bluuebunny/crossref_metadata_2025 huggingface dataset:
Folate Receptor 4-Expressing T cell Is Associated with Disease-Free Survival in Patients with Esophageal Squamous Cell Carcinoma
Authors: Zhang Xiangmei , Zhao Qi , Cao Miao , Li Xinhui , Chen Xin , He Ming , Liu Yunjiang , Zhao Jidong
Published: June 2022

Background. Folic acid receptor 4 (FR4) significantly downregulates the expression of regular T cells (Treg) and improves the effect of chemotherapy and PD-1/PD-L1 inhibitors. However, the FR4 expression in squamous cell carcinoma (ESCC) remains unclear. Methods. Patients with primary ESCC who visited our hospital between 1st February 2012 and 30th September 2016 were enrolled in this study. FR4 expressions in ESCC patients were detected by immunohistochemistry staining, and the association with clinical characteristics and the overall survival (OS) or disease-free survival (DFS) was analyzed. Results. One hundred and forty-eight qualified cases of ESCC patients were retrieved, including 34 females. Ninety-four cases had lymph node metastasis (63.51%), 104 patients received adjuvant therapy (70.27%), and the rate of FR4 positive was 67.57% (100/148). Among FR4 positive patients, 75 cases received adjuvant therapy, and patients who received chemotherapy were significantly better than that of patients who did not receive chemotherapy. In patients with FR4 negative expression, 48 cases received adjuvant therapy, which was significantly worse than that of patients who did not receive chemotherapy. Conclusions. Postoperative adjuvant chemotherapy prolonged the survival in FR4 positive ESCC patients, whereas adjuvant therapy in patients with FR4 negative needs to be further improved.
An Easy Way to Deploy the Re-ID System on Intelligent City: Cross-Domain Few-Shot Person Reidentification
Authors: Dai Xili , Yang Cheng , Liu Bin , Gong Haigang , Yuan Xiaojun
Published: June 2022

An intelligent urban system relies on different types of electronic and/or sensor technologies to collect data to facilitate education, security, healthcare, etc. Person reidentification (re-ID) plays a crucial role in intelligent security, in which significant progress has been made during the past few years. One example is using re-ID systems for law enforcement tasks such as suspect identification. One common obstacle is quickly deploying a re-ID system to new city, such as data label deficiency. For example, the lacking of enough labeled data to train an excellent model in a new city, only relying on a tiny amount of criminals’ pictures provided by witnesses. Fortunately, this can be modeled as a special application in unsupervised person re-ID of real-world scenarios, the study of which has become more prevalent in the re-ID community in recent years. In this paper, we first formulate our scenario as a cross-domain few-shot problem and discuss the difference between conventional supervised re-ID and unsupervised re-ID. Then, we introduce a reweighting instance method based on influence function (ReWIF) to guide the training procedure of the re-ID model. This method is motivated by the influence function, and we use two-step optimization to avoid the computation of Hessian matrices. We evaluate our proposed method on public datasets, including Market, Duke, and CUHK. Extensive experimental results show that our method can effectively address the domain bias of different datasets and the absence of labeled data on the target dataset, achieving state-of-the-art performance.
Window Opening Behavior of Residential Buildings during the Transitional Season in China’s Xi’an
Authors: Yang Xiaolong , Liu Jiali , Meng Qinglong , Wei Yingan , Lei Yu , Wu Mengdi , Shang Yuxuan , Zhang Liang , Lian Yingchen
Published: June 2022

Window opening behavior in residential buildings has important theoretical significance and practical value for improving energy conservation, indoor thermal comfort, and indoor air quality. Climate and cultural differences may lead to different window opening behavior by residents. Currently, research on residential window opening behavior in northwest China has focused on indoor air quality, and few probabilistic models of residential window behaviors have been established. Therefore, in this study, we focused on an analysis of factors influencing window opening behavior and the establishment of a predictive model for window opening behavior. Four typical residential buildings in different locations and building types in Xi’an were selected. The indoor and outdoor environments and window opening states were measured. Subsequently, a multivariate analysis of variance was used to determine the factors that had a significant effect on window opening behavior. Single‐ and multiparameter logistic regression models for window opening behavior were established. Of all the measured factors, we found that indoor temperature and CO2 concentration, outdoor temperature, and relative humidity had significant effects on window opening behavior, and indoor relative humidity and noise did not. Meanwhile, the temperature was positively correlated with the window opening probability, whereas indoor CO2 concentration and outdoor relative humidity were negatively correlated. The prediction accuracy of the multiparameter model was promising, at almost 75%, and the model can provide theoretical support for modelling residential buildings in Xi’an.
Teaching Mode of Japanese Intensive Reading in Colleges and Universities Based on Cloud Computing Intelligent Platform
Authors: Yu Xiaohuan , Huang Zhou
Published: June 2022

