tbuckley/cabot-search huggingface dataset:
Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma
Authors: Takahiko Otsuki, Taku Nakashima, Hironobu Hamada, Yusuke Takayama, Shin Akita, Takeshi Masuda, Yasushi Horimasu, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Yoshihiro Miyata, Masayuki Miyake, Nobuoki Kohno, Morihito Okada, Noboru Hattori
Journal: European Respiratory Journal (2018)

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear. In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells. High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone. Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.
Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer
Authors: Rasmi R. Mishra, Nevin Belder, Suhail A. Ansari, Merve Kayhan, Hilal Bal, Umar Raza, Pelin G. Ersan, Ünal M. Tokat, Erol Eyüpoğlu, Özge Saatci, Pouria Jandaghi, Stefan Wiemann, Ayşegül Üner, Caglar Cekic, Yasser Riazalhosseini, Özgür Şahin
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo. Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987–2001. ©2018 AACR.
Abstract P2-01-07: Isolation of viable CTCs from leukapharesis product with parsortix system enables subsequent culture
Authors: H Neubauer, A Franken, C Driemel, R Lampignano, B Behrens, F Reinhardt, D Niederacher, NH Stoecklein, JC Fischer, T Fehm
Journal: Cancer Research (2018)

Abstract Background: Solid tumors are constantly releasing circulating tumor cells (CTCs) into the circulatory system. They are genotypically and phenotypically different from the primary tumor. Especially viable CTCs can be of high interest to obtain further therapeutically relevant information. Their extremely low frequency is one of the main limiting factors to use them for further characterization. To overcome this challenge we tested to isolate viable CTCs from diagnostic leukapharesis (DLA) products obtained from breast cancer patients. Material/methods: 16 DLA samples and matched peripheral blood (PB) samples of metastasized breast cancer patients were collected and CTC numbers were determined by CellSearch® analysis. Viable cells were enriched from DLA product with Parsortix system. Genomic DNA of single cultured CTCs was isolated and amplified by whole genome amplification. Array-based comparative genomic hybridization of single cells was performed to analyze for genomic aberrations. Resulting profiles were compared to genomic aberration profiles of CTCs isolated before in vitro culture. Results: CTCs were detected in ten PB and matched DLA samples and in three more DLA samples whose corresponding blood samples were CTC-negative. CTC number per ml was increased by an average of 22.5 fold. Parsortix was optimized to enrich tumor cells from DLA product while keeping them best viable. An enrichment rate of 67.7% ± 11.3% and a harvesting rate of 65.3% ± 9.7% were determined with spiked MCF7 cells. We could grow viable CTCs from three out of eight CTC positive DLA samples from metastasized patients as determined by immune fluorescence analysis. The growing cells harbor genomic anomalies confirming their malignant origin. Most aberrations are widely identical to the aberrations detected in uncultured CTCs. Conclusions: DLA provides greater numbers of viable CTCs which can be enriched with Parsortix system in order to enable their in vitro cultivation. This workflow will allow functional studies. Citation Format: Neubauer H, Franken A, Driemel C, Lampignano R, Behrens B, Reinhardt F, Niederacher D, Stoecklein NH, Fischer JC, Fehm T. Isolation of viable CTCs from leukapharesis product with parsortix system enables subsequent culture [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-07.
Six in 10 GPs are considering early retirement, BMA survey finds
Authors: Abi Rimmer
Journal: BMJ (2014)

Nearly six in every 10 GPs are considering early retirement, and over half (54.1%) say that their current workload is unmanageable, a survey carried out by the BMA shows.1

Almost half those surveyed (47%) said that they always worked or trained outside their regular hours, and 37.2% did so often. Too much work was the reason 92.5% of respondents gave for working overtime, while nearly a fifth (19.6%) cited staff shortages.

The online survey was based …
Seven nights in row to end for junior doctors in Scotland, government says
Authors: Abi Rimmer
Journal: BMJ (2014)

Junior doctors in Scotland will no longer work seven full night shifts in a row, the Scottish government has said.

