tbuckley/cabot-search huggingface dataset:
Characterization of recombinant <i>Trypanosoma brucei gambiense</i> Translationally Controlled Tumor Protein (r<i>Tbg</i>TCTP) and its interaction with <i>Glossina</i> midgut bacteria
Authors: Géraldine Bossard, Manon Bartoli, Marie-Laure Fardeau, Philippe Holzmuller, Bernard Ollivier, Anne Geiger
Journal: Gut Microbes (2017)

In humans, sleeping sickness (i.e. Human African Trypanosomiasis) is caused by the protozoan parasites Trypanosoma brucei gambiense (Tbg) in West and Central Africa, and T. b. rhodesiense in East Africa. We previously showed in vitro that Tbg is able to excrete/secrete a large number of proteins, including Translationally Controlled Tumor Protein (TCTP). Moreover, the tctp gene was described previously to be expressed in Tbg-infected flies. Aside from its involvement in diverse cellular processes, we have investigated a possible alternative role within the interactions occurring between the trypanosome parasite, its tsetse fly vector, and the associated midgut bacteria. In this context, the Tbg tctp gene was synthesized and cloned into the baculovirus vector pAcGHLT-A, and the corresponding protein was produced using the baculovirus Spodoptera frugicola (strain 9) / insect cell system. The purified recombinant protein rTbgTCTP was incubated together with bacteria isolated from the gut of tsetse flies, and was shown to bind to 24 out of the 39 tested bacteria strains belonging to several genera. Furthermore, it was shown to affect the growth of the majority of these bacteria, especially when cultivated under microaerobiosis and anaerobiosis. Finally, we discuss the potential for TCTP to modulate the fly microbiome composition toward favoring trypanosome survival.
Inactivation of the SETD2 Tumor Suppressor Gene in Mast Cell Leukemia
Authors: Simona Soverini, Caterina De Benedittis, Michela Rondoni, Manuela Mancini, Cristina Papayannidis, Viviana Guadagnuolo, Elisa Leo, Luca Zazzeroni, Raffaele Calogero, Elisa Zago, Anna Scandola, Marianna Garonzi, Alberto Ferrarini, Paolo Savini, Oliviero Quercia, Livio Pagano, Roberta Zanotti, Omar Perbellini, Giorgina Specchia, Serena Merante, Chiara Elena, Domenica Gangemi, Giovanni Poletti, Massimo Delledonne, Sabine Cerny-Reiterer, Michele Cavo, Peter Valent, Giovanni Martinelli
Journal: Blood (2014)
The impact of quality and quantity of visceral fat on survival outcome of early-stage breast cancer patients with prior chemotherapy.
Authors: Toshiaki Iwase, Takafumi Sangai, Masahiro Sakakibara, Takeshi Nagashima, Masayuki Ohtsuka
Journal: Journal of Clinical Oncology (2017)

