tbuckley/cabot-search huggingface dataset:
Abstract 15100: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS
Authors: Hsiang-Chun Chang, Rongxue Wu, Meng Shang, Hossein Ardehali
Journal: Circulation (2015)

Introduction: Iron can catalyze the formation of reactive oxygen species (ROS) and promote tissue damage. While some studies suggested benefits with iron chelation therapy in ischemic heart disease (IHD), several others failed to show any benefits. Mitochondria are a major site of iron utilization and ROS production, and mitochondrial iron accumulation has been associated with increased oxidative stress. We therefore hypothesized that mitochondrial iron plays a causative role in ischemia/reperfusion (I/R) damage, and a decrease in mitochondrial iron (as opposed to cytoplasmic iron) would be sufficient to protect against I/R injury. Results: We observed an increase in cardiac mitochondrial iron in mice after I/R injury. Using two iron chelators with distinct mitochondrial permeability, i.e., 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that does not modulate mitochondrial iron), we demonstrated that mice pretreated with BPD but not DFO were protected against I/R injury. Similar results were obtained in vitro . Since these two iron chelators also modulate iron in other subcellular compartments, we used transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 to confirm that modulation of mitochondrial iron alone is sufficient to confer protection. ABCB8 TG mice had significantly lower mitochondrial iron (but normal cytosolic iron) in the heart compared to nontransgenic (NTG) littermates at baseline, but exhibited normal cardiac function. After I/R, ABCB8 TG mice displayed significantly less apoptosis and lower levels of markers of ROS and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury, most likely through a reduction in ROS. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is sufficient to protect against I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for the treatment of IHD.
An International Human Cell Atlas Consortium Takes Shape
Authors: Jennifer Abbasi
Journal: JAMA (2017)

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Structure-function studies of disease-associated transforming growth factor type II receptor mutations
Authors: Aparna Kareddula, Savita Bharathy, Sjoerd de Vries, Janet Huang, Alexandre Bonvin, Gaetano Montelione, Michael Reiss
Journal: Cancer Research (2007)

3170   Activation of Transforming Growth Factor-β (TGFβ) signaling enhances cancer invasion and metastasis. Although TGFβ pathway antagonists are in development for cancer treatment, accurate biomarkers for TGFβ “pathway addiction” have not been identified. To test the hypothesis that TGFβ receptor gene mutations are indicative of pathway addiction and, therefore, predictive of response to antagonists, we studied 40 cancer-associated missense mutations of the type II TGFβ receptor gene (TGFBR2) and 50 TGFBR2 germline mutations associated with genetic connective tissue disorders.  To ascertain the functional significance of disease-associated TGFBR2 mutations, we began by generating an optimized 3D model of the TGFBR2 cytoplasmic domain based on the TGFBR1 structure as template using the Homology Modeling Automatic (HOMA) protocol. Disease-associated mutations have a predilection for residues at the TGFBR2 molecular surface. To address the question whether these mutations might affect protein-protein interactions, we used the ProMate and WHISCY algorithms. ProMate predicts the location of protein-protein binding sites according to biophysical and structural characteristics. WHISCY predicts protein-protein interfaces based on a combination of sequence conservation and structural information. Both ProMate and WHISCY modeling predicted that subdomain XI of the TGFBR2 kinase was likely involved in protein-protein interactions. A second potential interface in subdomain IX predicted by ProMate was not substantiated by the WHISCY algorithm. Each of the 90 disease-associated human TGFBR2 mutations was then subjected to both ProMate and WHISCY modeling. Using unsupervised clustering, the ProMate models of TGFBR2 mutants segregated into four major groups, each distinct from the wild type protein. Moreover, mutations of residues located in physical proximity to each other tended to cluster together, as did different substitutions of the same residue. Although WHISCY-derived models of TGFBR2 mutants also segregated into major clusters, these did not correlate with physical location of the mutated residue, nor did different substitutions of the same residue segregate together.  A small number of disease-associated TGFBR2 mutants were subjected to functional studies using TGFβ-mediated Smad2 phosphorylation and induction of 3TP-Lux reporter gene activity as read-outs. TGFBR2 mutants varied in their ability to mediate Smad2 phosphorylation and to induce 3TP-Lux reporter gene activity. Interestingly, loss-of-function mutants and mutants that retained signaling capability segregated into distinct ProMate clusters. In summary, in silico modeling may be used to predict the functional consequences of disease-associated TGFBR2 gene mutations. Moreover, a subset of these mutants appears to retain signaling capability, and may be predictive of response to TGFβ pathway antagonists.
Abstract 2638: Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma
Authors: Sung Yong Lee, Jae Kyeom Shim, Jee Youn Oh, Kyung Hoon Min, Gyu Young Hur, Jae Jeong Shim, Kyung Ho Kang, Bong Kyung Shin, Young Seok Lee
Journal: Cancer Research (2017)

