bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 969: B-Raf activation loop phosphorylation is crucial for efficient MAPK signalling in vivo
Authors: Koehler Martin , Roering Michael , Braun Sandra , Brummer Tilman 
Published: August 2015

Abstract
Raf proteins are evolutionary conserved protein serine/threonine kinases and represent the MAPKKKs of the ERK-pathway. This pathway plays a crucial role in embryogenesis and is deregulated in multiple diseases. B-Raf represents the most potent MEK kinase of the Raf family and mutations in B-Raf or its upstream activators (e.g. Ras) are well-described in malignancies. So far, targeting the kinase function directly is flawed by paradoxical ERK activation in presence of oncogenic Ras. Therefore, a better understanding of its activation and finding an alternative targeting strategy is crucial. Phosphorylation of the T599VKS602-motif within the B-Raf activation loop is essential for full in vitro kinase activity stimulated by oncogenic Ras and is mimicked by oncogenic mutations such as V600E. To validate the importance of activation loop phosphorylation in vivo, we established a novel conditional BrafAVKA knock-in mouse that, upon Cre-mediated recombination, expresses the B-RafAVKA protein in which T599 and S602 are replaced by alanine residues.
Strikingly and in strong contrast to Braf knock-out mice, homozygous BrafAVKA mice are viable and show no early developmental defects suggesting that kinase impairment but not loss of the protein can be tolerated during embryogenesis. Additionally, these findings suggest that the B-RafAVKA mutant protein does not provoke a paradoxical ERK activation like the kinase dead B-RafD594A. However, neurological abnormalities such as ataxia or aberrant locomotion occur in older animals. This phenotype correlates with decreased MEK/ERK phosphorylation in total brain lysates. Also, signalling capacity of the ERK MAPK module, immediate early gene induction and proliferation are impaired in B-RafAVKA expressing MEFs.
Our findings support the concept that T599VKS602-motif phosphorylation is necessary for full B-Raf kinase activity in vivo. Therefore, blocking activation loop phosphorylation could be used to suppress aberrant ERK-pathway activity, e.g. by oncogenic Ras or RTKs, and circumventing paradoxical ERK activation in vivo.
Citation Format: Martin Koehler, Michael Roering, Sandra Braun, Tilman Brummer. B-Raf activation loop phosphorylation is crucial for efficient MAPK signalling in vivo. [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 969. doi:10.1158/1538-7445.AM2015-969
Abstract 979: Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression
Authors: Li Jie , Kozono David , Nitta Masayuki , Sampetrean Oltea , Gonda David , Kushwaha Deepa S. , Merzon Dmitry , Ramakrishnan Valya , Zhu Shan , Zhu Kaya , Matsui Hiroko , Harismendy Olivier , Hua Wei , Mao Ying , Kwon Chang-Hyuk , Saya Hideyuki , Carter Bob S. , Pizzo Donald P. , VandenBerg Scott R. , Chen Clark C. 
Published: August 2015

Abstract
Glioblastoma is the most common form of primary brain cancer and remains one of the deadliest of human cancers with near-uniform fatality. Increasing evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells with self-renew ability and tumorigenicity, termed as tumor initiating cells. The mechanism how the tumor initiating cells maintain and gain tumorigenicity in glioblastoma still remains unclear.
Here, we used sphere formation and tumor propagating potential to measure the tumorigenicity in established cell line and primary glioblastoma cells. The results indicated that glioblastoma tumorigenicity appears largely deterministic, though spontaneous gain and loss of this property occur at low frequency. Mechanically, this dynamic transition in tumorigenicity was governed by MYC level which was modulated epigenetically by the lysine-specific demethylase 1 (LSD1). Elevated MYC expression, in turn, regulates OLIG2, SOX2 and POU3F2, a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors facilitates transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.
Importantly, the effect of LSD1 on tumorigenity is “Janus”-like; partial depletion of LSD1 caused increased MYC expression and a pro-tumorigenic state. In contrast, complete suppression of LSD1 induced cell death. As such, therapeutic strategies targeting LSD1 and other targets manifesting similar “Janus” effect should be designed to prevent unintended induction of tumorigenesis during treatment.
Citation Format: Jie Li, David Kozono, Masayuki Nitta, Oltea Sampetrean, David Gonda, Deepa S. Kushwaha, Dmitry Merzon, Valya Ramakrishnan, Shan Zhu, Kaya Zhu, Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang-Hyuk Kwon, Hideyuki Saya, Bob S. Carter, Donald P. Pizzo, Scott R. VandenBerg, Clark C. Chen. Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression. [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 979. doi:10.1158/1538-7445.AM2015-979
Abstract 986: Role of Gpr43 in intestinal inflammation and carcinogenesis
Authors: Sivaprakasam Sathish , Gurav Ashish , Vadivel Ganapathy , Singh Nagendra 
Published: August 2015

