bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a Consistent Interpretation of AIOps Models
Authors: Lyu Yingzhe , Rajbahadur Gopi Krishnan , Lin Dayi , Chen Boyuan , Jiang Zhen Ming (Jack) 
Published: November 2021

Artificial Intelligence for IT Operations (AIOps) has been adopted in organizations in various tasks, including interpreting models to identify indicators of service failures. To avoid misleading practitioners, AIOps model interpretations should be consistent (i.e., different AIOps models on the same task agree with one another on feature importance). However, many AIOps studies violate established practices in the machine learning community when deriving interpretations, such as interpreting models with suboptimal performance, though the impact of such violations on the interpretation consistency has not been studied.
In this article, we investigate the consistency of AIOps model interpretation along three dimensions: internal consistency, external consistency, and time consistency. We conduct a case study on two AIOps tasks: predicting Google cluster job failures and Backblaze hard drive failures. We find that the randomness from learners, hyperparameter tuning, and data sampling should be controlled to generate consistent interpretations. AIOps models with AUCs greater than 0.75 yield more consistent interpretation compared to low-performing models. Finally, AIOps models that are constructed with the Sliding Window or Full History approaches have the most consistent interpretation with the trends presented in the entire datasets. Our study provides valuable guidelines for practitioners to derive consistent AIOps model interpretation.
PARP Inhibitors – Trapped in a Toxic Love Affair
Authors: Krastev Dragomir B. , Wicks Andrew J. , Lord Christopher J. 
Published: November 2021

Abstract
It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination–defective cancers. In 2012, nearly a decade after the first PARPi entered clinical development, work from Murai and colleagues demonstrated that clinical PARPi not only inhibit the catalytic activity of PARP1, PARylation, but also “trap” PARP1 on DNA; this latter effect being responsible for much of the tumor cell cytotoxicity caused by these drugs. We discuss how this work not only changed our understanding about how PARPi work, but also stimulated subsequent dissection of how PARP1 carries out its normal function in the absence of inhibitor.
See related article by Murai and colleagues, Cancer Res 2012;72:5588–5599.
Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor
Authors: Wichmann Jürgen , Rynn Caroline , Friess Thomas , Petrig-Schaffland Jeannine , Kornacker Martin , Handl Cornelia , Emmenegger Jasmin , Eckmann Jan , Herting Frank , Frances Nicolas , Hunziker Daniel , Krummenacher Daniela , Rüttinger Dominik , Ribeiro Alison , Bacac Marina , Brigo Alessandro , Hewings David S. , Dummer Reinhard , Levesque Mitchell P. , Schnetzler Gabriel , Martoglio Bruno , Bischoff James R. , Pettazzoni Piergiorgio 
Published: November 2021

Abstract

Purpose:
Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi.

Experimental Design:
The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi.

Results:
Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples.

Conclusions:
The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.
Abstract PO-016: Directed evolution generates novel oncolytic H-1 parvoviruses with improved therapeutic efficacy in virus-resistant pancreatic cancer cells
Authors: Garcin Pierre , Kazemimanesh Monireh , Lulka Hubert , Dusetti Nelson , Labrousse Guillaume , Benuzzi Emilie , Buscail Louis , Cordelier Pierre 
Published: November 2021

Abstract
Despite considerable promise and emerging clinical success, several challenges impede the broader implementation of novel immunotherapies such as oncolytic virus(OV)-based gene therapy, including for patients with pancreatic cancer (PDAC). One of such challenge is inter-patient variability that may impact on OV selectivity and killing efficacy for tumor cells. For this study, we selected the rat parvovirus H-1 (H-1PV) that is nonpathogenic in humans and has a natural oncolytic activity in several cancer models. The safety and tolerability of H-1PV was recently demonstrated in early clinical trials for glioma and PDAC. However, we report here that H-1PV infection, oncolytic and pro-apoptotic activity are limited in PDAC cells, including patient-derived primary cells. To address this concern, we applied a directed evolution strategy to generate H-1PV variants with specific activity towards PDAC cells. Following selection using patient primary cells, we managed to isolate clonal, PDAC-adapted H-1PVs that induce PDAC cells lysis as compared to parental H-1PV while infection of normal pancreatic cells remained negligeable. Genome sequencing of the tumor adapted virus reveals mutations in promoting and viral capsid sequences. In vivo, the tumor-adapted H1PV demonstrates greater anti-tumor effect than parental H-1PV, following intravenous administration in an experimental model of orthotopic pancreatic tumors engrafted in immunodeficient mice. To our knowledge, we report here for the first time the production of highly selective and potent OV using directed evolution to override PDAC resistance to virotherapy. While the molecular mechanisms involved are still under investigation, this project is a first step towards precision medicine strategies based on OV.
Citation Format: Pierre Garcin, Monireh Kazemimanesh, Hubert Lulka, Nelson Dusetti, Guillaume Labrousse, Emilie Benuzzi, Louis Buscail, Pierre Cordelier. Directed evolution generates novel oncolytic H-1 parvoviruses with improved therapeutic efficacy in virus-resistant pancreatic cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-016.
Abstract PO-037: Development of an RGD CRISPR-modified Clostridium novyi NT spores as an intravenous oncotherapy
Authors: Dailey Kaitlin M. , Vance Krysten , McAndrews Kyle , Jacobson Reed I. , Delgado Jandro , Johnson Paige R. , Woolery Taylor M. , Orr Megan , Kim Jiha , Mallik Sanku , Bayles Kenneth W. , Hollingsworth Michael A. , Brooks Amanda E. 
Published: November 2021

