bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise during pregnancy mitigates negative effects of parental obesity on metabolic function in adult mouse offspring
Authors: Laker Rhianna C. , Altıntaş Ali , Lillard Travis S. , Zhang Mei , Connelly Jessica J. , Sabik Olivia L. , Onengut Suna , Rich Stephen S. , Farber Charles R. , Barrès Romain , Yan Zhen
Published: December 2020

Maternal or paternal obesity causes metabolic impairment in adult offspring in mice. Maternal exercise during gestation can completely mitigate metabolic impairment. Maternal obesity, but not paternal obesity, results in hypermethylation of the Pgc-1α promoter at CpG-260, which can be abolished by maternal exercise.
Regulating Intestinal Microbiota in the Prevention and Treatment of Alcohol-Related Liver Disease
Authors: Chi Xin , Pan Calvin Q. , Liu Shunai , Cheng Danying , Cao Ziwen , Xing Huichun
Published: December 2020

When alcohol-related liver disease occurs, the number and composition ratio of intestinal microorganisms will accordingly change. The alcohol-induced changes in the intestinal microbiota play a pivotal role in the process of developing the alcohol-related liver disease through the translocation of microbial products due to increased intestinal permeability. In recent years, therapeutic interventions with a concentration on regulating intestinal microbiota have been conducted for patients with alcohol-related liver disease. We aimed to provide a critical review and updates on the prevention and treatment of alcohol-related liver disease through regulating intestinal microbiota. A literature search was performed on the PubMed database for studies published in English about the therapeutic intervention with microbiota using animal models and patients with alcohol-related liver disease (1/2010–4/2020). The accumulating pieces of evidence suggest that the therapeutic use of probiotics, prebiotics, antibiotics, phages, or fecal microbial transplantation may have several influences on alcohol-related liver disease patients. Emergent data unveiled that these interventions can further regulate the composition of intestinal microbiota, minimize the negative impact of microbiota on the liver, and prevent disease progression from mild to severe alcoholic hepatitis, fibrosis, cirrhosis, or even liver cancer. The current review provides updates on the advances of therapeutic interventions with the effects of regulating intestinal microbiota on patients who have alcohol-related liver disease. In addition, the data gaps and research directions on further exploration of the role of intestinal microbiota for the management of the alcohol-related liver disease are also discussed.
The Extraction Method of Gearbox Compound Fault Features Based on EEMD and Cloud Model
Authors: Zhao Ling , Gong Jiaxing , Chong Hu
Published: December 2020

When a compound fault occurs, the randomness and ambiguity of the gearbox will cause uncertainty in the collected signal and reduce the accuracy of signal feature extraction. To improve accuracy, this research proposes a gearbox compound fault feature extraction method, which uses the inverse cloud model to obtain the signal feature value. First, EEMD is used to decompose the collected vibration signals of gearbox faults in normal and fault states. Then, the mutual information method is used to select the sensitive eigenmode function that can reflect the characteristics of the signal. Subsequently, the inverse cloud generator is used to extract cloud digital features and construct sample feature sets. On this basis, the concept of synthetic cloud is introduced, and the cloud-based distance measurement principle is used to synthesize new clouds, reduce the feature dimension, and extract relevant features. Finally, a simulation experiment on a rotating machinery unit with a certain type of equipment verifies that the proposed method can effectively extract the feature of gearbox multiple faults with less feature dimension. And comparing with the feature set extracted by the single cloud model, the results show that the method can better represent the fault characteristic information of the signal.
Recycled Aggregate Concrete including Various Contents of Metakaolin: Mechanical Behavior
Authors: Younis Khaleel H. , Amin Abdulfattah A. , Ahmed Hemin G. , Maruf Shelan M.
Published: December 2020

This experimental research investigates the effect of utilizing metakaolin (MK) on the behavior of recycled aggregate concrete (RAC). The RAC incorporates recycled coarse aggregate (RCA) originated from crushing construction and demolition waste. The investigated parameters were RCA and MK contents. Tests of workability and mechanical properties such as compressive strength, splitting tensile strength, flexural strength, and modulus of elasticity were conducted to evaluate the influence of MK on workability and mechanical behavior of RAC. In total, 19 mixes were prepared. These mixes are divided into four groups. Group zero (G0) includes a reference mix containing normal coarse aggregate (NCA) and 3 mixes made with 35%, 70%, and 100% of RCA. Each one of the other three groups (G1, G2, and G3) was made with one content of the three contents of RCA, and each group includes five mixes made with the contents of 4%, 8%, 12%, 16%, and 20% of MK. Empirical models among the mechanical properties of the RAC mixes were developed and compared with models of standard codes of practice such as ACI 318, BS 8110, and Eurocode 2. It was found that MK reduces the workability of the RAC mixes. Nonetheless, the outcomes reveal that MK can improve the compressive, splitting tensile, and flexural strengths and the elastic modulus of RAC. This strength improvement enhances as the content of MK increases. The proposed models for the mechanical properties of RAC made with MK showed good correlations. The developed model for modulus of elasticity is quite close to the Eurocode 2 model, whereas the models of ACI 318 and BS 8110 underestimate the values of the modulus of elasticity.
The Role of Deep Geofluids in the Enrichment of Sedimentary Organic Matter: A Case Study of the Late Ordovician-Early Silurian in the Upper Yangtze Region and Early Cambrian in the Lower Yangtze Region, South China
Authors: Zhang Kun , Peng Jun , Liu Weiwei , Li Bin , Xia Qingsong , Cheng Sihong , Yang Yiming , Zeng Yao , Wen Ming , Liu Dongmei , Huang Yizhou , Zhong Li , Liu Pei , Jiang Xiaojun
Published: December 2020