Abstract
Consumption of dietary fiber is positively correlated with lower incidence of inflammation and carcinogenesis in intestine. In colon dietary fibers are fermented by gut microbiota into short chain fatty acids (SCFA, acetate, propionate and butyrate). Several studies demonstrate that SCFA play a key role in protection of intestine from inflammation and carcinogenesis. However, detail molecular mechanisms underlying the biological effects of SCFA on intestine health are not fully understood. Gpr43 is cell surface receptor for SCFA and recent evidences suggest that it regulates colonic inflammation in a context dependent manner. Intestinal inflammation is one of the risk factor for development of cancer in gut. Based on these findings, role of Gpr43 in regulation of colon carcinogenesis was evaluated. Colitis associated colon cancer in wild type (WT) and Gpr43-/- mice was induced by single intraperitoneal injection of azoxymethane (AOM) and repeated cycles of dextran sulfate sodium (DSS) in drinking water. Gpr43-/- mice showed drastically reduced survival, severe weight loss and increased diarrhea and rectal bleeding than WT mice. At the end of treatment, colons of Gpr43-/- mice exhibited increased number of polyps than that of WT mice. Reciprocal bone marrow chimera experiments revealed that Gpr43 expression in non-hematopoietic cells play a major role in suppression of colonic inflammation and carcinogenesis. The data presented here suggest a model in which Gpr43 plays a critical role in facilitating positive effects of dietary fiber and gut microbiota on intestinal health.
Citation Format: Sathish Sivaprakasam, Ashish Gurav, Ganapathy Vadivel, Nagendra Singh. Role of Gpr43 in intestinal inflammation and carcinogenesis. [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 986. doi:10.1158/1538-7445.AM2015-986
Abstract 990: Saxifragifolin D induces autophagy via activating IRE1α/ JNK pathway in breast cancer cells
Authors: Bai Liang-Liang , Shi Jun-Min , Chen Min-Feng , Zhang Dong-Mei , Wang Ying , Ye Wen-Cai 
Published: August 2015

Abstract
Background and Objective: Saxifragifolin D (SD) was isolated from Androsace umbellata by our group. It has been reported to inhibit some types of cancer cells, such as Hep3B, HepG2, SK-OV-3, A549, HCT-115 and multidrug resistante cell line HepG2/ADM. However, the growth inhibitory effect of SD on breast cancer cells and the mechanisms is still unclear. In this study, we explored the underlying molecular mechanisms of SD-induced autophagy in breast cancer cells.
Methods and Results: The autophagosomes, double membrane vacuolar structures, were observed in SD-treated MCF-7 and MDA-MB-231 cells by transmission electronic microscopy. And the autophagic vacuoles labeled by MDC were also increased in a time-dependent manner significantly. Besides, the autophagic ratio, quantified by using Cyto-ID® detection kit, was enhanced in a dose-dependent manner in these two cells. What's more, the marker of autophagy, LC3, was activated in MCF-7 and MDA-MB-231 cells treated with SD showed by western blot assay, further confirmed autophagy induced by SD. We also found that IRE1α which associated with endoplasmic reticulum (ER) stress was activated, and the JNK and Bcl-2 were phosphorylated in SD-treated MCF-7 and MDA-MB-231 cells by western blot assay. Accordingly, the up-regulation of Beclin1, Vps34, Atg5 and Atg16L were also detected in these two cells. Furthermore, suppression of autophagy by pretreating with Beclin1 siRNA or bafilomycin A1 decreased apoptosis and cell death, and resulted in decreases in expression of LC3- II and cleaved PARP. It's worth noting that inhibition of ER stress by IRE1α siRNA or TUDCA suppress autophagy and apoptosis, and the down-expression of LC3- II and cleaved PARP were measured.
Conclusion: SD induces autophagy associated with IRE1α/ JNK pathway in breast cancer cells and these findings will provide molecular bases for molecular mechanistic studies of SD-treated breast cancer cells.
Key words: Saxifragifolin D, autophagy, breast cancer.
Citation Format: Liang-Liang Bai, Jun-Min Shi, Min-Feng Chen, Dong-Mei Zhang, Ying Wang, Wen-Cai Ye. Saxifragifolin D induces autophagy via activating IRE1α/ JNK pathway in breast cancer cells. [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 990. doi:10.1158/1538-7445.AM2015-990
Abstract 993: The relationship between autophagy, senescence, and DNA repair
Authors: Alotaibi Moureq R. , Povirk Lawrence , Gewirtz Daivd 
Published: August 2015