In a letter to NHS health boards, Paul Grey, chief executive of NHS Scotland, set out several initiatives to reduce junior doctors’ working hours. The letter said that NHS boards will by February 2015 end the practice of rostering junior doctors for seven full night shifts in a row.

It said that boards will simplify the process for monitoring working hours and review rotas with a view to …
P034 Cell surface sialylation of B-cell subsets from patients with rheumatoid arthritis
Authors: L Johnston, L Ouboussad, A Aslam, MH Buch
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> B-cells have a well-established role in the pathogenesis of rheumatoid arthritis (RA), illustrated by the successful treatment of RA with B-cell depletion therapy.<sup>1</sup>Sialic acid (SA) is a 9-carbon backbone sugar involved in many immune system functions including cell migration, adhesion and activation.<sup>2</sup> In RA, sialylation of the B-cell surface, including membrane bound IgM, has been found to differ from healthy control B-cells. These changes have been attributed to alterations in antibody glycosylation which lead to the highly inflammatory phenotype of disease-specific autoantibodies.<sup>3</sup> Recently it has been shown that surface glycosylation of regulatory T-cells is altered by activating stimuli – suggesting functional consequences for cell surface glycans.<sup>4</sup> Functional effects of surface glycans in B-cells in RA have not been well established. <h3>Objectives</h3> The aim of this study is to investigate surface sialylation of B-cells from patients with RA at different stages of disease, and to examine functional consequences of B-cell surface sialylation. <h3>Methods</h3> Sialylation of peripheral blood mononuclear cells isolated from 7 patients with either 'pre-RA' or RA (3 patients with ACPA+ 'pre-RA', 1 patient with a diagnosis of new onset, ≤12 months symptom duration, and 3 patients with established disease) was analysed by flow cytometry using biotinylated Sambucus Nigra (SNA) Lectin, to bind to α2,6 SA, with PE-conjugated streptavidin. MESF beads were used to standardise the measurement of fluorescence intensity. B-cells were activated in culture with anti-CD40 and anti-IgM. <h3>Results</h3> Initial data suggests that B-cell surface sialylation may be higher in patients with pre-RA (MESF: 13765±170) or new onset RA (13094) than in patients with established RA (12431.3±339). Sialylation also tended to be higher on plasmablasts (1396±991) than on memory (13067±496) or naïve B-cells (13127±710). Upon <i>in vitro</i> activation with anti-CD40 and anti-IgM, sialylation tended to decrease in plasmablasts (20042±679 vs 16200.5±1261). <h3>Conclusions</h3> Preliminary results suggest that B-cell surface sialylation may vary according to stage of disease and B-cell subset. Sialylation may also be related to B-cell activation. Further investigations will be carried out to better understand variations in surface sialic acid and examine the relationship between B-cell function and surface sialylation. <h3>References</h3> . Mok CC. Drug Des Devel Ther2014;8:87–100. . Varki A, Gagneux P. Ann N Y Acad Sci2012;1253(1):16–36. . Pfeifle R, et al. Nature Immunology2017;18:1. . Cabral J, et al. Frontiers in Immunology2017;8:987. <h3>Disclosure of interest</h3> None declared
Time to Rethink the Approach to Treating Acute Respiratory Distress Syndrome
Authors: Luciano Gattinoni, John J. Marini, Michael Quintel
Journal: JAMA (2018)

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Sensitization of neuroendocrine prostate cancer by RRx-001.
Authors: Donna Peehl, Honguan Zhao, Shoucheng Ning
Journal: Journal of Clinical Oncology (2018)

