tbuckley/cabot-search huggingface dataset:
Abstract 1146: Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents
Authors: Liankun Song, Shan Xu, Kia Arabzadehkaffash, Ali Fazelpour, Dongjun Fu, Matthew Tippin, Xiaolin Zi
Journal: Cancer Research (2020)

Abstract S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten or p53 deficient mice. We therefore have aimed to establish CRISPR human Skp2 (hSkp2) knock-in in the prostate of mouse to examine its role in prostate carcinogenesis. In addition, Skp2 overexpressing organoids are being developed for convenient and efficient screening of specific Skp2 inhibitors. cDNA of hSkp2 and porcine teschovirus-1 (P2A) was introduced into immediate upstream of mouse probasin coding sequencing using CRISPR knock-in targeting approach to establish transgenic mice specifically overexpressing hSkp2 in the prostate glands. Quantitative PCR, western blot and immunohistochemistry (IHC) were used to identify the expression levels of Skp2 and histopathological analyses were performed after H&amp;E staining. Prostate glands were dissected and digested for organoid culture, then morphological features and viability of organoids were evaluated following treatments of potential Skp2 inhibitors. Prostate glands and other tissues from mice of three transgenic lines which were genotyped positive were dissected and hSkp2 was detected in ventral, dorsal and lateral prostate lobes, but not in testis, kidney, spleen, and liver. Line 10092 was found to have the highest expression of hSkp2 among these three lines. Prostate weight slightly increased in transgenic mice compared to that of wild-type control mice. Hyperplasia, prostatic intraepithelial neoplasia (PIN), and carcinoma were noted, which suggested that overexpression of hSkp2 in the prostate of mice promoted proliferation and prostate tumorigenesis. Organoids that were derived from the prostate of hSkp2 transgenic mice recapitulated prostatic phenotypic features and maintained a high level of hSkp2. A novel Flavokawain A derivative was found to selectively alter the morphology of hSkp2 organoids and decrease the viability. Prostatic lesions found in the hSkp2 knock-in mice demonstrated a potential role of hSkp2 in early prostate carcinogenesis and organoids overexpressing hSkp2 have the utility for screening out compounds targeting Skp2 in prostate cancer. Citation Format: Liankun Song, Shan Xu, Kia Arabzadehkaffash, Ali Fazelpour, Dongjun Fu, Matthew Tippin, Xiaolin Zi. Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1146.
КИСТЫ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ: СОВРЕМЕННЫЕ ПРЕДСТАВЛЕНИЯ О ПАТОГЕНЕЗЕ, ДИАГНОСТИКЕ И ЛЕЧЕБНО-ДИАГНОСТИЧЕСКОЙ ТАКТИКЕ
Authors: V.М. Ratchik, V.V. Shevelyov, D.V. Orlovsky
Journal: GASTROENTEROLOGY (2014)

Актуальность лечения кист поджелудочной железы (ПЖ) определяется увеличением заболеваемости панкреатитом, значительным количеством осложнений и высокой летальностью. В последние десятилетия отмечается неуклонный рост деструктивных форм панкреатита, соответственно увеличивается количество кист ПЖ. Кисты поджелудочной железы в 18–68 % вызывают различные осложнения (нагноение, перфорация, кровотечение, внутренние и наружные свищи, малигнизация), что определяет высокую летальность — 9,2–53 %. Характер и объем оперативного вмешательства зависят от этиологии, наличия или отсутствия связи кисты с протоковой системой, наличия осложнений. Хирургический способ лечения при кистах поджелудочной железы остается методом выбора. Широкое применение получили малоинвазивные хирургические вмешательства. Большая распространенность кистозных поражений ПЖ, трудности выбора оптимального способа лечения требуют создания рационального, удобного для клинической практики диагностически-лечебного алгоритма. Неудовлетворенность результатами лечения и большое количество осложнений побуждают к поискам нового, так называемого золотого стандарта лечения больных и определению реального места мини-инвазивных и открытых хирургических методов.
Abstract 4679: Investigating the role of cryptochrome 2 in human cancer
Authors: Alanna Chan, Katja Lamia
Journal: Cancer Research (2020)