584 Background: Obesity not only increases morbidity, but also chemo-resistance of breast cancer (BC). Several studies focusing on body mass index (BMI) of BC patients have been performed; however, a recent report suggested that the quality of visceral adipose tissue (VAT) plays a crucial role in fat cell function. We set out to clarify the effect of quality and quantity of VAT on survival outcome of BC patients who underwent chemotherapy. Methods: From 2,230 patients who underwent treatment for BC at our institution from January 2004 to December 2015, we included 271 patients who received chemotherapy in neo-adjuvant (NAC) or adjuvant setting. Quantification was performed using computed tomography (CT) 3-dimensional volumetric software and quality of VAT was assessed based on the CT Hounsfield Unit of VAT (VAT-HU) using electrically stocked CT images. The correlation between BMI, amount of VAT (aVAT), and VAT-HU were analyzed using Pearson’s correlation test. The effect of these factors on pathologic complete response (pCR) was evaluated using Logistic regression model with the following covariates: menopausal status, size, nodal status, and subtype. Furthermore, survival analysis for distant disease-free survival (DDFS) was performed using Kaplan Meier method and Cox proportional hazard model. Results: aVAT and VAT-HU were significantly correlated with patient BMI (p&lt;0.05). Forty-six patients achieved pCR (24%). Logistic regression model for pCR showed that aVAT and VAT-HU did not affect pCR (p=0.60 and 0.36). After a median follow-up of 112 months, tertile stratification revealed that the third tertile of aVAT had significantly shorter DDFS in the NAC setting (p&lt;0.05). When adjusted by covariates in the Cox proportional regression model, aVAT and VAT-HU demonstrated significant contribution to worse DDFS ([p&lt;0.05, hazard ratio {HR} 1.39; 95% confidence interval {CI} 1.11 to 1.75] and [p&lt;0.05, HR 1.20, 95% CI 1.01 to 1.43], respectively). Conclusions: The quantity and quality of VAT was significantly related to the survival outcome especially in the NAC setting. This new insight would enable prediction of recurrence risk in obese BC patients with prior chemotherapy.
08.02 Alpha-enolase promotes pro-inflammatory phenotype of monocytes-derived macrophages in vitro
Authors: Manuel Fréret, Pascal Rottenberg, Sébastien Calbo, Thierry Lequerré, Olivier Vittecoq
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatism. RA is multifactorial involving genetic, environmental, endocrine, psychological and immunological factors. In 2002, our research team has discovered alpha-enolase (ENO1) as an autoantigen in RA and has recently demonstrated its effect on monocytes, inducing inflammation mediated through CD14-dependent TLR4 signalling pathway. Monocytes can differentiate into dendritic cells, osteoclasts or macrophages. Macrophages are involved in RA pathophysiology and can be polarised in different phenotypic profiles, pro-inflammatory (M1 macrophages) or immuno-regulatory (M2 macrophages). The main objective of this study was to determine the effect of ENO1 on monocytes differentiation into macrophages and on their polarisation. <h3>Materials and methods</h3> Monocytes of healthy donors were cultured with M-CSF (Macrophage-Colony Stimulating) or GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) for 5 days for their differentiation into macrophages and for 3 supplemental days with IFN-γ and/or LPS or IL-4 and/or IL-10 for M1 or M2 polarisation respectively. Monocytes and monocytes-derived macrophages were also cultured with recombinant ENO1 (produced in <i>E. coli</i>), or control BSA, to investigate its effect on monocytes differentiation and macrophages polarisation. Microscopy, flow cytometry and ELISA were performed to determine the macrophages polarisation profile (M1 or M2) induced by ENO1. <h3>Results</h3> Firstly, we showed that ENO1 did not induce monocytes differentiation into macrophages in contrast to M-CSF and GM-CSF. However, in macrophages differentiated with M-CSF or GM-CSF, ENO1 induces M1 polarisation in terms of morphology, surface markers and cytokines production. ENO1 can also initiate repolarization in M1 of macrophages previously polarised in M2. Finally, we showed that ENO1 induced a cytokine inflammatory response higher in macrophages differentiated with GM-CSF compared to M-CSF. <h3>Conclusions</h3> These results showed for the first time the potential role of native ENO1 in the inflammatory process of RA through its interaction with macrophages, promoting their polarisation into pro-inflammatory M1 profile. Our project, aimed to understand the role ENO1 in RA pathophysiology, opens interesting research perspectives on cell types derived from monocytes.
Margaret McCartney: Prescribing incentives feel grubby because they are
Authors: Margaret McCartney
Journal: BMJ (2017)

Last week it emerged that Oxfordshire Clinical Commissioning Group has suggested that GPs should review patients in nursing homes and “rationalise” prescribing. If enough drugs are stopped or switched to meet the threshold, the GPs keep half the cash saved. Cue righteous outrage from the national press.1 It feels grubby because it is.

There’s little doubt that incentive programmes, particularly the Quality and Outcomes Framework in general practice, have led to reflex prescribing and overprescribing. Doctors must satisfy their paymasters’ suspicions in justifying why they haven’t prescribed,2 rather than why they have. Yet clear evidence shows that single disease guidelines for …
Abstract AP21: LIPID DESATURATION IS A METABOLIC MARKER AND THERAPEUTIC TARGET OF OVARIAN CANCER STEM CELLS
Authors: Junjie Li, Salvatore Condello, Jessica Thomes-Pepin, Xiaoxiao Ma, Yu Xia, Thomas D. Hurley, Ji-Xin Cheng, Daniela Matei
Journal: Clinical Cancer Research (2017)