280 Background: RRx-001 is a first-in-class dinitroazetidine nontoxic anticancer agent. Its actions include upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis, epigenetic modulation and induction of viral mimicry. In a phase II clinical study (NCT02489903), RRx-001 reversed resistance to reintroduced platinum doublets in small cell lung cancer (SCLC) and other tumor types. RRx001 demonstrated clinical activity with a complete metabolic response of metastatic castration-resistant neuroendocrine prostate cancer (NEPC) after treatment with RRx-001 and reintroduced platinum doublets. Here, we used a preclinical model to further investigate RRx-001 sensitization of NEPC to platinum therapy. Methods: NCI-H660 spheroids were pre-treated with 1 mM RRx-001 or vehicle prior to treatment with carboplatin or docetaxel and cell proliferation was assessed. Cells were also pre-treated with both 1 mM RRx-001 and 10 mM N-acetyl cysteine (NAC) or 1 mM Buthionine-S,R-sulfoximine (BSO) to investigate the role of reactive oxygen species (ROS) in RRx-001 activity. NCI-H660 xenografts were pre-treated with RRx-001 (mimicking clinical activity) or vehicle prior to treatment with carboplatin, and tumor volume and body weight were monitored. Results: RRx-001 pre-treatment significantly decreased the IC50 of carboplatin from ~86 mM to 36 mM in vitro, whereas no significant effect was observed on the IC50 of docetaxel. The ROS inhibitor NAC reversed &gt; 70% of RRx-001 sensitization to carboplatin, while co-pre-treatment with the ROS generator BSO significantly enhanced RRx-001 activity. In vivo, pre-treatment with RRx-001 prior to carboplatin significantly decreased tumor volume compared to vehicle, with ~50% greater reduction in mean tumor volume at 30 days. Body weight was not affected by RRx-001. Conclusions: This preclinical study supports the concept that “priming” with RRx-001 may be an effective therapeutic strategy to resensitize NEPC to initially highly effective platinum doublets. A phase 3 trial is planned, and studies with additional preclinical NEPC models will identify the mechanism of action of RRx-001.
I am a final year medical student who is very interested in a career in dermatology. Which jobs will be beneficial for my future career?
Authors: Susannah Baron
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
Migraine and risk of cardiovascular diseases: Danish population based matched cohort study
Authors: Kasper Adelborg, Szimonetta Komjáthiné Szépligeti, Louise Holland-Bill, Vera Ehrenstein, Erzsébet Horváth-Puhó, Victor W Henderson, Henrik Toft Sørensen
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort. <h3>Design</h3> Nationwide, population based cohort study. <h3>Setting</h3> All Danish hospitals and hospital outpatient clinics from 1995 to 2013. <h3>Participants</h3> 51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year. <h3>Main outcome measures</h3> Comorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis. <h3>Results</h3> Higher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 <i>v</i> 17 for myocardial infarction, 45 <i>v</i> 25 for ischaemic stroke, 11 <i>v</i> 6 for haemorrhagic stroke, 13 <i>v</i> 11 for peripheral artery disease, 27 <i>v</i> 18 for venous thromboembolism, 47 <i>v</i> 34 for atrial fibrillation or atrial flutter, and 19 <i>v</i> 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking. <h3>Conclusions</h3> Migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases.
Episodic memory isn't essentially autonoetic
Authors: Peter Carruthers
Journal: Behavioral and Brain Sciences (2018)

Abstract I argue that the function attributed to episodic memory by Mahr &amp; Csibra (M&amp;C) – that is, grounding one's claims to epistemic authority over past events – fails to support the essentially autonoetic character of such memories. I suggest, in contrast, that episodic event memories are sometimes purely first order, sometimes autonoetic, depending on relevance in the context.
Image Gallery: Immunohistochemical detection of parvovirus B19 <scp>VP</scp> 2 in periflexural primary infection in an adult female patient
Authors: C. Santonja, L. Requena, J. Polo Sabau, U. Pielasinski Rodríguez
Journal: British Journal of Dermatology (2018)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A skin biopsy of a 28‐year‐old woman with fever and a papular‐petechial periflexural rash (Fig. a–c) showed superficial mononuclear inflammatory infiltrate (Fig. d). An immunohistochemical study of parvovirus (PV)B19 VP2 (Fig. e) detected viral protein within the cytoplasm of dermal endothelial cells.1 IgM antibodies to PVB19 were identified in serum. She recovered from mild pancytopenia without incident. The rash that accompanies PVB19 primary infection is attributed to an immunological reaction, but because endothelial cells contain the virus receptor (globoside or P antigen), this could well be the mechanism of entrance (possibly through antibody‐mediated enhancement, which is common in other viruses including Ebola, HIV‐1 and dengue viruses).2
Autonoesis and dissociative identity disorder
Authors: John Morton
Journal: Behavioral and Brain Sciences (2018)