Organic matter is the material basis for shales to generate hydrocarbon, as well as the main reservoir space and seepage channel for shale gas. When the thermal evolution degree is consistent, the organic carbon content in present shales is subject to the abundance of primitive sedimentary organic matter. Deep geofluids significantly influence the sedimentary organic matter’s enrichment, but the mechanism remains unclear. This paper is aimed at determining how hydrothermal and volcanic activities affected the enrichment of sedimentary organic matter by studying lower Cambrian shales in the lower Yangtze region and upper Ordovician-lower Silurian shales. Oxidation-reduction and biological productivity are used as indicators in the study. The result shows that hydrothermal or volcanic activities affected the enrichment of sedimentary organic matter by influencing climate changes and the nutrients’ sources on the waterbody’s surface and reducing water at the bottom. In the lower Cambrian shales of the Wangyinpu Formation in the lower Yangtze region, hydrothermal origin caused excess silicon. During the sedimentary period of the lower and middle-upper Wangyinpu Formation, vigorous hydrothermal activities increased the biological productivity on the waterbody’s surface and intensified the reducibility at the bottom of the waterbody, which enabled the rich sedimentary organic matter to be well preserved. During the sedimentary period of the lower upper Ordovician Wufeng Formation and the lower Silurian Longmaxi Formation in the upper Yangtze region, frequent volcanic activities caused high biological productivity on the waterbody surface and strong reducibility at the bottom of the waterbody. As a result, the abundant organic matter deposited from the water surface can be well preserved. During the sedimentary period of the upper Longmaxi Formation, volcanic activities died down gradually then disappeared, causing the biological productivity on the water surface to decrease. Besides, the small amount of organic matter deposited from the water surface was destroyed due to oxidation.
Gear Fault Diagnosis Based on VMD Sample Entropy and Discrete Hopfield Neural Network
Authors: Ding Jiakai , Xiao Dongming , Huang Liangpei , Li Xuejun
Published: December 2020

The gear fault signal has some defects such as nonstationary nonlinearity. In order to increase the operating life of the gear, the gear operation is monitored. A gear fault diagnosis method based on variational mode decomposition (VMD) sample entropy and discrete Hopfield neural network (DHNN) is proposed. Firstly, the optimal VMD decomposition number is selected by the instantaneous frequency mean value. Then, the sample entropy value of each intrinsic mode function (IMF) is extracted to form the gear feature vectors. The gear feature vectors are coded and used as the memory prototype and memory starting point of DHNN, respectively. Finally, the coding vector is input into DHNN to realize fault pattern recognition. The newly defined coding rules have a significant impact on the accuracy of gear fault diagnosis. Driven by self-associative memory, the coding of gear fault is accurately classified by DHNN. The superiority of the VMD-DHNN method in gear fault diagnosis is verified by comparing with an advanced signal processing algorithm. The results show that the accuracy based on VMD sample entropy and DHNN is 91.67% of the gear fault diagnosis method. The experimental results show that the VMD method is better than the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) and empirical mode decomposition (EMD), and the effect of it in the diagnosis of gear fault diagnosis is emphasized.
A Study of Deep Neural Network Controller-Based Power Quality Improvement of Hybrid PV/Wind Systems by Using Smart Inverter
Authors: Ab-BelKhair Adel , Rahebi Javad , Abdulhamed Mohamed Nureddin Abdulbaset
Published: December 2020