Abstract OBJECTIVES: Lack of sensitive single-cell analysis tools has limited the characterization of the metabolic activity of cancer stem cells (CSCs). The objectives of this study were to identify and target metabolic pathways specifically deregulated in ovarian CSCs. METHODS: We developed a new technique based on hyperspectral stimulated Raman scattering imaging of single living cells coupled with electrospray ionization mass spectrometry (ESI-MS) analysis of extracted lipids to identify unique metabolic spectra of ovarian CSCs. SiRNA knockdown and pharmacological inhibitors were used to block fatty acid desaturases and to measure effects on the ovarian CSCs charcateristics. RESULTS: We report significantly increased levels of unsaturated lipids in flow-sorted ovarian CSCs (ALDH+CD133+) compared to non-CSCs (ALDH-CD133-). Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells derived from human ovarian tumors. ESI-MS identified that the elevated unsaturation in lipid droplets involved an enhanced conversion from saturated fatty acids (18:0) to unsaturated fatty acids (18:1). Expression of fatty acid desaturases was increased in ovarian CSCs compared to non-CSCs. Pharmacological inhibition or siRNA knockdown of lipid desaturases Δ9 (SCD1) or Δ6 effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo, as measured by a tumor initiation dilution assay. Mechanistically, the lipid desaturase inhibitors suppressed ovarian cancer cell stemness by blocking the NF-κB survival pathway. Chromatin immunoprecipitation and overexpression of RelA demonstrated that NF-κB transcriptionally regulates SCD1 expression. Collectively, our data suggest that a positive feedback loop involving lipid desaturases, NF-κB, and the stem cell marker ALDH1 can be effectively blocked by SCD1 inhibitors, suppressing ovarian CSCs. CONCLUSIONS: These results demonstrate that increased lipid unsaturation is a novel metabolic marker for ovarian CSCs and a target for CSC-specific therapy. Citation Format: Junjie Li, Salvatore Condello, Jessica Thomes-Pepin, Xiaoxiao Ma, Yu Xia, Thomas D. Hurley, Ji-Xin Cheng, Daniela Matei. LIPID DESATURATION IS A METABOLIC MARKER AND THERAPEUTIC TARGET OF OVARIAN CANCER STEM CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP21.
Abstract P251: Mechanical Stretch Induces Phosphorylation of Cardiac Myosin Binding Protein-C
Authors: Yang Liu, Hao Feng, FNU Gerilechaogetu, Sakthivel Sadayappan, David E Dostal, Carl W Tong
Journal: Circulation Research (2011)

Normal hearts increase contractile force in response to mechanical stretch caused by increasing volume. Although this phenomenon has been extensively studied from myofilaments’ spacing perspective, possible coupling of mechanical-sensing signaling to modulation of myofilament function remains unknown. Cardiac myosin binding protein-C (MyBPC3) is a component of heart muscle thick filament. Phosphorylation of MyBPC3 releases its inhibition on cross-bridge cycling to increase cardiac contractility. Thus, we postulate that mechanical stretch of the myocardium causes phosphorylation of MyBPC3 to increase contractility. We tested this hypothesis by performing static stretch of 20% from baseline on cultured neonatal rat cardiac myocytes (NRCM) at durations of 2, 5, 15, 30, and 60 minutes. NRCM culture provides the advantage of cells living in an environment free of adrenergic stimulation to avoid catecholamine stimulation mediated phosphorylation of MyBPC3. Site-specific phospho-serine antibodies were used to detect phosphorylation of rat equivalent of S282 and S302 of mouse MyBPC3. We used MyBPC3 antibody made from a different species than site-specific phospho-serine antibodies to account for loading. S282P transiently peaked after 5 minutes of stretch, whereas S302P continued to increase with time through 60 minutes (see figure ). Consequently, our data show that mechanical stretch alone can cause phosphorylation of MyBPC3 as a mechanism that couples different signaling pathways to myofilament function.
Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR : a randomised, placebo-controlled phase 3 trial
Authors: Felix Ratjen, Christopher Hug, Gautham Marigowda, Simon Tian, Xiaohong Huang, Sanja Stanojevic, Carlos E Milla, Paul D Robinson, David Waltz, Jane C Davies, Margaret Rosenfeld, Timothy Starner, George Retsch-Bogart, James Chmiel, David Orenstein, Carlos Milla, Ronald Rubenstein, Seth Walker, Alexandra Cornell, Fadi Asfour, Philip Black, John Colombo, Deborah Froh, Susanna McColley, Fadel Ruiz, Diana Quintero, Alicia Casey, Gary Mueller, Patrick Flume, Floyd Livingston, Michael Rock, Brian O'Sullivan, Howard Schmidt, Thomas Lahiri, John McNamara, Aaron Chidekel, Laura Sass, Thomas Keens, David Schaeffer, Melinda Solomon, Mark Chilvers, Larry Lands, Sibylle Junge, Matthias Griese, Doris Staab, Tacjana Pressler, Silke van Koningsburggen-Rietschel, Lutz Naehrlich, Alastair Reid, Ian Balfour-Lynn, Don Urquhart, Timothy Lee, Anne Munck, Isabelle Sermet Gaudelus, Christiane De Boeck, Philippe Reix, Anne Malfroot, Stéphanie Bui, Hiranjan Selvadurai, Philip Robinson, Claire Wainwright, Barry Clements, Jodi Hilton, Lena Hjelte
Journal: The Lancet Respiratory Medicine (2017)
Dynamic relationship between cycling kinetics of triple-negative breast cancer and tumor infiltrating immune cells.
Authors: Ishita Choudhary, Sergey Klimov, Padmashree C.G. Rida, Angela Ogden, Andrew R. Green, Mohammed A. Aleskandarany, Emad A. Rakha, Ian O. Ellis, Elia Biganzoli, Surojit Sarkar, Vandana Kalia, Ritu Aneja
Journal: Journal of Clinical Oncology (2017)