Abstract Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) containing a component of spindle cell or giant cell. Because the prevalence of PSC is very rare, there is insufficient data about clinical feature, therapeutic strategy and prognosis. Method: We reviewed the medical records of 26 patients diagnosed with PSC from January 2009 to June 2015, and analyzed the clincopathological characteristics, treatment modality and their outcome, and risk factors of overall survival (OS). Programmed death ligand 1 (PD-L1) expression was tested in 13 patients by using archival tissues (PD-L1 IHC 22C3 pharmDx assay). Results: The median age of PSC patients was 69.5 years. 23 patients were male. 25 patients were current or former heavy smokers. Pleomorphic carcinoma was the most common subtype, and epidermal growth receptor mutation (EGFR) was positive in 2 of 11 patients who were tested. Among 13 patients tested for programmed death ligand 1 (PD-L1), eight showed PD-L1 high expression (tumor proportion score, TPS ≥ 50%). Four patients showed low expression (1% ≤ TPS ≤ 49%), and one patient showed no expression (TPS &amp;lt; 1%). The median OS of all patients was 286 days. Age and the time from symptom onset to diagnosis were significantly associated with OS. PD-L1 expression showed the trend of positive prognostic value on OS in univariate analysis but was insignificant in multivariate analysis. 12 patients were treated with chemotherapy: 9 with platinum-based doublet therapy, 2 with tyrosine kinase inhibitor and 1 with docetaxel. 7 patients showed partial response or stable disease. The median OS and progression free survival of patients receiving chemotherapy were 260 days and 85 days, respectively. Conclusions: It has poor prognosis compared with ordinary NSCLC. However, PSC patients showed comparatively fair response to chemotherapy and generally showed higher PD-L1 expression. Active treatment with cytotoxic chemotherapy, EGFR TKIs or immune checkpoint inhibitors are necessary to achieve a better results of PSC management. Citation Format: Sung Yong Lee, Jae Kyeom Shim, Jee Youn Oh, Kyung Hoon Min, Gyu Young Hur, Jae Jeong Shim, Kyung Ho Kang, Bong Kyung Shin, Young Seok Lee. Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma [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 2638. doi:10.1158/1538-7445.AM2017-2638
Obesity Paradox in Lung Cancer Prognosis: Evolving Biological Insights and Clinical Implications
Authors: Xueli Zhang, Yamin Liu, Hua Shao, Xiao Zheng
Journal: Journal of Thoracic Oncology (2017)

The survival rate of lung cancer remains low despite the progress of surgery and chemotherapy. With the increasing comorbidity of obesity in patients with lung cancer, new challenges are emerging in the management of this patient population. A key issue of interest is the prognostic effect of obesity on surgical and chemotherapeutic outcomes in patients with lung cancer, which is fueled by the growing observation of survival benefits in overweight or obese patients. This unexpected inverse relationship between obesity and lung cancer mortality, called the obesity paradox, remains poorly understood. The evolving insights into the heterogeneity of obesity phenotypes and associated biological connections with lung cancer progression in recent years may help explain some of the seemingly paradoxical relationship, and well-designed clinical studies looking at the causal role of obesity-associated molecules are expected. Here, we examine potential biological mechanisms behind the protective effects of obesity in lung cancer. We highlight the need to clarify the clinical implications of this relationship toward an updated intervention strategy in the clinical care of patients with lung cancer and obesity.
Abstract 4014: Blood-brain-barrier spheroids: Next-generation screening platform for brain-penetrating agents
Authors: Choi-Fong Cho
Journal: Cancer Research (2017)

