tbuckley/cabot-search huggingface dataset:
PD-1 Controls Follicular T Helper Cell Positioning and Function
Authors: Jingwen Shi, Shiyue Hou, Qian Fang, Xin Liu, Xiaolong Liu, Hai Qi
Journal: Immunity (2018)

Follicular T helper (Tfh) cells highly express the programmed cell death-1 (PD-1) molecule. Whereas inhibition of T cell receptor (TCR) signaling and CD28 co-stimulation is thought to be the primary mode of PD-1 functions, whether and how PD-1 regulates Tfh cell development and function is unclear. Here we showed that, when engaged by the ensemble of bystander B cells constitutively expressing PD-1 ligand 1 (PD-L1), PD-1 inhibited T cell recruitment into the follicle. This inhibition involved suppression of PI3K activities downstream of the follicle-guidance receptor CXCR5, was independent of co-signaling with the TCR, and necessitated ICOS signaling to overcome. PD-1 further restricted CXCR3 upregulation on Tfh cells, serving to concentrate these cells toward the germinal center territory, where PD-L1-PD-1 interactions between individual Tfh and B cells optimized B cell competition and affinity maturation. Therefore, operating in both costimulation-independent and -dependent manners, PD-1 controls tissue positioning and function of Tfh cells.
Abstract 352: Pulmonary Vein Thrombosis can make Pulmonary Vein Acidic States, which may be Associated with Atrial Fibrillation.
Authors: HidekazuTakeuchi
Journal: Circulation Research (2014)

Atrial fibrillation can cause ischemic stroke. To prevent atrial fibrillation (AF) is crucial to prevent ischemic stroke. The pulmonary vein has a myocardial layer that can generate spontaneous or triggered action potentials. The myocardial layer is extended from the left atrial myocardium. Pulmonary vein myocardium sleeve is known to be associated with generating and maintaining AF. Pulmonary vein myocardium can be classified into two types. One is short and thin myocardium sleeve, which has no potential to cause atrial fibrillation (AF). And the other is long and thick myocardium sleeve, which has potential to cause AF. The mechanisms of such myocardium sleeve changes are not understood well. Pulmonary vein thrombosis (PVT) is believed to be rare, which was reported as a rare complication of chest surgeries such as lobectomy or lung cancers. But since 2012, I reported seven cases of PVT in elderly patients without such conditions, which suggests that PVT is not uncommon. That is a novel notion. PVT prev...
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing
Authors: Barry Boland, Wai Haung Yu, Olga Corti, Bertrand Mollereau, Alexandre Henriques, Erwan Bezard, Greg M. Pastores, David C. Rubinsztein, Ralph A. Nixon, Michael R. Duchen, Giovanna R. Mallucci, Guido Kroemer, Beth Levine, Eeva-Liisa Eskelinen, Fanny Mochel, Michael Spedding, Caroline Louis, Olivier R. Martin, Mark J. Millan
Journal: Nature Reviews Drug Discovery (2018)
Abstract 3740: Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate cancer
Authors: Wenxing You, Yuliang Wang, Leung Chan
Journal: Cancer Research (2018)