In order to improve the effect of Japanese teaching in colleges and universities, this study uses the variance of the bias error of the data channel of the cloud transmission platform to represent the intensity of the bias error between the data channels of the cloud transmission platform. Moreover, this study uses the perfect reconstruction filter algorithm to compensate for the frequency-dependent mismatch error of the broadband signal, obtains the value at the ideal sampling point from the sampling sequence estimation, and then corrects the delay deviation. In addition, this study constructs the overall structure of the Japanese intensive reading teaching system in colleges and universities based on the network cloud platform, proposes a method for solving the correction filter, and conducts simulation verification. Finally, this study constructs a teaching system for Japanese intensive reading in colleges and universities based on the network cloud platform. Through experimental research, it is verified that the teaching mode of Japanese intensive reading in colleges and universities based on the cloud computing intelligent platform has certain feasibility.
Optimal Control and Stability Analysis of an SEIR Model with Infectious Force in Latent Period
Authors: Jiayi Li , Sixian Li , Weixuan Shi , Manfeng Hu , Jingxiang Zhang
Published: June 2022

In this paper, an SEWIR epidemic model with the government control rate and infectious force in latent period is proposed. The conditions to the existence and uniqueness of disease-free and endemic equilibrium points in the SEWIR model are obtained. By using the Hurwitz criterion, the locally asymptotic stability of disease-free and endemic equilibrium points is proved. We show the global asymptotic stability of the disease-free equilibrium point by the construction of Lyapunov function and LaSalle invariance principle. The globally asymptotic stability of the endemic equilibrium is verified by numerical simulation. Several optimal control strategies are proposed on controlling infectious diseases.
A Case of Traumatic Catheterisation leading to Rectal Perforation and Periprostatic Abscess
Authors: Cullivan Orla , David Silviu , Jaffry Syed
Published: June 2022

A 79-year-old gentleman presented to the Emergency Department (ED) with catheter-related issues on a background of a long-term catheter for previous urinary retention, Hartmann’s procedure for colorectal cancer, and brachytherapy for prostate cancer. A 3-way silicone catheter was placed by ED staff and bladder irrigation commenced. The urine draining following catheterisation was found to be dark and thick, and irrigation fluid was noted to be draining per rectum. CT imaging was performed and demonstrated the catheter tip extending through the posterior wall of the urethra and into the rectum. The patient was admitted under the urology team, and urinary diversion was achieved with a suprapubic catheter. Subsequent imaging demonstrated a periprostatic abscess, which was initially managed with antimicrobial therapy, followed by attempted image-guided drainage. Repeat imaging following a 6-week course of antibiotics failed to show an improvement in the collection. During his inpatient stay, he contracted COVID-19 and passed away suddenly. This case demonstrates the potential catastrophic consequences associated with urethral catheterisation.
For Indirect Orthodontic Attachment Placement, Adding a Custom Composite Resin Base Is Not Beneficial: A Split-Mouth Randomized Clinical Trial
Authors: Hassan Mohamed S. , Abdelsayed Fatma A. , Abdelghany Amany H. , Morse Zac , Aboulfotouh Mai H.
Published: June 2022

Aim. The aim of this study was to compare the chairside time, bond failure rate, and accuracy of bonding between two orthodontic attachment indirect bonding techniques. Methods and Materials. Two indirect bonding techniques were studied: unaltered base attachment (UA) and custom base attachment (CBA) methods. Eighty-four orthodontic attachments were bonded on six patient stone models. Preoperative models were digitally scanned, and subsequently, attachments were transferred with the aid of a single but sectioned vacuum-formed tray to their corresponding patients. Finally, participants were scanned after attachment bonding to make the postoperative digital replicas. Chairside time and immediate bond failure rates were measured and compared between both techniques. Postoperative and preoperative digital models were then superimposed in order to measure the accuracy of bonding in the three dimensions of space. Results. No differences existed between the two techniques regarding chairside time (

P
=
0.87

) and bond failure rates (

P
=
0.37

). There were also no differences found for the total attachment movement (

P
=
0.73

), mesiodistal (

P
=
0.10

), occlusogingival (

P
=
0.31

), torquing (

P
=
0.21

), and rotational measurements (

P
=
0.18

). The UA technique, however, proved to be more accurate for buccopalatal linear directions (

