bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model Study of Penetration of Cl− Ions from Solution into Organic Self-Assembled-Monolayer on Metal Substrate: Trends and Modeling Aspects
Authors: Kokalj Anton , Costa Dominique 
Published: June 2021

Organic molecules that form self-assembled-monolayers on metal substrates may provide efficient corrosion protection. Herein we study how such self-assembled-monolayers hinder the penetration of

Cl

−

ions from aqueous solution toward the metal substrate. We first elucidate some aspects that are relevant for modeling charged ions near surfaces with slab models that utilize periodic-boundary-conditions, in particular: (i) solvation effects, (ii) inter-ion electrostatics, (iii) depolarization effects, and (iv) effects of periodic-boundary-conditions along lateral directions and, for multi-slab models, also along the surface normal direction. The last two effects are artifacts hence they can be avoided or at least minimized by proper modeling. We further present a simple scheme that describes the activation barrier for

Cl

−

penetration into self-assembled-monolayer as a function of the electrode potential and show that the activation barrier decreases as the electrode potential increases, as would be intuitively expected, however, for thick self-assembled-monolayers the barrier remains sizable even at rather positive potentials, which may be one of the reasons why dense and sufficiently thick self-assembled-monolayers can efficiently inhibit corrosion. By utilizing a simple model where metal substrate, organic layer, and aqueous solvent are described implicitly by dielectric continuum slabs, we analyze two important effects by which self-assembled-monolayers hinder the penetration of

Cl

−

ions toward the metal substrate. The first effect is due to inferior solvation of ions in organic layer compared to that in aqueous solvent and the estimated difference is larger than 1 eV. This effect is independent of the thickness of the organic layer, provided that the layer is sufficiently thick (≳10 Å). The second effect is due to electric field at the electrochemical interface and the extent by which it affects the penetration of

Cl

−

depends on the electrode potential and on the thickness of the organic layer. Other effects, such as local deformation of organic layer during

Cl

−

penetration, cannot be described by current simple models and will be considered in our next publication. Finally, calculations indicate that due to stronger solvation of Na+ counter-ions their penetration into organic layer is inferior to that of

Cl

−

. Energetically the most favorable way for Na+ to penetrate is in the form of Na+/

Cl

−

ion-pairs, but it is inferior to penetration of

Cl

−

alone.
Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data
Authors: Anwar Munawar , Chen Qitong , Ouyang Dengjie , Wang Shouman , Xie Ning , Ouyang Quchang , Fan Peizhi , Qian Liyuan , Chen Gannong , Zhou Enxiang , Guo Lei , Gu Xiaowen , Ding Boning , Yang Xiaohong , Liu Liping , Deng Chao , Xiao Zhi , Li Jing , Wang Yunqi , Zeng Shan , Hu Jinhui , Zhou Wei , Qiu Bo , Wang Zhongming , Weng Jie , Liu Mingwen , Li Yi , Tang Tiegang , Wang Jianguo , Zhang Hui , Dai Bin , Tang Wuping , Wu Tao , Xiao Maoliang , Li Xiantao , Liu Hailong , Li Lai , Yi Wenjun 
Published: June 2021

Abstract

Purpose:
Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce.

Experimental Design:
This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed.

Results:
Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR).

Conclusions:
Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.
Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors
Authors: Thompson Patricia A. , Huang Chuan , Yang Jie , Wertheim Betsy C. , Roe Denise , Zhang Xiaoyue , Ding Jie , Chalasani Pavani , Preece Christina , Martinez Jessica , Chow H.-H. Sherry , Stopeck Alison T. 
Published: June 2021

Abstract

Purpose:
To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer.

Experimental Design:
An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy.

Results:
In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40).

Conclusions:
This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Byrne Katelyn T. , Betts Courtney B. , Mick Rosemarie , Sivagnanam Shamilene , Bajor David L. , Laheru Daniel A. , Chiorean E. Gabriela , O'Hara Mark H. , Liudahl Shannon M. , Newcomb Craig , Alanio Cécile , Ferreira Ana P. , Park Byung S. , Ohtani Takuya , Huffman Austin P. , Väyrynen Sara A. , Dias Costa Andressa , Kaiser Judith C. , Lacroix Andreanne M. , Redlinger Colleen , Stern Martin , Nowak Jonathan A. , Wherry E. John , Cheever Martin A. , Wolpin Brian M. , Furth Emma E. , Jaffee Elizabeth M. , Coussens Lisa M. , Vonderheide Robert H. 
Published: June 2021

Abstract

Purpose:
CD40 activation is a novel clinical opportunity for cancer immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological effects and treatment-related modulation of the tumor microenvironment (TME) remain poorly understood.