Abstract The inability of most systemically delivered therapeutics to cross the blood-brain-barrier (BBB) is considered a major barrier to effective brain cancer treatment. In malignant glioma the tumor neovasculature is known to be leaky, however invasive cells remain protected behind an intact BBB, and continue to thrive within the brain, ultimately leading to tumor regrowth and patient death. This leaves us with an urgent unmet need for the development of next-generation therapeutics with improved brain delivery. For the first time, we describe here the utility of 3D multicellular BBB spheroids made of human brain endothelial cells (ECs), pericytes and astrocytes as a screening tool for brain-penetrating agents. We show that the outer surface of the spheroids, composed primarily of ECs and pericytes, form a tight barrier which is permeabilized in the presence of VEGF. The barrier is characterized by the presence of intact tight junctions and efflux-pump activity (i.e., P-glycoprotein). Furthermore, we have used this model to successfully demonstrate the transport of angiopep-2 (a well-known brain delivery vector) and its conjugates (containing cargoes of various sizes such as peptide, protein and affibody), thereby displaying the versatility of this model to screen and study a wide range of therapeutic agents. We demonstrate that this model is superior to the conventional transwell model in maintaining essential BBB characteristics (i.e., tight/adherens junctions and P-glycoprotein expression) and as a drug-screening tool. We have utilized the spheroid model to screen a panel of cell-penetrating peptides (CPPs) to identify several candidates with high brain-penetration potential. We then verified the ability of the top 4 candidate CPPs to cross the BBB in mice. This high-throughput model can lead to better design and analysis of first-in-class glioma therapeutics, and improve prediction of drug penetration in a living model, paving the way for breakthrough discoveries in brain cancer. Citation Format: Choi-Fong Cho. Blood-brain-barrier spheroids: Next-generation screening platform for brain-penetrating agents [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 4014. doi:10.1158/1538-7445.AM2017-4014
A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation
Authors: Nisha Patel, Arif O. Khan, Maher Al-Saif, Walid N. Moghrabi, Balsam M. AlMaarik, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Tarfa Alshidi, Eman Alobeid, Rana A. Alomar, Saad Al-Harbi, Mohamed Abouelhoda, Khalid S. A. Khabar, Fowzan S. Alkuraya
Journal: Genome biology (2017)

Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic. We report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3′ UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3′ UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein. This novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3′ UTR mutations with tissue-specific pathology.
Abstract 1405: A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies
Authors: Kyungjae Myung, Yongliang Zhang, Young-Un Park
Journal: Cancer Research (2017)

Abstract Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells, are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a mismatch repair-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSα-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSα-deficient xenograft tumors and inhibits the growth of AOM-DSS-induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. Citation Format: Kyungjae Myung, Yongliang Zhang, Young-Un Park. A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies [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 1405. doi:10.1158/1538-7445.AM2017-1405
Abstract 499: IgH enhancers hs3b/hs4 are dispensable for c-<i>Myc</i> deregulation in mouse plasmacytomas with T(12;15) translocations
Authors: Alexander L. Kovalchuk, Herbert C. Morse
Journal: Cancer Research (2017)