P
=
0.04

), whilst the CBA technique showed more accuracy for tipping angular deviations (

P
<
0.01

). There was a statistically significant directional bias for the UA towards the occlusal (

P
<
0.01

) and palatal (

P
=
0.02

) directions with mesial-out angular deviation (

P
=
0.02

). Conclusion. The two indirect bonding techniques were comparable for chairside time, bond failure rates, and most linear and angular measurements. The UA technique was, however, superior in buccopalatal directions, while the CBA method showed more tipping accuracy. Both techniques were efficient and reliable for indirect bonding.
Abstract 1002: Targeting adaptation to cancer treatment by drug combinations
Authors: Wang Heping , Luna Augustin , Yan Gonghong , Li Xubin , Babur Ozgun , Sander Chris , Mills Gordon
Published: June 2022

Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves the co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation, and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of antiapoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.

Citation Format: Heping Wang, Augustin Luna, Gonghong Yan, Xubin Li, Ozgun Babur, Chris Sander, Gordon Mills. Targeting adaptation to cancer treatment by drug combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1002.
Abstract 1004: Growth hormone upregulates tumor-derived exosomal distribution of EMT mediators and multi-drug efflux pumps in melanoma
Authors: Kulkarni Prateek , Basu Reetobrata , Kopchick John J.
Published: June 2022

Melanoma is the most aggressive form of skin cancer with a dismal 5-year survival rate of 16% at the metastatic stage of the disease. Exosomes have recently emerged as a critical mediator of cancer therapy resistance by regulating epithelial to mesenchymal transition (EMT) and drug efflux. Exosomes are extracellular vesicles (diameters 30-150nm) released from almost all types of cells including tumor cells which package and transfer proteins, RNA, and lipids (often called cargo) from one cell to another. This intercellular communication via exosomes has been reported to induce a drug-resistant phenotype across the tumor by transporting ABC multidrug transporters and mediators of EMT. Multiple studies have established that pituitary-, or tumor- or tumor microenvironment-derived growth hormone (GH) promotes EMT and drug resistance in cancer by binding to GHR-expressing tumor cells. A question arises: Does GH exert this effect across the tumor population via modulating tumor-derived exosomal cargo? No study has yet directly assessed the effect of GH on exosomes in terms of modulating EMT or drug resistance. We isolated exosomes from human melanoma cells with differential levels of GHR expression, following treatment with combinations of GH, anti-cancer drugs, and the GHR antagonist, pegvisomant. We observed no change in the quantity of tumor-derived exosomes with changes in GH action. However, we found significant upregulation of multidrug efflux pumps ABCB1, ABCC1, ABCC2, and ABCG2 in GH-treated tumor exosomes. Importantly, treatment of naïve melanoma cells with these exosomes increased their drug efflux rate and reduced drug retention. Exosomes derived from pegvisomant treated melanoma cells showed markedly reduced ABC transporter contents and did not increase the efflux rate of naïve tumor cells. A similar trend in matrix metalloproteinases (MMP2, MMP9) and TGFb levels in isolated exosomes as well as TGFb signaling and invasion capacity in naïve tumor cells treated with isolated exosomes were observed. These results present a unique effect of GH on tumor-derived exosomal content modulation towards propagating a drug-resistant tumor phenotype in naïve cancer cells.

Acknowledgment: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.

Citation Format: Prateek Kulkarni, Reetobrata Basu, John J. Kopchick. Growth hormone upregulates tumor-derived exosomal distribution of EMT mediators and multi-drug efflux pumps in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1004.
Abstract 1036: Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer
Authors: Koo Junghui , Seong Chang-Soo , Dwivedi Bhakti , Tucker-Burden Carol , Marcus Adam I. , Gilbert-Ross Melissa
Published: June 2022