Patients and Methods:
Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy to 16 patients with resectable pancreatic ductal adenocarcinoma (PDAC) before surgery followed by adjuvant chemotherapy and CD40 mAb.

Results:
The toxicity profile was acceptable, and overall survival was 23.4 months (95% confidence interval, 18.0–28.8 months). Based on a novel multiplexed immunohistochemistry platform, we report evidence that neoadjuvant selicrelumab leads to major differences in the TME compared with resection specimens from treatment-naïve PDAC patients or patients given neoadjuvant chemotherapy/chemoradiotherapy only. For selicrelumab-treated tumors, 82% were T-cell enriched, compared with 37% of untreated tumors (P = 0.004) and 23% of chemotherapy/chemoradiation-treated tumors (P = 0.012). T cells in both the TME and circulation were more active and proliferative after selicrelumab. Tumor fibrosis was reduced, M2-like tumor-associated macrophages were fewer, and intratumoral dendritic cells were more mature. Inflammatory cytokines/sec CXCL10 and CCL22 increased systemically after selicrelumab.

Conclusions:
This unparalleled examination of CD40 mAb therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting CD40 in cancer.
Abstract A10: Quantitative biophysical analysis defining key components modulating KRAS recruitment to the plasma membrane
Authors: Lakshman Bindu , Messing Simon , Schmid Eva M. , Clogston Jeffrey D. , Gillette William K. , Esposito Dominic , Kessing Bailey , Fletcher Daniel A. , Nissley Dwight V. , McCormick Frank , Stephen Andrew G. , Jean-Francois Frantz L. 
Published: June 2021

Abstract
The KRAS fraction in the plasma membrane (PM) correlates with activation of the MAPK pathway and subsequent cellular proliferation. Understanding KRAS interaction with the PM constitutes a challenge given the complexity of the cellular environment. To gain insight on key components necessary for KRAS signal transduction at the membrane, we make use of reconstituted liposomes and giant unilamellar vesicles as synthetic membranes. Using surface plasmon resonance (SPR) spectroscopy, we demonstrate that KRAS and RAF1 domains interact with these membranes primarily through electrostatic interactions with negatively charged lipids reinforced by additional interactions involving phosphatidyl ethanolamine and cholesterol. RAF1 52-188 (RBDCRD) interacts with the membrane significantly more strongly than the isolated RBD or CRD domains and synergizes KRAS membrane partitioning. Calmodulin and PDE6 delta, but not galectin3, passively sequester KRAS and prevent it from binding to the PM. RAF1 RBDCRD interacts with membranes preferentially at non-raft lipids domains. The carboxyterminal O-methylation is crucial for KRAS membrane localization. These results contribute to a better understanding of how KRAS-membrane interaction can be tuned by multiple factors.
Citation Format: Bindu Lakshman, Simon Messing, Eva M. Schmid, Jeffrey D. Clogston, William K. Gillette, Dominic Esposito, Bailey Kessing, Daniel A. Fletcher, Dwight V. Nissley, Frank McCormick, Andrew G. Stephen, Frantz L. Jean-Francois. Quantitative biophysical analysis defining key components modulating KRAS recruitment to the plasma membrane [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A10.
Abstract A11: Screening the Ras proteome microenvironment using APEX2
Authors: Mo Stephanie P. , Coulson Judy M. , Prior Ian A. 
Published: June 2021

Abstract
Ras proteins are small GTPases that regulate cellular growth and proliferation. The three RAS genes KRAS, HRAS and NRAS are ubiquitously expressed and share almost complete sequence homology; despite this they exhibit isoform-specific signaling in vitro and in vivo. Differences in localization, including nanoclustering on the cell surface, have been suggested to determine isoform-specific signaling. Currently, over 20 Ras effectors have been identified, although most work has focused on the Raf-MAP kinase and PtdIns 3-kinase (PI3K) pathways downstream of Ras. It has been shown that Ras isoform-specific signaling is highly context-dependent with significant cell type-dependent differences in coupling to canonical effector pathways. While the main Ras signaling network is understood, proteins regulating localization and interactions within the Ras network are still being identified. Here, we have performed a comprehensive analysis of the Ras isoform-specific interactome with particular interest in the role of cell surface nanoclustering and plasma membrane organization. We have screened the proteome microenvironment in living mammalian cells via APEX2, an engineered promiscuous peroxidase, which biotinylates vicinal proteins to the protein of interest. Here, APEX2-tagged Ras was used to identify proximal proteins to KRAS, HRAS and NRAS using mass spectrometry. Our preliminary data have shown that APEX2 is a suitable screening tool for the Ras proteome microenvironment. This method has allowed us to observe differences between the Ras isoforms, which are undergoing validation.
Citation Format: Stephanie P. Mo, Judy M. Coulson, Ian A. Prior. Screening the Ras proteome microenvironment using APEX2 [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A11.
Abstract A21: Loss of Argonaute 2 leads to oncogene-induced senescence in mutant RAS-driven cancer
Authors: Siebenaler Ronald F. , Shankar Sunita , Tien Jean C. , Dommeti Vijaya L. , Zelenka-Wang Sylvia , Waninger Jessica , Mody Malay , Chugh Seema , Kumar-Sinha Chandan , Chinnaiyan Arul M. 
Published: June 2021

