bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2805: Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis
Authors: Shirakami Yohei , Sakai Hiroyasu , Kochi Takahiro , Ideta Takayasu , Miyazaki Tsuneyuki , Shimizu Masahito , Seishima Mitsuru 
Published: August 2015

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to have effects against colorectal cancer (CRC), since evidence has emerged that people who routinely use NSAIDs show a lower risk of CRC. Among NSAIDs, cyclooxygenase-2 (COX2) inhibitors are thought to exert its anti-cancer effect through blocking prostaglandin (PG) E2 whose actions are mediated by signaling via four receptors EP1, EP2, EP3, and EP4. Previous animal experiments have demonstrated that the development of colon tumor is suppressed by knocking down of either EP1 or EP4. In the present study, we investigate the effect of a novel small molecule EP4 antagonist on rat colon tumorigenesis. Employed animal is Kyoto Apc Delta (KAD) rat which has Apc mutation and is susceptible to chemically-induced CRC. Five-week-old KAD rats received injection of azoxymethane (20 mg/kg i.p.) and 2% dextran sodium sulfate in drinking water for two weeks, and then they were divided into two groups: no treatment (control) group and the group treated with an EP4 antagonist RQ-00015986 (RQ-15986) which was kindly provided by AskAt Inc. RQ-15986-treated 17-week-old KAD rats showed lower colon tumor incidence (37.5% vs 100% in control group, P &lt; 0.05) and smaller multiplicity (1.33 ± 0.58 vs 2.86 ± 0.69 in control group, P &lt; 0.05). The expression levels of inflammatory cytokines, including TNF-alpha and IL-6, in colonic mucosa were decreased in RQ-15986-treated group. By treatment with RQ-15986, the expression levels of monocyte chemo-attractant protein-1 (MCP-1) and indoleamine 2,3-dioxygenase (IDO) were also down-regulated in colon mucosa. Immunohistochemical analyses of colonic membrane revealed that PCNA-labeling index was lower and that F4/80 positive cells were fewer in RQ-15986-treated group. These findings suggest that RQ-15986 may suppress CRC development through mediating immune system and controlling chronic inflammation in the colon.
Citation Format: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima. Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2015-2805
Abstract 2810: Identification of a natural compound as mammalian target of rapamycin kinase inhibitor
Authors: Jang Jeong-Hoon , Lee Cheol-Jung , Lee Mee-Hyun , Surh Young-Joon , Cho Yong-Yeon 
Published: August 2015

Abstract
The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, plays a critical role in the regulation of Akt signaling-mediated cell proliferation and transformation. Although several synthetic chemical compounds have developed to inhibit mTOR kinase activity, only few publications have been reported on the identification of natural compounds to target the mTOR kinase active pocket. In this study, we found that AME, a natural compound, inhibited cell proliferation by impairment of G1/S cell cycle transition when cells were co-treated with tumor promoters, such as epidermal growth factor. AME directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not with PI3K and PDK1. We further confirmed that AME inhibited phosphorylation of Akt at Ser473, which is a target amino acid of mTOR complex 2 (mTORC2), and Akt-mediated GSK3β phosphorylation at Ser9, which resulted in activation of GSK3β. The activated GSK3β inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through an ubiquitination-mediated proteasomal degradation pathway. Notably, decreased c-Jun stability by AME treatment suppressed EGF-induced neoplastic cell transformation in JB6 Cl41 mouse skin epidermal cells and HaCaT human skin keratinocytes in soft agar assay. Taken together, these results demonstrated that AME might be a natural chemopreventive agent targeting mTOR kinase active pocket.
Key words: Natural compound, ATP-competitive mTOR kinase inhibitor, mTORC2/Akt/GSK3 signaling, chemoprevention
Citation Format: Jeong-Hoon Jang, Cheol-Jung Lee, Mee-Hyun Lee, Young-Joon Surh, Yong-Yeon Cho. Identification of a natural compound as mammalian target of rapamycin kinase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2810. doi:10.1158/1538-7445.AM2015-2810
Abstract 2814: Inhibition of PhIP/DSS-induced colon carcinogenesis by different forms of tocopherols in CYP1A-humanized mice
Authors: Yang Chung S. , Chen Jayson X. , Liu Anna B. , Wang Hong , Lee Marlon , Yu Siyuan , Zhao Chunfang , Kuo Ying-Yi , Chi Eric , Suh Nanjoo 
Published: August 2015