Lung cancer is among the most commonly diagnosed cancers and the leading cause of cancer-related death globally, with approximately 85% of all lung cancers having non-small cell lung cancer (NSCLC). The protein kinase LKB1 is the 3rd most frequently mutated gene in lung adenocarcinoma, and serves as a master regulator of cell metabolism and growth. LKB1-inactivating mutations have a significant impact on NSCLC development. Although KRAS mutation is most frequently co-mutated with the tumor suppressor p53, the strongest cooperation was seen with homozygous inactivation of LKB1. Loss of LKB1 on a KRAS-mutant (KL) background leads to increased tumor burden, shortened survival time and increased metastasis compared to loss of TP53 (KP). Furthermore, inactivation or loss of LKB1 correlated with poor prognosis, where tumors are typically aggressive and chemoresistant. To discover therapeutic vulnerabilities for this aggressive genetic subtype of lung adenocarcinoma, we evaluated the contribution of multiple single- and double-genetic alterations (KRAS G12D (K), LKB1 knockdown (L), and p53 knockdown (P)) to 3D invasion phenotypes using immortalized human bronchial epithelial cells (HBEC3-KT) and conducted RNA transcriptome profiling of the invading HBEC3-KT 3D spheroids. We found that bone morphogenetic protein 6 (BMP-6) is upregulated in invasive KL spheroids only compared to K and KP, suggesting that the loss of both KL drives increased BMP6 expression. Consistent with this finding, the iron regulator hepcidin, which is regulated by BMP6 is also upregulated in KL spheroids. Both BMP-6 and hepcidin expression can be repressed by restoring exogenous LKB1 in KL spheroids suggesting that LKB1 loss is at least in part responsible for the overexpression of the BMP6/hepcidin pathway. In addition, inhibition of BMP-6 signaling via BMP type I receptor ALK2 using small molecule inhibitor LDN214117 suppressed of cell invasion in 3D culture and decreased tumor growth in a KL syngeneic mouse model. Collectively, our findings show that upregulation of hepcidin via BMP6 signaling and followed by iron sequestration in tumor cells is part of the metastatic invasion strategy of LKB1 inactivated NSCLC. Therefore, current clinical strategies targeting BMP6 signaling could improve outcomes for LKB1-mutant lung cancer patients.

Citation Format: Junghui Koo, Chang-Soo Seong, Bhakti Dwivedi, Carol Tucker-Burden, Adam I. Marcus, Melissa Gilbert-Ross. Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1036.
Abstract 105: Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian cancer cells
Authors: Shin So-Jin , Lee Seungmee , Chung Hyewon , Cho Chi-Heum , Ha Eunyoung , Kim Jin Young , Seo Ji Hae
Published: June 2022

Ovarian cancer is a leading cause of death of women in worldwide. Frequent recurrence and becoming resistant to chemotherapy are one of the causes that makes ovarian cancer deadly. Since recent studies have demonstrated that aberrant Wnt signaling plays an important role in cancer stem cells (CSCs) which are responsible of recurrence, metastasis and treatment failure, we tested whether regulation of Wnt signaling can be effective in ovarian cancer treatment. By treating CWP232228 which is a potent inhibitor of Wnt signaling to ovarian cancer cell lines and to a mouse model, we found CWP232228 effectively inhibits the growth of ovarian cancer cells which expresses high level of b-catenin and induce apoptosis of ovarian cancer cells. Furthermore CWP232228 reduces ovarian cancer cell migration, invasion and colony formation ability. Moreover CWP232228 reduces key features of CSCs. Taken together, our study suggests CWP232228 as a potential substance which might be effective in treating epithelial ovarian cancer with avoiding treatment failure.

Citation Format: So-Jin Shin, Seungmee Lee, Hyewon Chung, Chi-Heum Cho, Eunyoung Ha, Jin Young Kim, Ji Hae Seo. Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 105.
Abstract 109: The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation
Authors: Morel Marion , Long Weiwen
Published: June 2022

F-box proteins are essential components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases in that they bind to SKP1 through the F-box motif and bring the substrate to the E3 ligase complex for ubiquitination. FBXL16 is a poorly studied F-box protein. FBXL16 doesn’t interact with Cul1 and might not form a functional SCF-E3 ligase complex. Unexpectedly, we recently found that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, such as SRC-3 and c-myc, by antagonizing the activity of another F-box protein, FBW7. By data mining, we found that FBXL16 is highly upregulated in many cancers, including lung adenocarcinomas (LUADs), and its upregulation is associated with poor overall survival. LUAD is the most common form of lung cancer, and about 30% of LUADs harbor constitutively active oncogenic KRAS mutants. However, currently no drug is available for effectively treating LUADs expressing KRAS mutants. Hence, there is an unmet need to identify new therapeutic targets. Here, we report that FBXL16 protein level is selectively upregulated and is strongly correlated with insulin receptor substrate-1 (IRS1) protein expression in LUAD cell lines with activating KRAS mutations. By cycloheximide treatment, we found that FBXL16 greatly increases IRS-1 protein stability and level, leading to upregulation of IGF-1 (Insulin)/IRS1/PI3K Akt signaling. Importantly, the upregulation of IRS1 protein and its signaling by FBXL16 was confirmed in mouse lungs with conditional overexpression of FBXL16 transgene. Moreover, depletion of FBXL16 by RNA interference inhibits IGF-1-induced lung cancer cell proliferation and migration. Taken together, our findings reveal FBXL16 as a potential target for treating LUADs with KRAS activating mutations.

Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 109.
Abstract 110: Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D
Authors: Wang Qing , Yang Hsin-Sheng
Published: June 2022

Lung cancer is the most devastating disease and leading cause of cancer death in men and women. Platycodin D is one of the major bioactive components of the Platycodon grandiflorum, a herb that is frequently used for the treatment of lung diseases in Chinese medicine. Platycodin D is a triterpenoid monomer with activities of antioxidant, anti-obesity, and anti-inflammatory. Studies have also shown that platycodin D has an anti-tumor effect on various types of cancer. However, the mechanism by which platycodin D suppresses tumorigenesis remains elusive and some experimental results are controversial. In this study, we aim to understand the effect of platycodin D on the growth of non-small lung cancer cells (NSCLC) and the underlying mechanism. We found that NSCLC cells (H1299, H2030, and A549 cells) treated with platycodin D significantly reduced the cell viability, decreased the number of colonies, impaired the mitochondrial function, and induced apoptosis. To understand the mechanism, the protein levels of the Bcl-2 protein family were examined and p53 upregulated modulator of apoptosis (PUMA) was found elevated by platycodin D treatment. The induction of PUMA expression by platycodin D treatment was through activation of the c-Jun N-terminal kinase (JNK) and AP-1 dependent transcription since JNK inhibitor or over-expression of dominant negative c-Jun abolished the elevated PUMA expression. Moreover, knockdown of JNK1, but not JNK2, significantly decreased the level of platycodin D-induced PUMA and cleaved caspase 3, indicating the essential role of JNK1 in platycodin D-induced apoptosis. Furthermore, platycodin D efficiently suppressed the tumor growth in the H1299 xenograft. Taken together, activation of JNK1 by platycodin D is essential for induction of apoptosis in suppression of growth of NSCLC, providing a new mechanism of how platylcodin D suppresses NSCLC.

Citation Format: Qing Wang, Hsin-Sheng Yang. Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 110.
Abstract 113: Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells
Authors: Campbell Taaliah , Hawsawi Ohuod , Bowen Nathan , Odero-Marah Valerie
Published: June 2022

Prostate cancer (PCa) is one of the most commonly diagnosed malignancies among men worldwide and remains the second leading cause of cancer related death in the United States. Oxidative stress has been shown to be increase in several cancers including prostate cancer. In fact, oxidative stress in prostate cancer is suggested to be a direct result of cell exposure to reactive oxygen species (ROS). High mobility group A 2 (HMGA2), a non-histone protein, is an oncogene that is up-regulated in several cancers. This protein has ability to undergo chromosomal rearrangement and alternative splicing, causing its full length/wild type HMGA2 (HMGA2-WT) to become the truncated losing its 3’UTR leading to the generation of HMGA2 truncated (HMGA2-TR). We have previously shown HMGA2-WT’s involvement in epithelial mesenchymal transition (EMT), however, the functional role of HMGA2-TR has not yet been dissected. We hypothesize that truncated HMGA2’s involvement with oxidative stress leads to prostate cancer progression. We analyzed the baseline expression of wild-type vs.truncated HMGA2 in prostate patient tissue and cells lines by real-time PCR and western blot analyses. Prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2with increasing tumor grade, when compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing HMGA2-WT, HMGA2-TR, or empty vector (Neo) control revealed thatHMGA2-TR cells display increased oxidative stress compared to HMGA2-WT or Neo control cells. This was also confirmed by analysis of basal reactive oxygen species (ROS) levels, and the ratio of GSH/GSSG andNADP/NADPH utilizing metabolomics. Additionally, proteomic analysis showed that HMGA2-TR protein interacted with several proteins, including a cytoplasmic stress granule protein G3BP1 that responds to oxidative stress. Transient knockdown of G3BP1 increased ROS in HMGA2-TR cells. These studies may therefore uncover novel role for truncated HMGA2 in oxidative stress.