Abstract
The RAS gene family is among the most commonly mutated genes within cancer, but little progress has been made in successfully targeting RAS mutations. Targeting binding partners of mutated RAS, however, presents a promising alternative therapeutic strategy. With the goal of uncovering novel interactors of RAS, we recently identified Argonaute 2 (AGO2) of the RNA-induced silencing complex (RISC) as a novel partner of the Switch II domain of KRAS. In order to assess the role of AGO2 in KRAS-G12D driven disease, we developed a mouse model of pancreatic cancer with conditional loss of AGO2. While AGO2 knockout did not prevent development of early precursor pancreatic intraepithelial (PanIN) lesions, loss of AGO2 prevented progression to late-stage PanINs, pancreactic ductal adenocarcinoma (PDAC), and metastatic disease. AGO2 null lesions displayed increased activation of the EGFR-RAS signaling axis during PanIN development. This signaling resulted in an increase in WT RAS-GTP activation, pEGFR-Y1068, and pERK levels leading to the development of oncogene-induced senescence in these PanIN lesions. Furthermore, we observed that EGFR-mediated phosphorylation of AGO2-Y393 disrupted the interaction between WT RAS and AGO2. This regulation by EGFR, however, was blocked in cells expressing mutant KRAS. These results suggested that the interaction of mutant RAS and AGO2 was vital to tumor development. To better assess the role of AGO2 loss in mutant RAS driven cancer, we performed AGO2 knockdown in multiple cell lines expressing mutations in either NRAS or HRAS isoforms. In each cell line, AGO2 directly interacted with KRAS, NRAS, and KRAS. In addition to suppressing growth in mutant RAS-driven cells (T24: HRAS-G12V, SK-MEL-2: NRAS-Q61H), loss of AGO2 produced marked increases in beta-galactosidase and p16 expression, as well as a decrease in cyclin D1, suggesting development of oncogene-induced senescence. Interestingly, upon AGO2 loss, cells displayed induction of pEGFR and pERK similar to what was observed in our pancreatic mouse model, and despite decreased expression of mutant RAS, WT RAS-GTP loading upon AGO2 loss was strongly induced. Together these results suggest a unique EGFR-AGO2-RAS signaling axis that requires AGO2-RAS interaction to prevent induction of oncogene-induced senescence in mutant RAS-driven cancers.
Citation Format: Ronald F. Siebenaler, Sunita Shankar, Jean C. Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Jessica Waninger, Malay Mody, Seema Chugh, Chandan Kumar-Sinha, Arul M. Chinnaiyan. Loss of Argonaute 2 leads to oncogene-induced senescence in mutant RAS-driven cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A21.
Abstract A28: USP21 promotes stemness of pancreatic cancer cells and bypass of KRAS extinction
Authors: Hou Pingping , Ma Xingdi , Ackroyd Jeffery , Zhang Jianhua , Jiang Shan , Wang Alan Y. , DePinho Ronald A. 
Published: June 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths, with an estimated 44,330 deaths per year in the United States alone. Deubiquitinases play fundamental roles in maintenance of cellular homeostasis, and deregulation of ubiquitin-specific proteases (USPs), the largest group of deubiquitinases, has been reported in multiple cancer types. In particular, we found that USP21 is amplified in 22% of PDAC cases in the patient dataset from the University of Texas Southwestern Medical Center, and it is the most frequently deregulated USP. However, little is known about the role of USP21 in PDAC. To examine biologic function of USP21 amplification in PDAC, we employed a novel “iKPC” mouse model, harboring tetO-LSL-KrasG12D (a transgenic allele with doxycycline-controlled tet-ON system regulating transcriptionally activated KRASG12D), ROSA26-LSL-rtTA, p53L/+ and p48Cre. We induced overexpression of USP21 in PDAC cells isolated from iKPC mice and found that USP21 promotes iKPC pancreatic tumor growth in vivo and drives KRAS-independent pancreatic tumor growth after blockage of KRAS expression. USP21 has a nuclear export signal and shuttles between the nucleus and cytoplasm. By modulating its subcellular localization, we discovered different functions of USP21 in supporting pancreatic cancer growth. Specifically, the nuclear function of USP21 supports pancreatic tumor growth by increasing tumor cell stemness via enhanced activation of the Wnt/beta-catenin signaling pathway. We showed that USP21 directly regulates proteasome pathway-dependent degradation of TCF7 protein. The cytoplasmic function of USP21 stimulates tumor cells to bypass KRAS extinction via MARK3, which phosphorylated its substrates and blocked their function by generating 14-3-3 binding sites. We found that MARK3 interacts with and is deubiquitinated by USP21. Knockdown of Ptpn3, a reported substrate of MARK3, increased protein level of PDGFRA, overexpression of which bypassed KRAS extinction. Moreover, we showed that inhibition of PDGF receptor pathway impairs KRAS-independent PDAC tumor growth driven by USP21 in vivo. Thus, our work demonstrated distinct oncogenic functions of USP21 in the presence and absence of KRAS signaling in PDAC, suggesting that KRAS-mutant PDAC patients with USP21 amplification may become resistant to KRAS inhibition.
Citation Format: Pingping Hou, Xingdi Ma, Jeffery Ackroyd, Jianhua Zhang, Shan Jiang, Alan Y. Wang, Ronald A. DePinho. USP21 promotes stemness of pancreatic cancer cells and bypass of KRAS extinction [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A28.
Abstract A34: Defining KRAS mutation-specific kinome signatures and vulnerabilities in colorectal cancer
Authors: Srivastava Nishi , Kurimchak Alison , Montavez Carlos , Chernoff Jonathan , Duncan James 
Published: June 2021

