tbuckley/cabot-search huggingface dataset:
Abstract 548: Characterization of myeloid cells in bladder cancer
Authors: Neelam Mukherjee, Xiang Ru Zhao, Niannian Ji, Robert S. Svatek
Journal: Cancer Research (2016)

Abstract Both cancer-associated inflammation and tumor-mediated immune suppression have been linked with expansion of myeloid cells in multiple tumor types, including bladder [1]. We previously observed a predominance of M2-like macrophages in mouse bladder tumors [2]. However, little is known about the characteristics of these myeloid cells in human bladder cancer. In this study, we analyzed myeloid cells from tumor tissues collected from patients with muscle-invasive bladder cancer. We used flow cytometry to characterize the different subsets of these myeloid cells.Myeloid cells were identified in the bladder tissue. Our results showed that bladder cancer patients have two major CD11b+CD33+ myeloid derived suppressor cell subsets: granulocyte-type HLADR−CD15+ cells and monocyte-type HLADR+CD14+ cells. Analysis of CD45+ CD11b+cells demonstrated that bladder tumors are dominated by phenotypical M2-like (CD163+ CD80lo) CD163+ M2 macrophages. The primary treatment modality for bladder cancer is Bacillus Calmete-Guerin (BCG), a live attenuated mycobacterium that is instilled into the bladder via a urethral catheter [3]. This agent remains one of the most effective immune therapies to date. However, though it is effective in prevention of tumor recurrence, response is heterogeneous and tumor recurrence is observed in up to 50% of patients over time. The predominance of immunosuppressive myeloid cells subsets among TILs in human bladder cancer suggests myeloid cells could be potential targets for therapeutic intervention in bladder cancer. We investigated the role of macrophages in BCG therapy in the MB49 bladder cancer model. Depletion of macrophages by liposomal clodronate (LC) during MB49 tumor challenge resulted in decreased tumor growth compared to BCG monotherapy suggesting that macrophages have a critical role in BCG immunotherapy. This study characterizes these myeloid populations in bladder cancer patients and also investigates their potential role in bladder cancer development and therapeutic response. References: 1. Eruslanov, E., et al., Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. International journal of cancer. Journal international du cancer, 2012. 130(5): p. 1109-1119. 2. Svatek, R.S. et al., Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial. Clinical Cancer Research, 2015. 21(2): p. 303-11 3. Askeland, E.J., et al., Bladder Cancer Immunotherapy: BCG and Beyond. Advances in urology, 2012. 2012: p. 181987. Citation Format: Neelam Mukherjee, Xiang Ru Zhao, Niannian Ji, Robert S. Svatek. Characterization of myeloid cells in bladder 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 548.
Acupuncture: what's the point?
Authors: Adam Meakins
Journal: British Journal of Sports Medicine (2016)

Acupuncture is a widely used treatment in many different fields from pain management to sports medicine, and it often creates much discussion and debate. What actually constitutes acupuncture? Traditional Eastern acupuncture involves piercing the skin with fine filament needles at specific points located on meridians around the body to restore the flow of energy called Qi, which when blocked is believed to cause pain and dysfunction.1

However, in the Western hemisphere, acupuncture is explained in more physiological terms of local tissue inflammatory responses and descending pain inhibition. Recently, another needle-based treatment called ‘dry needling’ has grown in popularity. It places needles not into specific points on meridians but rather directly into areas that are believed to be hypertonic muscle knots or bands referred to as ‘trigger points’. Dry needling explains its effects as the disruption of these areas by the needle touching or tapping the motor end plates and other small nociceptive nerve endings in or …
Public Health England recommends vitamin D supplements in autumn and winter
Authors: Susan Mayor
Journal: BMJ (2016)

Children and adults should take a daily supplement containing 10 micrograms of vitamin D in autumn and winter to protect bone and muscle health because it is difficult to meet this intake from dietary sources, Public Health England has recommended after the Scientific Advisory Committee on Nutrition reviewed available evidence.

The Department of Health asked the committee to update the vitamin D dietary reference values for the UK population by reviewing research evidence on the vitamin’s role in musculoskeletal health, including bone mineral density, fractures, and muscle strength, as well as in non-musculoskeletal conditions such as heart disease and cancer.