Acknowledgements: These studies were supported by the NIH/NIMHD/RCI Grant #5G12MD007590-31,NIH/NIGMS/RISE Grant #5R25GM060414

Citation Format: Taaliah Campbell, Ohuod Hawsawi, Nathan Bowen, Valerie Odero-Marah. Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 113.
Abstract 1130: CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity
Authors: Bacanu Smaranda , Liang Ying Yu , Ramos Anderson D. , Prabhu Nayana , Nordlund Pär
Published: June 2022

Introduction: Our current understanding of the mechanism of action (MoA) of many cancer drugs is still incomplete. This hampers efforts in establishing efficient personalised medicine regimens, the optimisation of combination therapies, and the development of next generation drugs.

Results: Here, we apply a high-resolution implementation of the proteome-wide cellular thermal shift assay (CETSA) to follow protein interaction changes induced by the antimetabolite 5-fluorouracil (5-FU) and related nucleosides. We focus on the relatively early drug effects, up to 12 hours, when this time frame is less accessible to other omics methods, while critical for defining drug MoAs. We confirm anticipated effects on the known main target, thymidylate synthase (TYMS), and enzymes in pyrimidine metabolism and DNA damage pathways. However, most interaction changes we see are for proteins previously not associated with the MoA of 5-FU, including wide-ranging effects on RNA modification and processing pathways. Attenuated responses of specific proteins in a resistant cell model identify key components of the 5-FU MoA, where intriguingly the abrogation of TYMS inhibition is not required for cell proliferation.

Conclusions: When 5-FU is one of the most used and studied cancer drugs, this novel information significantly expands our understanding of the 5-FU MoA and will be important to direct further work towards dissecting its complete MoA. Furthermore, the CETSA responses of several proteins now provide ideal readouts for directly monitoring whether the required 5-FU effects are accomplished and can now be examined as CETSA-based candidate biomarkers in clinical studies. Together, this work also validates an efficient strategy for dissecting the MoA of cancer drugs, which could be broadly applicable to other cancer drugs in clinical use or in development.

Citation Format: Smaranda Bacanu, Ying Yu Liang, Anderson D. Ramos, Nayana Prabhu, Pär Nordlund. CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1130.
Abstract 1146: A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma
Authors: BARRETTE ANNE MARIE , Deshpande Krutika , Cadiente Marvin , Bei Anji , Wang Xi , Mirabella Teodelinda , Sun Dongxu
Published: June 2022

Characterized by rapid growth and diffusely infiltrative spread, glioblastoma (GBM) is the most common and most malignant primary brain cancer with a very poor prognosis and a standard of care that hasn’t been improved in over 15 years. The need for new therapies that can directly or indirectly target heterogeneous tumor cell populations to inhibit cell migration in addition to proliferation is highlighted by the recent efforts to develop targeted therapies to treat the vast majority of GBM patients whose tumors impede gross-total resection and develop resistance to chemoradiation. Galectin-3, a carbohydrate-binding protein overexpressed in astrocytes, microglia/macrophages, and the stroma of GBM tumors is a potent modulator of cell proliferation, migration, angiogenesis, T-cell inhibition, and M2 macrophage polarization. We and others have confirmed the association of Galectin-3 expression to lower survival in glioma patients. Additionally, tumor Galectin-3 levels have been shown to increase following exposure to temozolomide or radiation alone or in combination, thus more greatly increasing the need for targeting Galectin-3 in GBM patients following initial treatment. Here, we characterize the therapeutic effects of the anti-Galectin-3 antibody (Gal3 Ab) we have developed for the ability to inhibit GBM tumorigenic and metastatic potential in several in vitro assays and in vivo in heterotopic and orthotopic mouse models. Human GBM cells treated with Gal3 Ab show a significant decrease in cell viability, migration, and invasion in vitro. In vivo, the Gal3 Ab decreases tumor burden and provides a survival benefit in combination with temozolomide compared to the current standard-of-care treatment alone. Our studies indicate the potential for our novel anti-Galectin-3 to be added to the very limited arsenal of potential treatments for GBM.