Abstract Liver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. In prostate cancer, LRH-1 is reported as a potent transcription factor to facilitate the formation of CRPC (castration-resistant prostate cancer cells) which is resistant to androgen deprivation therapy (ADT). However, it is still elusive how LRH-1 responses to ADT and facilitates the growth of CRPC. After deprivation of androgen in mouse prostate cancer xenograft model, LRH-1 mRNA was upregulated dramatically at a very low androgen level. After CRPC formation, LRH-1 mRNA was downregulated when androgen level recovered. KLK3/PSA is an important downstream target of activated AR (Androgen receptor), whose expression level at 4 days after castration is downregulated, while upregulated after relapse. Since PSA level/AR signaling activity showed an opposite expression pattern to LRH-1, we hypothesized that LRH-1 was suppressed by androgen in a negative-feedback manner. With androgen treatment of an androgen-sensitive prostate cancer cell line LNCaP, LRH-1 was downregulated in both dose- and time-dependent manner, while PSA shows an opposite expression pattern. And knocking down of AR blocked the suppression of androgen on LRH-1, indicating that androgen suppresses LRH-1 through AR. Furthermore, AR antagonist Enzalutamide can block the binding of androgen to AR thus upregulate LRH-1. According to ChIP-seq data, AR binds to the promoter and enhancer of LRH-1,and the binding intensity increased with androgen treatment. Through ChIP-qPCR, several binding sites of AR on LRH-1 promoter and enhancer were validated. The transcription activity of luciferase reporter with these AR binding sites was also suppressed by treatment of androgen. In the future work, to find out the epigenetics modifiers in the AR complexes when suppressing LRH-1 will be critical for the understanding of the detailed mechanism. Citation Format: Wenxing You, Yuliang Wang, Leung Chan. Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in 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 3740.
Abstract 52: A genomic editing approach for purification of viable quiescent cancer cells
Authors: Ting La, Margaret Farrelly, Xu Guang Yan, Hamed Yari, Yuanyuan Zhang, Yuchen Feng, Seyed Hessamedin Tabatabaeehatambakhsh, Tao Liu, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2018)

Recurrent and metastatic cancer lesions often undergo a period of dormancy, which is closely associated with cancer cell quiescence, a state whereby cancer cells exit the cell cycle and are reversibly arrested in G0 phase. Quiescent cancer cells are inherently resistant to cell death and refractory to therapeutic drugs. However, the mechanisms responsible for the resistance remain largely undefined. This is closely associated with the lack of understanding of their biological properties as a consequence of technical hurdles in the isolation and analysis of viable quiescent cells. Nevertheless, it is known that quiescent cells are characteristically negative for the proliferation marker Ki67 and express high levels of the cyclin-dependent kinase (CDK) inhibitor p27. In this study, we developed a CRISPR/Cas9-based system to fuse a green fluorescent protein (EGFP) gene with endogenous CDKN1B, the gene encoding p27, and a red fluorescent protein (mCherry) gene with endogenous MKI67, the gene encoding Ki67 in the genome of human melanoma cells. By using this system, we have successfully isolated viable p27high/Ki67- melanoma cells using fluorescence-activated cell sorting (FACS). The quiescent state of these cells was confirmed by dual nucleic acid staining (DNA with Hoechst-33342, and RNA with Pyronin Y). This approach provides a unique research tool for further characterization of the biological properties of quiescent cells. Comparative RNA-seq and proteomics analyses are being currently carried out to reveal molecular networks involved in regulating cell quiescence, and to identify molecular targets for overcoming resistance of quiescent melanoma cells to treatment.Citation Format: Ting La, Margaret Farrelly, Xu Guang Yan, Hamed Yari, Yuanyuan Zhang, Yuchen Feng, Seyed Hessamedin Tabatabaeehatambakhsh, Tao Liu, Lei Jin, Xu Dong Zhang. A genomic editing approach for purification of viable quiescent cancer 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 52.
Vesicular nanocarrier based treatment of skin fungal infections: Potential and emerging trends in nanoscale pharmacotherapy
Authors: Shivani Verma, Puneet Utreja
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Occurrence of skin fungal infections is increasing nowadays and their presence is more prominent in patients suffering from immunocompromised diseases like AIDS. Skin fungal infections are a major cause of visits by patients to dermatology clinics. Although, a large number of antifungal agents are available for treatment of skin fungal infections, but, their toxic profile and physicochemical characteristics reduce therapeutic outcome. When these antifungal agents are delivered topically using conventional formulations like creams and gels, they may cause various side effects like redness, burning, and swelling at the site of application. Therefore, various vesicular formulations (phospholipid based or non phospholipid based) have been explored by pharmaceutical scientists to treat skin fungal infections topically. Vesicular formulation explored for the purpose are liposomes, ethosomes, transfersomes, transethosomes, niosomes, spanlastics, oleic acid vesicles, and nanoparticles. These formulations show various advantages like bioavailability enhancement of bioactives, high skin permeation power, no side effects at application site, dosing frequency reduction, and sustained drug release. Therefore, in the present article, we have discussed about the utility of various vesicular nanocarrier systems to treat skin fungal infections.
Abstract 3711: Smart therapy: Using <i>CCND1-</i>targeted siRNA-loaded liposomes to sensitize mantle cell lymphoma cells to cisplatin
Authors: Tanvi N. Gandhi, Chioniso P. Masamha, Sudip K. Das, Nandita G. Das
Journal: Cancer Research (2018)