Abstract
Tocopherols (T), which exist as α-, β-, γ-, and δ-T are important dietary antioxidants. Our previous studies have demonstrated that a mixture of tocopherols (γ-TmT), δ-T, and γ-T effectively inhibited colon carcinogenesis in AOM/DSS-treated mice or AOM-treated rats. However, the effects of different forms of tocopherols on carcinogenesis in animal models and in humans remain controversial. In the present study, we investigated the inhibitory effects of α-T, γ-T, and δ-T on colon carcinogenesis induced by a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS) in CYP1A-humanized (hCYP1A) mice. At 5-6 weeks age, male hCYP1A mice were fed the AIN93M diet or diet supplemented with 0.2% α-T, γ-T, or δ-T for 1 week before PhIP treatment (2x 100mg/kg b.w., 3 days apart), which was followed by DSS (1.5% in drinking water for 4 days) treatment. The mice were sacrificed 10 weeks after the first dose of PhIP. Significant inhibition of colon tumor incidences was caused by dietary δ-T and γ-T, but not by α-T. In addition, oxidative and nitrosative stress markers (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory stress markers (i.e., PGE2, LTB4, NFκB and p-STAT3) were significantly reduced by δ-T. Dietary treatment with δ-T and γ-T significantly increased the δ-T and γ-T levels, respectively, in the blood and tissues, but their levels were still lower than the levels of α-T. However, the levels of their side-chain degradation metabolites (δ-T and γ-T forms of carboxyethyl hydroxychroman and carboxymethylbutyl hydroxychroman) were much higher than their parent tocopherols in blood and tissues. Altogether, we demonstrated the inhibitory effects of δ-T and γ-T in a dietary carcinogen-induced colon carcinogenesis model. The inhibition is possibly due to the antioxidative, reactive nitrogen species-trapping, and anti-inflammatory activities δ-T and γ-T. (Supported by NIH grants F31CA168333, RO1CA120915 and RO1AT007036 as well as shared facilities funded by CA72720 and ES05022)
Citation Format: Chung S. Yang, Jayson X. Chen, Anna B. Liu, Hong Wang, Marlon Lee, Siyuan Yu, Chunfang Zhao, Ying-Yi Kuo, Eric Chi, Nanjoo Suh. Inhibition of PhIP/DSS-induced colon carcinogenesis by different forms of tocopherols in CYP1A-humanized mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2015-2814
Abstract 2816: 2′-Hydroxyflavanone inhibits lung cancer growth by inhibiting tumor cell proliferation and angiogenesis
Authors: Singhal Sharad S. , Figarola James , Singhal Jyotsana , Nagaprashantha Lokesh , Awasthi Sanjay 
Published: August 2015

Abstract
Lung cancer remains the number one cause of cancer mortality in the US. Although systemic chemotherapy and novel biologic agents have been shown to improve survival, toxicities are often severe and effective preventive therapy has not been defined. Intake of flavonoids from citrus fruits has been shown to decrease the risk of lung cancer in large scale epidemiologic studies. Hence, we studied the biologic anti-lung cancer effects of 2HF, a naturally occurring compound in citrus fruits. Our in-vitro investigations revealed that 2HF inhibits the growth of bronchogenic adeno-, squamous and small cell lung carcinoma. This was associated with G2/M arrest, collapse in mitochondrial membrane potential (Δψm), and apoptosis. We demonstrated a down-regulation of fibronectin and key signaling proteins of the PI3K pathway. RLIP76 expression was significantly reduced by 2HF, and the survival as well as 14C-DOX transport on purified reconstituted-proteoliposomes prepared from H1618 and H358 cells was significantly inhibited, an effect which was synergistic with anti-RLIP76 IgG. Our in-vivo studies in mice xenografts confirmed our in-vitro results by marked reduction of tumor growth, which was paralleled by a reduction in Ki67 and CD31, as proliferative and angiogenic markers, respectively. Importantly, 2HF also reduced the level of vimentin and increased E-cadherin, reversing the phenotype of epithelial-to-mesenchymal transition. In summary, 2HF demonstrated strong anti-proliferative, anti-angiogenic and pro-differentiation effects on in-vitro and in-vivo lung cancer models, whilst sparing normal cells. This holds not only great promise for therapeutic use but also suggests a role for 2HF in the prevention of lung cancer (Supported by NIH grant CA 77495 and Beckman Research Institute of the City of Hope).
Citation Format: Sharad S. Singhal, James Figarola, Jyotsana Singhal, Lokesh Nagaprashantha, Sanjay Awasthi. 2′-Hydroxyflavanone inhibits lung cancer growth by inhibiting tumor cell proliferation and angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2816. doi:10.1158/1538-7445.AM2015-2816
Abstract 2829: Discovery and in vitro and in vivo characterization of aminopyrazoline-based SMYD2 inhibitors
Authors: Stresemann Carlo , Hartung Ingo , Stellfeld Timo , Barak Naomi , Mowat Jeffrey , Christ Clara , ter Laak Antonius , Koehr Silke , Weiske Jörg , Hillig Roman , Badock Volker , Stoeckigt Detlef , Ziegelbauer Karl , Weinmann Hilmar , Gekeler Volker 
Published: August 2015