Citation Format: ANNE MARIE BARRETTE, Krutika Deshpande, Marvin Cadiente, Anji Bei, Xi Wang, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1146.
Abstract 1160: Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides
Authors: Mukashyaka Patience , Pour Ali Foroughi , Chuang Jeffrey H.
Published: June 2022

Advances in digital pathology have streamlined use of deep learning methodologies to connect morphology and phenotype in hematoxylin and eosin(H&E) stained images. Whole slide images (WSIs) are gigantic, necessitating a tile-based analysis: a WSI is broken into smaller images called tiles, each tile is analyzed separately, and tile level information are then combined to get a slide level prediction. Context aware models integrating tiles of different sizes have been used to combine morphological features present at different scales, and attention-based pipelines have successfully been used to combine tile level information. Pipelines that combine attention-based and context aware learning are less studied. While both methodologies have shown utility when used individually, models that combine both tend to suffer from a large number of parameters to estimate, which frustrates reliable training. Here we show percentiles of deep learning features extracted at different scales serve as a crude multiscale attention mechanism. The proposed model separates TCGA-BRCA invasive ductal and lobular carcinoma FFPE WSIs (AUC=0.85±0.02), which improves upon the performance of the fully tile-based model of [1] (AUC=0.80 ±0.04). The proposed approach enjoys higher average AUC and lower standard deviation across multiple random train/test splits of data. Our results suggest percentile-based feature construction is an interesting alternative when reliable training of fully deep learning models is challenging.

References:

[1] Noorbakhsh, J., Farahmand, S., Foroughi pour, A. et al. Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images. Nat Commun 11, 6367 (2020). https://doi.org/10.1038/s41467-020-20030-5

Citation Format: Patience Mukashyaka, Ali Foroughi Pour, Jeffrey H. Chuang. Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1160.
Abstract 1180: Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation
Authors: Xu Shuichan , Tran Tam , Zhu Dan , Shi Tao , Mikolon David , Leisten Jim , Chamberlain Philip , LeBrun Laurie , Bahmanyar Sogole , Jiang Ning , Zhao Jingjing , Malek Mehnaz , Filvaroff Ellen , Raymon Heather , Hubbard Robert , Boylan John
Published: June 2022

CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223. Broad kinase selectivity profiling identified ERK1/2 and NLK as targets of CC-91516. Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994. This unique binding mode of CC-91516 leads to a slow off-rate for its ERK binding with long residence time disrupting both the active and inactive ERK forms. Consequentially, CC-91516 causes sustained inhibition of the MAPK pathway in BRAF mutant colorectal cancer cells. In addition, CC-91516 also regulates Wnt/β-catenin and YAP pathways in multiple cancer cell lines. CC-91516 shows potent yet selective anti-proliferative activity against a large panel of cancer cell lines. Activating mutations in BRAF or CTNNB1 gene associate with sensitivity to CC-91516-mediated anti-proliferative activity while mutations in RB and PI3K/PTEN pathway associate with resistance. CC-91516 inhibits ex vivo colony formation of PDX models with BRAF and CTNNB1 mutations. In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro. CC-91516 has good oral bioavailability and shows excellent anti-tumor activity in vivo against both BRAF and CTNNB1 mutant xenograft models. DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development.

Citation Format: Shuichan Xu, Tam Tran, Dan Zhu, Tao Shi, David Mikolon, Jim Leisten, Philip Chamberlain, Laurie LeBrun, Sogole Bahmanyar, Ning Jiang, Jingjing Zhao, Mehnaz Malek, Ellen Filvaroff, Heather Raymon, Robert Hubbard, John Boylan. Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1180.
Abstract 1195: BC-BET v2.0: Updates to an online Bladder Cancer Biomarker Evaluation tool
Authors: Dancik Garrett M.
Published: June 2022

The Bladder Cancer Biomarker Evaluation Tool (BC-BET) is a web application for quickly evaluating candidate diagnostic and prognostic biomarkers in bladder cancer, based on publicly available gene expression datasets. Specifically, BC-BET evaluates whether a selected gene is differentially expressed between normal cells and tumor samples; between low- and high- grade tumors; and between non-muscle invasive and muscle-invasive tumors. BC-BET also evaluates whether a selected gene is significantly associated with survival, and whether the gene is associated with survival in two clinically important patient subsets: patients with low-grade, non-muscle invasive tumors; and patients with high-grade, muscle invasive tumors. Here we describe updates to BC-BET that include the inclusion of additional patient cohorts, and new features including multi-gene search, data visualization, additional data export options, and faster search times. BC-BET v2.0 contains gene expression data from 17 cohorts (N = 1846), and users can now query up to 500 genes at a time in order to quickly identify genes associated with bladder cancer. For single gene queries, dot plots can be generated for visualization of gene expression across groups; while Kaplan-Meier curves can be generated for survival analyses. BC-BET v2.0 also allows users to export the gene expression and clinical data, which would allow researchers to generate their own visualizations or to carry out additional analyses. Finally, the BC-BET backend was re-designed, resulting in more than a 2x fold increase in performance efficiency. We hope that this tool will continue to serve the bladder cancer research community and will ultimately lead to a better understanding of and treatment of this disease. The BC-BET web application as well as its source code is freely available from https://gdancik.github.io/BC-BET/.