Presently, climate change and global warming are the most uncontrolled global challenges due to the extensive fossil fuel usage for power generation and transportation. Nowadays, most of the developed countries are concentrating on developing alternative resources; consequently, they did huge investments in research and development. In general, alternative energy resources including hydropower, solar power, and wind energy are not harmful to nature. Today, solar power and wind power are very popular alternative energy sources due to their enormous availability in nature. In this paper, the photovoltaic cell and wind energy systems are investigated under various weather conditions. Based on the findings, we developed an advanced intelligent controller system that tracks the maximum power point. The MPPT controller is a must for the renewable energy sources due to unpredictable weather conditions. The main objective of this paper is to propose a new algorithm that is based on deep neural network (DNN) and maximum power point tracking (MPPT), which was simulated in a MATLAB environment for photovoltaic (PV) and wind-based power generation systems. The development of an advanced DNN controller that improves the power quality and reduces THD value for the microgrid integration of hybrid PV/wind energy system was performed. The MATLAB simulation tool has been used to develop the proposed system and tested its performance in different operating situations. Finally, we analyzed the simulation results applying the IEEE 1547 standard.
Abstract A05: Uncovering the role of Vps34 in pancreatic autophagy and its relation to chronic pancreatitis, a risk factor for pancreatic cancer
Authors: Ramos Fernanda , Guillermet-Guibert Julie
Published: December 2020

Vps34 is the only member of class III of phosphoinositide-3-kinases (PI3Ks) and the main producer of phosphatidylinositol-3-monophosphate (PI3P), a lipid involved in regulating intracellular vesicular trafficking. Vps34 and its regulatory subunit, Vps15, can be found in multiple protein complexes mediating autophagy and endocytic sorting processes. Recent studies have investigated the organismal role of Vps34 by using innovative gene targeting strategies; nonetheless, the role of Vps34 and that of its lipid product, PI3P, in pancreatic physiopathology remain largely unknown. Chronic pancreatitis (CP) is a pathology characterized by progressive tissue destruction, inflammation, and fibrosis of the exocrine pancreas. The pancreas, in spite of being considered a plastic organ, is only capable of limited regeneration. A central regulator of cell regeneration is autophagy and its role in pancreatic pathologies such as type II diabetes and pancreatic cancer is well established; however, its role in CP is just emerging. CP patients present a higher risk for developing pancreatic cancer. Here, we aim to uncover the role of Vps34 in maintaining the differentiation and regenerative potential of exocrine acinar cells through a constant regulation of the autophagic flux. We generated a mouse strain with an inducible Vps34 inactivation in acinar cells, Elas-CreER/Vps34lox/lox (V34 mice) and compared them to control mice. Mice were injected intraperitoneally with tamoxifen (TAM) at the age of 4 weeks to induce gene recombination. Physical examinations, histopathologic analysis, and activity assays were performed at different time points (2, 4, 8, and 16 weeks) to assess the effects of Vps34 inactivation. Under TAM treatment, as compared to control mice, V34 mice presented severely dilated ducts, considerable immune infiltration, moderate to severe fibrosis, and significant fatty replacement of whole lobules of the pancreas (20-35% of pancreatic mass), reminiscent of human CP histology. However, up to 16 weeks, V34 mice did not present yet any remarkable symptoms observed in CP. Our results show that Vps34 inactivation in acinar cells leads to a replacement of pancreatic parenchyma by cells with another differentiated phenotype (adipocytes, duct cells). Since acinar cells are considered as the pancreas alternative progenitor cells, further investigations are needed to understand how Vps34 regulates cell fate in pancreatic pathology, paving the way for novel therapeutic interventions.

Citation Format: Fernanda Ramos, Julie Guillermet-Guibert. Uncovering the role of Vps34 in pancreatic autophagy and its relation to chronic pancreatitis, a risk factor for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A05.
Abstract A07: Role of the class IA PI3K p110β subunit in pancreatic cancer
Authors: Arcucci Silvia , Therville Nicole , Basset Céline , Vertut Aurélie , Guillermet-Guibert Julie
Published: December 2020

Introduction: Class I PI3K signaling is constitutively active and correlated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). The modest effect of pan-PI3Ks inhibitors (targeting all p110 isoforms) clinically tested on different types of cancer highlighted the need to understand the roles of each PI3K isoform in cancer cell, with isoform-specific inhibitors of PI3K and murine models that conditionally target their activity. My team has developed unique mouse models that recapitulate the carcinogenesis of PDAC and that conditionally target the activity of p110α or p110β specifically in pancreatic epithelial cells.

Methods: We analyzed the biologic impact of pancreas-restricted genetic inactivation of p110β during pancreatic cancer progression induced by oncogenic Kras with or without mutated p53 combined with experimentally induced risk factor conditions such as inflammation. In particular, we searched the mechanisms of action of p110β in pancreatic cancerogenesis and in lesion-driven stroma formation.

Results: Inhibition of p110β prevented tumor progression towards metastatic cancer and led to the formation of low-grade neoplastic lesions, demonstrating the role of this isoform in pancreatic carcinogenesis. We found that upon genetic inactivation of the p110β isoform, the only present lesions are duct-like preneoplastic structures. Besides, mice harboring genetic inactivation of p110β in their pancreas are protected from mutated Kras and p53-induced lethality. Interestingly, p110β inactivation in pancreatic epithelial cells is responsible for changing the immune cell recruitment and the stromal response to epithelial oncogenic Kras signal or to inflammation.

