tbuckley/cabot-search huggingface dataset:
<i>Pseudomonas aeruginosa</i>infection and exacerbations in bronchiectasis: more questions than answers
Authors: Miguel Angel Martinez-García
Journal: European Respiratory Journal (2018)

Apart from the presence of comorbidities [1], there are two other circumstances that have demonstrated a negative impact on the natural history of bronchiectasis: chronic bronchial infection (CBI) by Pseudomonas aeruginosa and exacerbations. Many studies have shown an association between CBI by P. aeruginosa and reduced quality of life [2], a steep decline in lung function [3], increased inflammation (both bronchial and systemic) [4], higher healthcare costs [5], and even a higher mortality rate [6]. One recent meta-analysis concluded that this association is more evident with CBI by P. aeruginosa rather than by other pathogenic microorganisms [7]. Similarly, exacerbations (particularly multiple and/or severe exacerbations) have been associated with various parameters of severity in bronchiectasis [3], including a higher mortality rate [8, 9]. It is hardly surprising, therefore, that the three validated multidimensional scores published to date to evaluate the severity or prognosis of bronchiectasis [8–10] include the presence of a CBI by P. aeruginosa as one of their variables, and that two of the three [8, 9] also include the frequency and/or severity of exacerbations. Accordingly, some authors have even suggested that those bronchiectasis patients with CBI by P. aeruginosa and those who present multiple exacerbations could represent two distinct clinical phenotypes of bronchiectasis patients, each with their own clinical characteristics and prognoses [11, 12]. Finally, it should be stressed that both these circumstances are extremely important from a therapeutic standpoint. In fact, the vast majority of the treatments on the market or in development are primarily aimed at infection by P. aeruginosa , with a drop in the number of exacerbations as the main objective [13]. Both chronic infection by P. aeruginosa and exacerbations have a negative impact in bronchiectasis prognosis <http://ow.ly/pjR230hJR9h>
Errors of judgment⇓
Authors: Nicola Sharp
Journal: BMJ (2004)

“This did not happen. I'm not really here.” Martha Millstone sat on Hubert's desk and did up her bra strap.

“How can you say that?” Hubert slid his hairy hand inside Martha's bra.

“I say what I mean,” said Martha. “This last hour did not happen. You must erase it from your memory.” Martha pushed Hubert's hand away and pulled her shirt on.

“I will not forget a minute of it.” Hubert was completely naked. His right arm and shoulder were covered in thick black hair. The rest of his body was pallid and hairless.

“Think of it as a mistake,” said Martha. “You're used to making mistakes. Like selling the doctors' residence.” She pulled her tights on.

“I didn't sell the doctors' residence, nor did David.”

“You are the chief executive.”

“So you assume I have some power? I am a cog in a badly functioning system.”

“Stop making excuses.”

“Martha, I've waited nearly two years for you to come back to me. Let's not spoil it by arguing.” Hubert looked at Martha's legs.

“It didn't happen.” Martha picked up her jacket.

“Stay with me,” said Hubert.

“I've a clinic to do and people to see.” Martha marched out of the …
The role of glucokinase and insulin receptor substrate-2 in the proliferation of pancreatic beta cells induced by short-term high-fat diet feeding in mice
Authors: Naoyuki Kitao, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Kiyohiko Takahashi, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
Journal: Metabolism (2018)
Cumulative risk of skin tumours in patients with Lynch syndrome
Authors: F. Adan, M.B. Crijns, W.S.E. Zandstra, M.W. Bekkenk, F.E. Bleeker, E. Dekker, M.E. van Leerdam
Journal: British Journal of Dermatology (2018)

Lynch syndrome (LS) is an autosomal-dominant disorder characterized by a predisposition to colorectal cancer and extracolonic malignancies. LS is caused by a germline mutation in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or loss of expression of MSH2 due to deletion in the EPCAM gene. Muir-Torre syndrome (MTS) is considered a variant of LS, in which patients present with sebaceous neoplasms and/or keratoacanthomas. A few studies and case reports suggest a relation between LS and other benign and (pre)-malignant skin tumours. Currently only patients presenting with sebaceous carcinoma are advised to be referred to a dermatologist for surveillance.