The committee …
PTU-151 Risk of community-acquired pneumonia among patients with coeliac disease compared to the general population: a population based cohort study: Abstract PTU-151 Table 1
Authors: F Zingone, A Abdul Sultan, CJ Crooks, L Tata, C Ciacci, J West
Journal: Gut (2015)

<h3>Introduction</h3> Our aim was to quantify the risk of community-acquired infective pneumonia (CAP) among patients with coeliac disease (CD), vaccinated and unvaccinated against pneumococcus, compared to the general population. <h3>Method</h3> We identified all subjects with diagnosed CD within the Clinical Practice Research Datalink linked with Hospital Episodes Statistics between 1<sup>st</sup>April 1997 and 31<sup>st</sup>March 2011 and up to 10 controls per CD patient by frequency matching within 10-year age bands. We calculated rates per 1000 person-years of the first CAP among all patients with CD and controls, separately in those vaccinated and unvaccinated against pneumococcus, and in CD patients before and after their diagnosis. We used a Cox regression model to estimate the hazard ratio (HR) of pneumonia among CD patients compared to the controls. <h3>Results</h3> Among 9,803 CD patients and 101,755 controls, respectively there were 179 (1.82%) and 1864 (1.83%) CAP events. The overall rate of CAP in CD was 3.42 per 1000 person-years and 3.12 per 1000 person-years in controls. We found an increased risk of pneumonia among the unvaccinated CD patients compared to unvaccinated controls (HR 1.28, 95% CI 1.02–1.60), but not in vaccinated CD patients compared to vaccinated controls (HR 0.88, 95% CI 0.70–1.10). The increased risk in unvaccinated CD subjects was limited to those younger than 65 years, was particularly increased around the time of diagnosis (HR 2.31, 95% CI 1.03–5.19 within 1 year after diagnosis) and was maintained for more than 5 years after diagnosis (Table 1). <h3>Conclusion</h3> Unvaccinated people with CD under the age of 65 have a higher risk of CAP compared to the general population around the time of diagnosis and subsequently. Pneumococcal vaccination in people with CD following diagnosis and treatment would appear to be good medical advice. <h3>Disclosure of interest</h3> None Declared.
Creative method of removing a giant fibrovascular polyp under endoscopic guidance
Authors: Wei Jiang, Yongjun Wang, Peng Li, Fujing Lv, Wei Li, Ming Ji, Shutian Zhang
Journal: Endoscopy (2016)

A 59-year-old man was admitted to the Beijing Friendship Hospital with progressive dysphagia for solid foods. He had been coughing for 20 days, which resulted in the repeat regurgitation of the polyp into his mouth followed by swallowing of the polyp [1]. Results of laboratory tests on admission were negative.
Stimulating therapy for obstructive sleep apnoea
Authors: Patrick J Strollo, Atul Malhotra
Journal: Thorax (2016)

The burden of obstructive sleep apnoea (OSA) is increasing due to the worldwide obesity epidemic and the ageing of the population.1 ,2 The treatment of OSA is unsatisfactory for some patients since tolerance of the gold standard treatment positive airway pressure (PAP) is quite variable. Among patients who tolerate PAP, results are excellent; however, effectiveness is limited by variable adherence.3 ,4 Improvements in our understanding of OSA pathogenesis have led to a concept that the mechanism (endotype) underlying OSA is highly variable across individuals such that some patients have primarily an upper airway anatomical problem, whereas others have dysfunction in upper airway dilator muscles, some have unstable control of breathing and some may have combinations of abnormalities.1 This realisation has led to the concept of personalised medicine in OSA such that therapies could theoretically be targeted to the mechanism underlying apnoea rather than using a ‘one-size-fits-all’ approach.5

Efforts to improve treatment are ongoing by developing new therapeutic approaches (eg, hypoglossal nerve stimulation).6 ,7 This approach augments the neural output to upper airway …
Abstract 4015: Exposure of lymphatic endothelial cells to ionizing radiation increases the surface expression levels of integrin ligands
Authors: Maria E. Rodriguez-Ruiz, Saray Garasa, Inmaculada Rodriguez, Alba Yanguas, Álvaro Teijeira, Ignacio Melero, Ana Rouzaut
Journal: Cancer Research (2016)