Abstract
SMYD2 (SET and MYND domain-containing protein 2) is a protein lysine methyltransferase (PKMT) which was initially described as a histone H3K36 and H3K4 methyltransferase involved in transcriptional regulation. SMYD2 has recently been reported to methylate and regulate several non-histone cancer relevant proteins such as p53, retinoblastoma protein (Rb) and the estrogen receptor alpha. Given the reports that overexpression of SMYD2 is linked to poor prognosis in certain cancers, SMYD2 is proposed to be an oncogene and an attractive cancer drug target.
Here we report the discovery of a novel potent and selective SMYD2 inhibitor, SMYD2-BAY-01, by high throughput screening and extensive biophysical validation. The co-crystal structure revealed that SMYD2-BAY-01 binds to the substrate binding site and occupies the hydrophobic pocket for lysine binding using an unprecedented hydrogen bond pattern. The competitive behavior of the inhibitor in biochemical assays is consistent with the binding mode observed in the crystal structure.
Further optimization generated SMYD2-BAY-02, which shows improved low nanomolar potency and is selective against kinases and other PKMTs. Furthermore, SMYD2-BAY-02 specifically inhibits SMYD2 methylation activity in a cellular assay with similar potency and reduces methylation of the tumor suppressor protein p53. Based on promising in vitro and in vivo DMPK data, SMYD2-BAY-02 was further characterized in vivo for SMYD2-specific methylation inhibition. In vivo activity could be shown upon in vivo administration at doses as low as 30 mg/kg p.o. in a SMYD2 overexpressing esophageal squamous cell carcinoma model. In summary, SMYD2-BAY-02 is a promising selective and potent SMYD2 inhibitor in vitro and in vivo and may represent a new treatment option for cancers overexpressing SMYD2.
Citation Format: Carlo Stresemann, Ingo Hartung, Timo Stellfeld, Naomi Barak, Jeffrey Mowat, Clara Christ, Antonius ter Laak, Silke Koehr, Jörg Weiske, Roman Hillig, Volker Badock, Detlef Stoeckigt, Karl Ziegelbauer, Hilmar Weinmann, Volker Gekeler. Discovery and in vitro and in vivo characterization of aminopyrazoline-based SMYD2 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2829. doi:10.1158/1538-7445.AM2015-2829
Abstract 2875: p53 regulation of PDL1 is mediated through miR-34a
Authors: Cortez Maria A. , Valdecanas David , Wang Xiaohong , Ivan Cristina , Peltier Heidi , Ye Huiping , Araujo Luiz , Carbone David , Giri Dipak K. , Komaki Ritsuko , Krishnan Sunil , Skoulidis Ferdinandos , Heymach John , Calin George , Bader Andreas G. , Welsh James W. 
Published: August 2015