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Impact of new agents (NAs) on survival of metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A single-Institution retrospective analysis.
Authors: Orazio Caffo, Stefania Kinspergher, Francesca Maines, Sveva Macrini, Antonello Veccia
Journal: Journal of Clinical Oncology (2018)

323 Background: Until few years ago, docetaxel (DOC) was the only agent able to significantly prolong overall survival (OS) of mCRPC pts: at the time of disease progression, other drugs without any survival benefit (mitoxantrone, vinorelbine, cyclophosphamide) or DOC re-challenge (DOC-re) in selected cases could be proposed. In the last years several NAs [abiraterone (AA), cabazitaxel (CAB), enzalutamide (ENZ), radium 223(RA223)] have been introduced in the clinical practice since they demonstrated an OS improvement. Moreover, a hypothetical cumulative OS advantage could derive from their sequential use. The present report is aimed to assess the impact on NAs on mCRPC pts’ OS in the daily clinical practice. Methods: We retrospectively evaluated all mCRPC pts treated in our Institution from 02/2002 to 06/2015 and recorded their medical history, anticancer treatments and survival outcomes. For the purpose of the present study, we consider pts who never received at least one NA (group A) and pts who received at least one NA (group B). To avoid selection bias due to a fast performance status worsening preventing further treatments, we consider only pts who received at least one agent after first line progression. For the OS analysis we considered the start of mCRPC first line. Results: We selected a consecutive series of 212 pts: 80 not treated (Group A) and 132 treated (Group B) with NAs. In the Group A 50 pts received first-line DOC followed by DOC-re only, while the remaining 30 pts received also agents different than DOC. In the group B 78, 35, and 19 pts received one, two, and three NAs, respectively. Group A pts were significantly younger and had higher baseline levels of PSA and lactate dehydrogenase (LDH). The OS was significantly longer in Group B than in Group A (36.0 vs 19.6 mos, p &lt; 0.0001). The impact of NAs use on OS was confirmed at the multivariate analysis comprising the other factors which significantly affected OS (hemoglobin, LDH, alkaline phosphatase, pain, performance status, PSA). Conclusions: Although the limitation due to its retrospective nature, our analysis confirms that the introduction of NAs in the daily clinical practice led to an OS improvement.
GENDER-SPECIFIC VARIATION IN PULMONARY VEIN RECONNECTION RATE AFTER CATHETER ABLATION FOR ATRIAL FIBRILLATION
Authors: Sanghamitra Mohanty, Chintan Trivedi, Carola Gianni, Vivek Bhupathi, Domenico Giovanni Della Rocca, John Burkhardt, Javier Sanchez, Patrick Hranitzky, Gerald Gallinghouse, Amin Al-Ahmad, Rodney Horton, Luigi Di Biase, Andrea Natale
Journal: Journal of the American College of Cardiology (2018)
Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.
Authors: Jang Ho Cho, Sung Won Lim, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Journal: Journal of Clinical Oncology (2018)

80 Background: Alterations in claudin expression can impair tight junction functioning, influence signaling pathways, and act as a tumor promoting event in some epithelial cancers. Recently, IMAB362, a highly potent and tumor cell-selective therapeutic antibody to claudin 18.2, has been developed and investigated in clinical trials. Methods: We prospectively conducted claudin 18.2 immunohistochemistry on 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Results: Most patients (414/430, 96.2%) were evaluable for claudin 18.2 expression by immunohistochemistry. In total, 4.1% (17/414) were deemed claudin 18.2+, including patients with pancreatic (16.7%, 1 of 6), gastric (14.1%, 12 of 85), biliary tract (6.3%, 1 of 16), genitourinary/miscellaneous (2.2%, 1 of 46), and colorectal (0.9%, 2 of 203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers; this subgroup showed no statistical difference by gender, age, disease extent, primary tumor site, pathologic differentiation, HER2 status, or EBV status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared to diffuse-type by Lauren classification (p = 0.026). There was no significant difference in overall survival between patients with and without claudin 18.2 expression (p = 0.101). Conclusions: Our results add to the emerging literature on claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of IMAB362.
Evaluation of a 29 gene classifier for basal/non basal prediction in muscle-invasive bladder cancer FFPE samples.
Authors: Yves Allory, Nanor Sirab, Damien Drubay, David Gentien, AurÃ©lien De ReyniÃ¨s, Benoit Albaud, Aurélie Kamoun, Pascale Soyeux, Pascale Maille, Thierry Lebret, Simone Benhamou, Xavier Paoletti, Francois Radvanyi
Journal: Journal of Clinical Oncology (2018)