Abstract Through numerous epidemiological studies, The World Health Organization (WHO) deemed disruption of circadian rhythms a probable carcinogen. Circadian rhythms regulate many physiological and cellular processes, while maintaining a ~24hr period. The molecular mechanisms by which disrupted circadian rhythms promote tumorigenesis remain unclear. Recently, our lab found that Cryptochrome 2 (CRY2) acts as an adapter to recruit c-MYC to the E3 ligase complex SKP-CULLIN-FBXL3 (SCFFBXL3) to promote degradation of c-MYC, a known proto-oncogene transcription factor. We identified five recurrent CRY2 mutations (CRY2 D347H, S436R, R460C, D467N and S532L) in a variety of human cancers from The Cancer Genome Atlas (TCGA) (referred to as CRY2 TCGA mutations). We hypothesized that these mutations may disrupt the interactions between CRY2, FBXL3, and c-MYC and thereby promote c-MYC accumulation. We performed several biochemical and functional assays in parallel to investigate the impact of these mutations on CRY2 activities. While three of the mutants tested reduce the association of CRY2 with FBXL3 as expected, we unexpectedly found that one of the CRY2 TCGA mutants abolishes interaction between CRY2, CLOCK, and BMAL1 without affecting its ability to interact with FBXL3 or c-MYC. Thus, this mutation prevents the normal function of CRY2 within the circadian clock and affects two-dimensional colony formation, which could impact cellular transformation as well. Citation Format: Alanna Chan, Katja Lamia. Investigating the role of cryptochrome 2 in human cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4679.
Abstract 3951: Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma
Authors: Gloria E. Marino, Filipe V. Almeida, Ying Liu, Gretchen M. Alicea, Mitchell E. Fane, Ashani T. Weeraratna
Journal: Cancer Research (2020)

Abstract Older melanoma patients (&amp;gt;55 years) have worse prognoses than younger patients (&amp;lt;45 years) independent of other clinical prognostic factors. Further, while younger patients have more lymph node metastases, older patients have more distal metastases which significantly impacts their survival. We have shown that age-dependent loss of a secreted factor from dermal fibroblasts, HAPLN1, contributes to increased distal metastasis in vivo via ECM reorganization. Previous work from our lab has shown that age-dependent loss of HAPLN1 confers fewer lymphatic metastases but more lung metastases, consistent with clinical observations. We have demonstrated that this is due to ECM structural degradation and loss of lymphatic vasculature integrity. However, the biological mechanisms by which dermal ECM structure influences metastatic spread and localization are still largely unknown. Here we report that age-dependent loss of HAPLN1 contributes to increased intratumoral neoangiogenesis and decreased vascular integrity. Using immunohistochemistry, we have shown that tumors from aged mice treated with recombinant HAPLN1 have significantly fewer neoangiogenic blood vessels than untreated aged mice, suggesting that HAPLN1 may signal to inhibit neoangiogenesis. Additionally, the intratumoral blood vessels in aged mice treated with recombinant HAPLN1 have increased levels of the adherens junction protein VE-cadherin consistent with levels seen in the tumor vasculature of young mice. Given the pivotal role of intratumoral vasculature in metastasis, we hypothesize that these changes in vessel number and permeability contribute to the increased incidence of lung metastasis in older patients. Further, our data utilizing two-photon microscopy indicate that aged mice have aberrant collagen structure surrounding intratumoral vessels, but that treatment with recombinant HAPLN1 is sufficient to restore a collagen pattern similar to what is seen in young mice. We have additionally demonstrated using an in vitro impedance-based assay that endothelial cell monolayers have a reduced ability to maintain barrier function in the context of ECM without HAPLN1. Given that dermal ECM structural complexity is essential for maintaining vascular integrity, loss of HAPLN1 seems to contribute to this “leaky” vasculature phenotype. In all, these data may provide clues as to why young and aged patients exhibit differential routes of metastases via lymphatic vs. hematogenous dissemination. Citation Format: Gloria E. Marino, Filipe V. Almeida, Ying Liu, Gretchen M. Alicea, Mitchell E. Fane, Ashani T. Weeraratna. Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3951.
Abstract 1090: Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis
Authors: Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa de Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen
Journal: Cancer Research (2020)

Abstract The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors. Citation Format: Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa de Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1090.
Abstract 5483: An image-based mechanistic computational model for early prediction of organ-confined untreated prostate cancer growth
Authors: Guillermo Lorenzo, Thomas J. Hughes, Alessandro Reali, Hector Gomez, Thomas E. Yankeelov
Journal: Cancer Research (2020)

