tbuckley/cabot-search huggingface dataset:
Highlights of the North American Cystic Fibrosis Conference 2008
Authors: Tom Hilliard, Kathy Wedlock, Helen Mcgowan, Charlotte Hayward, Damian Downey
Journal: Journal of the Royal Society of Medicine (2009)

The North American Cystic Fibrosis Conference (NACFC) is the world's largest international CF conference. It presents a superb opportunity for the CF professional community to join together to hear results of the latest therapeutic studies, the latest advances in basic science and to further their understanding of CF care. The 2008 conference was held in Orlando, Florida, and with over 3500 delegates, it did not disappoint. The majority of those attending the NACFC are naturally from North America, but there is a sizeable minority from Europe and Australasia. Five members of our team (two consultants, two clinical nurse specialists and one specialist physiotherapist) attended, and we willingly took up the invitation to report our highlights on our return to the RSM conference.

Attending an overseas international conference is often not an easy undertaking, not least financially. Including travel, accommodation and conference registration, our attendance cost approximately £5000, a significant sum when there is appropriate limitation of commercial sponsorship. It is therefore a relevant exercise to consider one's reasons to attend an overseas conference, and to regard participation once there with apt seriousness. Although this may be obvious to some, we have listed in Box 1 what we considered our motivation. We tell our patients and their families each year when we are going to the NACFC and they are always interested, and in particular they see this as a way that we can connect with new therapies and keep ourselves up to date. Knowing that we were going to report on the conference provided an extra stimulus, and this is perhaps a good lesson for all CF teams.

Box 1
Motivation for attending overseas conferences

Presenting our own work

Keeping ourselves up to date with new practice

Allowing our practice to be influenced by others within our field

Hearing about developing therapies

Meeting other teams from our own country and internationally

Refreshing our enthusiasm to provide first‐rate care

Team bonding
Successful Prospective Prediction of Type 1 Diabetes in Schoolchildren Through Multiple Defined Autoantibodies
Authors: James M. LaGasse, Michael S. Brantley, Nicola J. Leech, Rachel E. Rowe, Stephanie Monks, Jerry P. Palmer, Gerald T. Nepom, David K. McCulloch, William A. Hagopian
Journal: Diabetes Care (2002)

OBJECTIVE—Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population. RESEARCH DESIGN AND METHODS—Autoantibodies to pancreatic islets (islet cell antibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test &amp;gt;99th percentile. RESULTS—Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25–75%) and 100% sensitivity (58–100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86–99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers. CONCLUSIONS—Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years.
Skin Toxicity Evaluation Protocol With Panitumumab (STEPP), a Phase II, Open-Label, Randomized Trial Evaluating the Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities and Quality of Life in Patients With Metastatic Colorectal Cancer
Authors: Mario E. Lacouture, Edith P. Mitchell, Bilal Piperdi, Madhavan V. Pillai, Heather Shearer, Nicholas Iannotti, Feng Xu, Mohamed Yassine
Journal: Journal of Clinical Oncology (2010)

Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the United States and Europe for the treatment of refractory metastatic colorectal cancer (mCRC). Skin toxicities are the most common adverse events with EGFR inhibitors. This is the first study designed to examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with mCRC for any EGFR inhibitor.Patients receiving panitumumab-containing therapy were randomly assigned 1:1 to pre-emptive or reactive treatment (after skin toxicity developed). Pre-emptive treatment included use of skin moisturizers, sunscreen, topical steroid, and doxycycline. The primary end point of the study was the incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI).Of 95 enrolled patients, 48 received pre-emptive treatment, and 47 received reactive treatment. The incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. Mean DLQI score change from baseline to week 3 was 1.3 points and 4.2 points in the pre-emptive and reactive groups, respectively.The pre-emptive skin treatment regimen was well tolerated. The incidence of specific >or= grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.
Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart
Authors: A Kluge
Journal: Cardiovascular Research (1997)