Conclusion: Our data suggest that p110β in pancreatic lineage plays an important role in murine pancreatic cancer initiation induced by genetic alterations commonly found in pancreatic cancer, by impacting cell dedifferentiation and reprogramming tumor microenvironment.

Citation Format: Silvia Arcucci, Nicole Therville, Céline Basset, Aurélie Vertut, Julie Guillermet-Guibert. Role of the class IA PI3K p110β subunit in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A07.
Abstract A23: Dissecting the SMAD4 metastasis suppressor complex to identify novel prognostic biomarkers and therapeutic targets for colon cancer
Authors: Wong Chen Khuan , Thiagalingam Sam
Published: December 2020

Colon cancer is the second most lethal cancer in men and women in the United States and metastasis is the primary cause of mortality. Hence, there is an urgent need to elucidate the molecular mechanisms underlying metastasis to identify new prognostic biomarkers and therapeutic targets. Previous studies reported that SMAD4 is either mutated frequently (10-20%) or exhibits low expression, which is associated with poor prognosis, presence of metastases, and resistance to 5-fluorouracil (5-FU), the common chemotherapeutic agent for colon cancer. Our analyses confirmed that the probability of overall survival (OS) and relapse-free survival (RFS) is worse in patients with low levels of SMAD4 expression and found that it is associated with resistance to both 5-FU and irinotecan, two of the most widely used chemotherapeutic agents for treating colon cancer. Since our previous studies found that SMAD4 interacts with and inhibits HIF1α, leading to reduced expression of HIF1α target genes such as VEGF (angiogenesis) and GLUT1 (glucose uptake), we hypothesized that SMAD4 forms a metastasis suppressor complex to inhibit colon cancer progression. Here, we report the identification of the components in the SMAD4 metastasis suppressor complex using co-immunoprecipitation and mass spectrometry, with potential roles in regulating metastasis and for conferring resistance to chemotherapy. We will discuss the characterization of candidate genes, which include PI3K/mTOR pathway genes that might serve as biomarkers in predicting disease progression/prognosis and as therapeutic targets to treat metastatic colon cancer.

Citation Format: Chen Khuan Wong, Sam Thiagalingam. Dissecting the SMAD4 metastasis suppressor complex to identify novel prognostic biomarkers and therapeutic targets for colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A23.
Abstract A24: CD146-Rictor interaction reveals a pathway linking mTORC2 activation with extracellular stimuli
Authors: Xu Wenyi , Luo Yongting , Cui Wei
Published: December 2020

In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs to regulate many fundamental cellular processes such as cell growth and metabolism. The mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. However, it remains enigmatic how extracellular stimuli regulates mTOR signaling, particularly for mTORC2. Here, we demonstrate that in human umbilical vein endothelial cells (HUVEC), vascular endothelial growth factor (VEGF) promotes the activation of mTORC2 signaling, exhibited as phosphorylation of Akt /PKCα/SGK1. Cell adhesion molecule CD146, as VEGFR2 co-receptor, plays the pivotal role in mediating mTORC2 activation in response to VEGF. Deletion of CD146 resulted in dramatic reduction in mTORC2 activity, without affecting other PI3K/Akt/mTOR signaling pathways, such as mTORC1 and PI3K/PDK1, indicating that CD146 specifically regulates mTORC2 activity. By means of co-immunoprecipitation (co-IP) assay, CD146 is bestowed to interact with Rictor via its juxta-membrane KKGK motif upon VEGF stimulation, CD146-Rictor (mTORC2) interaction not only stabilizes Rictor from ubiquitin-proteasome-mediated degradation but also activates mTORC2 signaling, thus promoting VEGF-induced endothelial cell proliferation and survival. Collectively, our findings have identified a previously unanticipated mechanism by which mTORC2 signaling pathway is directly under the control of extracellular stimuli, linking environmental cues with mTORC2 activity, and implicate that targeting CD146-mTORC2 axis might be a novel strategy for diseases driven by uncontrolled cell proliferation.

Citation Format: Wenyi Xu, Yongting Luo, Wei Cui. CD146-Rictor interaction reveals a pathway linking mTORC2 activation with extracellular stimuli [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A24.
Abstract B06: Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses Kras-mutated non-small cell lung cancer
Authors: Wang Yu-xiang , Li Xian , Liu Xue-ling , Wang Bo-bo , Chen Yi , Yang Chun-hao , Ding Jian , Meng Ling-hua
Published: December 2020

