4, IGF1RA, and IGF1RB, respectively. Among target molecules in glucose metabolism, LD was significantly associated with pCR(OR=0.251; p-=0.016) and distant disease-free survival (HR= 2.29; P=0.019). Plus, LD expression shows a trend for a high SUVmax of primary tumor 18F-FDG PET/CT(OR=1.797 P=0.060).
Conclusion: Tumoral expression of lactate dehydrogenase can be considered as a predictive marker for pCR to NAC and plus prognostic marker for survival in patients with breast cancer.
Citation Format: In Hee Lee, Soo Jung Lee, Jeeyeon Lee, Ho Yong Park, Jin Hyang Jung, Nora Jee-Young Park, Ji-Young Park, Yee Soo Chae, Byeongju Kang. LDH as a surrogate marker for both pCR and survival in breast cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2146.
Abstract 216: Profiling single cell and spatial transcriptomes in FFPE archived tissues
Authors: Chen Jasmine Ying-Jiun , Le Quynh , Kang Chris , Tam Roy , Tai Brian , Lo Kelly , Rahmatpour Nasim , Wasdin Perry 
Published: April 2023

Abstract
Single cell and single nuclei RNA sequencing (scRNA-seq and snRNA-seq) have helped to identify cell type and subtypes that are present in complex tissues in both healthy samples and disease states. So far, scRNA-seq and snRNA-seq can only be performed in fresh tissues, or fresh frozen tissues. Most archived tissues are formalin-fixed, and paraffin-embedded (FFPE), making them inaccessible to the modern technology for characterization. Recently, 10x Genomics release a new reagent enabling single-cell fixed RNA characterization from fixed samples. The initial release is for fresh samples being fixed and then profiled later. However, FFPE archived tissues are not supported yet. We showed here two protocols to dissociate single cells and single nuclei from a 10-year-old FFPE human gastric tumor. We then profile them with 10x Genomics’ fixed RNA profiling kit. We further compare the data with the 10x Genomics’ Visium data obtained from the same tissues to understand the performance of these two protocols. In summary, we show that such technology will help to further characterize archived tissues that already have pathology annotation as well as clinical data and help biomarkers identification.
Citation Format: Jasmine Ying-Jiun Chen, Quynh Le, Chris Kang, Roy Tam, Brian Tai, Kelly Lo, Nasim Rahmatpour, Perry Wasdin. Profiling single cell and spatial transcriptomes in FFPE archived tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 216.
Abstract 2348: Mapping the interactome of matrisome targets using extracellular proximity labeling (ePL)
Authors: Peeney David , Gurung Sadeechya , Rich Josh , Coates-Park Sasha , Liu Yueqin , Stetler-Stevenson William G. 
Published: April 2023

Abstract
Classical methods to investigate protein-protein interactions (PPIs) are generally performed in non-living systems, yet in recent years new technologies utilizing proximity labeling (PL) have given researchers the tools to explore PPIs in living systems. PL has distinct advantages over traditional protein interactome studies, such as the ability to identify weak and transient interactions in vitro and in vivo. Most PL studies are performed on targets within or on the cell membrane. We describe a method to investigate PPIs within the extracellular compartment, using both BioID2 and TurboID, that we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigate the interactome of the widely expressed matrisome protein Tissue inhibitors of metalloproteinases 2 (TIMP2). Tissue inhibitors of metalloproteinases (TIMPs) are a family of multi-functional proteins that were initially defined by their ability to inhibit the enzymatic activity of matrix metalloproteinases (MMPs), the major mediators of ECM breakdown and turnover. TIMP2 is a unique family member, with a broad expression profile that is expressed in both normal and diseased tissues, even in those with minimal metalloproteinase activity. Understanding the functional transformation of matrisome regulators, like TIMP2, during the evolution of tissue microenvironments associated with disease progression is essential to the development of ECM targeted therapeutics. This knowledge may also garner understanding of therapeutic resistance and the failure of conventional and next-generation cancer therapies. Using carboxyl- and amino-terminal fusion peptides of TIMP2 with BioID2 and TurboID, we describe the TIMP2 interactome in unique tissue compartments. We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell lines, and with different reaction kinetics (BioID2 vs. TurboID); demonstrating the power of this technique and comparing our findings with classical PPI methods. We propose that the screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.
Citation Format: David Peeney, Sadeechya Gurung, Josh Rich, Sasha Coates-Park, Yueqin Liu, William G. Stetler-Stevenson. Mapping the interactome of matrisome targets using extracellular proximity labeling (ePL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2348.
