bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA04: Stroma-driven resistance to PI3K/mTOR inhibition
Authors: Muranen Taru 
Published: December 2020

Abstract
PI3/mTOR pathway, a major regulator of cellular growth and metabolism, is mutated in ~70% of breast cancers and conveys resistance towards estrogen receptor- and HER2-targeted therapies. Unfortunately, targeting the PI3K pathway in the clinic has been hampered by emergence of drug resistance, often through rewiring of their signaling pathways rather than through mutations, a phenomenon called adaptive resistance that is often observed with targeted therapies. Our previous data have shown that adaptive resistance requires input from the tumor microenvironment. Cancer cells require the presence of extracellular matrix proteins to elicit drug resistance; without matrix contact the tumor cells died. Our data also show that fibroblasts secrete matrix proteins that increase cellular survival of epithelial cells under starvation and PI3K and mTOR inhibition. To investigate the identity and role of the secreted proteins that drive resistance, we performed mass-spectrometry and cytokine analysis of fibroblast secretomes treated with PI3K inhibitors. These data have identified several candidate proteins as potential drivers of stroma-mediated drug resistance, and we will discuss how targeting these proteins can increase the efficacy of PI3K- and mTOR-targeted therapies.
Citation Format: Taru Muranen. Stroma-driven resistance to PI3K/mTOR 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 IA04.
Abstract IA07: Identifying metabolic dependencies in pancreatic cancer
Authors: Kimmelman Alec 
Published: December 2020

Abstract
Pancreatic cancers are highly resistant to currently available therapeutics, which results in a 5-year survival rate of approximately 6%. We believe that this resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism, allowing carbon sources to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Ongoing studies from our group are exploring targeting various aspects of metabolism as therapeutic approaches. Additional studies from our group have demonstrated that pancreatic cancers have elevated basal autophagy, which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer. Recently, we have identified an autophagy-dependent metabolic crosstalk that exists between pancreatic tumor cells and the surrounding stroma. Ongoing work from our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors. These and other aspects of pancreatic cancer metabolism will be discussed.
Citation Format: Alec Kimmelman. Identifying metabolic dependencies 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 IA07.
Abstract IA08: Pooled CRISPR screens for novel autophagy-related factors identify TMEM41, an ER-resident protein predicted to be a channel
Authors: Denic Vladimir 
Published: December 2020

Abstract
The power of forward genetics in yeast is the foundation on which the field of autophagy research firmly stands. Complementary work on autophagy in metazoans has revealed both the deep conservation of this process, as well as novel mechanisms by which autophagy is regulated in the context of development, immunity, and neuronal homeostasis. The recent emergence of new CRISPR/Cas9-based technologies has begun facilitating efforts to define novel autophagy factors and pathways by forward genetic screening in mammalian cells. Here, we set out to develop an expanded and improved toolkit of autophagy reporters for CRISPR/Cas9 screening. Genome-wide screening of our reporters in mammalian cells recovered virtually all known ATG factors as well as previously uncharacterized factors including VPS37A, TMEM251, ALS2, ACP1, and TMEM41B. To validate this dataset, we used quantitative microscopy and biochemical analyses to show that one novel hit, TMEM41B, is required for a late step in phagophore maturation. We found that TMEM41B is an integral ER membrane protein distantly related to the established autophagy factor VMP1, and our data show that these two factors play related, albeit not fully overlapping, roles in autophagosome biogenesis. In sum, our work uncovers new ATG factors, reveals a malleable network of autophagy receptor genetic interactions, and provides a valuable resource (http://crispr.deniclab.com) for further mining of novel autophagy mechanisms.
Citation Format: Vladimir Denic. Pooled CRISPR screens for novel autophagy-related factors identify TMEM41, an ER-resident protein predicted to be a channel [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 IA08.
Abstract IA10: Structure and dynamics of Rag heterodimers in a complex with mTORC1
Authors: Anandapadamanaban Madhan , Perisic Olga , Berndt Alex , Masson Glenn R , Kaufman Jonathan , McLaughlin Stephen H. , Johnson Chris M. , Sabatini David M. , Williams Roger L. 
Published: December 2020