467 Background: Recent and independent muscle-invasive bladder cancer (MIBC) molecular classifications identified the basal / squamous-like (BASQ) tumours as an intrinsic and robust subtype, with a poor outcome and possible chemosensitivity to cisplatin based regimen, making mandatory the development of a diagnostic tool for their identification in routine samples. Our study aimed to evaluate the diagnostic accuracy of a Nanostring classifier for tumor subtype prediction on FPPE specimens. Methods: Two series of MIBC were used (CIT n = 51 &amp; Stransky n = 22) for which BASQ tumours were identified previously using Affymetrix transcriptome data obtained from frozen samples (Rebouissou, Science Trans Med 2014). 29 genes were selected to predict the basal subtype, RNA expression of matched frozen and FFPE samples was studied using Nanostring technology. To define the classifiers for Affymetrix, frozen and FFPE Nanostring expression matrix on CIT samples the centroid of each cluster was calculated using the expression of 29 genes. Internal validation used leave-one-out cross-validation to train and test the prediction accuracy of the new classifier. For external validation, the CIT samples were used as training set and the Stransky samples as validation set. Predictive accuracy expressed as percentage of correctly classified samples is provided. Results: Correlations between Affymetrix, frozen and FFPE Nanostring data set were checked for gene expression and samples. Using CIT samples as train and test set, the predictive accuracy for BASQ tumour identification was for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers, 90.20% [78.59%; 96.74%], 88.24% [76.13%; 95.56%] and 92.16% [81.12%; 97.82%], respectively. Using training on CIT samples and test on Stransky samples, this predictive accuracy was 90.91% [70.84%; 98.88%] both for Affymetrix, frozen Nanostring and FFPE Nanostring classifiers. Conclusions: The 29 gene expression Nanostring codeset was able to identify reliably basal / squamous like tumours on FFPE samples from MIBC in comparison with the gold standard approach based on transcriptomic profile, appearing as a promising diagnostic tool.
The CD20-specific engineered toxin antibody MT-3724 exhibits lethal effects against mantle cell lymphoma
Authors: Shengjian Huang, Changying Jiang, Hui Zhang, Taylor Bell, Hui Guo, Yang Liu, Yixin Yao, Dongfeng Zeng, Makhdum Ahmed, Krystle Nomie, Leo Zhang, Michael Wang
Journal: Blood Cancer Journal (2018)
Abstract 18111: Flecainide Exerts its Antiarrhythmic Action in CPVT Through Blockade of Neuronal Na+ channel-mediated Arrhythmogenic Diastolic Ca2+ Release
Authors: Przemyslaw Radwanski, Hsiang-Ting Ho, Björn Knollmann, Andriy Belevych, Sándor Györke
Journal: Circulation (2015)