Abstract According to the American Cancer Society, prostate cancer (PCa) is the most common newly-diagnosed cancer and the second leading cancer-related cause of death among men in the US in 2019. The current clinical protocols of PCa are based on two key strategies: regular screening of men over fifty and patient triaging in risk groups. Prostatic tumors are usually detected at an early organ-confined stage, which poses a low to intermediate risk to the patient and may not produce any symptoms or require treatment for long time. However, most patients are prescribed a radical treatment immediately after diagnosis (e.g., surgery or radiation therapy), which may adversely impact their lives without necessarily prolonging their longevity or quality of life. Moreover, some patients who initially delay their treatment ultimately succumb to PCa due to an inaccurate initial diagnosis. Thus, while regular screening enables the detection of the majority of tumors at an early and mild stage, the limited individualization of patient monitoring and treatment has led to significant rates of both overtreatment and undertreatment. To overcome these fundamental limitations in the clinical management of PCa, we propose the use of a mechanistic mathematical model for which we can perform computer simulations to forecast patient-specific tumor growth. This computational model is based on a set of partial differential equations that describe the main mechanisms involved in organ-confined PCa growth. The model is parameterized using longitudinal multiparametric magnetic resonance (MR) images and the available clinical data for each patient. Tumor growth is simulated over the patient's prostate extracted from T2-weighted MR images. We use isogeometric analysis to accurately and efficiently address the computational challenges arising in this application. Our preliminary simulation results show that our computational technology can predict tumor growth and associated serum Prostate Specific Antigen (PSA, a key biomarker in clinical management of PCa) with reasonable accuracy. We also explore the potential of model parameters and variables to characterize tumor aggressivity. Thus, we believe that our imaging-based modeling approach could be a promising tool capable of being implemented in current PCa protocols to assist physicians in the clinical management of PCa. Citation Format: Guillermo Lorenzo, Thomas J. Hughes, Alessandro Reali, Hector Gomez, Thomas E. Yankeelov. An image-based mechanistic computational model for early prediction of organ-confined untreated prostate cancer growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5483.
Abstract CT274: Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose
Authors: Di Dong, Bingxi He, Boyu Kong, Lei Zhang, Lixia Tong, Feng Huang, Dong Han, Zhipei Huang, Huimao Zhang, Jie Tian
Journal: Cancer Research (2020)

Abstract Purpose: The routinely used diagnostic scheme of cancers follows the process of signal-to-image-to-diagnosis. It is essential to reconstruct the visible images from the signal of medical device so that the human doctor can perform diagnosis. However, the huge amount of information inside the signal is not optimally mined, which causes the current unsatisfactory performance of image based diagnosis. In this study, for the first time, we developed an AI based diagnostic scheme for lung nodules directly from the signal (rawdata) to diagnosis, skipping the reconstruction step. Experimental Design: In this study, we focused on the discrimination of malignant from benign lung nodules using CT rawdata. We collected a simulation dataset (n=606, from LUNA public dataset; rawdata was generated from CT images) and a prospective dataset (n=268, from the First Hospital of Ji Lin University, China; Clinical trials: NCT04241614). In the prospective dataset, all patients underwent preoperative CT scan (both rawdata and CT images were available) and had pathologically confirmed result of the nodules. We used 3D-CNN (Convolutional Neural Networks) to generate a model from rawdata (Model_rawdata) and another model from CT image (Model_image). The performances of the two models were compared with area under curve (AUC). In addition, we explored the additional value of rawdata to image-based diagnostic scheme. Results: The simulation study showed that rawdata could distinguish malignant lung nodules (AUCs for training and validation cohorts were 0.88 and 0.80, respectively). In the prospective study using only the lung area, both Model_rawdata and Model_image had good classification performance (both AUCs were greater than 0.65). In the prospective study using only the nodule area, the Model_rawdata performed similar with Model_image (both AUCs were greater than 0.7). The stratification analysis showed that the Model_rawdata was not affected by CT scanning parameters. Furthermore, the addition of rawdata to image (Model_combination) could improve the diagnostic performance. Conclusions: Without reconstruction, the rawdata from CT system had comparative performance to image-based diagnosis. The rawdata could provide additional diagnostic value to images. This research breaks the routinely used circle of imaged based diagnosis, which may open up a new field for AI based diagnosis. Citation Format: Di Dong, Bingxi He, Boyu Kong, Lei Zhang, Lixia Tong, Feng Huang, Dong Han, Zhipei Huang, Huimao Zhang, Jie Tian. Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT274.
Abstract 5653: Discovery of Anti-NKG2A antibody from immunized phage display approach
Authors: Teddy Yang, Jing Gao, Jingyun Yao, Dongxu Wang, Ken Dai
Journal: Cancer Research (2020)