Abstract
Eukaryotic cells coordinate growth with the availability of nutrients through the protein kinase complex mTORC1, which is part of a pathway that is often upregulated in cancer. The mTORC1 complex is activated by association with two types of GTPases, Rags and RHEB. The heterodimeric Rag GTPases are key components in the activation of the mTORC1 pathway in response to amino acids. The Rag heterodimer interacts with the RAPTOR subunit of mTORC1 in a manner dependent on the nucleotide-bound states of its constituent GTPases. We used hydrogen/deuterium exchange mass spectrometry (HDX-MS) to map the interface of RAPTOR with an active Rag heterodimer, and we determined X-ray crystal structures of human Rag heterodimers in several nucleotide-bound states. Our high-resolution crystal structure of an oncogenic mutant heterodimer enabled us to interpret the cryo-EM structure of a complex of mTORC1 with the mutant RagA/C heterodimer. The cryo-EM structure shows that the G-domains from both Rags contact helical repeats of the RAPTOR subunit of mTORC1, but the GTP-bound RagA G domain forms almost all of the interface. The structure suggests how the nucleotide state of RagA is coordinated with the nucleotide state of RagC. The conformation of mTORC1 in a complex with the Rags is nearly identical to the apo mTORC1 complex, suggesting that the primary role of Rag binding is to recruit the mTORC1 complex to the lysosomal surface in the presence of the Ragulator complex.
Citation Format: Madhan Anandapadamanaban, Olga Perisic, Alex Berndt, Glenn R Masson, Jonathan Kaufman, Stephen H. McLaughlin, Chris M. Johnson, David M. Sabatini, Roger L. Williams. Structure and dynamics of Rag heterodimers in a complex with mTORC1 [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 IA10.
Abstract IA26: Reprogramming tumor-associated macrophages by targeting PI3K-gamma with IPI-549
Authors: Kutok Jeffery L. 
Published: December 2020

Abstract
The PI3 kinases (PI3K) belong to a family of signal-transducing enzymes that mediate key cellular functions in cancer and immunity. The PI3K-gamma (γ) isoform is highly expressed in myeloid cells/macrophages and plays an important role in M2 macrophage polarization (Kaneda, Nature 2016). PI3K-γ knockout mice also demonstrated the role for PI3K-γ in tumor growth and immune tolerance (Gunderson, Cancer Discovery 2015; Kaneda, 2016). IPI-549 is an oral, potent, and selective inhibitor of PI3K-γ that shows single-agent antitumor activity in multiple murine tumor models (Kaneda, 2016) and enhanced antitumor activity and improved survival when combined with immune-checkpoint blockade (ICB) (De Henau, Nature 2016). This antitumor activity is dependent on the presence of both immune-suppressive tumor-associated CD11b+ myeloid cells and CD8+ cytotoxic T cells. IPI-549 can reduce the suppression of T-cell activity by both murine and human myeloid-derived suppressor cells in vitro and in vivo. IPI 549 treatment of tumor-bearing mice leads to a shift in tumor-associated myeloid cells from an immunosuppressive M2 phenotype to a proinflammatory M1 phenotype and an increased frequency of circulating tumor-specific T cells and tumor-infiltrating CD8+ T cells. In addition, preclinical tumor model systems show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells (De Henau, Nature 2016). Treatment of ICB-resistant 4T1 and B16GMCSF tumor-bearing mice with IPI-549 and anti-PD1 for 14 days led to a significant antitumor activity and an increased CD8+/T-reg cell ratio, confirming that selective pharmacologic targeting PI3K-γ by IPI-549 restores sensitivity to ICB. We are conducting a Ph 1/1b study IPI-549-01 (ClinicalTrials.gov NCT02637531) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunomodulatory activity of IPI-549 to determine its recommended phase 2 dose and preliminary clinical activity, as both a monotherapy and in combination with nivolumab, in patients with advanced solid tumors.
Citation Format: Jeffery L. Kutok. Reprogramming tumor-associated macrophages by targeting PI3K-gamma with IPI-549 [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 IA26.
Abstract PR05: Regulation of mRNA N6-adenosine methylation by the mTOR signaling
Authors: Lee Gina , Cho Sungyun , Pickering Brian F. , Jang Cholsoon , Rabinowitz Joshua D. , Jaffrey Samie R. , Blenis John 
Published: December 2020