Background: Flecaininde is an effective antiarrhythmic in management of CPVT. Its antiarrhythmic action has been attributed to direct effect on RyR2 and reduced cellular excitability through the inhibition of cardiac-type Na + channels. Recently we demonstrated that neuronal Na + channels (nNa v s) colocalize with the ryanodine receptors (RyR2) Ca 2+ release channels on the sarcoplasmic reticulum. Here we explore a novel mechanism that may contribute to the antiarrhythmic effect of flecainide, mainly uncoupling of aberrant Na + /Ca 2+ signaling through nNa v inhibition. Methods: To study the effects of flecainide on Ca 2+ signaling we used a murine model of cardiac calsequestrin-associated CPVT. We performed confocal microscopy in intact isolated ventricular myocytes to assess Ca 2+ handling and recorded late Na + current (I Na ) during various pharmacological interventions. Surface electrocardiograms were performed during catecholamine challenge to monitor arrhythmic activity in vivo . Results: During catecholamine stimulation with isoproterenol (Iso; 100 nM) disruption of the cross-talk between nNa v s and RyR2 by nNa v blockade with 100nM tetrodotoxin (TTX) and riluzole (10μM) as well as flecainide (2.5μM) reduced Iso-promoted late I Na and DCR in isolated intact CPVT cardiomyocytes. To further examine the role of nNa v -mediated late I Na in genesis of DCR we augmented nNa v channel activity with β-Pompilidotoxin (β-PMTX, 40μM). Effects of β-PMTX in CPVT cardiomyocytes were reversed by nNa v blockade with TTX and riluzole as well as flecainide. This reduction in late I Na and DCR frequency with riluzole and flecainide in the presence of β-PMTX on cellular level translated to decreased ventricular arrhythmias in CPVT mice. Conclusion: These data suggest that disruption of nNa v -mediated late I Na can prevent arrhythmogenic DCR in CPVT. Importantly, the antiarrhythmic effects of flecainide can be attributed, at least in part, to its nNa v blocking properties.
A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II
Authors: Hiroyuki Sonoda, Hideto Morimoto, Eiji Yoden, Yuri Koshimura, Masafumi Kinoshita, Galina Golovina, Haruna Takagi, Ryuji Yamamoto, Kohtaro Minami, Akira Mizoguchi, Katsuhiko Tachibana, Tohru Hirato, Kenichi Takahashi
Journal: Molecular Therapy (2018)

Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to accumulation of GAGs in most cells in all tissues and organs, resulting in severe somatic and neurological disorders. Although enzyme replacement therapy with human IDS (hIDS) has been used for the treatment of MPS II, this therapy is not effective for defects in the CNS mainly because the enzyme cannot cross the blood-brain barrier (BBB). Here, we developed a BBB-penetrating fusion protein, JR-141, which consists of an anti-human transferrin receptor (hTfR) antibody and intact hIDS. The TfR-mediated incorporation of JR-141 was confirmed by using human fibroblasts in vitro. When administrated intravenously to hTfR knockin mice or monkeys, JR-141, but not naked hIDS, was detected in the brain. In addition, the intravenous administration of JR-141 reduced the accumulation of GAGs both in the peripheral tissues and in the brain of hTfR knockin mice lacking Ids, an animal model of MPS II. These data provide a proof of concept for the translation of JR-141 to clinical study for the treatment of patients with MPS II with CNS disorders.
Abstract 19899: Cardiac MR Stress Perfusion With Regadenoson or Dobutamine in Children Single Center Experience in Repaired & Unrepaired Congenital & Acquired Heart Disease
Authors: Cory V Noel, Ramkumar Krishnamurthy, Silvana Molossi, Brady Moffett, Rajesh Krishnamurthy
Journal: Circulation (2016)

Introduction: Myocardial perfusion assessment in children is a growing need given improved survival of congenital heart disease and increasing acquired coronary disease. Pharmacologic stress cardia...
Abstract 59: Relationship Between Duration of Untreated Cardiac Arrest and Neurological Dysfunction and Injury in a Porcine Model of Cardiac Arrest and CPR
Authors: Francesca Fumagalli, Marcella De Maglie, Claudia Foray, Valentina Locatelli, Claudia Balducci, Teresa Letizia, Joseph Windheim, Angelisa Frasca, Fabio Fiordaliso, Serge Masson, Davide Pravettoni, Gianluigi Forloni, Roberto Latini, Eugenio Scanziani, Angelo Belloli, Markus B Skrifvars, Giuseppe Ristagno
Journal: Circulation (2014)