Abstract
The efficacy of current oncotherapeutics is largely limited by an inability to access avascular tissues, which is in part responsible for forty years of stagnant pancreatic cancer statistics where the median survival remains a mere six months. Oncolytic bacteria such as Clostridium novyi-NT overcome this challenge with its ultrasensitive, innate affinity for hypoxic/necrotic areas found at the center of solid tumors and their metastases. While preclinical and clinical data from intratumoral injections of C. novyi-NT are promising, many tumors are inaccessible to such injections. Preclinical trials of analogous IV injections have uncovered other obstacles such as rapid clearance of C. novyi-NT by the immune system independent of septic complications. To mitigate rapid clearance, CRISPR/Cas9n was used to genetically modify a non-toxic form of C. novyi-NT to express a tumor targeting RGD peptide on the spore surface. Through this novel, first of its kind, methodology, spores with stronger affinity to a surface coated with the targeted binding partner of RGD, aVb3 integrin, have been generated. Importantly, there was no statistically significant difference in the genetically modified spore’s capacity for sporulation or germination when compared to unmodified C. novyi-NT spores, nor was a difference in lytic capacity observed, suggesting no relevant off-target effects from genomic modification. Biodistribution and efficacy of non-toxic RGD-modified spores was evaluated in an immunocompetent, syngeneic, pancreatic cancer murine model. Ongoing efforts to characterize the biodistribution and efficacy of the intravenously injected RGD-modified C. novyi-NT include the application of multiplex immunofluorescence, laser microdissection, and live, whole animal imaging. Supported as a pilot project by funds from NIH COBRE grant 1P20GM109024, Doctoral Dissertation Funds to KMD from NDSU, and by discretionary funds from investigators at UNMC.
Citation Format: Kaitlin M. Dailey, Krysten Vance, Kyle McAndrews, Reed I. Jacobson, Jandro Delgado, Paige R. Johnson, Taylor M. Woolery, Megan Orr, Jiha Kim, Sanku Mallik, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E. Brooks. Development of an RGD CRISPR-modified Clostridium novyi NT spores as an intravenous oncotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-037.
Abstract PO-038: LAMC2: New player in stemness and tumor progression in pancreatic cancer
Authors: Cave Donatella Delle , Iavazzo Tea Teresa , Mangini Maria , Andolfi Gennaro , Pirozzi Teresa , Di Domenico Annalisa , De Luca Annachiara , Lonardo Enza 
Published: November 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating and essentially incurable disease, typically characterized by high chemoresistance and metastatic spread attributable to cancer stem cells (CSCs). This subpopulation is critical for tumor initiation and recurrence, but the mechanism through which they acquire metastatic traits is not well understood. Hence, targeting the CSC niche and their plasticity could be a complementary therapeutic strategy against cancer. Laminin subunit-γ-2 (LAMC2) is an epithelial basement membrane protein, which controls cell motility and adhesion and is widely expressed in the majority of human tumors. However, its role in PDAC remains largely unknown. In several patient cohorts we observed that high levels of LAMC2 significantly correlated with shorter overall survival. In addition, the tissue microarray analysis on PDAC sections revealed prognostic significance of LAMC2 expression in tumor with high grade of aggressiveness (i.e., G2 and G3). To determine the role of LAMC2 in sustaining tumorigenicity, we knocked down it in patient-derived xenografts (PDX) cells using lentiviral shRNA constructs. The silencing of LAMC2 resulted in decreased self-renewal, invasiveness, tumorigenicity and gemcitabine resistance both in vitro and in vivo. To identify or track the LAMC2 tumor cell population in an intact environment we engineered primary PDAC cells that carry EGFP cassette knocked in the LAMC2 locus through the CRISPR-Cas9 technique. Analysis of LAMC2-EGFP+ cells isolated from tumor demonstrated that these cells express a gene program similar to that of highly metastatic stem cells and that they initiate and propagate both the primary tumor and the metastasis to recipient mice very efficiently compared to their counterpart. In conclusion, we identified a highly metastatic subpopulation of cancer stem cells, characterized by high levels of LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in combination with conventional therapy.
Citation Format: Donatella Delle Cave, Tea Teresa Iavazzo, Maria Mangini, Gennaro Andolfi, Teresa Pirozzi, Annalisa Di Domenico, Annachiara De Luca, Enza Lonardo. LAMC2: New player in stemness and tumor progression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-038.
Abstract PO-051: PANOVA-3: A phase III study of tumor treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma
Authors: Picozzi Vincent J. , Macarulla Teresa , Philip Philip A. , Becerra Carlos R. , Dragovich Tomislav 
Published: November 2021