Abstract
Activating mutations in KRAS occur in about half of colorectal cancers (CRC) and are associated with drug resistance and poor survival. A number of distinct oncogenic mutations in KRAS have been identified in CRC, including mutations in exon 2-producing (G12D, G12V, and G13D) and in exon 4 (A146T and A146V). Importantly, emerging clinical and basic science data indicate that these KRAS mutations are not all equal in their oncogenic properties and sensitivity to targeted therapies. To access and exploit the distinct kinase programs engaged by the different KRAS mutants, we employed an innovative mass spectrometry-based technique that enables the majority of the human kinome to be analyzed simultaneously, providing the means to explore the KRAS-induced kinome and its response to targeted therapy in an unbiased fashion. Using multiplexed inhibitor beads and mass spectrometry (MIB/MS), we measured differences in protein kinase signaling between the distinct KRAS mutants (G12D, G12V, G13D and A146T) at both baseline and in response to targeted MEK inhibitors in isogenic KRAS mutant xenografts. Kinome profiling of the tumors demonstrated that each KRAS mutant exhibits a unique basal activation signature, with G12D and A146T mutations showing the most divergence from wild-type (WT) KRAS kinome(s). Tumors harboring G12D or A146T knockin mutations displayed intrinsic resistance to MEKi trametinib, while G13D remained sensitive to MEK inhibition comparable to KRAS WT tumors. Notably, tumors expressing G12V KRAS mutations showed enhanced tumor regression relative to KRAS WT, suggesting G12V mutations may sensitize CRC cells to MEK inhibition. Analysis of kinome adaptations to trametinib using MIB/MS revealed that each mutant reprogrammed their kinome(s) uniquely, supporting the design of individualized MEK inhibitor combination therapies tailored to specific KRAS mutations. Our kinome profiling studies further support the notion that not all KRAS mutations are created equal in CRC and demonstrate mutation-specific kinome activation signatures that can be therapeutically exploited in kinase inhibitor combination therapies.
Citation Format: Nishi Srivastava, Alison Kurimchak, Carlos Montavez, Jonathan Chernoff, James Duncan. Defining KRAS mutation-specific kinome signatures and vulnerabilities in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A34.
Abstract A36: Neoadjuvant-like Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and creates new therapeutic vulnerabilities
Authors: Gargiulo Gaetano 
Published: June 2021

Abstract
Kras-driven non-small cell lung cancers (NSCLC) are a leading cause of death with limited therapeutic options. Many NSCLC exhibit high levels of Ezh2, the enzymatic subunit of the Polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agent or prior to chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-kB and genes residing in PRC2-regulated chromatin. During this process tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-kB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide-bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLC.
Citation Format: Gaetano Gargiulo. Neoadjuvant-like Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and creates new therapeutic vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A36.