Abstract
Radiotherapy is used along with other modalities such as surgery, chemotherapy, and immunotherapy to either shrink tumors before surgery or kill surviving tumor cells post surgery. Although radiation (and chemotherapy) induce different modes of cell death, recurrence of cancer may occur. It has been shown that DNA damage can induce cells to undergo both autophagy and senescence where both responses can function either as a pro-survival mechanism or in promoting loss of self-renewal capacity in the tumor cell. The relationship between autophagy, senescence, and the DNA repair system has not been well-characterized. The primary aims of this work were to understand whether autophagy and senescence might be permissive for DNA repair, thereby allowing the tumor cells to overcome the persistent DNA damage and recover using HCT116 WT and HCT116 Ligase IV (-/-) human colon carcinoma cells. Irradiation caused HCT116 Ligase IV (-/-) cells to lose their capacity to proliferate followed by delayed cell death, whereas HCT116 WT cells showed proliferative recovery 72 hours post-treatment, consistent with deficiencies in DNA repair in the Ligase IV (-/-) cells. Irradiation of both cell lines resulted in enlargement in cell size and accumulation of acidic vacuoles, indicative of the induction of autophagy. Inhibition of autophagy by Bafilomycin and Choroquine resulted in radio-sensitization in HCT116 WT cells but not in HCT116 Ligase IV (-/-) cells, indicating that radiation-induced autophagy in HCT116 WT cells is likely to be cytoprotective. Both repair competent HCT116 colon carcinoma cells and Ligase IV deficient cells demonstrated significant increases in senescent populations upon irradiation based on β-galactosidase staining and enlargement of treated cells. The PARP inhibitor, Olaparib, enhanced the efficacy of radiation through interference with DNA repair and the promotion of both autophagy and senescence but not apoptosis. Taken together, it appears that both autophagy and senescence may facilitate DNA repair during exposure to genotoxic stress, and that autophagy and senescence are closely linked responses in irradiated tumor cells.
Citation Format: Moureq R. Alotaibi, Lawrence Povirk, Daivd Gewirtz. The relationship between autophagy, senescence, and DNA repair. [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 993. doi:10.1158/1538-7445.AM2015-993
Abstract 996: Retinoic acids activate autophagy in breast cancer cells through the FOXO3A-RARA pathway and blocking autophagy enhances retinoic acid-mediated cell death
Authors: Schlaefli Anna M. , Garattini Enrico , Tschan Mario P. 
Published: August 2015