Abstract The inhibitory receptor NKG2A-CD94 is mainly expressed on NK cells and some T cell and mediates an inhibitory signal through association with a non-classical MHC class I molecule HLA-E, which is commonly over-expressed in human cancers. Targeting NKG2A with monoclonal antibody holds potentials in immunotherapy of cancer. However, proteins with homologous sequences such as NKG2C/CD94 or NKG2E/CD94 complexes generally deliver an activating signal upon ligand binding. NKG2A-specific antagonizing antibodies would be needed to further explore therapeutic potentials of targeting NKG2A for immunotherapy of cancer. We have developed and characterized panels of monoclonal antibodies (mAbs) that specifically recognize NKG2A. Balb/c and SJL mice had been immunized with recombinant NKG2A/CD94 protein, recombinant plasmids encoding hNKG2A or stable cell line with ectopic expression of hNKG2A. Splenocytes from such immunized animals were collected for construction of phage-displayed antibody library in a single chain variable fragment (scFv) format. The NKG2A-specific antibodies, that had no detectable binding to NKG2C, NKG2E or CD94, were isolated through multiple rounds of phage panning and ELISA-based screening. Such antibodies also block HLA-E ligand binding and enhanced cytotoxicity of NK cell lines and primary NK cells on cancer cells. The final lead is a humanized antibody which behaves well in stability test. Lab scale processes are successfully developed and confirmed. The safety and efficacy will be further validated. Citation Format: Teddy Yang, Jing Gao, Jingyun Yao, Dongxu Wang, Ken Dai. Discovery of Anti-NKG2A antibody from immunized phage display approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5653.
Abstract 4887: Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes
Authors: Xueqing Zou, Gene Koh, Scott Nanda, Andrea Degasperi, Katie Urgo, Wendy Bushell, Chukwuma Agu, Vanesa Perez-Alonso, Daniel Rueda, Julia Foreman, Rebecca Harris, Josef Jiricny, Bill Skarnes, Serena Nik-Zainal
Journal: Cancer Research (2020)

Abstract Cancer whole-genome sequencing has revealed characteristic mutational signatures associated with defective DNA repair that underpin human genetic diseases. To define the direct mutagenic effects of DNA repair deficiency at the genome-wide level, we investigate mutational signatures generated by CRISPR-Cas9-based knockouts of 42 genes involved in DNA repair/replication using a human-induced pluripotent stem cell line. Knockouts (Δ) of nine DNA repair genes reveal substitution/indel mutational signatures. Notably, dissection of signatures of defective mismatch repair (MMR) uncovers gene-specific characteristics including distinguishing features of ΔMLH1, ΔMSH2, and ΔMSH6 from ΔPMS2. This gene-specificity is also exhibited by hIPSCs derived from patients with autosomal recessive Constitutional Mismatch Repair Deficiency (CMMRD) that carry biallelic germline mutations of MMR genes. Furthermore, gene-specificity manifests in whole genome sequenced primary human cancers. Additionally, detailed analyses reveal putative sources of endogenous DNA damage that contribute to MMR signatures, including guanine oxidation, errors of DNA polymerases and reversed template slippage or double slippage. Finally, we find that using all mutational signatures of MMR-deficiency as identified in this study results in improved sensitivity and specificity in classifying MMR-deficient tumors, critical for accurate patient stratification for therapeutic intervention. Citation Format: Xueqing Zou, Gene Koh, Scott Nanda, Andrea Degasperi, Katie Urgo, Wendy Bushell, Chukwuma Agu, Vanesa Perez-Alonso, Daniel Rueda, Julia Foreman, Rebecca Harris, Josef Jiricny, Bill Skarnes, Serena Nik-Zainal. Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4887.