Abstract
N6-adenosine methylation (m6A) is the most abundant chemical modification on eukaryotic mRNA. Emerging evidence shows that alterations in m6A modifications on mRNAs encoding oncogenes and tumor suppressors drive cancer initiation and progression including leukemia, glioma, breast and lung cancers. A methyltransferase complex METTL3/METTL14/WTAP deposits methyl groups on mRNA, and then the m6A-marked mRNAs undergo various fates including changes in stability, localization, and translation efficiency. Through phosphoproteomic and transcriptomic analyses of mTOR signaling, we identified the methyltransferase complex as a novel downstream target of the mTOR pathway. We have also found that mTOR signaling, potentially through m6A methylation, regulates expression of the one-carbon metabolic pathway enzymes, which provide building blocks and methyl donors for growing cells. Together, our results indicate that mTOR signaling controls the activity of the methyltransferase complex to govern the m6A modifications of key mRNAs impacting tumor growth.
This abstract is also being presented as Poster A11.
Citation Format: Gina Lee, Sungyun Cho, Brian F. Pickering, Cholsoon Jang, Joshua D. Rabinowitz, Samie R. Jaffrey, John Blenis. Regulation of mRNA N6-adenosine methylation by the mTOR signaling [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 PR05.
Abstract PR08: AKT mutant allele-specific activation dictates pharmacologic sensitivities
Authors: Bhattarai Tripti Shrestha , Shamu Tambudzai , Patel Swati , Gorelick Alexander , Chang Matthew T. , Gavrila Elena I. , Gao JianJong , Donoghue Mark T.A. , Gao Paul S. , Soumerai Tara , Abida Wassim , Smyth Lilian M. , Hyman David M. , Solit David B. , Taylor Barry S. 
Published: December 2020

Abstract
The objective of this study is to explore the biochemical characteristics and therapeutic sensitivity profiles of novel, non-E17K, less frequent AKT1 mutations, and thereby expand the biomarker of sensitivity to AKT inhibition in molecularly defined cancer patients. AKT is a critical signaling node that translates phosphoinositide 3-kinase (PI3K) pathway stimulation into diverse cellular effects. Gain-of-function AKT1 mutations arise in diverse human cancers, of which E17K is the most common. Presence of AKT1 E17K mutation renders these tumors susceptible to AKT inhibition. Nevertheless, the long tail of potentially activating mutations in AKT is largely uncharacterized, thereby limiting our ability to act clinically in prospectively sequenced advanced cancer patients. We performed a population-scale candidate driver mutation discovery analysis in AKT1, AKT2 and AKT3 in a cohort of 41,075 retrospectively and prospectively sequenced primary and metastatic cancers and explored both their functional and biologic impact as well as their therapeutic sensitivity. Our results demonstrated that some, but not all, of the identified AKT missense mutations activated PI3K signaling in a growth factor-independent manner, and sensitized tumor cells to diverse AKT inhibitors. By contrast, we discovered a different class of small in-frame paralogous AKT duplication mutants that induced distinctive structural changes, leading to a far greater degree of membrane affinity, AKT activation, pathway dependence, and hypersensitivity to ATP-competitive AKT inhibitors, while conferring resistance to allosteric AKT inhibitors. Leveraging a co-clinical trial framework, we are now enrolling patients on the basis of these mutations in a basket study involving AKT alterations. One such case was that of a castration-resistant metastatic prostate cancer patient who harbored AKT2 duplication mutant, and subsequently responded to AKT inhibition. Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacologic sensitivities to AKT inhibition.
This abstract is also being presented as Poster B20.
Citation Format: Tripti Shrestha Bhattarai, Tambudzai Shamu, Swati Patel, Alexander Gorelick, Matthew T. Chang, Elena I. Gavrila, JianJong Gao, Mark T.A. Donoghue, Paul S. Gao, Tara Soumerai, Wassim Abida, Lilian M. Smyth, David M. Hyman, David B. Solit, Barry S. Taylor. AKT mutant allele-specific activation dictates pharmacologic sensitivities [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 PR08.
Global Commons and the Law of the Sea: China’s Lawfare Strategy in the South China Sea
Authors: Hermez Marta 
Published: December 2020