Abstract
A series of pre-clinical studies showed promising anti-cancer effects of retinoic acids (RA) in breast cancer models. However, clinical studies were mostly disappointing possibly also due to the trial design and emerging resistances. One way to confer resistance to a given treatment is activation of protective autophagy. Autophagy is a cellular recycling mechanism that is characterized by the formation of double-membraned autophagosomes. Autophagosomes engulf bulk cytoplasm or selected contents thereof and transfer them to lysosomes for degradation. Activation of autophagy upon anti-cancer treatment may allow prolonged survival of the tumor cells. We therefore asked if autophagy is activated by all-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, in mammary tumor cells and if autophagy might protect the cells from the pro-apoptotic effects of ATRA. We found that ATRA induces autophagic flux in ATRA-sensitive SKBR3 but not in -resistant MD-MBA- 453 human breast cancer cells as seen by increased LC3B-II protein abundance and turnover of long-lived proteins. Moreover, using RA receptor alpha (RARA), RARB and RARG agonists as well as RARA knockdown breast cancer cells we demonstrated that activation of autophagy by RA depends on RARA expression. RA-treatment also caused induction of the transcription factor FOXO3A, a known transcriptional target of RARA. Since the expression of several autophagy genes namely the ATG8 family members, Beclin-1 and PI3KC3 are controlled by FOXO3A, we tested if FOXO3A might link ATRA-mediated signaling to autophagy activation. Indeed, depleting FOXO3A in SKBR3 cells resulted in significantly decreased autophagic activity and autophagy gene expression upon RA treatment. Importantly, blocking autophagy by knocking down the key autophagy genes ATG5 or ATG7 in breast cancer cells resulted in significantly increased apoptosis under ATRA treatment. Of note, inhibition of autophagy also attenuated cyto-differentiation similarly to the phenotype seen in RARA knockdown breast cancer cells. In summary, our data demonstrate for the first time that retinoic acids induce autophagy in breast cancer cells via the FOXO3A-RARA axis. Furthermore, inhibition of autophagy results in enhanced ATRA-mediated apoptosis representing a potential new treatment strategy for a selected group of breast cancer patients.
Citation Format: Anna M. Schlaefli, Enrico Garattini, Mario P. Tschan. Retinoic acids activate autophagy in breast cancer cells through the FOXO3A-RARA pathway and blocking autophagy enhances retinoic acid-mediated cell death. [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 996. doi:10.1158/1538-7445.AM2015-996
Abstract CT113: A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut
Authors: Bertrand Yves , Baruchel Andre , Thomas Xavier , Blin Nicolas , Tavernier Emmanuelle , Perel Yves , Vey Norbert , Gandemer Virginie , ElHariry Iman , Godfrin Yann 
Published: August 2015

Abstract
Asparaginases are a cornerstone in the treatment of ALL, but their utility is limited by toxicities including hypersensitivity. ERY001 improves pharmacokinetics and tolerability, while maintaining circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane.
This phase III study enrolled pts with primary relapsed/refractory Ph- ALL. The co-primary endpoints were the duration of ASPA activity equal or greater than 100IU/L and the incidence of ASPA hypersensitivity during induction. Patients, aged 1-55 years, without prior ASPA hypersensitivity were randomized to ERY001 (150 IU/kg) or L-ASP(10.000IU/m2) in combination with COOPRALL. The patients with prior ASPA hypersensitivity received ERY001.
ERY001 significantly reduced the incidence of ASPA hypersensitivity (0% vs 43%; p100IU/l significantly longer than L-ASP (20.5±5.2 vs 9.2±7.5 days; p&lt;0.001). CR and clotting parameters were also significantly improved in the ERY001 arm. Other adverse events were generally similar in. One-year OS was 77% in the ERY001 arm vs 68% in L-ASP arm. ASPA activity was not reduced in hypersensitive patients.
These highly encouraging results show that ERY001 is a suitable option for patients with relapsed ALL maintaining ASPA efficacy with improved tolerability.
Citation Format: Yves Bertrand, Andre Baruchel, Xavier Thomas, Nicolas Blin, Emmanuelle Tavernier, Yves Perel, Norbert Vey, Virginie Gandemer, Iman ElHariry, Yann Godfrin. A phase III, multicenter, randomized study evaluating the efficacy and safety and efficacy of erythrocyte encapsulated l-asparaginase (Ery001) versus native l-asparaginase (L-asp) in combination with COOPRALL regimen in patients with first relapse of acut [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 CT113. doi:10.1158/1538-7445.AM2015-CT113
Abstract CT126: Phase II study of CEPSP chemotherapy for newly diagnosed stage IV extranodal natural killer (NK)/T-cell lymphoma, nasal type
Authors: Zheng Jun , Zhao Yajun , Xue Hui , Bai Xiufeng , Wang Ke , Zhang Mengqi , Du Chanyuan , He Shuyang , Wang Xiaoming , He Sanhu , Sun Moyi , Li Gang 
Published: August 2015

