tbuckley/cabot-search huggingface dataset:
The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration
Authors: Michal Dudek, Nan Yang, Jayalath PD Ruckshanthi, Jack Williams, Elzbieta Borysiewicz, Ping Wang, Antony Adamson, Jian Li, John F Bateman, Michael R White, Raymond P Boot-Handford, Judith A Hoyland, Qing-Jun Meng
Journal: Annals of the Rheumatic Diseases (2016)

Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Methods Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2 ::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1 . Results Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. Conclusions We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.
Contribution of Emerging Risk Markers to Global Cardiovascular Risk Assessment
Authors: Maryam Kavousi, Maarten Leening, Arfan Ikram, Jan Heeringa, Gabriel Krestin, Matthijs Oudkerk, Moniek de Maat, Joost Rutten, Frank Leebeek, Francesco Mattace-Raso, Jan Lindemans, Peter Koudstaal, Albert Hofman, Anton van den Meiracker, Bruno Stricker, Oscar Franco, Ewout Steyerberg, Aad van der Lugt, Jacqueline Witteman
Journal: Circulation (2012)
Do Not Try To Run Before You Can Walk: Empirical and Meta-Ethical Presuppositions of Using Ethical Theory in Clinical Ethics Consultation
Authors: Joschka Haltaufderheide, Marcel Mertz, Jochen Vollmann, Jan Schildmann
Journal: The American Journal of Bioethics (2016)

In their article on the roles of ethical theories in clinical ethics consultation (CEC), Magelssen and colleagues (2016) carefully consider potential roles and benefits of having knowledge of ethic...
Analysis of gemcitabine therapy for relapsed or refractory malignant lymphoma in one institute
Authors: Kentaro Serizawa, Yasuyoshi Morita, Yosaku Watatani, Yasuyo Oyama, Chikara Hirase, Hirokazu Tanaka, Junichi Miyatake, Yoichi Tatsumi, Takashi Ashida, Itaru Matsumura
Journal: Annals of Oncology (2015)
Abstract 1129: EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma
Authors: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari
Journal: Cancer Research (2016)

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.
Abstract LB-313: Upregulation of lactate dehydrogenase A by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression
Authors: Chia-Chi Chang, Chenyu Zhang, Ozgur Sahin, Qingling Zhang, Hai Wang, Jian Zhang, Sumaiyah Rehman, Ping Li, Dihua Yu
Journal: Cancer Research (2016)

Abstract Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby facilitating cellular adaptation to the adverse environment and sustaining rapid proliferation. Recently, new evidence has emerged that abnormal metabolic reprogramming may occur at the early-stages of neoplasia and critically contribute to early transformation and cancer initiation. Previously, we reported that 14-3-3ζ overexpression is an early event in human breast cancer, taking place as early as in the atypical ductal hyperplasia (ADH) stage. We therefore hypothesized that 14-3-3ζ overexpression in breast epithelial cells may trigger metabolic reprogramming by elevating glycolysis that contributes to cancer initiation. In the present study, our bioinfomatics analysis of microarray profiling data from the early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of genes of the canonical glycolytic pathway, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human non-transformed mammary epithelial cells (hMECs), MCF10A and MCF12A, transcriptionally up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation of hMECs. Conversely, knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis by activating the MEK-ERK-CREB signaling axis and transcriptionally up-regulating LDHA, thereby critically contributes to human breast cancer initiation. Citation Format: Chia-Chi Chang, Chenyu Zhang, Ozgur Sahin, Qingling Zhang, Hai Wang, Jian Zhang, Sumaiyah Rehman, Ping Li, Dihua Yu. Upregulation of lactate dehydrogenase A by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-313.
pVAX14 DNA, An Immunoadjuvant, Extends Life-Span As Add-On Treatment To Azacitidine (AZA) In A Mouse Model Of High Risk Myelodysplastic Syndrome (HR-MDS)
Authors: Gorombei Petra, Le Pogam Carole, Patricia Krief, Satyananda Patel, Guerenne Laura, West Robert, Pla Marika, Fenaux Pierre, Chomienne Christine, Rose Ann Padua
Journal: Blood (2013)
Abstract 2391: Flow cytometric sorting of subpopulations followed by RNASeq reveals distinct phenotypes in PDX model of basal breast cancer
Authors: Warren Porter, Friedrich Hahn, Eileen Snowden, Mitchell Ferguson, Frances Tong, Shannon Dillmore, Joel S. Parker, Aaron Middlebrook, Smita Ghanekar, Rainer Blaesius
Journal: Cancer Research (2016)