Abstract Mantle cell lymphoma (MCL) is the most aggressive subtype of B-cell non-Hodgkin's lymphoma, due to its refractory nature and high relapse rate. It is characterized by the aberrant overexpression of the cell cycle regulatory oncogene, cyclin D1 (CCND1), which occurs as a result of a t (11; 14) chromosomal translocation event, the initiating lesion for MCL tumorigenesis. Current therapy includes a series of different chemotherapy regimens often involving a combination of at least four drugs, but there is no gold standard combination treatment regimen. One of the most commonly used drugs in combination treatment is the chemotherapeutic agent, cisplatin. High concentrations of cisplatin in the body cause nausea, vomiting, loss of taste and, more severely, nephrotoxicity. A commonly used approach to reduce the concentration of a chemotherapeutic agent is to use it in combination with a molecular targeting agent. Since cyclin D1 is overexpressed in MCL, we hypothesize that knocking down CCND1 by using siRNA will sensitize MCL cells to cisplatin. We developed CCND1 primers to detect reduction in CCND1 mRNA levels after RNAi using PCR. The greatest challenge against siRNA delivery is its poor stability in vivo and low efficacy of transfection into tumor cells. Our objective is to formulate a dosage form that could be practically adapted in a clinical setting in the future. We developed a liposome formulation that uses a balanced ratio of neutral and cationic lipids to serve as a carrier for the siRNA and improves delivery to tumor cells. Our CCND1 siRNA and control siRNA-loaded liposomes have an average particle size below 150 nm and an overall cationic charge less than 30V. These characteristics are important for the trafficking of the liposome carrier in vivo and its eventual uptake into tumor tissue. Fluorescence assays were used to detect and quantify the amounts of siRNA bound to the liposome. We determined the effect of the liposomes in combination with cisplatin on MCL cell viability using a colorimetric MTT assay. The novel CCND1 siRNA-loaded liposome combined with cisplatin was found to show a dose-dependent decrease in cell viability and was more potent than either CCND1 siRNA liposomes or cisplatin alone (p&amp;lt;0.05). In conclusion, our preliminary studies indicate a potential advantage of using smart therapy by co-administering cisplatin with CCND1 siRNA-loaded liposomes. Citation Format: Tanvi N. Gandhi, Chioniso P. Masamha, Sudip K. Das, Nandita G. Das. Smart therapy: Using CCND1-targeted siRNA-loaded liposomes to sensitize mantle cell lymphoma cells to cisplatin [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 3711.
Bone Marrow Stem Cells Prevent Left Ventricular Remodeling of Ischemic Heart Through Paracrine Signaling
Authors: RyotaUemura, MeifengXu, NaumanAhmad, MuhammadAshraf
Journal: Circulation Research (2006)