Abstract 2349: Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression
Authors: Mahgoub Bayan , Xiao Weikun , Hill Reginald 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 11%. Current treatments that mostly target the cancer cells themselves, have not been able to significantly improve survival rates, meaning there is an urgent need for novel therapies. PDAC is unique among solid tumors because it exhibits extensive desmoplasia that is characterized by an abundance of extracellular matrix (ECM) components. In recent years, an increasing body of work has shown that cancer tissue is stiffer than normal tissue by a factor of 3 or more. This change in ECM stiffness has been shown to play an important role in affecting cell to cell communication as well as cancer progression and chemoresistance. However, how ECM stiffness affects macrophages, an important immune component of the pancreatic tumor microenvironment (TME), and macrophage-derived exosome secretion is still understudied.
Preliminary studies have shown that macrophages are highly sensitive to the mechanical environment. How cell-cell information transfer through exosomes may regulate this process in the PDAC tumor microenvironment (TME) needs to be explored. Elucidating these potential changes can provide us with insights on how stiffness affects therapeutic outcome in PDAC.
Our previous studies utilizing a biomimetic model that allows us to tune stiffness, showed that increased stiffness resulted in significantly higher exosome secretion from fibroblasts. Based on this finding, we hypothesize that increasing stiffness will result in hypersecretion of macrophage-derived exosomes that increases the chemoresistance of PDAC. 2D culture of macrophages on varying stiffness plates was used to study these changes in vitro. We then examined how changes in ECM stiffness affected the function and polarization of tumor associated macrophages, as well as elucidating how exosome hypersecretion and uptake, regulate these “stiffness enhanced” macrophages’ ability to affect PDAC progression. Understanding how macrophage-derived exosome signaling changes due to ECM stiffness may provide us with insights needed to develop novel therapies.
Citation Format: Bayan Mahgoub, Weikun Xiao, Reginald Hill. Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2349.
Abstract 2357: Fibroblast activation protein (FAP) expression as a target for colorectal cancer treatment
Authors: Lippert Anna L. , Johnson Katherine A. , Pasch Cheri A. , Zhang Wei , Matkowskyj Kristina A. , LeBeau Aaron M. , Deming Dustin A. 
Published: April 2023

Abstract
Background: Fibroblast Activation Protein (FAP) is a protein expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of epithelial cancers. There is potential interest in the use of FAP as a way to selectively target cancers, including colorectal cancer (CRC). Here we examine the expression of FAP in human colorectal cancers across stages and compare that expression to expression in normal colon and liver tissue. Additionally, we examine the correlation of FAP expression with key CRC clinical and biologic features to aid in potentially determining which CRC patients would be the most likely to benefit from FAP-directed therapies.
Methods: CRC and adjacent normal tissue samples spanning all stages of disease were collected across 243 patients. Immunohistochemistry (IHC) was used to evaluate FAP, MMP2, αSMA, and PDPN expression and quantified on an intensity scale from 0-3+. These scores were split into low (average score &lt;2) and high (average score &gt;/=2) groups. IHC was used to determine mismatch repair status by staining for MLH1, MSH2, MSH6, and PMS2. Separate samples from these patients were sequenced with the Qiagen Comprehensive Cancer Panel and analyzed for APC, KRAS, BRAF, PIK3CA, and TP53 mutations.
Results: Of 149 normal colon tissue sections, 99% had low FAP expression and 94% of those had no FAP expression. Of the 87 normal liver tissue sections, 99% had low FAP expression. In CRC sections, 58% had high FAP expression. Those patients &gt;50 years of age had cancers with a higher rate of FAP expression (p=0.02). There was no correlation with FAP expression and sex, stage of disease, or sidedness. In cancers with BRAF V600 mutations, 91% have high FAP expression (x2 = 0.02). There is a trend for higher FAP expression in cancers possessing APC, KRAS, PIK3CA, or TP53 mutations (x2=NS). In correlating FAP with other CAF markers, MMP2 had the greatest correlation (Spearman’s Rho = 0.56). FAP is moderately associated with αSMA and PDPN (Spearman’s Rho = 0.33, 0.38).
Conclusion: FAP is an exciting therapeutic target for CRC due to its cancer selectivity. Here, we demonstrate that FAP marks a rather independent subset of CRCs, though there is particular interest in the BRAF V600 mutant cancers given the high expression and poor prognosis of this subtype. Further investigation is needed to further develop FAP-directed therapies.
