tbuckley/cabot-search huggingface dataset:
Death to the neutrophil! A resolution for acute respiratory distress syndrome?
Authors: Brittney N.V. Scott, Paul Kubes
Journal: European Respiratory Journal (2018)

<b>Neutrophil death pathways and clearance are impaired in human ARDS and interventions targeting these processes may help in the resolution of inflammation for this deadly syndrome</b>http://ow.ly/ed2N30kW1L6
Abstract 4604: Long noncoding RNA Linc00162, as a novel prognostic marker, modulates cancer stem cell properties in triple-negative breast cancer
Authors: Lichao Sun, ChangChing Lin, Joseph Burnett, Hebao Yuan, Duxin Sun
Journal: Cancer Research (2018)

Abstract Trastuzumab is an effective treatment for HER2+ breast cancer. However, trastuzumab resistance in HER2+ breast cancer may induce the epithelial-to-mesenchymal transition (EMT), transforming HER2+ to triple-negative breast cancer with cancer stem cell properties in some cancer cell populations. Long noncoding RNAs (lncRNAs) have been reported to be upregulated in many types of cancer tissues, and might play significant regulatory roles in cancer progression. However, the mechanisms of lncRNA in trastuzumab resistance still remain largely unknown. Here, we systematically analyzed the levels of LincRNA between BT474 (HER2+trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) by using RNA-sequencing, and identified that Linc00162 was significantly overexpressed in BT474 PTEN- LTT cells. In vitro functional assay indicated that downregulation of Linc00162 in BT474 PTEN-LTT cells completely inhibited the cell proliferation. To further evaluate the role of Linc00162 in BCSC self-renewal, we found that inhibition of Linc00162 led to a significant reduction in the number and the size of LTT cells sphere by using the mammosphere formation assay. Next, we examined Linc00162 expression levels in breast cancer tissues, and identified that Linc00162 was markedly increased. Clinicopathologic relevance analysis showed that Linc00162 expression was correlated with advanced clinical stage, lymph node metastasis and the depth of invasion. Furthermore, upregulation of Linc00162 was correlated with TRNB phenotype. In Kaplan-Meier survival analysis, high levels of Linc00162 was significantly associated with unfavorable survival in breast cancer patients. These findings suggest that Linc00162 can be used as a clinically relevant novel biomarker in breast cancer and may serve as a target for future drug development. Citation Format: Lichao Sun, ChangChing Lin, Joseph Burnett, Hebao Yuan, Duxin Sun. Long noncoding RNA Linc00162, as a novel prognostic marker, modulates cancer stem cell properties in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4604.
Abstract 19470: Predicted Impact of Carotid Artery Atherosclerotic Disease for Screening of Abdominal Aortic Aneurysm in Women
Authors: Yoshitaka Shiratori, Naoyuki Yokoyama, Ken Kozuma, Takaaki Isshiki, Yasuyuki Maruyama
Journal: Circulation (2015)

Introduction: Screening of abdominal aortic aneurysm (AAA) for women has not been established. The aim of this study was to determine the predictive factors associated with ultrasonographic screening for AAA in patients who receive coronary angiogram (CAG) for suspicion of coronary artery disease (CAD). Methods: Study patients were consisted with 310 consecutive women over 65 years undergoing initial CAG. Both abdominal and carotid arterial ultrasonography were performed for all patients. Patients with known AAA were excluded in this study. AAA was defined as abdominal aortic diameter ≥30 mm by ultrasonographic examination. Carotid artery atherosclerotic disease (CAAD) was defined as a ≥50% stenosis of internal carotid artery (ICA) in NASCET criteria or ≥150cm/sec of ICA peak systolic velocity. Ankle branch pressure index (ABI) was also performed for all patients, and peripheral arterial disease (PAD) was defined as a ≤0.9 of ABI. CAD was defined as a ≥75% reduction in diameter in at least one major vessel in coronary angiography. Multivariate logistic regression analysis was used to study multiple risk factors (age, hypertension, diabetes, dyslipidemia, smoking, hemodialysis, cerebral infarction, CAD, CAAD and PAD) for AAA. Results: Of 310 patients, incidental AAA was detected in 10 patients (3.2%) and 1 had AAA diameter of ≥50mm. Patients with CAD included higher prevalence of AAA than those without (5.6% vs 0.7%, P=0.021). Multivariate analysis revealed that age (RR 1.3, 95% CI 1.1 to 1.5, p = 0.001) and CAAD (RR 8.5, 95% CI 1.3 to 55.7, p= 0.025) were significantly associated with a higher prevalence of AAA. Conclusions: Older age and presence of CAAD should be taken into account as a possible criterion for selective AAA ultrasonographic screening in women over 65 years for suspicion of CAD.
Abstract LB-132: MOSPD2: A novel target for Bi-specific Ab mediated killing of tumor cells
Authors: Itzhak Mendel, Yaniv Salem, Niva Yacov, Osharat Prhopheta-Meiran, Pinhas Kafri, Eyal Breitbart
Journal: Cancer Research (2018)