Abstract Dissociative identity disorder is characterised by the presence in one individual of two or more alternative personality states (alters). For such individuals, the memory representation of a particular event can have full episodic, autonoetic status for one alter, while having the status of knowledge or even being inaccessible to a second alter. This phenomenon appears to create difficulties for a purely representational theory and is presented to Mahr &amp; Csibra (M&amp;C) for their consideration.
REVERSE STRESS INDUCED CARDIOMYOPATHY IN A PATIENT WITH PRIOR APICAL STRESS INDUCED CARDIOMYOPATHY: CHALLENGING THE BETA RECEPTOR GRADIENT THEORY
Authors: Ahmed Rashed, Mohamed Shokr, Ahmed Subahi, Fayez Siddiqui, Aziz Alkatib, Luis Afonso
Journal: Journal of the American College of Cardiology (2018)
Abstract P1-07-21: Relationship between hereditary cancer syndromes and oncotype DX recurrence score
Authors: S Toltzis, N Casasanta, S Lipinski, A Marino, A McHenry, N Denduluri, P Rodriguez, R Kaltman
Journal: Cancer Research (2018)

Abstract Background Oncotype DX Recurrence Score (RS) is used to stratify breast tumors into those likely to respond to cytotoxic chemotherapy. Women and men with hereditary cancers tend to have tumors that are chemosensitive. We hypothesize that a high RS may harbor a signal of potential hereditary risk. This analysis aims to identify whether breast cancer patients with hereditary cancer syndromes have a disproportionate amount of high RS compared to sporadic cases. Methods Individuals with a personal history of breast cancer who received treatment at participating research facilities and had hormone receptor positive breast cancer, Oncotype DX testing and hereditary cancer mutation testing were included. Oncotype DX RS was recorded along with the type of genetic testing and the genetic testing results. RS was categorized as low (0-17), intermediate (18-30), and high (31+). Those with deleterious mutations in any known hereditary cancer gene were considered positive. Individuals with a variant of uncertain significance (VUS) or negative genetic testing result were considered negative. Difference in distribution of tumors with low, intermediate, and high Oncotype DX results in those with hereditary breast cancers compared to those with sporadic breast cancers was determined with Chi-square. Results 419 patients with Oncotype DX testing from two clinical sites were collected from 2013. Of those, 123 underwent genetic risk assessment. Mutations identified included the following genes: BRCA1 (1), BRCA2 (5); CHEK2 (3); BRIP1 (3); NBN (2); MSH6 (1). Of those testing positive for a deleterious mutation, the number of patients with RS results in each category were 5, 4 and 6 for low, intermediate and high, respectively. For those considered negative on hereditary cancer panel testing, the RS results were 76, 52 and 8, respectively. Of those with high RS, 43% had deleterious mutations. Chi square test was statistically significant for a difference between the RS of those with deleterious hereditary mutations versus those with sporadic cancers (p = 0.000086). Conclusions High RS may indicate a higher likelihood of harboring a hereditary cancer syndrome. Further investigation with larger numbers and multivariate analysis is needed to validate if a high RS serves as an independent predictor of benefit from genetic counseling and testing. Citation Format: Toltzis S, Casasanta N, Lipinski S, Marino A, McHenry A, Denduluri N, Rodriguez P, Kaltman R. Relationship between hereditary cancer syndromes and oncotype DX recurrence score [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-21.