Citation Format: Anna L. Lippert, Katherine A. Johnson, Cheri A. Pasch, Wei Zhang, Kristina A. Matkowskyj, Aaron M. LeBeau, Dustin A. Deming. Fibroblast activation protein (FAP) expression as a target for colorectal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2357.
Abstract 2365: Visualizing exosome structure in Dasatinib resistant colon cancer cells
Authors: Koo Hui Min , Lu Yi-Wen , Tseng Yu-Chi , Tseng Kai-Yu , Lu Yen-Tse , Chao Wei-Ting 
Published: April 2023

Abstract
Cells release molecules through vesicles or into specific locations through exocytosis. Extracellular vesicle is divided into ectosomes and exosomes. Exosomes has been the main mechanism of discussion in recent studies and cancer research. As Exosomes with a diameter of ~30-160 nm (with an average diameter of 100 nm) carries intracellular molecules such as DNA, RNA, miRNA, proteins, and lipids. The physiological function of exosomes is not fully understood at present, it is important to understand the role of exosome in cancer. Src is highly activated in colon cancer and Src inhibition is the potential treatment strategy in colon cancer. In this study, colon cancer cells HT-29 were used to investigate the difference sizes of exosomes that response to Src inhibitor treatment. In the preliminary results, the exosome from HT-29 cultured medium were isolated and examined by transmission electron microscopy (TEM). The micrograph showed the average size of exosome is around 100 nm. When HT-29 were treated with Dasatinib (DST) the Src inhibitor, the drug resistant (DSTR) cells were grown, the secreted exosome from DSTR were collected and demonstrated the bigger size of exosome with average diameter of 130 nm. The role of the size changes of exosome in response to Dasatinib resistant will be further investigated, however, this study provides the clues that exosome detection can be applied in monitoring drug resistance.
Citation Format: Hui Min Koo, Yi-Wen Lu, Yu-Chi Tseng, Kai-Yu Tseng, Yen-Tse Lu, Wei-Ting Chao. Visualizing exosome structure in Dasatinib resistant colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2365.
Abstract 2373: Combination treatment with pH modulating drugs and immune checkpoint inhibitors increases TALL-104 cytotoxicity in preclinical co-culture experiments
Authors: Malpass Ryan , Huntington Kelsey E. , Brown Thomas , Zhou Lanlan , Zhang Leiqing , Navaraj Arunasalam , El-Deiry Wafik S. , Maxwell Aaron 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM) are leading causes of death worldwide, with therapeutic options limited to surgical resection and trans-arterial chemoembolization (TACE). TACE is a minimally-invasive approach to induce cancer cell death through a local hypoxia-dependent mechanism, and intrahepatic catheterization further enables the delivery of therapeutic agents to the tumor microenvironment (TME). Phase 1 clinical trials are ongoing for treatment of primary liver cancer and uveal melanoma with liver metastases using pressure-enabled drug delivery of SD-101 in combination with systemic immune checkpoint inhibitors (ICIs). Since acidosis is associated with immunosuppression in the TME, pH modulating drugs (PMDs) may restore physiologic conditions and augment treatment response for patients undergoing TACE with immunotherapy. Pre-clinical studies using PMDs with ICIs or adoptive immune cell transfer have demonstrated increased tumor lymphocyte infiltration, increased survival, and reduced tumor volume compared to ICI treatment or T cell infusion alone. High-throughput fluorescent imaging of HCC or CRC lines co-cultured with TALL-104 cells indicates increased cancer cell death with PMD treatment alone, while imaging studies of combination PMD and ICI treatment are underway. In addition, Luminex 200 cytokine profiling of Hep3B indicates that the NHE1 inhibitor cariporide decreases HCC production of IL-8 and GDF-15 under normoxia and the proton pump inhibitor lansoprazole increases GDF-15 and MIF and decreases B2M, IL-8, CXCL10, and CXCL5. Combination PMD and ICI studies are needed to inform drug combinations and dosages in syngeneic murine models of primary liver cancer and CRCLM. Subcutaneous and orthotopic tumor models are expected to demonstrate the efficacy of local PMD treatment with systemic immunotherapy.
Citation Format: Ryan Malpass, Kelsey E. Huntington, Thomas Brown, Lanlan Zhou, Leiqing Zhang, Arunasalam Navaraj, Wafik S. El-Deiry, Aaron Maxwell. Combination treatment with pH modulating drugs and immune checkpoint inhibitors increases TALL-104 cytotoxicity in preclinical co-culture experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2373.