Abstract
The portions of the South China Sea which fall outside the jurisdiction of any coastal state, are some of the world’s most important global maritime commons. Disputes over the maritime features and their surrounding waters of the South China Sea therefore threaten the governance of this global commons, both from a preservation and security perspective. This contribution analyses China’s lawfare strategy in the South China Sea by deconstructing its legal discourse on the matter. It will to that end scrutinize elements of China’s official and academic rhetoric, domestic legislation and operational conduct related to the South China Sea. The contribution will lay some groundwork for an enhanced engagement with China in the battle of the arguments on the South China Sea. In the same vein, it ultimately calls for further deepening our knowledge on China’s interpretation of the law of the sea and an increased interaction thereon in order to be better equipped to face China’s incremental geopolitical and discourse power and their influence on the future development of the legal global governance structure of the oceans.
Pregabalin does not decrease acute pain or postoperative nausea and vomiting after hysterectomy: a meta-analysis
Authors: Ni Jie , Jiang Juan , Mao Shiqin , Sun Rui-fang 
Published: December 2020

Objective Hysterectomy is associated with severe postoperative pain. The relative efficacy of pregabalin compared with other treatments for post-hysterectomy pain is unclear. Methods We searched the PubMed, Cochrane Library, and Web of Science databases for studies that compared the use of pregabalin and placebo for reducing pain in patients undergoing hysterectomy. Results This meta-analysis showed that pregabalin had limited pain-relieving effects at 2, 6, 24, and 48 hours after hysterectomy compared with placebo. Pregabalin significantly reduced postoperative nausea and vomiting. However, there was no significant difference in postoperative sedation or visual disturbances between patients treated with pregabalin and placebo. Conclusions Pregabalin is not clinically superior to placebo in terms of reducing pain intensity and morphine consumption in patients undergoing hysterectomy. However, the limitations of this meta-analysis mean that more high-quality randomized controlled trials are necessary to verify our pooled results.
Comparison of functional exercise capacity, quality of life and respiratory and peripheral muscle strength between patients with stable angina and healthy controls
Authors: Huzmeli Irem , Ozer Aysel-Yildiz , Akkus Oguz , Katayıfcı Nihan , Sen Fatih , Yurdalan Saadet Ufuk , Polat Mine Gulden 
Published: December 2020