Abstract
Background Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), little is known of how PDL1 expression is regulated. We previously found that miR-200s directly regulate PDL1; here we show that PDL1 is regulated by miR-34a and p53.
Methods We confirmed that PDL1 is a direct target of miR-34a with western blotting and luciferase assays. We then used in vitro models (p53-/- and p53+/+ HCT116 cells, p53-inducible H1299 cells, and p53-knockdown H460 cells) to determine if p53 regulates PDL1 via miR-34a. Next, we analyzed p53, PDL1, and miR-34a expression in formalin-fixed paraffin-embedded specimens from patients with NSCLC. Finally, we used a p53R172HΔg/+K-rasLA1/+ syngeneic mouse model to deliver miR-34a-loaded liposomes (MRX34) plus radiotherapy and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs).
Results We found that p53 regulates PDL1 via miR-34a, which directly binds to the PDL1 3′ untranslated region, in NSCLC. Delivery of MRX34 (previously tested in a phase I clinical trial) promoted CD8+ TILs and reduced CD8+PD1+ cells in vivo. Further, MRX34 plus radiotherapy increased CD8+ cell numbers more than either therapy alone. Finally, we showed that miR-34a delivery reduced the numbers of radiation-induced macrophages and T regulatory cells.
Conclusions We identified a novel mechanism by which tumor immune evasion is regulated by p53 and miR-34a via PDL1. Our results suggest that delivery of miR-34a combined with standard therapies, such as radiotherapy, may represent a novel therapeutic approach for lung cancer.
Citation Format: Maria A. Cortez, David Valdecanas, Xiaohong Wang, Cristina Ivan, Heidi Peltier, Huiping Ye, Luiz Araujo, David Carbone, Dipak K. Giri, Ritsuko Komaki, Sunil Krishnan, Ferdinandos Skoulidis, John Heymach, George Calin, Andreas G. Bader, James W. Welsh. p53 regulation of PDL1 is mediated through miR-34a. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2875. doi:10.1158/1538-7445.AM2015-2875
Abstract 2882: Calorie-induced silencing of the tumor suppressive guanylin-GUCY2C paracrine axis underlies colorectal cancer in obesity
Authors: Blomain Erik S. , Lin Jieru E. , Colón-González Francheska , Kim Gilbert W. , Hyslop Terry , Zhan Tingting , Snook Adam E. , Waldman Scott A. 
Published: August 2015

Abstract
Despite a well-characterized epidemiological association, mechanisms underlying the relationship between obesity and colorectal cancer remain incompletely defined. An emerging paradigm suggests that colorectal cancer arises through silencing of the GUCY2C tumor suppressor by loss of the hormone guanylin, a gene product universally lost in colorectal cancer. The present studies demonstrate that obesity is linked to colorectal cancer through suppression of guanylin expression, resulting in silencing of the GUCY2C tumor suppressor and epithelial dysfunction underlying tumorigenesis. In mice, obesogenic diets suppress the expression of guanylin protein, silencing GUCY2C and increasing epithelial dysfunction including DNA damage, crypt hyperproliferation and metabolic reprogramming, associated with amplification of colorectal tumorigenesis. Mouse models uncoupling caloric intake and weight revealed that suppression of guanylin by obesogenic diets reflected ingested calories, rather than the endocrine, adipokine and inflammatory milieu associated with obesity. Further, suppression of guanylin expression by obesogenic diets in wild type mice could be reversed by switching to a lean diet. Importantly, genetically enforced tissue-specific expression of guanylin eliminated epithelial dysfunction and colorectal tumorigenesis in transgenic mice. Taken together, the present studies highlight the guanylin-GUCY2C axis as a principle mechanistic link between colorectal cancer and the increased caloric intake characterizing obesity. Moreover, they highlight a unique opportunity to prevent colorectal cancer in obese patients by oral replacement with FDA-approved GUCY2C ligands.
Citation Format: Erik S. Blomain, Jieru E. Lin, Francheska Colón-González, Gilbert W. Kim, Terry Hyslop, Tingting Zhan, Adam E. Snook, Scott A. Waldman. Calorie-induced silencing of the tumor suppressive guanylin-GUCY2C paracrine axis underlies colorectal cancer in obesity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2882. doi:10.1158/1538-7445.AM2015-2882
Abstract 2904: Induction of autophagy reveals a cytoprotective mechanism by which DNA polymerase gamma (pol-γ) prevents UVB-induced skin cancer
Authors: Dhar Sanjit K. , Bakthavachalu Vasu , Izumi Tadahide , Chen Jing , Zhu Haining , St. Clair Daret K. 
Published: August 2015