Abstract
Purpose: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is rare, it takes longer to make a definite diagnosis when compared with other head and neck malignancy, and its standard therapy has not been well established. To explore a more effective treatment for newly diagnosed stage IV ENKL, we conducted a phase II study of the Cisplatin + Etoposide + Pingyangmycin + Semustine + Prednisone (CEPSP) regimen.
Patients and Methods: We retrospectively reviewed the medical records of 21 patients diagnosed with ENKL who were enrolled to our hospital between January 1993 and June 2013. Patients with newly diagnosed stage IV and a performance status of 0 to 2 were eligible. Two cycles of CEPSP chemotherapy via temporal shallow artery intubation were administered as the protocol treatment with little adjustment in individual. The primary endpoints were overall response rate (ORR) and complete remission rate after the protocol treatment. The secondary endpoints were 3-year overall survival, 3-year progression-free survival, and toxicity.
Results: A total of 21 eligible patients were enrolled. The median age was 41 years (range, 20 to 69 years), and the male vs female ratio was 13:8. The disease status was newly diagnosed stage IV in 21 patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first patient died from myelosuppression. No treatment-related deaths were observed after the revision. The ORR and complete remission rate after two cycles of CEPSP chemotherapy were 86% (92% CI, 61% to 85%) and 63%, respectively. In the 21 patients who completed the protocol treatment, 7 underwent blood component transfusion. The 2-year overall survival rate was 68% (93% CI, 41% to 65%). Grade 4 neutropenia was observed in 89% of the patients. The most common nonhematologic complication was gastrointestinal reaction (58%).
Conclusion: CEPSP chemotherapy via temporal shallow artery intubation is an effective treatment for newly diagnosed stage IV ENKL. During the period of treatment, myelosuppression and gastrointestinal reaction should be treated carefully.
Citation Format: Jun Zheng, Yajun Zhao, Hui Xue, Xiufeng Bai, Ke Wang, Mengqi Zhang, Chanyuan Du, Shuyang He, Xiaoming Wang, Sanhu He, Moyi Sun, Gang Li. Phase II study of CEPSP chemotherapy for newly diagnosed stage IV extranodal natural killer (NK)/T-cell lymphoma, nasal type. [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 CT126. doi:10.1158/1538-7445.AM2015-CT126
Abstract CT304: Phase Ib trial of trastuzumab emtansine (TE) in combination with lapatinib (L) plus nab-paclitaxel (A) in metastatic HER2-neu overexpressed breast cancer patients: STELA trial results
Authors: Patel Tejal , Mejia Jaime , Rodriguez Angel , Chang Jenny 
Published: August 2015

Abstract
Background: Multiple large randomized clinical trials have demonstrated that dual HER2 targeted therapies are synergistic and result in improved efficacy. We conducted a phase Ib trial of trastuzumab-emtansine (TE) and lapatinib (L), together with Nab paclitaxel (A) in patients with HER2 over-expressed stage IV breast cancer.
Methods: Key inclusion criteria are stage IV HER2 positive breast cancer, LVEF ≥ 45%, and Peripheral neuropathy &lt; grade 2. Primary phase Ib objective was to evaluate the maximum tolerated dose (MTD) of TE with L and A using a standard 3+3 dose de-escalation design for up to 9 patients. Safety, tumor response and pharmacokinetics (PK) were also assessed. Dose limiting toxicities (DLTs) were defined as ≥ grade 3 non hematological toxicity attributed to the study drugs.
Results: Nine patients, median age 47 (range 44-64) years were enrolled. All patients are currently off the study. The DLTs were grade 3 diarrhea (n = 1) and grade 3 elevated transaminase (n = 1). Grade 3-4 hematological toxicities included neutropenia (N = 6) and thrombocytopenia (N = 1). Other AEs included grade 1-2 mucositis (n = 2), diarrhea (N = 2), and liver function tests abnormality (N = 5). The 24 hour trough levels of each of the drug were within the range of the values reported in the literature. The MTD of TE, L and A was reached at: TE 3.0 mg/kg, Lapatinib 750mg and Abraxane (A) 80 mg/m2. Eight patients, with a median of 1 prior metastatic therapy (range 0-5) were evaluable for response. Five patients, 62.5% derived clinical benefit, including 1 patient with complete response and 4 patients with partial response.
Conclusions: TE plus L and A therapy was well tolerated with antitumor activity observed. STELA Ib trial has been expanded to include twelve additional patients for safety and efficacy evaluation.
Citation Format: Tejal Patel, Jaime Mejia, Angel Rodriguez, Jenny Chang. Phase Ib trial of trastuzumab emtansine (TE) in combination with lapatinib (L) plus nab-paclitaxel (A) in metastatic HER2-neu overexpressed breast cancer patients: STELA trial results. [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 CT304. doi:10.1158/1538-7445.AM2015-CT304