Abstract
Tumor Treating Fields (TTFields) are a non-invasive, loco-regional antimitotic treatment modality, approved for the treatment of glioblastoma and malignant pleural mesothelioma. TTFields at a specific frequency (150-200 kHz) are delivered via arrays placed on the skin surrounding the tumor site. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study, the first trial testing TTFields in pancreatic cancer patients, demonstrated the safety and preliminary efficacy of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on day 1, 8, and 15 of a 28 day cycle. The protocol has recently been amended to incorporate the use of a smaller, lighter (weight reduced from 6 to 2.7 lbs.) TTFields device. TTFields (150 kHz) will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q4w, including a CT scan of the chest and abdomen q8w. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint. Progression-free survival, objective response rate, rate of resectability, quality of life, and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%.
Citation Format: Vincent J. Picozzi, Teresa Macarulla, Philip A. Philip, Carlos R. Becerra, Tomislav Dragovich. PANOVA-3: A phase III study of tumor treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-051.
Abstract PO-057: Targeting ErbB2 degradation via the ubiquitin–proteasome pathway to inhibit the metastasis of pancreatic cancer
Authors: Zhang Bo , Teng Fei , Lin Nengming 
Published: November 2021

Abstract
Objective: Pancreatic cancer is currently one of the most lethal human cancers and continues to be a major unsolved health problem in the 21st century. Since pancreatic cancer has a high metastatic potential, chemotherapy is inevitable for most pancreatic cancer patients, whereas the clinical responses to anticancer agents are not satisfied. In this work, we designed and synthesized a novel compound, termed as 6-MPA, and found that 6-MPA could improve the proteasomal degradation of ErbB2 pancreatic cancer cells. Methods: The inhibitory effects of 6-MPA on migration and invasion was measured by scratch experiment, wound healing assay and transwell experiment. Clone formation and CCK-8 assay was used to determine the cytotoxicity of 6-MPA. Real-time PCR and western blotting was used to determine the expression of indicated genes or proteins respectively. Immunoprecipitation was used to characterize protein–protein interactions. Results: 4, 8, and 16 μM of 6-MPA exhibited an inhibitory effects on the migration of SW1990 cells and the inhibition rates reached 40.2±10.1%, 58.2±11.2%, and 65.2±9.9% in vitro, respectively. RNA-seq showed that 6-MPA treatment manipulated ErbB2 level and its downstream PI3K/AKT/mTOR signaling pathways, which was verified by western blotting assay. Treatment with 6-MPA could enhance the interaction between ErbB2 and ubiquitin, and thus promote the proteasomal degradation of ErbB2. Conclusion: In this study, we obtained a novel small molecule 6-MPA, which could specifically degrade ErbB2 through the activation of protein ubiquitinination. And we found that 6-MPA possessed potent inhibitory effects on migration and invasion of pancreatic cancer cells. Therefore, our work illustrated a novel structure skeleton that could be used to target ErbB2, and potentially suppressed the metastasis of pancreatic cancer.
Citation Format: Bo Zhang, Fei Teng, Nengming Lin. Targeting ErbB2 degradation via the ubiquitin–proteasome pathway to inhibit the metastasis of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-057.
Abstract PO-076: Murine adapted FOLFIRINOX for standard-of-care in KPC mice
Authors: Whittle Martin C. , Palkar Aditi , Fasnacht Rachael , Yan James , Kheng Borith , Sinfuego Kianna , Thorsen Shelley , Hingorani Sunil R. 
Published: November 2021

