tbuckley/cabot-search huggingface dataset:
Abstract 5567: A scalable and integrated computational and experimental workflow to identify new driver genes in cancer genome data
Authors: Heiko Horn, Michael S. Lawrence, Candace R. Chouinard, Yashaswi Shrestha, Jessica Xin Hu, Elizabeth Worstell, Emily Shea, Nina Ilic, Eejung Kim, Atanas Kamburov, Alireza Kashani, William C. Hahn, Joshua D. Campbell, Jesse S. Boehm, Gad Getz, Kasper Lage
Journal: Cancer Research (2017)

Abstract High throughput sequencing has revolutionized the study of the cancer genome, enabling numerous discoveries in basic and clinical research. However, considerable sample sizes are required to find cancer driver genes with intermediate and low mutation frequencies, and for a large proportion of patients the molecular cause (e.g. driver gene(s)) of disease is unknown. Here, we describe an integrated computational and experimental workflow that combines cancer genome data, molecular network information, multiplexed in vivo tumorigenesis assays, and reanalysis of driver-gene-negative cancer patients to predict and validate new driver genes. We develop a statistic, network mutation burden, that combines molecular network information with data from 4,742 cancer genomes to accurately classify known driver genes across 21 tumor types and predict 62 driver gene candidates.Of these, 35 gene candidates were tested in multiplexed in vivo tumorigenesis cell assays using sensitized immortalized human embryonic kidney (HA1E-M) and immortalized human lung epithelial (SALE-Y) cell lines.Tumor formation in vivo was observed for 11 genes (2 in HA1E-M, 3 in SALE-Y, 6 in both). By reanalyzing 242 lung adenocarcinoma patients with an unknown molecular cause of disease we show that two of these candidates, TFDP2 and AKT2, are significantly amplified in multiple samples.Overall, we describe a scalable combined computational and experimental framework to predict and validate driver genes across many tumor types. Our proof-of-concept approach should become increasingly useful as the number of cancer genomes continues to grow. Citation Format: Heiko Horn, Michael S. Lawrence, Candace R. Chouinard, Yashaswi Shrestha, Jessica Xin Hu, Elizabeth Worstell, Emily Shea, Nina Ilic, Eejung Kim, Atanas Kamburov, Alireza Kashani, William C. Hahn, Joshua D. Campbell, Jesse S. Boehm, Gad Getz, Kasper Lage. A scalable and integrated computational and experimental workflow to identify new driver genes in cancer genome data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5567. doi:10.1158/1538-7445.AM2017-5567
A Bacterial IgG-Degrading Enzyme to Unhinge Antibodies
Authors: Julie R. Ingelfinger
Journal: New England Journal of Medicine (2017)

The number of patients awaiting renal transplantation heads ever upward (in the United States alone, more than 105,000 patients are currently on the waiting list for a kidney from a deceased donor, according to the United Network for Organ Sharing), and many of those patients are unlikely to receive kidneys, because they have preformed antibodies to HLA or other antigens.1 Such sensitized patients, if they ultimately receive kidneys at all, may wait years before an appropriate organ becomes available, unless the antibody titer diminishes, which is an unlikely event without therapy. Furthermore, many allografts — an estimated 5000 annually in . . .
Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring
Authors: Juan Jose Ramos-Rodriguez, Daniel Sanchez-Sotano, Alberto Doblas-Marquez, Carmen Infante-Garcia, Simon Lubian-Lopez, Monica Garcia-Alloza
Journal: Molecular Neurodegeneration (2017)

Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term. Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system. Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.
Abstract 4757: Radioresistance is linked with stem-like properties via activation of aryl hydrocarbon receptor
Authors: SHuang Liu, Bin Yan, Yongguang Tao
Journal: Cancer Research (2017)