Abstract The recognition of tumor tissue as an interactive ecosystem of distinct cell types has recently emerged as a very promising basis for more successful treatment of cancer patients. While intratumor heterogeneity (ITH) as a phenomenon has been known for decades it is only recent that its functional significance can be investigated with effective tools. Starting with a correlation of cellular heterogeneity with aggressiveness, metastatic potential and drug susceptibility of a cancerous lesion the current focus on functional differences between various tumor cell compartments is revealing a number of distinct functions and interactions. The discovery of communication between various tumor cells through soluble factors as well as differences in implantation of homogeneous vs. heterogeneous cell populations into immune compromised mouse models suggest a “division of labor” among cell types within many tumor tissues. We have investigated the surface marker distribution of more than 8 different PDX tumor models by flow cytometry and detected extensive immunophenotypic heterogeneity. Using a range of markers associated with cancer stem cells, EMT and invasiveness (e.g. CD 24, 44, 133, 184, 326 (EpCAM), and CD45) we find heterogeneity with respect to many surface markers as well as individual immunophenotypic signatures for each model. Building on this characterization we chose several markers for sorting of subpopulations and performed gene expression analysis. Transcriptome analysis of a breast cancer model revealed two phenotypic signatures which suggest a strong proliferative population alongside a second population which is far less proliferative but much more active in angiogenesis, ECM organization and secretion of various soluble factors. This observation suggests a very clear example of distinct roles of multiple cell types to form a tumor tissue. Our findings could have implications for therapeutic strategies directed at more than one cell type as well as development of better diagnostic tools which take into account the presence of various phenotypically distinct cell populations. Citation Format: Warren Porter, Friedrich Hahn, Eileen Snowden, Mitchell Ferguson, Frances Tong, Shannon Dillmore, Joel S. Parker, Aaron Middlebrook, Smita Ghanekar, Rainer Blaesius. Flow cytometric sorting of subpopulations followed by RNASeq reveals distinct phenotypes in PDX model of basal breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2391.
The use of transjugular intrahepatic portosystemic shunt should be cautious in patients without cirrhosis with obliterative portal vein thrombosis
Authors: Xiaoze Wang, Xuefeng Luo, Li Yang
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Financial Support: This work was supported by grants (81570554 & 81501566) from National Natural Science Foundation of China. TO THE EDITOR: Kallini et al. reported 5 patients without cirrhosis with chronic obliterative portal vein thrombosis (PVT) who underwent trans‐splenic intrahepatic portosystemic shunt with portal vein recanalization (PVR‐TIPS) in Hepatology recently.1 We appreciate the novel innovation; however, several issues about the application of TIPS in the current case series may need to be discussed here. Variceal bleeding in patients with noncirrhotic portal vein occlusion is usually well tolerated, and bleeding‐related mortality is much lower than in patients with cirrhosis.2 Endoscopic therapy or beta‐blocker is considered the first‐line treatment for secondary prophylaxis in such patients.2 In the study by Sarin et al., both esophageal variceal ligation and propranolol are effective in the second prevention of variceal bleeding (23.5% vs. 18%), and no death occurred during a median follow‐up period of 23 months.4 Yet, the urgency of TIPS is doubtful in 2 of 5 patients who had no history of bleeding.1 Regular endoscopic screen with the use of band ligation or beta‐blocker may be more reasonable. For the remaining 3 patients, the details of previous band ligation and propranolol administration were not provided. We believe that TIPS would be justified for patients who failed conservative treatments. Previous studies have demonstrated that percutaneous recanalization of obstructed portal vein alone is feasible and effective in patients with or without cirrhosis.5 The application of a decompression procedure like TIPS should be cautious in patients with extrahepatic portal vein occlusion. However, because of lack of detail information of severity and scope of PVT, the actual feasibility and efficacy of portal vein recanalization in these cases are unknown. Finally, the stent (Supporting Fig. S7) was deployed in the splenic vein in the presented case, which is not common practice. We understand that sufficient backflow is important for long‐term patency of the shunt and the adequate decompression of portal venous system. Even so, extending TIPS into the splenic vein may negatively impact the blood flowing of the mesenteric venous system. In conclusion, further studies are required to define the appropriate role of TIPS in patients without cirrhosis with chronic portal vein occlusion and symptomatic portal hypertension.
Predictive value of exhaled nitric oxide in the management of asthma: a systematic review
Authors: Lauri Lehtimäki, Péter Csonka, Eeva Mäkinen, Jaana Isojärvi, Sirpa-Liisa Hovi, Anneli Ahovuo-Saloranta
Journal: European Respiratory Journal (2016)