Abstract Introduction: We have previously described motile sperm domain-containing protein 2 (MOSPD2) as essential for breast cancer metastasis in vitro and in vivo. In this study, we detected high expression of MOSPD2 in different organ tumors and cancer cells, and subsequently developed CD3xMOSPD2 BiTE, a firstly generated bi-specific antibody that directs killing of MOSPD2 expressing cancer cells. Experimental procedure: The prevalence of MOSPD2 was evaluated by IHC in tissue microarrays layered with cores, representing multiple organ tumors and normal tissue. MOSPD2 abundance was scored according to the staining intensity on a scale from 0 to 3. Human monoclonal antibody against the extracellular region of human MOSPD2 was generated. To determine the presence of cell surface MOSPD2 expression, FACS analysis was performed on cell lines derived from different tumor origins. BiTE was generated to comprise the scFv region of anti-human CD3 and the scFv region of a human anti-human MOSPD2. Cancer cell lines were co-cultured with freshly isolated T-cells or effector CD8 T-cells in the presence of CD3xMOSPD2 or a control BiTE. Cancer cell survival rate and T cell activation was determined after 2-3 days by FACS. Results: MOSPD2 expression was evident in the majority of organ tumors, with high prevalence in tumors such as colon, liver and breast. Normal tissue was either devoid of MOSPD2, or had low expression relative to its parallel tumor tissue. Within normal or normal adjacent tissue (NAT), staining could be detected primarily in lymphoid tissues where myeloid cells abundantly reside. FACS staining using a human anti-MOSPD2 mAb demonstrated that MOSPD2 is expressed on the surface of different cancer cell lines. Employing CD3xMOSPD2 BiTE on myeloid or solid tumor-derived cell lines induced T-cell activation and yielded profound killing of cancer cells. Conclusions: IHC staining demonstrates MOSPD2 expression profile supportive of targeting cancer cells. CD3xMOSPD2 BiTE directs T-cells to MOSPD2 expressing cancer cells and induces their destruction in-vitro. Therefore, we propose CD3xMOSPD2 bi-specific antibodies as a potential therapy for the treatment of cancer via a unique target, directed for the destruction of hematological cancers and solid tumors expressing MOSPD2. Citation Format: Itzhak Mendel, Yaniv Salem, Niva Yacov, Osharat Prhopheta-Meiran, Pinhas Kafri, Eyal Breitbart. MOSPD2: A novel target for Bi-specific Ab mediated killing of tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-132.
Abstract 19578: Title: Natural Killer T cells Play a More Critical Role in Reperfusion Injury Than in the Hyperglycemic Exacerbation of Infarct Size
Authors: Yaqin Xu, Robert S Smith, Zequan Yang, Victor E Laubach, Irving L Kron, Brent A French
Journal: Circulation (2012)

Introduction: Invariant Natural Killer T (iNKT) cells express a T cell receptor encoded by the Jalpha18 gene that recognizes glycolipid antigens presented by CD1d. These same iNKT cells have recently been implicated in the hyperglycemic exacerbation of lung ischemia/reperfusion injury. Thus, we hypothesized that Jalpha18-/- mice, which lack iNKT cells, would similarly be protected against the hyperglycemic exacerbation of cardiac injury in the mouse model of reperfused myocardial infarction (MI). Methods: Reperfused MI was performed in euglycemic (n=8) and hyperglycemic (n=7) C57Bl/6 wild-type (WT) mice, as well as in congenic euglycemic (n=11) and hyperglycemic (n=8) Jalpha18-/- mice. MI consisted of 30 min coronary occlusions followed by 2 h reperfusion. Infarct size was determined by digital planimetry after TTC and Phthalo blue staining, and was reported as infarct size as percent area-at-risk (%A@R). Results: Infarct size was reduced by 56% in euglycemic Jalpha18-/- mice compared to euglycemic WT mice (18±3% vs. 41±5%, mean±SEM, p&lt;0.05). Infarct size was also reduced in hyperglycemic Jalpha18-/- mice compared to hyperglycemic WT mice, albeit to a much lesser extent (52±3% vs. 63±3%, p&lt;0.05). Further, the areas at risk as percent of the left ventricular (LV) mass were similar for all groups (p=NS). Conclusions: With regard to mechanism, these results clearly demonstrate that iNKT cells and innate immune responses contribute importantly to reperfusion injury. From a translational perspective, the results predict that interventions focused on suppressing the innate immune response during reperfusion will be significantly more effective in euglycemic patients than in those suffering from stress hyperglycemia.
William McBride: alerted the world to the dangers of thalidomide in fetal development
Authors: Ned Stafford
Journal: BMJ (2018)