Activating KRAS mutation is the most common driver mutation in the initiation and promotion of non-small cell lung cancer (NSCLC). Direct inhibition of the enzymatic activity of mutated Kras has been proved unsuccessful. Deregulation of PI3K-Akt-mTOR signaling, one of the most important downstream effectors of Kras, plays important roles in tumorigenesis and drug resistance in NSCLC. In this study, we found that a novel PI3Kα-specific inhibitor, CYH33, possessed variable activity against a panel of Kras-mutated NSCLC cell lines. Though CYH33 blocked Akt phosphorylation in all tested cells, phosphorylated Rb decreased in CYH33-sensitive but not resistant cells, which was consistent with G1 phase arrest in CYH33-sensitive cells. Consequently, combination of a CDK4/6 inhibitor PD0332991 with CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and -resistant cells, which was accompanied with enhanced cell population in G1 phase compared to single-agent treatment. Moreover, downregulation of cyclin D1 with siRNA sensitized A549 and H23 cells to CYH33. Reciprocally, CYH33 abrogated PD0332991-induced upregulation of phosphorylated Akt and cyclin D1 in A549 cells. Cotreatment of these two drugs demonstrated synergistic activity against A549 and H23 xenografts with enhanced inhibition on the phosphorylation of Akt and Rb compared to administration of CYH33 or PD03332991 alone. Thus, simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against Kras-mutated NSCLC and provided a mechanistic rationale for a combination approach using PI3Kα inhibitor and CDK4/6 inhibitor CYH33 for the therapy of Kras-mutated NSCLC.

Citation Format: Yu-xiang Wang, Xian Li, Xue-ling Liu, Bo-bo Wang, Yi Chen, Chun-hao Yang, Jian Ding, Ling-hua Meng. Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses Kras-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B06.
Abstract B09: Structural biology of the PI3K pathway: On with phosphorylation, down with ubiquitination
Authors: Gabelli Sandra
Published: December 2020

The regulation of the PI3K pathway is central to cell growth and is deregulated in diseases such as cancer and cardiovascular disease. We are using biochemistry, structural biology, and chemical biology to probe the activation and inhibition mechanisms of the nodes of the pathway PI3Ka, AKT and PTEN. We have determined the roles of Lys776, His 936 and His 917 in the lipid and protein activity of PI3Ka. While H936A inactivates the lipid kinase activity without affecting auto-phosphorylation, H197 abolishes both the lipid and protein kinase activities of PI3Ka. The signature aspect of the Ser/Thr protein kinase Akt's regulation involves its C-terminal phosphorylation, classically understood to be the mTORC2-mediated phosphorylation of Ser473, which converts the Akt kinase into its active conformation. Using a multi-technique approach we determined that pS473-Akt activation is driven by an intramolecular interaction between the C-tail and the PH-domain linker to relieve autoinhibition. In contrast, the activating pSer477/pThr479 modifications of Akt have a different mechanism in which the relief from autoinhibition is by binding to the activation loop. All three nodes are regulated by NEDD4-family of ligases.

Note: This abstract was not presented at the conference.

Citation Format: Sandra Gabelli. Structural biology of the PI3K pathway: On with phosphorylation, down with ubiquitination [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B09.
Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB
Authors: Biondini Marco , Rose April , Annis Matthew , Ferrario Cristiano , Puertollano Rosa , Basik Mark , Siegel Peter
Published: December 2020

The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011).

Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.
Abstract B12: Examining EGFR-mediated PI3K/Akt pathway in combination therapy of cetuximab and dynamin inhibition
Authors: Chew Hui Yi , Panizza Benedict , Cooper Caroline , Dolcetti Riccardo , Coward Jim , McCluskey Adam , Robinson Phillip J. , Wells James W. , Simpson Fiona
Published: December 2020

Adenoid cystic carcinoma (ACC) is a rare and highly aggressive malignant tumor that affects the salivary glands, lacrimal and ceruminous glands of the head and neck region. ACC tends to spread to neighboring regions via perineural methods and metastasize from the primary region to the lung, liver and bones. Current treatment includes surgical resection of the primary lesion followed by radiotherapy. However, about 80% of the patients develop metastatic disease with poor prognosis; hence, new treatment is necessary for ACC patients. EGFR is known to be overexpressed in most of salivary gland carcinomas, particularly ACC. Numerous targeted therapies, including anti-EGFR monoclonal antibody, have been trialed in ACC patients, with disease stabilization reported in approximately half of the trial patients. Our laboratory is examining a combination therapy in which we combined the use of a dynamin inhibitor with monoclonal antibody to enhance antibody-dependent cellular cytotoxicity (ADCC) response in murine models and now in clinical trial. As preclinical data, we examined the signaling profile of the tumor cells in the combination therapy with different dynamin inhibitors.