1100 Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.
Obstructive sleep apnoea and related comorbidities in incident idiopathic pulmonary fibrosis
Authors: Thomas Gille, Morgane Didier, Marouane Boubaya, Loris Moya, Angela Sutton, Zohra Carton, Fanny Baran-Marszak, Danielle Sadoun-Danino, Dominique Israël-Biet, Vincent Cottin, Frederic Gagnadoux, Bruno Crestani, Marie-Pia d'Ortho, Pierre-Yves Brillet, Dominique Valeyre, Hilario Nunes, Carole Planès
Journal: European Respiratory Journal (2017)

The objectives of this prospective study were: 1) to determine the prevalence and determinants of obstructive sleep apnoea (OSA) in patients with newly diagnosed idiopathic pulmonary fibrosis (IPF); 2) to determine whether OSA was associated with cardiovascular disease (CVD) as well as increased oxidative stress and levels of IPF biomarkers in the blood.A group of 45 patients with newly diagnosed IPF attended polysomnography. The prevalence of CVD and the severity of coronary artery calcification were investigated by high-resolution computed tomography. The levels of 8-hydroxydeoxyguanosine (8-OH-DG) and various IPF biomarkers in the blood were compared between patients with no or mild OSA (apnoea-hypopnoea index (AHI) <15 events·h-1), with moderate OSA (15 ≤AHI <30 events·h-1) and with severe OSA (AHI ≥30 events·h-1).The prevalence of moderate-to-severe OSA and severe OSA was 62% and 40%, respectively. AHI did not correlate with demographic or physiological data. All patients with severe OSA had a medical history of CVD, versus 41.2% and 40% of those with no or mild OSA, or with moderate OSA, respectively (p<0.0001). Ischaemic heart disease (IHD) and moderate-to-severe coronary artery calcifications were strongly associated with severe OSA. The 8-OH-DG and matrix metalloproteinase-7 serum levels were significantly increased in the severe OSA group.Moderate-to-severe OSA is highly prevalent in incident IPF and severe OSA is strongly associated with the presence of CVD, particularly IHD.
Results for Phase II Clinical Trial of LCL161, a SMAC Mimetic, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF) or Post-Essential Thrombocytosis Myelofibrosis (post-ET MF)
Authors: Naveen Pemmaraju, Bing Z Carter, Hagop M. Kantarjian, Jorge E. Cortes, Tapan M. Kadia, Guillermo Garcia-Manero, Courtney D DiNardo, Prithviraj Bose, Sherry Pierce, Lingsha Zhou, Zeev Estrov, Carla Kay Tuttle, Karina Salinas, Po Yee Mak, Srdan Verstovsek
Journal: Blood (2016)
Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).
Authors: Chee Khoon Lee, Clare L. Scott, Geoffrey John Lindeman, Emma Gibbs, Heath D. Badger, Robin John Paterson, Lauren Macnab, Edmond Michael Kwan, Frances M. Boyle, Michael Friedlander
Journal: Journal of Clinical Oncology (2017)

1104 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8 th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.
Development of a breast and lung cancer research panel to target therapeutically relevant copy number and gene fusion variants from blood.
Authors: Varun Bagai, Jeoffrey Schageman, Dumitru Brinza, Yanchun Li, Jian Gu, Kelli Bramlett
Journal: Journal of Clinical Oncology (2017)

e12518 Background: With recent advances in next-generation sequencing (NGS) technologies, it is now possible to detect somatic mutations with allele frequencies in blood samples as low as 0.1% from circulating tumor DNA. A natural extension to this achievement is adding the ability to simultaneously detect copy number variants and gene fusions. A panel such as this addresses a full repertoire of variant classes found to be linked with certain tumors and would enable researchers additional tools to profile cancer samples more dynamically thus enriching current diagnostic tool sets. Here, we present progress on such an approach and apply current NGS technology to achieve our goals. Methods: Samples were sequecned using the Ion S5™ system. Results: Using control samples, we can reproducibly demonstrate detection of ERBB2 (HER2/neu) gene amplifications with high statistical significance and as low as a 2 fold difference versus non-amplified loci in titration experiments. In addition, this ERBB2 gene amplification was detected in the context of a validated breast cancer somatic mutation panel in which no negative impact was exhibited and mutation detection specificity and sensitivity were both greater than 90%. Lastly, we developed an additional panel to detect gene fusions relevant to lung cancer. Using the titration approach above, the EML4-ALK fusion variant was shown to have a limit of detection near 1% with no negative impact on detection sensitivity and specificity when combined with the validated lung cfDNA somatic mutation panel. Conclusions: From the outcomes of these experiments, we have shown the ability to reproducibly and simultaneously detect copy number and gene fusion variants as well as somatic mutations at very low limits of detection in a cell free DNA background derived from blood samples.