In December 1961, the Australian obstetrician William McBride warned in a letter to the Lancet that he had observed “multiple severe abnormalities” in babies delivered from women who had taken the drug thalidomide during pregnancy.1 He concluded his letter by asking: “Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy?”

The letter, thought to be the first published suggestion from a doctor of teratogenicity of thalidomide in humans, was brief—only five sentences. McBride’s concerns about thalidomide were subsequently confirmed by researchers in Europe, and the drug was banned around the world, saving countless infants from being born with birth defects.

An article in The BMJ in 2016 about a documentary film chronicling the lives of people who had birth defects as a result of the drug stated: “The thalidomide scandal stands as one of the worst ever medical disasters.”2

For helping alert the world to the dangers of thalidomide taken during pregnancy, McBride gained global recognition. In his native Australia he was hailed as a national hero, and a glow of honour hovered over him for the following three decades. He had a thriving practice in Sydney, and he received a CBE in 1969 and the Order of Australia in 1977.

But a later chapter of McBride’s life was not so pleasant. In 1993, at the age of 65, McBride was found guilty of scientific fraud by a medical tribunal for knowingly publishing false and misleading research. He was removed from the medical register.3

William Griffith McBride was born on 25 May 1927 in Sydney, but because of his mother’s ill health he spent much of his childhood living with an aunt on a dairy farm. He studied medicine at Sydney University Medical School. After qualifying …
Abstract 3201: A theranostic approach using photodynamic therapy to efficiently kill neuroblastoma cancer cells through induction of apoptosis
Authors: Lester M. Davids, Anja Schwar, Dirk Lang
Journal: Cancer Research (2018)

Abstract Neuroblastoma is an extra-cranial tumour of childhood and arises from the sympatho-adrenal lineage of the neural crest tissue. Despite advances in treatment strategies, significant complications in curing this cancer remain. Furthermore, severe consequential effects on patient health have been associated with chemotherapy and/or radiation. Photodynamic therapy (PDT) with the photosensitiser hypericin (HYP) presents an attractive and efficient adjunctive therapy alternative for this aggressive cancer. HYP, an extract from Hypericum perforatum (St John's Wort) species, has a high quantum yield following photo-activation and a low dark toxicity and genotoxiciy. This study tests the anti-cancer efficacy of HYP-PDT in SK-N-SH neuroblastoma cells using an in vitro tissue culture model. Results show through detailed uptake kinetics that HYP is absorbed effectively by SK-N-SH cells after 6 hours of incubation and live fluorescent confocal microscopy revealed primary localisation of HYP to lysosomes and mitochondria. Through cell viability assays it was determined that 2, 3 and 4μM HYP-PDT resulted in 45.6±5.1% cell death within 24 hours of treatment. Additionally, 24 hours post 0.25μM and 2μM HYP-PDT, we observed distinct morphological changes in SK-N-SH cells using phase contrast microscopy, and determined a high apoptotic mode of cell death using Fluorescent Activated Cell Sorting (FACS). These results demonstrate that HYP-PDT is effective in killing neuroblastoma cells and that the mode of cell death is apoptotic in nature. This study is ongoing with further investigation into the signalling underlying this photo-toxicity with particular emphasis on cell death resistance mechanisms in neuroblastoma cells. Citation Format: Lester M. Davids, Anja Schwar, Dirk Lang. A theranostic approach using photodynamic therapy to efficiently kill neuroblastoma cancer cells through induction of apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3201.
Psoriasis is not associated with cognition, brain imaging markers, and risk for dementia: The Rotterdam Study
Authors: Elena Pezzolo, Unal Mutlu, Meike W Vernooij, Emmilia A Dowlatshahi, Paolo Gisondi, Giampiero Girolomoni, Tamar Nijsten, M Arfan Ikram, Marlies Wakkee
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 2593: AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate cancer
Authors: Sarah Q. To, Edmond Kwan, Heidi Fettke, Andrew Mant, Maria Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad
Journal: Cancer Research (2018)