The clinical value of measuring fractional exhaled nitric oxide ( F eNO ) in asthma is not clear. We aimed to assess whether F eNO can reliably predict clinical outcomes in asthma treated with inhaled corticosteroids (ICS). We also evaluated whether its predictive role is influenced by different inflammatory phenotypes of asthma. We conducted a systematic review focusing on five clinically relevant questions. Two authors independently screened search results, extracted data and assessed quality of the included studies. Data were synthesised by qualitative methods. 12 prospective studies were included, answering partly three of the five questions. In steroid-naïve asthma, a high F eNO level probably predicts good response to ICS. In ICS-treated asthmatics, a low F eNO level probably predicts low risk of exacerbation, and the patient is unlikely to benefit from increasing ICS dose. There were scarce data to conclude whether F eNO predicts exacerbations when ICS treatment is stopped in well-controlled asthma. Only one study reported results separately in different asthma phenotypes. The current evidence on the predictive value of F eNO and its role in the management of asthma is incomplete. Future studies should focus on clinically meaningful questions and probably target only eosinophilic phenotypes where F eNO is best associated with the activity of airway inflammation.
Abstract 3285: HTLV-1 viral oncogene Hbz induces leukemia with osteolytic bone involvement in mice
Authors: Alison Esser, Dan Rauch, Jingyu Xiang, John Harding, Nicole Kohart, Patrick Green, Stefan Niewiesk, Thomas Rosol, Lee Ratner, Katherine Weilbaecher
Journal: Cancer Research (2016)