Abstract Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with a poor prognosis for cancer patients. The molecular pathways that drive the enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that the aryl hydrocarbon receptor (AhR) plays a vital and previously unrecognized role in the maintenance of stem-like cells that are isolated from radioresistant epithelial lung cancer and nasopharyngeal carcinoma. AhR promotes the stem-like phenotype and drives metastasis by directly targeting the promoters of ‘stemness’ genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Cancer cell populations enriched for ABCG2 expression (CD338+) show an elevated ‘stemness’ signature and are more prone to cancer progression in vitro and in vivo. Ubiquitin C-terminal hydrolase-L3 (UCHL3), a deubiquitinating enzyme, may counteract AhR, while IKKα, a bone fide chromatin modifier, may directly activate stemness related genes. The radioresistant cancer cell sublines are associated with a hybrid state in epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), and elevated tumor associated macrophages and proinflammatory factors. Moreover, the radioresistant sublines display high levels of oncometabolites, including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties through activation of the AhR. Thus AhR is functionally linked with radioresistance in lung cancer and nasopharyngeal carcinoma, and it drives tumorigenesis by an epithelial and mesenchymal composition, tumor associated macrophages and oncometabolites. Note: This abstract was not presented at the meeting. Citation Format: SHuang Liu, Bin Yan, Yongguang Tao. Radioresistance is linked with stem-like properties via activation of aryl hydrocarbon receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4757. doi:10.1158/1538-7445.AM2017-4757
Prognostic Impact of Morphology, MYC Gene Partner and BCL2/BCL6 Translocation Status in "High Grade B-Cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements"
Authors: Ellen D. McPhail, Matthew J Maurer, Rhett P. Ketterling, William R. Macon, Andrew L Feldman, Paul J Kurtin, Thomas E. Witzig, Rakhee Vaidya, Thomas M. Habermann
Journal: Blood (2016)
Abstract 4854: Evaluating HDAC6 as a causal factor in metastatic breast cancer to develop immunotherapy
Authors: Debarati Banik, Melissa Hadley, Jennifer Kim, Tessa Knox, Jayakumar Nair, Alan Kozikowski, Sida Shen, Charu Vyas, Ashleyn Donohue, Eduardo Sotomayor, Alejandro Villagra
Journal: Cancer Research (2017)

Abstract Histone deacetylases (HDACs), originally described as histone modifiers, have recently been demonstrated to modify a variety of other proteins involved in diverse cellular processes unrelated to the chromatin environment, including the modulation of proteins related to cell cycle/apoptosis and immune regulation. In contrast to the well-documented effects of HDAC inhibitors (HDACi) in the control of cell cycle and apoptosis, their role in immune-biology is incompletely understood. We have found that the pharmacological or genetic abrogation of a single HDAC, i.e. HDAC6, inactivates the STAT3 pathway and modulates the expression of immuno-regulatory proteins, including the down-regulation of PD-L1, PD-L2 and B7-H4, important negative regulators of immune function, often over-expressed in cancer cells; including breast cancer. HDAC6 has been also involved in a number of structural functions related to cellular motility, shape and intracellular transport through the regulation of the acetylation of numerous targets, including tubulin and cortactin. This function is strongly suggestive of HDAC6 being a key player in metastatic cancer progression. In our initial studies we observed that the selective HDAC6 inhibitor Nexturastat A is capable of reducing the tumor growth in a highly aggressive murine mammary carcinoma that mimics human triple negative breast cancer (TNBC), under both orthotopic and subcutaneous conditions of implantation. Additionally, we observed that the size and number of secondary tumor nodules in lungs were significantly diminished after the HDAC6i treatment. In order to boost the anti-tumor T-cell response, we also tested check-point inhibitors against the tumor (such as anti PD-1 and CTLA4 antibodies). While each of the standalone treatments showed a certain degree of success in reducing tumor growth and enhancing intra-tumoral IFNγ, we demonstrated that HDAC6i improves anti-tumor immune responses when combined with immune check-point blockade. Citation Format: Debarati Banik, Melissa Hadley, Jennifer Kim, Tessa Knox, Jayakumar Nair, Alan Kozikowski, Sida Shen, Charu Vyas, Ashleyn Donohue, Eduardo Sotomayor, Alejandro Villagra. Evaluating HDAC6 as a causal factor in metastatic breast cancer to develop immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4854. doi:10.1158/1538-7445.AM2017-4854
Abstract 538: The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) anti-apoptosis ability
Authors: Hsin-Han Hou, Chong-Jen Yu
Journal: Cancer Research (2017)

Abstract Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, has been shown to be upregulated in multiple cancers, including gastric, lung, breast, and prostate cancers, and the enzymatic activities of its extracellular metalloprotrease domain promote breast cancer proliferation and migration through mediating ErbB signaling pathway. The patients with ADAM15 high-expressing lung tumors have shorter survival time and ADAM15 has been proved to enhance synovial fibroblasts anti-apoptosis ability via focal adhesion kinase signaling pathway. We firstly demonstrated other than extracellular enzymetic activity, the longest isoform of ADAM15 (ADAM15 i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, significantly upregulated in primary lung cancer tissues and promoted NSCLC proliferation via growth factor receptor-bound protein 2 (Grb2) and Src homolog 2 domain containing (Shc) association. In this study, we further explore the roles of ADAM15 cytosolic domain in NSCLC apoptosis resistance. Overexpression of ADAM15 i6 promoted CL1-0 cell anti-apoptosis ability according to the trypan blue inclusion assay. Ablation of nephrocystin (NPHP1) attenuated the ADAM15 i6-promoted anti-apoptosis ability. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will shed light on the molecular mechanisms of ADAM proteins, and facilitate development of novel therapy in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) anti-apoptosis ability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 538. doi:10.1158/1538-7445.AM2017-538
Abstract 2768: Treosulfan induces differential gonadal toxicity profile compared with Busulfan
Authors: Mattan Levi, Salomon Stemmer, Jerry Stein, Ruth Shalgi, Irit Ben-Aharon
Journal: Cancer Research (2017)