Abstract
Until relatively recently, the standard-of-care (SOC) treatment for pancreas cancer was not appreciably superior to best supportive care in prolonging life, and potentially new treatment strategies had a relatively modest bar to surmount. New combination regimens have emerged and novel therapies should therefore be compared against the current SOC. However, in preclinical development of novel agents, efficacy is frequently compared against vehicle control and less commonly against cytotoxic chemotherapy. Furthermore, virtually all studies of cytotoxic chemotherapy for PDA in mice have used gemcitabine (gem) monotherapy as standard-of-care, although this is no longer the standard for this disease. One of the current standard regimens, gem+nab-paclitaxel, cannot be given in mice without inducing immune responses because of the incorporation of human albumin in developing the taxol nanoparticles. The other new standard, FOLFIRINOX, is a complex 4-agent regimen that includes a 46-hour continuous infusion component that has been prohibitively challenging to deliver to animals. We have now built an appropriate dosing regimen incorporating these 4 agents that required a deliberate, step-by-step, program of empiric testing of the drugs, first, one at a time, then in various doublets and triplets, and, finally, as a whole regimen. The studies included close clinical evaluations and serial blood tests to follow complete blood counts (CBC). We have incorporated this regimen as the new SOC in our Murine Clinical Trials Program (MCTP). We propose that this mur-FOLIFIRINOX regimen should represent the new standard for murine studies.
Citation Format: Martin C. Whittle, Aditi Palkar, Rachael Fasnacht, James Yan, Borith Kheng, Kianna Sinfuego, Shelley Thorsen, Sunil R. Hingorani. Murine adapted FOLFIRINOX for standard-of-care in KPC mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-076.
Abstract PO-092: Influence of the IL-13-receptor alpha 1 chain on the malignant phenotype of pancreatic cancer cells
Authors: Shi Jingwei , Kornmann Marko , Traub Benno 
Published: November 2021

Abstract
Introduction: Increasing evidence indicates salient activities of Interleukin (IL)-4, IL-13 and their specific Type-II-IL-4 receptor complex (IL-4Rα/IL-13Rα1) in carcinomas including pancreatic cancer. While IL-4 seems to be tumor-promoting in PDAC, the specific role of the IL-13/IL-13Rα1 axis was yet to be determined. Both cytokines are abundant in PDAC through cells of the tumor microenvironment. In this project, we planned to determine the specific effects of the IL-13Rα1-receptor chain on the malignant phenotype of pancreatic cancer cells. Methods: Expression of IL-13Rα1, IL-4Rα, and the human common gamma chain (γc) in cultured pancreatic cancer cell lines AsPC-1, Capan-1, PANC-1, MIA PaCa-2 and A818-6 as well as downstream signal transduction factors of IL13-Rα1 were detected by Western blot. The role of IL-13Rα1 in pancreatic cancer cell proliferation, mobility and migration was demonstrated based on the successful establishment of stable shRNA based IL-13Rα1-knockdown (KD) clones in Capan-1 and MIA PaCa-2 cell lines. Results: Not only the basal anchorage-dependent growth but also the anchorage-independent growth in soft agar were inhibited in Capan-1 and MIA PaCa-2 cells due to IL-13Rα1-downregulation. Mechanistically, IL-13Rα1-KD was associated with increased apoptosis. Additionally, signal transduction factors STAT3, STAT6, PI3K, Akt and ERK1/2 were activated in Capan-1 exposed to exogenous IL-4 and IL-13. Interestingly, IL-13Rα1-KD reduced the basal expression of STAT3, Akt and ERK1/2. IL-4 and IL-13 induced activation of STAT3, ERK1/2, Akt and STAT6 was significantly suppressed in Capan-1-IL-13Rα1-KD (C-KD) clones. Furthermore, IL-13Rα1-KD resulted in enhanced mobility and migration in Capan-1 cells. Conclusion: It was demonstrated that endogenous IL-13Rα1 is vital for pancreatic cancer cell growth with the involvement of STAT3/6, ERK1/2 and Akt. Surprisingly, IL-13Rα1-KD resulted in enhanced mobility and migration. Overall, IL-13Rα1 plays a critical but heterogenous role in PDAC. Our findings increase the understanding of the different functions and mechanisms involving IL-13Rα1 in pancreatic cancer progression.
Citation Format: Jingwei Shi, Marko Kornmann, Benno Traub. Influence of the IL-13-receptor alpha 1 chain on the malignant phenotype of pancreatic cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-092.