Abstract Adult T-cell leukemia/lymphoma (ATL) develops in a subset of patients infected with the HTLV-1 virus. Most ATL patients become refractory to chemotherapy and have a median survival time of 6 months. Although uncommon in hematologic malignancies, 80% of ATL patients develop osteolytic lesions and hypercalcemia of malignancy. Bone resident and metastatic tumors release paracrine factors that modulate the bone microenvironment to facilitate disease progression and decrease survival. HTLV-1 encodes 2 viral oncogenes, Tax and Hbz. Tax is critical to ATL development and regulates tumor growth and proliferation in part through trans-activation of NFκB and CREB. We have previously shown Tax expression driven by the Granzymbe B promoter is sufficient for the development of leukemia/lymphoma with osteolytic lesions and hypercalcemia. We and others have shown that Tax alters the expression of paracrine factors that modulate the bone microenvironment through effects on bone forming osteoblasts (OB) and bone resorping osteoclasts (OC). Tax is expressed in early lymphocyte transformation with low expression in advanced ATL. HBZ is expressed early in lymphocyte transformation and throughout ATL progression. We hypothesize that in ATL cells, HTLV-1 viral oncogenes Tax and Hbz cooperate to modulate bone metabolism in a paracrine manner to enhance ATL tumor growth and progression. Mice with Granzyme B driven Hbz expression (T and NK cells) develop leukemia/lymphoproliferative disease in lymph nodes correlating with increased spleen weight. We found that lymphoproliferative disease is also present in the bone marrow. Hbz mice have decreased trabecular bone at 18 months by microCT and radiographic analysis. These data suggest Hbz can alter bone metabolism. Future studies will define the effects of Hbz on bone formation, OB and OC specific effects and tumor progression. Understanding HTLV-1 oncogene modulation of the bone microenvironment will uncover critical pathways in tumor/bone cross talk enabling the development of novel targeted therapies for ATL patients. Citation Format: Alison Esser, Dan Rauch, Jingyu Xiang, John Harding, Nicole Kohart, Patrick Green, Stefan Niewiesk, Thomas Rosol, Lee Ratner, Katherine Weilbaecher. HTLV-1 viral oncogene Hbz induces leukemia with osteolytic bone involvement in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3285.
Abstract 2798: Enhanced HIF1α inhibition through dual inhibition of CDK and HSP90
Authors: Shuai Zhao, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Abstract A prevalent characteristic of solid tumors is the presence of hypoxic areas. Intratumoral hypoxia plays a well-known role in chemotherapy and radiotherapy resistance and is associated with poor prognosis as well as enhanced metastasis. Hypoxia-inducible factor 1α (HIF1α) is a major mediator of the cellular response to hypoxia, which promotes malignant proliferation and progression in cancers. HIF-1α expression is increased in a variety of tumors but this is not restricted to hypoxic regions. Understanding and targeting the mechanism of cancer-related HIF1α stabilization may help to improve current cancer treatments. We have previously shown that cyclin-dependent kinase 1 (CDK1) stabilizes HIF1α through direct phosphorylation of its Ser668 residue in a Von Hippel-Lindau (VHL)-independent manner both under hypoxia and at G2/M under normoxia (Warfel et al., Cell Cycle, 2013). Another previously acknowledged VHL-independent HIF1α stabilizer is the heat shock protein 90 (HSP90) that has been correlated with adverse prognosis and used as a therapeutic target in cancer. We investigated potential crosstalk between CDK1-mediated and HSP90-mediated HIF1α stabilization and the potential for therapeutic targeting. We found that under hypoxia, the interaction between HSP90 and HIF1α proteins is impaired by CDK1 inhibition in HCT116 colon cancer cells. Moreover, the level of HIF1α protein is increased by heat shock (40°C) treatment (as compared to 37°C), which can be reversed by the treatment with the HSP90 inhibitor, geldanamycin. Interestingly, administration of the CDK1 inhibitor, Ro-3306, is also able to decrease heat shock-induced HIF1α. Our results suggest that CDK1 activity may contribute to HSP90-mediated HIF1α stabilization. On the other hand, HIF1α level is decreased by HSP90 inhibition under hypoxia, which can be further reduced by the combination of HSP90 inhibition and CDK1 inhibition or knockdown. The joint inhibitory effect of CDK1 and HSP90 is observed in other cancer cell lines. In addition, we evaluated the combinational treatment of CDK4/HSP90 inhibition and found it robustly suppresses HIF1α expression in glioblastoma cell lines (i.e. T98G and SNB19). Ongoing studies are examining the biological function of CDK/HSP90 dual inhibition on cancer cell invasiveness as well as effects on cell viability. Our findings provide a rationale for targeting HIF1α through a novel combination of CDK and HSP90 inhibitors, a therapeutic strategy with clinical implications. Citation Format: Shuai Zhao, David T. Dicker, Wafik S. El-Deiry. Enhanced HIF1α inhibition through dual inhibition of CDK and HSP90. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2798.
Choosing Our Words Wisely
Authors: Margaret Lowenstein
Journal: JAMA Internal Medicine (2016)

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