In this study, we hypothesized that bone marrow stem cells (BMSCs) protect ischemic myocardium through paracrine effects that can be further augmented with preconditioning. In in vitro experiments, cell survival factors such as Akt and eNOS were significantly increased in BMSCs following anoxia. In the second series of experiments following coronary ligation in mice, left ventricles were randomly injected with the following: DMEM (G-1), BMSCs (G-2), and preconditioned BMSCs (G-3). Four days after myocardial infarction, BMSCs were observed within injured myocardium in G-2 and G-3. Apoptotic cardiomyocytes within periinfarct area were significantly reduced in G-3. Four weeks after myocardial infarction, smaller left ventricular (LV) dimension and increased LV ejection fraction were observed in G-3. Infarct area was significantly reduced in G-3. However, GFP+ cardiomyocytes were observed in low numbers within periinfarct area in G-2 and G-3. In conclusion, BMSCs secreted cell survival factors under ischemia,...
Abstract 4311: Rb may play a key role in green tea-induced growth inhibition of human myeloid leukemia cells
Authors: Darrell Henry, Sebastien Brumaire, Xiaotang Hu
Journal: Cancer Research (2018)

Abstract Although the benefits of green tea to human health including preventing cancer have been widely reported in recent years, the specific effect and action mechanisms of green tea on cancer cells are largely unclear. In this study, we presented evidence that green tea extract and its major chemical component, Epigallocatechin-3-gallate (EGCG), inhibit both suspension and adherence cancer cells through the regulation of pRb-CDK complexes. Addition of green tea extract to the culture of myeloid leukemia TF-1a and MV4-11 cells significantly inhibited their proliferation measured by XTT and BrdU assays. The inhibition is dose dependent with more than 35% inhibition being observed at a concentration of 4% (v/v) of the tea extracts derived from 8% (g/ml) green tealeaf in distilled water. The tea extract also markedly reduced the numbers of stem/progenitors derived from TF-1a, MV4-11, and Hep-G2 cells, determined by counting colony-forming cells in semi-solid clonal culture. EGCG showed a similar inhibitory effect on TF-1a, MV4-11, and Hep-G2 cells and their stem/progenitors. Next, we investigated what mechanism(s) is responsible for the green tea-induced growth inhibition of the cells. Surprised to us the expression of Rb was significantly upregualted with a maximal enhancement being observed when 0.00001% of EGCG (g/ml) or 4% (v/v) of green tea extracts were added to the cell culture. The upregulation of Rb was significantly blocked by pre-treatment with cycloheximade, a protein synthesis inhibitor. In contrast, green tea extract and EGCG downregulated dramatically phosphorylation of pRb. Addition of cycloheximade had no effect on the phosphorylation of Rb in the absence or presence of green tea extract or EGCG analyzed by Western blotting. We also found that green tea extract and EGCG had no significant effect on the expression of CDC2, CDK2, CDK4, CDK6, and CDK inhibitors, p21 and p27, but the formation of CDK4-pRb and CDK6-pRb complexes were significantly downregulated detected by immunoprecipitation. Taken together, our data suggest that green tea (the extract and EGCG) regulate Rb protein at both translation and post-translation levels. The upregulation of Rb synthesis, downregulation of Rb phosphorylation and CDK-Rb complexes all promote the binding of Rb to E2F transcription factors and inhibit the E2F-dependent transcription, leading to cell growth inhibition (supported by Barry Faculty Stimulating Grant 2017-2018). Citation Format: Darrell Henry, Sebastien Brumaire, Xiaotang Hu. Rb may play a key role in green tea-induced growth inhibition of human myeloid leukemia 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 4311.
When Tissue Is No Longer the Issue: Tissue-Agnostic Cancer Therapy Comes of Age
Authors: Shiuh-Wen Luoh, Keith T. Flaherty
Journal: Annals of Internal Medicine (2018)

Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances have found that the success of biomarker-driven cancer therapy may be relevant across sites of origin. For example, cancer types that show DNA mismatch repair deficiency, such as colon, biliary, and endometrial cancer, are more sensitive to immune checkpoint inhibition. Several large, ongoing clinical trials with a "basket" design are combining tumor tissue genomics with potential off-the-shelf therapies in drug development, and more tissue-agnostic biomarker therapies are reaching the bedside.
#Sportsuisse2018 – 15–16 November 2018 – Come and get a taste for the Swiss way, and have a Muesli with us
Authors: German Clénin, Boris Gojanovic
Journal: British Journal of Sports Medicine (2018)