Objective We aimed to compare functional exercise capacity, respiratory and peripheral muscle strength, pulmonary function and quality of life between patients with stable angina and healthy controls. Methods We compared 33 patients with stable angina (55.21 ± 6.12 years old, Canada Class II–III, left ventricular ejection fraction: 61.92 ± 7.55) and 30 healthy controls (52.70 ± 4.22 years old). Functional capacity (6-minute walk test (6-MWT)), respiratory muscle strength (mouth pressure device), peripheral muscle strength (dynamometer), pulmonary function (spirometer) and quality of life (Short Form 36 (SF-36)) were evaluated. Results 6-MWT distance (499.20 ± 51.91 m versus 633.05 ± 57.62 m), maximal inspiratory pressure (85.42 ± 20.52 cmH2O versus 110.44 ± 32.95 cmH2O), maximal expiratory pressure (83.33 ± 19.05 cmH2O versus 147.96 ± 54.80 cmH2O) and peripheral muscle strength, pulmonary function and SF-36 sub-scores were lower in the angina group versus the healthy controls, respectively. Conclusion Impaired peripheral and respiratory muscle strength, reduction in exercise capacity and quality of life are obvious in patients with stable angina. Therefore, these parameters should be considered in stable angina physiotherapy programmes to improve impairments.
‘Bharat Mata’ and ‘Ma Victoria’: Forms of Divine Motherhood in Colonial Bengal
Authors: Ghosh Sanmita 
Published: December 2020

This article attempts to explore the cult of the ‘Bharat Mata’ that was born out of the patriotic fervour of Indian nationalist leaders who transformed their nationalist passion into an image of the nation as mother, and the widely promoted idea of Queen Victoria as a mother to her subjects in the nineteenth-century Bengal. The image of ‘Bharat Mata’ was conceived with the rising tide of nationalism in the nineteenth century, the impetus provided by the Bengali novelist Bankimchandra Chattopadhyay’s novel Anandamath (1882). The image of Queen Victoria as a mother to her Indian subjects found its most emphatic projection in Bengali texts like Raja Sir Sourindro Mohun Tagore’s poem Srimad-Victoria-Mahatmyam, The Greatness of the Empress Victoria: A Sanskrit Poem, Set to Music with English Translation (1897). Composed on the occasion of the completion of 60 years of Queen Victoria’s reign, the poem was a ‘humble offering of loyalty’ to the Queen-Empress, whose reign over India was glorified and regarded auspicious. The article looks into the apparently contradictory nature of the worship of the feminine form as the ‘mother’ in a pre-independent nineteenth-century Bengal, through a consideration of texts like Anandamath, Srimad-Victoria-Mahatmyam and Girishchandra Ghosh’s play Hirak Jubilee (1897), among others. In this context, the article also takes into account the theoretical perspective of the cultural ‘Other’, inherent in a study involving the dynamics of colonial relations.
Could 30 years of political controversy on needle exchange programmes in Sweden contribute to scaling-up harm reduction services in the world?
Authors: Karlsson Niklas , Berglund Torsten , Ekström Anna Mia , Hammarberg Anders , Tammi Tuukka 
Published: December 2020

Aims: To end the hepatitis and AIDS epidemics in the world by 2030, countries are encouraged to scale-up harm reduction services and target people who inject drugs (PWID). Blood-borne viruses (BBV) among PWID spread via unsterile injection equipment sharing and to combat this, many countries have introduced needle and syringe exchange programmes (NEP), though not without controversy. Sweden’s long, complicated harm reduction policy transition has been deviant compared to the Nordic countries. After launch in 1986, no NEP were started in Sweden for 23 years, the reasons for which are analysed in this study. Methods: Policy documents, grey literature and research mainly published in 2000–2017 were collected and analysed using a hierarchical framework, to understand how continuous build-up of evidence, decisions and key events, over time influenced NEP development. Results: Sweden’s first NEP opened in a repressive-control drug policy era with a drug-free society goal. Despite high prevalence of BBV among PWID with recurring outbreaks, growing research and key-actor support including a NEP law, no NEP were launched. Political disagreements, fluctuating actor-coalitions, questioning of research, and a municipality veto against NEP, played critical roles. With an individual-centred perspective being brought into the drug policy domain, the manifestation of a dual drug and health policy track, a revised NEP law in 2017 and removal of the veto, Sweden would see fast expansion of new NEP. Conclusions: Lessons from the Swedish case could provide valuable insight for countries about to scale-up harm reduction services including how to circumvent costly time- and resource-intensive obstacles and processes involving ideological and individual moral dimensions.