Abstract Background: Treosulfan (L-treitol-1,4-bis-methanesulfonate), an alkylating agent with myeloablative and immunosuppressive traits, has been increasingly incorporated as a main conditioning protocol for hematopoietic stem cell transplantation (HSCT) in pediatric malignant and non-malignant diseases. Treosulfan has been shown to present lower toxicity profile compared with conventional myeloablative regimens such as busulfan. Yet, while busulfan is considered highly gonadotoxic, the gonadal toxicity profile of treosulfan remains to be elucidated. Our aim was to study the short and long term gonadal effect of treosulfan in comparison to busulfan. Methods: Mature 2 months old male and 3 months old female mice (“pubertal cohort”) were injected with treosulfan 2000 mg/kg or busulfan 40 mg/kg and were sacrificed one week, one month or six months post drug administration. Immature male and female mice (“prepubertal cohort”) were injected with treosulfan 750 mg/kg or busulfan 15 mg/kg and were sacrificed one week or three months post drug administration. Testicular function was assessed by measurements of sperm count and motility, testes and epididymides weight, serum anti-Mullerian Hormone (AMH) and testicular ID4 or GFRA1 mRNA (markers for stem spermatogonia). Immunohistochemistry was performed to evaluate testicular proliferation (Ki-67), apoptosis (TUNEL) and meiotic-active spermatocytes (DAZL-PCNA). Ovarian function was assessed by measurements of ovary weight, serum AMH, follicles count and ovarian SOHLH2, NOBOX of FIGLA mRNA (markers for primordial follicles). Immunohistochemistry was performed to evaluate ovarian proliferation (Ki-67), apoptosis (TUNEL) and growing follicles (AMH-PCNA). Results: Treosulfan testicular toxicity was milder compared to busulfan toxicity, in both mature and immature male mice, while stem spermatogonia were spared. However, ovarian toxicity of both treosulfan and busulfan was severe and permanent in both mature and immature female mice; possibly by a short term irreversible reduction of reserve primordial follicles in the ovaries. Conclusion: Our results indicate that treosulfan exerts a differential gonadal toxicity profile compared with busulfan, manifested by mild testicular toxicity and severe ovarian toxicity. Citation Format: Mattan Levi, Salomon Stemmer, Jerry Stein, Ruth Shalgi, Irit Ben-Aharon. Treosulfan induces differential gonadal toxicity profile compared with Busulfan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2768. doi:10.1158/1538-7445.AM2017-2768
Abstract 5663: A potential role for NKG2A to influence post-transplant outcomes in multiple myeloma
Authors: Jennifer Cooperrider, Paul D. Ciarlariello, Tiffany Hughes, Nita Williams, Craig Hofmeister, Robert Baiocchi, Don M. Benson
Journal: Cancer Research (2017)

Abstract While there is currently no clear consensus regarding optimal maintenance therapy after autologous stem cell transplant (autoSCT), the early post-transplant setting is a potential site of augmentation to improve post-transplant outcomes. We previously characterized stem cell graft lymphocytes in association with progression free survival (PFS) after autoSCT in multiple myeloma (MM), and showed that there was an inverse correlation between NKG2A expression on CD56dim NK cells and PFS. Therefore, we aimed to investigate a potential role for NKG2A modulation, especially in the post-transplant setting with maintenance chemotherapy. We performed immunophenotypic analyses of NK cells from patients in the immediate post-transplant setting as well as from patients at various time points after transplant on lenalidomide maintenance therapy. In the immediate post-transplant setting (mean time since transplant=13 days) NKG2A was upregulated on NK cells when compared with KIR2DL1 (p=0.001) and KIR2DL2 (p=0.002). Additionally, in immunophenotypic analyses of PBMC from MM patients on various treatments, patients receiving lenalidomide maintenance therapy that recently underwent stem cell transplant (mean time since transplant=0.53 years) had elevated NKG2A expression compared to patients receiving no treatment (p=0.029). Conversely, patients receiving lenalidomide maintenance therapy over years (mean time since transplant=4.21 years) after transplant showed reduced NKG2A expression compared to patients receiving no treatment (p=0.0161). In bone marrow aspirates from patients with MM, primary CD138-positive myeloma cells in the bone marrow express HLA-E, the cognate antigen for NKG2A, which makes the overexpression of NKG2A biologically relevant. These data suggest that the NKG2A/HLA-E checkpoint axis may be more biologically relevant than KIR in myeloma, particularly in the post-transplant setting. This has important potential implications for treatment, as it demonstrates that NKG2A could serve as a potential target for modulation in the immediate post-transplant setting to improve survival, especially in the setting of maintenance chemotherapy. Further investigation should be aimed delineating the potential effect of NKG2A modulation on immune recovery and tumor surveillance to increase survival in the post-transplant setting. Citation Format: Jennifer Cooperrider, Paul D. Ciarlariello, Tiffany Hughes, Nita Williams, Craig Hofmeister, Robert Baiocchi, Don M. Benson. A potential role for NKG2A to influence post-transplant outcomes in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5663. doi:10.1158/1538-7445.AM2017-5663
Abstract 4892: MOSPD2, a newly characterized protein, promotes breast cancer metastasis
Authors: Itzhak Mendel, Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Eyal Breitbart
Journal: Cancer Research (2017)