Citation Format: Garrett M. Dancik. BC-BET v2.0: Updates to an online Bladder Cancer Biomarker Evaluation tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1195.
Abstract 1196: Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium
Authors: Hu Lucas Zhongming , Douglass Eugene , Realubit Ron , Karan Charles , Alvarez Mariano , Califano Andrea
Published: June 2022

Traditional approaches to elucidate small molecule mechanism of action (MoA) are usually based on affinity binding assays. These often fail to detect lower affinity binding targets and secondary effectors that are usually highly tissue context-dependent. As such, these can vary dramatically across different cancer types. To address this challenge and facilitate more quantitative approaches to targeted cancer therapy, a more comprehensive picture of drug MoA, including poly-pharmacology and toxicity effects mediated by the full range of its high-affinity (primary), as well as its context-specific lower-affinity (secondary) and downstream effector (tertiary) targets. For this purpose, we generated transcriptional genome-wide RNA-Seq profiles of cancer cell lines, following compounds perturbation with FDA approved and late-stage experimental oncology drugs using a fully automated and highly efficient PLATE-Seq technology1. Compared to prior approaches, this provides (a) genome-wide readouts, rather than readouts limited to a small set of landmark genes, (b) in cell lines that were specifically selected as the highest-fidelity models for published human cancer cohorts, using the OncoMatch algorithm2, and (c) for a drug repertoire that is clinically relevant. In addition, to avoid confounding effects from drug stress/death response pathway activation—a common issue in previous studies—drugs were titrated at their maximum sub-lethal concentration (48-hr IC20) using 10-point dose response curves in each cell line. The ~20,000 molecular profiles generated by these assays were analyzed using the VIPER algorithm3 to reproducibly assess the effect of each drug on the activity of ~6,500 regulatory and signaling proteins compared to vehicle control. The resulting PanACEA (Pancancer Activity-based Compound Efficacy Analysis), a database comprising drug perturbation profiles for 23 different cancer cell lines and > 700 oncology drugs, representing the largest resources of functionally annotated, genome-wide perturbational profiles for clinically relevant drugs. Systematic analysis identified critical drug mechanism of action and drugs capable of reproducibly targeting undruggable proteins, such as MYC or KRAS. We also leveraged graph theory-based network approach to generate a conserved drug functional network and drug functional networks in different cancer contexts, which pinpoint critical novel poly-pharmacology effects.

Citation Format: Lucas Zhongming Hu, Eugene Douglass, Ron Realubit, Charles Karan, Mariano Alvarez, Andrea Califano. Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1196.
Abstract 1218: HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors
Authors: Su Kenong , Pang Minxing , Li Mingyao
Published: June 2022

Recent developments in spatially resolved transcriptomics (SRT) technologies have enabled the profiling of transcriptome-wide gene expression while retaining spatial location information of each measured spot within a tissue. Meanwhile, the corresponding histopathology images of tissue sections are readily available and can be aligned to the measured spots. Given that the histology images are practically more convenient and affordable to obtain, we designed HOPE2Net, a multi-layer perceptron architecture, that leverages information provided by SRT data to predict gene expression and pathway activities from histology images. Through systematic evaluations of different approaches for extracting deep image features and cellular morphology features, HOPE2Net performs feature selections from a pre-trained Vision Transformer, which is the state-of-art deep learning model for image recognition. After extracting histological image features, HOPE2Net further integrates with position embeddings, to optimize the gene expression and pathway activity prediction tasks. Through analyzing breast cancer and prostate cancer SRT datasets obtained from numerous tissue sections in multiple patients, we demonstrate that HOPE2Net can accurately predict the gene expression patterns for highly variable genes and the activities for significantly enriched domain-specific pathways. We further show that the predicted gene expression and pathway activities can help detect cancer subtypes and aid in treatment decision-makings. Given the growing interest in applying SRT in cancer genomics, we believe HOPE2Net holds the potential in identifying biomarkers from direct screenings of tissue histology images, which may be implemented in clinical studies for cancer diagnoses and decision-making processes.

Citation Format: Kenong Su, Minxing Pang, Mingyao Li. HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1218.