Abstract In 2014, a landmark study was published demonstrating that androgen receptor splice variant (AR-V) AR-V7 expression was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumor cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR splice variants and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Blood was taken in a PAXgene RNA tube at baseline prior to the commencement of therapy and at end of treatment (if applicable). 24% (9/37) of patients were AR-V-positive. Notably, PSA response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p=0.896). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 months vs. not reached; p=0.894). Additionally, we identified 2 patients who were AR-V7 negative at baseline but had converted to AR-V7 positive in their end-of-treatment sample. This was associated with much shorter PSA-PFS than those that remained negative (2.58 months vs. no reached), suggesting gain of AR-V expression may be a marker of acquired resistance. These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide. Citation Format: Sarah Q. To, Edmond Kwan, Heidi Fettke, Andrew Mant, Maria Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad. AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2593.
Abstract 3803: Immune escape from NK cells and activated CD8 T cells by miR-183 repression of MICA/B expression in human lung cancer
Authors: Nhan Tu, Thu Le Trinh, Sarah S. Donatelli, Melba M. Tejera, Danielle L. Gilvary, Jun-Min Zhou, Erika A. Egsioglu, Sheng Wei, Domenico Coppola, Julie Y. Djeu
Journal: Cancer Research (2018)

Abstract Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8+ T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3' untranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3'UTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by anti-sense TGFβ transfection into H1355 or H1299 tumor cells, which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8+ T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells. Citation Format: Nhan Tu, Thu Le Trinh, Sarah S. Donatelli, Melba M. Tejera, Danielle L. Gilvary, Jun-Min Zhou, Erika A. Egsioglu, Sheng Wei, Domenico Coppola, Julie Y. Djeu. Immune escape from NK cells and activated CD8 T cells by miR-183 repression of MICA/B expression in human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3803.
Abstract 2843: Calcium blockers modulate the steroid resistance in acute lymphoblastic leukemia
Authors: Hyun Joo Jung
Journal: Cancer Research (2018)

Abstract Background: Acute lymphoblastic leukemia (ALL) is one of common cancers in children and adults, and a fair number of ALL patients still die although the overall survival rate is approaching 90% with risk-directed therapy in many developed countries. Response to steroid is the most important prognostic factor of patients with ALL, and the development of steroid resistance is lethal to the ALL patients. To improve survival for steroid-resistant ALL patients, it is necessary to develop new concepts to overcome the steroid resistance of ALL. Methods: We generated the steroid-adapted subclones through prolonged cultures of ALL cell lines with gradually increased steroid concentration.Also, we used biochemical and molecular methodologies to demonstrate the signaling axis of tissue transglutaminase (TG2)-nuclear factor-kappa B (NF-kappa B) and cell cycle to evaluate the effect of calcium blockers on the steroid-resistant ALL cells. Results: Steroid-adapted ALL cells that were generated by culture with gradually increased steroid concentration were much more resistant to steroid than their parent ALL cells. We found that calcium blockers altered TG2 activity and nuclear factor-kappa B (NF-kappa B) expression in these steroid-resistant ALL cells. Also, calcium blockers induced the change of expression of NF-kappa B target genes in steroid-adapted ALL cells. In addition, calcium blockers induced the change of ABC transporter expression and the quiescence of steroid-resistant ALL cells. We also found that calcium blockers induced apoptosis of steroid-resistant ALL cells and reduced the steroid resistance of steroid-resistant ALL cells. Conclusion: This study shows that calcium blockers improved the cytotoxicity of steroid on steroid-resistant ALL cells via manipulation of TG2 and NF-kappa B activities and cell cycle. The combination of calcium blockers with chemotherapeutic agents may be a new alternative strategy to overcome the steroid resistance of ALL. Citation Format: Hyun Joo Jung. Calcium blockers modulate the steroid resistance in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2843.
Cardiac Sca-1 <sup>+</sup> Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair
Authors: Lu Zhang, Nishat Sultana, Jianyun Yan, Fan Yang, Fuxue Chen, Elena Chepurko, Feng-Chun Yang, Qinghua Du, Lior Zangi, Mingjiang Xu, Lei Bu, Chen-Leng Cai
Journal: Circulation (2018)

Background: For more than a decade, Sca-1 + cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. Methods: Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1 + cells. Results: With these novel genetic tools, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1 + cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. Conclusions: Our study provides definitive insights into the nature of cardiac resident Sca-1 + cells. The observations challenge the current dogma that cardiac resident Sca-1 + cells are intrinsic stem cells for myocardial development, renewal, and repair, and suggest that the mechanisms of transplanted Sca-1 + cells in heart repair need to be reassessed.