Abstract Radiotherapy has been proven an efficacious tool to combat cancer by directly destroying tumor cells. However, effects of radiotherapy have been also described that occur through the re-education of the immune tumor microenvironment, being leukocyte traffic regulation across the tumor vasculature of key importance. Here, we address the effects that radiotherapy may be causing on the adhesive properties of the tumor lymphatic vasculature. To study this, we irradiated primary and immortalized human and murine lymphatic endothelial cells grown in vitro, and fresh tumor explants obtained from colon cancer patients. As a result, we observed dose- and time- dependent increases in the expression of the integrin counter-receptors ICAM-1 and VCAM on the surface of the tumor lymphatic endothelial cells. These effects are also observed in vivo on colon (MC38) and melanoma (B16) tumors transplanted into syngeneic mice and irradiated with a single dose of 20 Gy. These findings are consistent with increased ICAM-1 and VCAM expression levels on Lymphatic endothelial cells in tumor biopsies from cancer patients which were taken before and four weeks after fractionated radiotherapy, including head and neck, colon and oropharyngeal human carcinomas. While the TGFβ pathway was found to be involved in these effects, NF-κB inhibitors did not hamper ICAM-1 or VCAM induction. In summary, these results show ICAM-1 and VCAM surface expression was enhanced on lymphatic vessels after radiotherapy and may explain differential leukocyte traffic following irradiation. Citation Format: Maria E. Rodriguez-Ruiz, Saray Garasa, Inmaculada Rodriguez, Alba Yanguas, Álvaro Teijeira, Ignacio Melero, Ana Rouzaut. Exposure of lymphatic endothelial cells to ionizing radiation increases the surface expression levels of integrin ligands. [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 4015.
Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death
Authors: Robert Esterberg, Tor Linbo, Sarah B. Pickett, Patricia Wu, Henry C. Ou, Edwin W. Rubel, David W. Raible
Journal: Journal of Clinical Investigation (2016)

Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure.
Abstract 4429: CCL20 regulation via TGFB /BMP signaling pathway in murine immortalized colonocytes and colonic epithelium
Authors: Tasia D. Brown, Anna Means, Tanner Freeman, Connie Weaver, Keith Wilson, R. Daniel Beauchamp.
Journal: Cancer Research (2016)

Abstract TGFβ and BMP signaling through receptor-mediated activation of SMAD proteins is crucial for normal homeostasis in intestinal epithelium. Alterations in this pathway contribute to the development of colorectal cancers. To understand the role of these pathways in homeostasis of the colon we conditionally deleted loxP-flanked alleles of Smad4 in adult mouse colon. We used Lrig1CreERT allele to achieve greater than 80% SMAD4 gene deletion and a CK19CreERT allele for mosaic deletion in colonic epithelium. Our data indicates that SMAD4 activity regulates multiple interactions between intestinal epithelium cells and surrounding stroma and that deletion of SMAD4 in adult mouse colonic epithelial cells alters expression of cytokines, increases immune cell infiltration and predisposes mice to tumorigenesis. Increases in the chemokine CCL20 have been reported in CRC tumors beginning at the adenoma stage and it may regulate both Tregs and Th-17 cells in an active immune response. Luminex cytokine/chemokine array analysis revealed increased levels of CCL20 protein in colonic mucosa and RNAseq data revealed that when SMAD4 is knocked out in the epithelium there is an upregulation of CCL20 and CCR6 (receptor) mRNA in the epithelium and stroma, respectively. To further explore the regulation of CCL20, we used immortalized mouse colonocytes (IMC cells) to further determine how the TGFβ and BMP signaling pathways may be involved in CCL20 expression. We found that CCL20 mRNA expression was suppressed by TGFβ1 and BMP2 and increased by inhibitors of these pathways. The inhibition of CCL20 by the TGFβ and BMP2 pathways occurs even in the presence of a known strong inducer of CCL20, such as TNFα. We have further observed in mice induced to undergo deletion of SMAD4 in the intestinal epithelium that treatment with DSS results in 100% of mice developing mucinous adenocarcinomas in the distal colon. We conclude that ligand-dependent Smad4-mediated signaling provides important negative homeostatic regulation of CCL20 expression in colonic epithelium. Loss of Smad4 results in increased CCL20 expression and we are currently testing the hypothesis that CCL20 overexpression contributes to the inflammation induced carcinogenesis in this mouse model. Citation Format: Tasia D. Brown, Anna Means, Tanner Freeman, Connie Weaver, Keith Wilson, R. Daniel Beauchamp. CCL20 regulation via TGFB /BMP signaling pathway in murine immortalized colonocytes and colonic epithelium. [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 4429.
Abstract 1571: PTEN is an important mediator of tumor and glia cell crosstalk in breast cancer brain metastasis
Authors: Harriet Wikman, Ina Hohensee, Han-Ning Chuang, Astrid Grottke, Stefan Werner, Alexander Schulte, Jakob Matschke, Markus Glatzel, Stefan Horn, Manfred Jücker, Tobias Pukrop, Klaus Pantel
Journal: Cancer Research (2016)