Have you ever tasted our very special Swiss Muesli?1 The famous Swiss breakfast invented by Dr Bircher around 1900 has since crossed neighbouring borders and conquered the world, with each country adding their own ingredients to a very healthy original recipe. We love our muesli, but we also love to share with you a particular fondness for a sports medicine muesli of a different kind, the British Journal of Sports Medicine ( BJSM ).  

BJSM has nourished a community of sports medicine and physiotherapy societies, sharing the goodness, connecting people and stimulating thoughts. Just like the Swiss muesli,2  BJSM is perfect food for thought: you can enjoy it in paper sitting at your table, or can grab it as the perfect snack on-the-go, with its fantastic …
Abstract 2403: SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival
Authors: Jordan A. Cockfield, Joshua A. Mason, Zachary T. Schafer
Journal: Cancer Research (2018)

Abstract Successful metastasis requires cancer cells to overcome both anoikis -caspase dependent cell death triggered by extracellular matrix (ECM) detachment—and ECM-detachment-induced metabolic defects that compromise cell survival. While studies have begun to elucidate signal transduction cascades responsible for anoikis evasion, less is known about the precise signals cancer cells use to overcome ECM-detachment induced metabolic deficiencies. Previously, we discovered that oncogenic Ras utilizes a PI(3)K/SGK-1 signaling cascade in order to promote glucose-mediated ATP generation and survival of ECM-detached cells. We have expanded these studies and found that SGK-1 signaling is required in a variety of cell types and oncogenic backgrounds (during ECM-detachment) for glucose-derived ATP production and anchorage independent growth. Our data demonstrate that SGK-1 is required for glucose uptake due to its regulation of the GLUT1 transporter. SGK-1 appears to not only promote GLUT1 localization at the plasma membrane, but also to dramatically promote its transcription. Once inside the cell, SGK-1 promotes the flux of glucose into the glycolytic and pentose phosphate pathways (PPP). When further examining the mechanism by which SGK-1 promotes ATP generation, we surprisingly found that uncoupling the mitochondria did not impact the ability of SGK-1 to promote ATP generation. These data suggest that the TCA cycle is not required for SGK-1 mediated ATP generation. Intriguingly, ATP generation instead requires flux through the PPP and consequent production of glyceraldehyde-3-phosphate (G3P). PPP-derived G3P is shuttled back to glycolysis where ATP production robustly occurs. This metabolic pathway appears to be critical for the anchorage-independent growth of cancer cells as genetic or pharmacological disruption of glucose flux through the PPP significantly abrogates colony formation in soft agar in a variety of distinct cell lines. Overall, these data uncover a novel metabolic pathway downstream of SGK-1 that is highly conserved across multiple epithelial cancer cell lines during ECM detachment. Citation Format: Jordan A. Cockfield, Joshua A. Mason, Zachary T. Schafer. SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival [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 2403.
Significance of the QX/QT Ratio and the QT Ratio (QTr) in the Exercise Electrocardiogram
Authors: Laurianroman, Samuelbellet
Journal: Circulation (1965)

Recently, a junctional depression of small amplitude (less than 2 mm.) of the ST segment was considered to be a positive or equivocal result for the electrocardiographic exercise test if the QX/QT ratio was ⪖ 50 per cent or the QTr ⪖ 1.08. In 150 normal, young students with no clinical evidence of heart disease, a junctional depression of the ST segment with a QX/QT ratio ⪖ 50 per cent or a QTr ⪖ 1.08 or both, was observed in 22 per cent. These observations, supported by other published reports concerning the QX/QT ratio and the QTr, indicate that these criteria are not reliable for the determination of a positive electrocardiographic exercise test.