Citation Format: Hui Yi Chew, Benedict Panizza, Caroline Cooper, Riccardo Dolcetti, Jim Coward, Adam McCluskey, Phillip J. Robinson, James W. Wells, Fiona Simpson. Examining EGFR-mediated PI3K/Akt pathway in combination therapy of cetuximab and dynamin inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B12.
Abstract IA14: mTOR as a central regulator of T-cell activation, differentiation, and function
Authors: Powell Jonathan , Patel Chirag , Sun Hong , Claiborne Michael
Published: December 2020

While the exquisite specificity of the T-cell receptor (TCR) MHC + peptide interaction heralds recognition, it is ultimately the cues from the immune microenvironment that dictate the outcome of this recognition. Our lab has proposed that mTOR plays a critical role in integrating signals and thus determining the outcome of antigen recognition. Indeed, we have demonstrated that mTORC1 and mTORC2 signaling can selectively guide CD4+ effector and regulatory T-cell differentiation and function as well as CD8+ effector and memory T-cell differentiation and function. Recent studies have revealed that mTOR performs this function in part by coordinating T-cell activation and function with metabolic reprogramming. Consequently, targeting downstream mTOR signaling and metabolism can promote T-cell effector function and persistence in order to enhance cancer immunotherapy. Likewise, targeting mTOR can inhibit T-effector function and promote the generation of regulatory T cells to treat autoimmune disease and prevent transplantation rejection.

Citation Format: Jonathan Powell, Chirag Patel, Hong Sun, Michael Claiborne. mTOR as a central regulator of T-cell activation, differentiation, and function [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA14.
Abstract IA19: PI3Kgamma control of antitumor immunity
Authors: Varner Judith A.
Published: December 2020

Macrophages play key roles in promoting immune suppression, tumor growth and resistance to therapy. Our recent studies show that tissue-resident macrophages (TRM) as well as bone marrow-derived macrophages (BMDM) play critical but unique roles in promoting tumor growth. While BMDM are recruited to tumors in a PI3K, integrin α4, and CCR2-dependent manner, TRMs accumulate in tumors independently of integrin α4, PI3Kγ, or the trafficking receptor CCR2. Gene expression and functional studies indicate that tumor-derived TRM are highly proliferative, immune suppressive, and distinct from BMDM. We show that TRM develop from macrophage progenitors that are abundant in tumors but not in normal tissues; purified progenitors differentiate into macrophages that potently stimulate tumor growth when adoptively transferred into mice. Notably, we found that the lipid kinase PI3Kγ promotes immune-suppressive polarization of TRM and BMDM. Inhibition of PI3Kγ repolarizes macrophages, induces dendritic cell maturation, and stimulates CD8+ T-cell recruitment to tumors and activation. Inhibition of PI3Kγ also synergizes with checkpoint inhibitors and chemotherapeutics to promote tumor regression and immunologic memory, leading to sustained tumor suppression. Our studies identify PI3Kγ as a valuable target for immune therapy of solid tumors.

Citation Format: Judith A. Varner. PI3Kgamma control of antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA19.
Abstract IA23: PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer
Authors: Wulf Gerburg , Konstantinopoulos Panos , Barry William , Sonzongi Olmo , Eismann Julia , Kucherlapati Bose , Matulonis Ursula
Published: December 2020

PI3K inhibitors reduce glucose uptake and utilization by tumors. Yet in solid tumor clinical trials the efficacy of PI3K -inhibitors as single agents has been limited. Therefore, we have focused on harnessing the antimetabolic efficacy of PI3K inhibitors to augment the efficacy of antineoplastic treatments. A recently completed clinical trial (NCT01623349) examined the combination of PI3Ki BYL719 and the PARPi olaparib in ovarian cancer (EOC). Of the 28 EOC patients, 10 (35.7%) had partial response (PR), 14 (50%) had stable disease (SD), 3 (10.7%) had progressive disease (PD), and 1 (3.6%) patient was unevaluable. ORR was 33.3% and 31.3% in platinum resistant/refractory gBRCAmut and gBRCAwt patients, respectively. These data show that combining BYL719 and olaparib is feasible with no unexpected toxicities and that the activity of olaparib/BYL719 in gBRCAwt platinum-resistant EOC appears significantly higher than expected compared to either olaparib or BYL719 monotherapies. Next-generation sequencing did not identify markers of responsiveness to this combination. To assess responsiveness to this combination functionally, we have developed novel methods to monitor the antimetabolic activity of PI3K inhibitors in vivo using functional MRI of tumors based on the interconversion of 13C-pyruvate to 13C-lactate as well as NMR spectroscopy of tumoral ATP stores.

Citation Format: Gerburg Wulf, Panos Konstantinopoulos, William Barry, Olmo Sonzongi, Julia Eismann, Bose Kucherlapati, Ursula Matulonis. PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA23.
Abstract IA25: Development of PI3K inhibitors in breast cancer
Authors: Ma Cynthia X.
Published: December 2020

The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is crucial to many aspects of cell growth and survival. PI3K pathway is frequently deregulated in breast cancer due to genetic or epigenetic alterations in components of this pathway and contributes to treatment resistance. Notably, PIK3CA mutation is the most frequent genetic event in estrogen receptor-positive (ER+) breast cancer, while loss of PTEN expression is commonly observed in triple-negative disease (TNBC). There has been significant interest in developing PI3K inhibitors in breast cancer. Several randomized clinical trials assessing the benefit of adding PI3K inhibitors to fulvestrant in patients with advanced ER+ breast cancer, including BELLE-2, BELLE-3, FERGI, and SANDPIPER, have been reported. Significant improvement in progression-free survival (PFS) has been observed in these trials. However, dose-limiting toxicities of pan-PI3K inhibitors are common, which limit their clinical application. Isoform selective inhibitors, such as alpha selective PI3K inhibitor, are in clinical trials with the hope to reduce toxicity. There is ongoing effect in the investigation of predictors of response and mechanisms of treatment resistance. This presentation will summarize clinical trial data in breast cancer and challenges in the development of PI3K inhibitors in breast cancer.