Abstract c-Myc deregulating t(12;15) chromosomal translocation is the hallmark cytogenetic abnormality of murine plasmacytomas (PCTs). In the great majority of PCTs, the immunoglobulin heavy chain (IgH) locus is broken between Eμ enhancer and the 3’ regulatory region (3’RR), making the latter the major candidate for orchestrating c-Myc deregulation. To elucidate the role of 3’RR in tumorigenesis, we induced PCTs in mice deficient for the major 3’RR enhancer elements, namely hs3b and hs4 (3’KO). Unexpectedly, and contrary to the previous observations made in a mouse lymphoma model, Hs3b/Hs4 3’KO mice did develop t(12;15)-positive PCTs, although with a lower incidence than wild-type controls. In heterozygous mice, there was no allelic bias in targeting IgH for the t(12;15). Molecular analysis of IgH/Myc junctions revealed dominance of Sμ region breakpoints compared to the prevalence of hits into Sγ or Sα in the controls. Analysis of c-Myc expression as well as Ig secretion in 3’KO PCT cell lines revealed no significant differences from the controls. Our current findings highlight the complexity of the 3’RR and the potential of its components to compensate for each other in the context of differentiation from B-lymphocyte to plasma cell. We next extended our observations to include a PCT model where Cre-mediated deletion can remove all four 3'IgH enhancers: hs3a, hs1,2, hs3b and hs4. In PCT cell lines where c-Myc is translocated to an IgH BAC transgene with a floxed 3’IgH enhancer region, induction of retrovirally-expressed Cre-recombinase causes gradual Myc downregulation and complete cell death within 96 hours. The later observation confirms the requirement of the full 3’RR for c-Myc deregulation by T(12;15). Citation Format: Alexander L. Kovalchuk, Herbert C. Morse. IgH enhancers hs3b/hs4 are dispensable for c-Myc deregulation in mouse plasmacytomas with T(12;15) translocations [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 499. doi:10.1158/1538-7445.AM2017-499
Abstract 2832: Class I histone deacetylase inhibitors impair tumor growth and metastatic programs
Authors: Oliver H. Krämer, Nicole Kiweler
Journal: Cancer Research (2017)

Abstract (a) introductory sentence indicating the purposes of the study Metastasis formation is associated with poor patient prognosis. Epithelial-mesenchymal and mesenchymal-epithelial (EMT/MET) transition cycles are key for the formation, survival, and homing of metastatic cells. Inhibitors against epigenetic modulators of the histone deacetylase family (HDACi) are promising, clinically tested epigenetic drugs that may combat cancer proliferation and spread. (b) brief description of pertinent experimental procedures We chose a systems toxicology approach to analyze the relevance of HDACs and their inhibitors for metastatic cell growth. We combined in vivo tests with morphological, cellular, functional, and global proteomic analyses. This strategy follows the 3R principle by Russel and Burch. Of the four classes of HDACs (I-IV), the class I subgroup is most important for tumorigenesis. We therefore analyzed how the pharmacological inhibition of class I HDACs affects the growth and spreading of syngeneic kidney cancer cells into the lungs of BALB/c mice and how such drugs affect tumor cell growth, apoptosis, migration, and gene expression patterns controlling EMT/MET in transformed kidney and breast cells. Furthermore, we investigated how the genetic elimination of HDACs affects cancer cell growth and EMT/MET. We used flow cytometry, immunoblot, immunofluorescence, qPCR, proteomics on a global scale, RNAi against the class I HDACs HDAC1/HDAC2, and in vivo tumor analyses. (c) summary of the new, unpublished data Both the inhibition as well as the elimination of HDAC1/HDAC2 evokes growth arrest, morphological alterations, and apoptosis. HDACi block tumor cell migration, integrin-dependent cell adhesion, and EMT induced by the cytokine TGF-β. Global proteomics and qPCR analyses illustrate that HDACi disrupt EMT/MET cycles and metastatic spread. Moreover, these assays reveal pathways through which HDACi propel cancer cell apoptosis. (d) statement of the conclusions Class I HDACi can modulate the EMT/MET balance that is required for the detrimental process of metastasis. Hence, HDACi should be considered further as clinical treatment option. Citation Format: Oliver H. Krämer, Nicole Kiweler. Class I histone deacetylase inhibitors impair tumor growth and metastatic programs [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 2832. doi:10.1158/1538-7445.AM2017-2832