Abstract Introduction: We have previously described motile sperm domain-containing protein 2 (MOSPD2), a protein which up until recently no function was ascribed to, as a key regulator of monocyte migration in-vitro. In this study, the role of MOSPD2 in promoting breast cancer migration and metastasis in-vitro and in-vivo was assessed. Experimental procedure: The prevalence of MOSPD2 was evaluated by IHC in tissue microarray layered with cores, representing different stages of invasiveness in breast cancer. MOSPD2 abundance was scored according to the staining intensity on a scale from 0 to 3. MOSPD2 expression was silenced in MDA-231 breast cancer cell line using lentiviral particles for sh-RNA or CRISPR-CAS9 (CRISPR). Cells were then tested by a trans-well assay for migration towards EGF in vitro as well as for lung dissemination following orthotopic or systemic inoculation in vivo. For mechanism studies, EGF-induced signaling events were analyzed. Results: Within normal adjacent tissue (NAT), 82% of the samples had no staining and the remaining 18% percent displayed an intensity of 1. In the tissue cores with in-situ carcinoma pathology, 79% of the samples had no staining intensity while the remaining 21% only scored 1 or 2. However, analysis of invasive and metastatic cancer demonstrated higher frequency in score of 2 and increased staining intensity up to score of 3 compared with NAT and in-situ carcinoma. Thus, the percent of combined scores 2 and 3 for invasive lobular carcinoma, invasive ductal carcinoma and metastatic invasive ductal carcinoma were 63%, 77% and 81%, respectively. MOSPD2-silenced cells, either by sh-RNA or by CRISPR, were severely impaired in their ability to migrate in-vitro towards EGF. Following EGF activation of CRISPR-Control MDA-231 cells, all tested proteins down-stream to the EGFR pathway, including AKT and p38, became phosphorylated. However, in CRISPR-MOSPD2 silenced cells, phosphorylation of all tested proteins excluding p38 were markedly inhibited. Moreover, activation with IGF of CRISPR-MOSPD2 MDA-231 cells did not hinder AKT phosphorylation. In vivo, SCID mice injected orthotopically or systemically with CRISPR-MOSPD2 silenced MDA-231 cells displayed significantly reduced number of metastases in the lungs relatively to mice injected with CRISPR-Control treated cells. Conclusions: We suggest that MOSPD2 promotes metastasis of breast cancer cells and is a potential target for the treatment of metastatic breast cancer. Citation Format: Itzhak Mendel, Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Eyal Breitbart. MOSPD2, a newly characterized protein, promotes breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4892. doi:10.1158/1538-7445.AM2017-4892
Abstract 3701: Mutant p53 cancers reprogram tumor-associated macrophages via exosomal miR-1246
Authors: Tomer Cooks, Ioannis S. Pateras, Lisa M. Jenkins, Keval M. Patel, Ana I. Robles, James Morris, Tim Forshew, Ettore Appella, Vassilis G. Gorgoulis, Curtis C. Harris
Journal: Cancer Research (2017)

Abstract TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOF) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated-macrophages, a hallmark of solid tumors, are typically correlated with poor prognosis. Here we report a non-cell-autonomous mechanism whereby mutp53 cancer cells reprogram TAM to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246 dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAM favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, observed also in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis. Citation Format: Tomer Cooks, Ioannis S. Pateras, Lisa M. Jenkins, Keval M. Patel, Ana I. Robles, James Morris, Tim Forshew, Ettore Appella, Vassilis G. Gorgoulis, Curtis C. Harris. Mutant p53 cancers reprogram tumor-associated macrophages via exosomal miR-1246 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3701. doi:10.1158/1538-7445.AM2017-3701