Citation Format: Cynthia X. Ma. Development of PI3K inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA25.
Abstract PR02: Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway
Authors: Shen Kuang , Huang Rick , Yu Zhiheng , Sabatini David M.
Published: December 2020

mTORC1 is a major regulator for cell growth and proliferation that coordinates nutrient inputs, such as amino acids, glucose, and growth factor, with anabolic and catabolic processes in cells. Amino acid signals are transmitted towards mTORC1 through the Rag GTPases, which directly recruit mTORC1 onto the lysosomal membrane. The Rag GTPase heterodimer has a unique architecture that consists of two GTPase subunits, RagA or RagB bound to RagC or RagD. Their nucleotide loading states are strictly controlled by several lysosomal or cytosolic protein complexes that directly process the amino acid signal. One such complex is GATOR1, a negative regulator on the cytosolic branch of the amino acid sensing pathway. GATOR1 comprises three subunits, Depdc5, Nprl2, and Nprl3, and is a GTPase Activating Protein (GAP) for RagA. It functions through a noncanonical GAP mechanism in which GATOR1 binds the Rag GTPases with two modes, an inhibitory mode that holds the Rag GTPase heterodimer and has been captured by structural determination, and a GAP mode that actually stimulates GTP hydrolysis by RagA but remains elusive. Here, we used biochemical approaches to probe the GAP mode of GATOR1 and found that a critical arginine finger on Nprl2, Arg78, is the catalytic residue, while a loop localized close to it provides the binding site for the Rag GTPases. Furthermore, we used cryo-EM to resolve the structure of the GATOR1-Rag-Ragulator complex at 4.1A resolution, which represents the architecture of the mTORC1-inhibiting complex on the lysosomal surface. Our results revealed the molecular bases for mTORC1 inactivation in human cells.

This abstract is also being presented as Poster B10.

Citation Format: Kuang Shen, Rick Huang, Zhiheng Yu, David M. Sabatini. Structural and functional analyses of GATOR1, a negative regulator of the mTORC1 pathway [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR02.
Abstract PR03: Selective degradation of mutant PIK3CA promotes increased mutant specificity in a subset of PI3K ATP-competitive inhibitors
Authors: Nguyen Lan , Edgar Kyle , Song Kyung , Schmidt Stephen , Schutz Victorai , Ishisoko Noriko , Torres Eric , Das Akash , Murali Divya , Sideris Steve , Wendorff Timothy , Saabye Matt , Purkey Hans , Sudhamsu Jawahar , Staben Steven , Hanan Emily , Hatzivassiliou Georgia , Friedman Lori , Endres Nicholas F.
Published: December 2020

Activating mutations in PIK3CA are among the most significant oncogenic events across all cancers, making it an important target for drug development. Yet the application of PI3K inhibitors in the clinic has been limited by the difficulty of achieving an adequate therapeutic window, due to the critical role that PI3K signaling plays in normal physiologic processes, such as glucose homeostasis. In theory, the therapeutic window could be improved if it were possible to design mutant selective inhibitors, as has been demonstrated with other oncogenes such as EGFR. However, unlike EGFR, the most predominant PIK3CA activating mutations do not reside in the kinase active site, presenting a major challenge for rational structure-based design. Nevertheless, it was recently shown that the PI3K inhibitor taselisib is able to achieve modest levels of mutant selectivity both across cancer lines as well as in cell lines that were engineered to express mutant or wild-type PIK3CA. Taselisib was also shown to selectively induce degradation of mutant versus wild-type PIK3CA, leading to the speculation that this degradation may be responsible for the observed selectivity. In order to better understand the origins of mutant selectivity for taselisib and several other PIK3CA inhibitors, we assessed these inhibitors in a variety of biophysical and biochemical assays under conditions designed to mimic physiologic settings. In parallel, we also investigated the mechanistic basis of this selectivity in our engineered cell lines. Our results are consistent with the hypothesis that selective degradation of mutant PIK3CA is the predominant mechanism underlying mutant selectivity for this class of PIK3CA active site inhibitors.

This abstract is also being presented as Poster B03.