Introduction:  Relationship between untreated ventricular fibrillation (VF) and neuronal injury was investigated in a porcine model.   Methods:  Twenty pigs (35-43kg) were subjected to 3 different durations of untreated VF: 8-10 min (n=8), 12-13 min (n=6), or 14-15 min (n=6), prior to mechanical CPR and defibrillation. Following resuscitation, blood samples were obtained for serum neuron specific enolase (NSE) assays. Animals were observed up to 96 hr for assessment of survival and neurological recovery. Brains were harvested for histopathology, biochemistry, and transmission electron microscopy.   Results:  All the animals were resuscitated, except for 2 in the 14-15 min VF duration. More than 80% of animals survived when VF duration was    Conclusions:  Neurological injury was affected by the duration of untreated VF.
Abstract 15615: Value of Mitral Annular Displacement by Speckle-tracking Echocardiography for Assessment of Left Ventricular Longitudinal Systolic Dysfunction in Patients With Severe Aortic Stenosis and Preserved Ejection Fraction
Authors: Takeshi Hozumi, Hiroki Emori, Kazushi Takemoto, Yuhichi Ozaki, Makoto Orii, Keishi Ohkochi, Takeyoshi Kameyama, Akio Kuroi, Tomoyoshi Yamaguchi, Tanimoto Takashi, Yoshiki Matsuo, Yasushi Ino, Takashi Kubo, Atsuhi Tanaka, Takashi Akasaka
Journal: Circulation (2016)

Background:  Previous studies have reported that left ventricular (LV) global longitudinal strain (GLS) can be used for detection of LV longitudinal dysfunction in patients with severe aortic stenosis (AS) and preserved ejection fraction (EF). Application of speckle-tracking echocardiography to the mitral annuls provides rapid assessment of mitral annular displacement (MAD). This simple method may be used as a new index for longitudinal dysfunction in patients with AS. Thus, we examined the value of MAD by speckle-tracking echocardiography for the assessment of LV longitudinal systolic dysfunction in patients with severe AS and preserved EF.   Methods:  We studied 50 patients with severe AS (aortic valve area ≤ 1.0 cm 2 ) and preserved EF (≥ 50%) in whom GLS was successfully obtained by speckle-tracking echocardiography (QLAB 10, Philips Medical Systems). MAD was automatically and quickly assessed with QLAB 10 as the base-to-apex displacement of mid-point of both septal and lateral annuls in 4-chamber view. The percentage of MAD to LV length from the mid-point of mitral annuls to the apex at end-diastole (% mid-MAD) was calculated (Figure). The study population was divided into two groups; 15 patients with decreased longitudinal systolic function (GLS > -16%; Group-A) and 35 patients with preserved longitudinal systolic function (GLS ≤ -16%; Group-B).   Results:  Both GLS and MAD were successfully assessed in 49 of 50 patients (98%). A good correlation was shown between GLS and % mid-MAD in the study patients (r=-0.80, p   Conclusions:  MAD which is rapidly estimated by speckle-tracking echocardiography is useful in the assessment of LV longitudinal systolic dysfunction in patients with severe AS and preserved EF.
MULTIMODALITY IMAGING IN ICD IMPLANTATION DECISION MAKING IN HEART FAILURE PATIENTS: ROLE OF 123-IODINE METAIODOBENZYLGUANITIDINE IMAGING AND CARDIAC MRI
Authors: Paola Scarparo, Nicolo’ Salvi, Lucia Ilaria Birtolo, Viviana Frantellizzi, Paolo Severino, Massimo Mancone, Viviana Maestrini, Giuseppe De Vincentis, Francesco Fedele
Journal: Journal of the American College of Cardiology (2018)
Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases
Authors: Jingxing Yang, Huilan Su, Wenshe Sun, Jiali Cai, Shiyuan Liu, Yimin Chai, Chunfu Zhang
Journal: Theranostics (2018)

Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases. Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection. Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules. Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.
BMA is accused of being “militant” over pension changes
Authors: Caroline White
Journal: BMJ (2012)

MPs have accused the BMA of taking a “more militant approach” than other public sector unions over the association’s response to the government’s public sector pensions bill, which is currently working its way through parliament.

The accusation was prompted by comments made by the BMA’s chairman of council, Mark Porter, to the parliamentary Public Service Pensions Bill Committee yesterday, in which he said that the current legislation was being “imposed” on doctors.

He described the 2008 agreement on pensions as “painful but nevertheless fair.” Crucially, he said, it had been “marked by partnership working and by what were perceived to …