Abstract With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Loss of Phosphatase and tensin homolog (PTEN) is correlated with occurrence of breast cancer brain metastases, but its functional role in metastases formation remains unclear. Here, we first assessed the clinical role of PTEN expression in brain metastases, by performing immunohistochemical analyses on a TMA consisting of 132 breast cancer brain metastases samples. Loss of PTEN protein expression was found in 48.6% of brain metastases, and significantly associated with the triple-negative breast cancer subtype (67.5%, p = 0.01). Loss of PTEN was furthermore significantly associated with shorter overall survival (p = 0.048). We then investigated the biological role of PTEN in breast cancer brain metastasis formation by overexpressing PTEN in the triple-negative brain metastatic breast cancer cell cline MDA-MB-231 BR. Overexpression of PTEN was shown to reduce the AKT pathway activation especially by reducing the Akt1 kinase activity. Coculture experiments with glia cells (astrocytes and microglia) showed that astrocytes can inhibit cell proliferation of the tumor cells in a PTEN dependent manner. Both astrocytes and microglia promote migration of MDA-MB-231 BR cells in a PTEN-dependent manner in vitro. Using an organotypic brain slice model as a representation of the brain tumor microenvironment, the PTEN-dependent invasion of tumor cells could be confirmed. Furthermore, PTEN overexpression reduced the astrocyte activation. Coculture experiments with glia cells showed PTEN-dependent, differential cytokine expression. We could identify an endocrine and paracrine regulation between tumor cells and astrocytes, where GM-CSF, CSF2RA, EGF and PTEN play an important role. In conclusion, loss of PTEN is associated with poor prognosis and is an important mediator of a “vicious circle” mediated by the cross talk between tumor cells and glia cells. Citation Format: Harriet Wikman, Ina Hohensee, Han-Ning Chuang, Astrid Grottke, Stefan Werner, Alexander Schulte, Jakob Matschke, Markus Glatzel, Stefan Horn, Manfred Jücker, Tobias Pukrop, Klaus Pantel. PTEN is an important mediator of tumor and glia cell crosstalk in breast cancer brain metastasis. [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 1571.
Abstract 2768: Global DNA hypomethylation is an important feature of melanoma
Authors: Goran Micevic, Nicholas Theodosakis, Janis M. Taube, Marcus W. Bosenberg, Nemanja Rodic
Journal: Cancer Research (2016)

Abstract Aberrant DNA methylation occurs nearly universally in cancer. Paradoxically, changes in DNA methylation are bi-directional: there is a focal increase in DNA methylation (hypermethylation), and a global overall decrease in DNA methylation (hypomethylation). Focal hypermethylation plays well described roles in silencing tumor suppressor genes in many malignancies, including melanoma. However, the functional role of global hypomethylation in tumorigenesis is relatively poorly understood. Melanoma is the deadliest form of skin cancer, accounting for approximately 74,000 new cases and 10,000 deaths in the United States in 2015. Changes in DNA methylation are also arguably one of the most common features of melanoma. Similar to other malignancies, most studies have focused on focal hypermethylation, identifying genomic loci differentially methylated between melanocytes and melanoma cells. However, global changes in DNA methylation have not been well described thus far. In this study, we describe global changes in DNA methylation in two melanoma clinical cohorts (JHH cohort, n = 13 nevi and n = 39 melanomas; NCI cohort n = 31 nevi and n = 97 melanomas) relative to benign nevi using a semi-quantitative immunohistochemistry based assay. We report a global decrease in DNA methylation levels in melanoma relative to benign melanocytic nevi consistent between both cohorts (p &amp;lt; 0.001, Student's t-test). Furthermore, we studied the functional effect of increasing the level of global DNA methylation in a panel of five early passage melanoma cell lines. Increases in global DNA methylation suppressed proliferation of melanoma cells (p &amp;lt;0.05, Student's t-test), and increased the proportion of apoptotic cells (p &amp;lt;0.01, Student's t-test). Global DNA hypomethylation is thus an important epigenetic feature of melanoma that may regulate proliferative capacity, and merits further investigation. Citation Format: Goran Micevic, Nicholas Theodosakis, Janis M. Taube, Marcus W. Bosenberg, Nemanja Rodic. Global DNA hypomethylation is an important feature of melanoma. [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 2768.
NHS England plans to heal relations between government and junior doctors
Authors: Adrian O’Dowd
Journal: BMJ (2016)

NHS England has concerns over the morale of NHS staff and will look again at the work conditions and training arrangements of junior doctors, NHS leaders have told MPs.

Relations have been strained by the recent industrial dispute and the government’s decision to impose a new contract on junior doctors later this summer despite that contract being rejected by a majority of junior doctor BMA members in a ballot.

MPs asked witnesses from NHS England, appearing before the parliamentary health committee during an evidence session on 19 July, what steps were being taken to improve relations.

Bruce Keogh, national medical director for NHS England, said that while NHS England had not been a party to any of the junior doctors’ contract negotiations he was “concerned about morale in the medical profession at the moment.”

He said, “The junior doctors are a young generation with a different set …