Citation Format: Lan Nguyen, Kyle Edgar, Kyung Song, Stephen Schmidt, Victorai Schutz, Noriko Ishisoko, Eric Torres, Akash Das, Divya Murali, Steve Sideris, Timothy Wendorff, Matt Saabye, Hans Purkey, Jawahar Sudhamsu, Steven Staben, Emily Hanan, Georgia Hatzivassiliou, Lori Friedman, Nicholas F. Endres. Selective degradation of mutant PIK3CA promotes increased mutant specificity in a subset of PI3K ATP-competitive inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR03.
Attività glottodidattiche web-based per studenti Erasmus
Authors: Cameranesi Manuela , Cañas Silvia , Santanchè Cecilia
Published: December 2020

Presentiamo un’attività glottodidattica per studenti universitari in procinto di partire per il progetto Erasmus in Italia, in Portogallo o in Spagna. La proposta operativa consiste in un WebQuest, ossia una inquiry-oriented activity che prevede il reperimento delle informazioni necessarie per la risoluzione del task assegnato, utilizzando siti web precedentemente selezionati dall’insegnante. L’autenticità dei documenti da consultare consente ai discenti di potenziare la competenza linguistico-comunicativa in campi semantici senz’altro utili per affrontare il periodo di studi all’Estero, attraverso lo svolgimento di un’attività didattica otivante e flessibile, in quanto può essere svolta sia online che in presenza, e adattabile ai diversi livelli di conoscenza della LS.
Duas Sátiras sobre a Descoberta da América: Performance e Engajamento no Teatro de Dario Fo
Authors: Ferrari Luís Felipe , Franco Márcia Maria de arruda
Published: December 2020

Neste artigo tentamos analisar duas peças de Dario Fo que tratam da descoberta e da colonização da América: Isabella, Tre Caravelle e un Cacciaballe e Johan Padan a la Descoverta de le Americhe. Nosso objetivo é demonstrar que a comédia de Fo desenvolve uma articulação íntima entre performance e engajamento político, na medida em que a construção da cena se mostra dependente da crítica da sociedade e da história.
JNK2, a Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca
2+
]
SR
Leak-Load Relationship
Authors: Yan Jiajie , Bare Dan J. , DeSantiago Jaime , Zhao Weiwei , Mei Yiming , Chen Zhenhui , Ginsburg Kenneth , Solaro R. John , Wolska Beata M. , Bers Donald M. , Chen S.R. Wayne , Ai Xun
Published: December 2020

Rationale:

We recently discovered pivotal contributions of stress kinase JNK2 (c-Jun N-terminal kinase isoform 2) in increased risk of atrial fibrillation through enhanced diastolic sarcoplasmic reticulum (SR) calcium (Ca
2+
) leak via RyR2 (ryanodine receptor isoform 2). However, the role of JNK2 in the function of the SERCA2 (SR Ca
2+
-ATPase), essential in maintaining SR Ca
2+
content cycling during each heartbeat, is completely unknown.

Objective:

To test the hypothesis that JNK2 increases SERCA2 activity SR Ca
2+
content and exacerbates an arrhythmic SR Ca
2+
content leak-load relationship.

Methods and Results:

We used confocal Ca
2+
imaging in myocytes and HEK-RyR2 (ryanodine receptor isoform 2-expressing human embryonic kidney 293 cells) cells, biochemistry, dual Ca
2+
/voltage optical mapping in intact hearts from alcohol-exposed or aged mice (where JNK2 is activated). We found that JNK2, but not JNK1 (c-Jun N-terminal kinase isoform 1), increased SERCA2 uptake and consequently elevated SR Ca
2+
content load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased maximal rate, without altering Ca
2+
affinity. Unlike the CaMKII (Ca
2+
/calmodulin-dependent kinase II)-dependent JNK2 action in SR Ca
2+
leak, JNK2-driven SERCA2 function was CaMKII independent (not prevented by CaMKII inhibition). With CaMKII blocked, the JNK2-driven SR Ca
2+
loading alone did not significantly raise leak. However, with JNK2-CaMKII–driven SR Ca
2+
leak present, the JNK2-enhanced SR Ca
2+
uptake limited leak-induced reduction in SR Ca
2+
, normalizing Ca
2+
transient amplitude, but at a higher arrhythmogenic SR Ca
2+
leak. JNK2-specific inhibition completely normalized SR Ca
2+
handling, attenuated arrhythmic Ca
2+
activities, and alleviated atrial fibrillation susceptibility in aged and alcohol-exposed myocytes and intact hearts.

Conclusions:

We have identified a novel JNK2-induced activation of SERCA2. The dual action of JNK2 in CaMKII-dependent arrhythmic SR Ca
2+
leak and a CaMKII-independent uptake exacerbates atrial arrhythmogenicity, while helping to maintain normal levels of Ca
2+
transients and heart function. JNK2 modulation may be a novel therapeutic target for atrial fibrillation prevention and treatment.