Abstract
DNA polymerase γ (polγ), a major mitochondrial DNA repair enzyme, is essential for replication and repair of the mitochondrial genome. It is well-established that mitochondrial genomic stability is important for healthy cell survival; however, whether and how polγ plays a role in autophagic response remain unknown. Our previous studies demonstrated that polγ is inactivated upon exposure to ultraviolet B (UVB) irradiation by a peroxynitrite-mediated mechanism. In this study, we identified tyrosine 964, which is near the active site of polγ, as the target of nitration-induced inactivation by the use of LC/MS/MS mass spectroscopy coupled to immunoprecipitation, Western blotting and a 3` to 5` exonuclease activity assay. Treatment of mouse skin epithelial cells with UVB radiation validated the presence of polγ nitration and reduction of its enzymatic activity in vivo. To determine the effect of UVB in autophagic responses, mouse skin epithelial (JB6) cells were transfected with GFP-labeled LC-3 cDNA and exposed to UVB radiation, or wild-type C57BL/6 mice were exposed to UVB radiation and examined for LC-3 cleavage products. UVB radiation of JB6 cells and mouse skin increased LC-3 cleavage products and beclin levels, suggesting increased autophagic response to UVB treatment both in vitro and in vivo. To elucidate the role of Polγ in autophagic responses, the expression of polγ in JB6 cells was inhibited by siRNA for polγ. Consistent with the role of polγ in preventing UVB-induced autophagy, knockdown of polγ led to an increase LC-3 cleavage products. Knockdown of polγ induced prosurvival autophagic responses via the mTOR-signaling-complex-1(mTORC1) and complex-2(mTORC2). Interestingly, the mTORC2 complex plays a prominent role in the prosurvival autophagy responses based on the bromodeoxyuridine uptake assay, following knockdown and overexpression approaches. Importantly, suppression of polγ alone leads to transformation and invasion ofJB6 cells, which are increased following UVB treatment. The results reveal a unique role of Polγ in autophagy and support the role of Polγ in the suppression of prosurvival autophagic response to UVB- mediated carcinogenesis.
Citation Format: Sanjit K. Dhar, Vasu Bakthavachalu, Tadahide Izumi, Jing Chen, Haining Zhu, Daret K. St. Clair. Induction of autophagy reveals a cytoprotective mechanism by which DNA polymerase gamma (pol-γ) prevents UVB-induced skin cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2015-2904
Abstract 2907: AMPK induction, lysosomal acidification and melanoma survival increased by p53 dysfunction are counteracted by inhibiting autophagy
Authors: Chavez-Perez Valery , Strasberg-Rieber Mary , Rieber Manuel 
Published: August 2015

Abstract
BACKGROUND. In contrast to the majority of human tumors which harbour p53 mutations, melanomas preferentially have BRAF V600E or NRAS(Q61K) mutations accompanied by dysfunction of the p53 tumor suppressor gene, which may help progression from nevi to invasive melanoma. Although ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53 (Viros A. et al, Nature. 2014;511:478-82), some evidences for an anomalous wt p53 response to radiation in melanomas are a dysfunctional pro-apoptotic DNA damage response which can be enhanced by radiation sensitizers like halogenated pyrimidines (Rieber M, Rieber MS.Cancer Biol Ther. 2008;7:1561-6), and a report that p53 knockdown in melanoma cells resulted in decreased proliferation (Avery-Kiejda KA1, Bowden NA, Croft AJ, Scurr LL, Kairupan CF, Ashton KA, Talseth-Palmer BA, Rizos H, Zhang XD, Scott RJ, Hersey P.BMC Cancer. 2011;11:203) .PURPOSE. Since activation of AMPK by AMP inhibits ATP-consuming metabolic pathways during metabolic stress which may cause autophagy, we investigated the possible role of melanoma p53 status in modulating response to AMPK activators and autophagy inhibitors, in physiological 5mM glucose. EXPERIMENTAL. Genetically-matched NRAS-mutant human melanoma cells with unequal p53 mutational status were exposed to different glucose levels in the presence of AMPK inducers including autophagy modulators. Formation of autophagic vesicles were quantitated by cytometric red/gree acridine orange fluorescence Apoptosis-associated PARP cleavage was studied by specific immune blotting. RESULTS. AMPK induction in response to AICAR was greater than that of metformin and was increased in mutant p53 cells, which also showed greater resistance to autophagy inhibition. Greater AMPK activation correlated with increased lysosomal acidification in mutant p53 cells. CONCLUSIONS. Our results identify a role for a) p53 dysfunction in enhancing the response to AMPK activators and autophagy to favour tumor cell survival, b) autophagy inhibitors in counteracting pro-survival AMPK signaling.
Citation Format: Valery Chavez-Perez, Mary Strasberg-Rieber, Manuel Rieber. AMPK induction, lysosomal acidification and melanoma survival increased by p53 dysfunction are counteracted by inhibiting autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2907. doi:10.1158/1538-7445.AM2015-2907