Coronary microembolisation in the pig heart induces angiogenesis in a model of sterile inflammation due to focal necrosis. We have recently shown in this model that insulin-like growth factor I (IGF-I) is involved in inflammation-linked angiogenic processes due to its enhanced transcription after 72 h of ischaemia by infiltrating monocytes in areas of microsphere-induced focal necrosis where capillary sprouting could be detected. To obtain further insights into this process we studied by means of Northern blot analysis and in situ hybridisation the gene expression of other members of the IGF family, i.e. the six IGF binding proteins (IGFBPs), the insulin receptor, and the type I IGF receptor.Myocardial injury was induced by injection of 25 microns non-radioactive microspheres into the left circumflex artery (LCx) in pigs that were killed after 3-24, 72, or 168 h of microembolisation. Tissue was collected from a non-ischaemic control area and the LCx region of the same heart for further analysis.We found decreased IGFBP-5 (2.7-fold; P < 0.02) mRNA concentrations after 72 h of microembolisation in ischaemic tissue versus control tissue from the same heart, preceded by a 1.9-fold elevated level of IGFBP-3 mRNA at 3-24 h (P < 0.05). IGFBP-6 was increased in ischaemic tissue at all time points studied. In situ hybridisation identified myocytes as the main producers of IGFBP-3 and IGFBP-6 mRNA. The mRNA levels of IGFBP-2, IGFBP-4, the insulin receptor, and the type I IGF receptor were constitutively expressed but did not change after microembolisation. Neither in heart nor in other organs studied transcripts of IGFBP-1 could be detected. Furthermore, we demonstrated that mRNA of the other components of the IGF system was expressed in almost all porcine organs except liver.These results indicate a coordinate gene expression of the IGF system in microembolised porcine myocardium, compatible with a role of IGF-I, IGFBP-3, IGFBP-5, and IGFBP-6 in inflammation-linked angiogenesis and/or repair processes.
ATM-Mediated DNA Damage Signals Mediate Immune Escape through Integrin-αvβ3–Dependent Mechanisms
Authors: Masahisa Jinushi, Shigeki Chiba, Muhammad Baghdadi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Koyu Ito, Hironori Yoshiyama, Hideo Yagita, Toshimitsu Uede, Akinori Takaoka
Journal: Cancer Research (2011)

Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
Editor's quiz: Protein, protein everywhere…but none to keep
Authors: Michael Pavlides, Palak Trivedi, Pelvender Gill, Shaun Appleton, Sue Cullen, Alistair McIntyre
Journal: Gut (2012)

A 72-year-old woman presented to the outpatient department with a 3-month history of non-bloody diarrhoea and weight loss. Her past medical history was notable for non-Hodgkin's lymphoma (splenectomy performed 10 years prior; no evidence of recurrence on follow-up) and cardiac pacemaker insertion
Clinical Implications of Gene Dosage and Gene Expression Patterns in Diploid Breast Carcinoma
Authors: Toshima Z. Parris, Anna Danielsson, Szilárd Nemes, Anikó Kovács, Ulla Delle, Ghita Fallenius, Elin Möllerström, Per Karlsson, Khalil Helou
Journal: Clinical Cancer Research (2010)

Deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells. In cancer, regulation of gene transcription can be mediated in a variety of ways. The purpose of this study was to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels, and to associate these genomic changes with clinicopathologic parameters.We screened 97 invasive diploid breast tumors for DNA copy number alterations and changes in transcriptional levels using array comparative genomic hybridization and expression microarrays, respectively.The integrative analysis identified an increase in the overall number of genetic alterations during tumor progression and 15 specific genomic regions with aberrant DNA copy numbers in at least 25% of the patient population, i.e., 1q22, 1q22-q23.1, 1q25.3, 1q32.1, 1q32.1-q32.2, 8q21.2-q21.3, 8q22.3, 8q24.3, and 16p11.2 were recurrently gained, whereas 11q25, 16q21, 16q23.3, and 17p12 were frequently lost (P < 0.01). An examination of the expression patterns of genes mapping within the detected genetic aberrations identified 47 unique genes and 1 Unigene cluster significantly correlated between the DNA and relative mRNA levels. In addition, more malignant tumors with normal gene dosage levels displayed a recurrent overexpression of UBE2C, S100A8, and CBX2, and downregulation of LOC389033, STC2, DNALI1, SCUBE2, NME5, SUSD3, SERPINA11, AZGP1, and PIP.Taken together, our findings suggest that the dysregulated genes identified here are critical for breast cancer initiation and progression, and could be used as novel therapeutic targets for drug development to complement classical clinicopathologic features.
Peak Expiratory Flow Variability, Bronchial Responsiveness, and Susceptibility to Ambient Air Pollution in Adults
Authors: MARIKE BOEZEN, JAN SCHOUTEN, BERT RIJCKEN, JUDITH VONK, JORRIT GERRITSEN, SASKIA van der ZEE, GERARD HOEK, BERT BRUNEKREEF, DIRKJE POSTMA
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Bronchial hyperresponsiveness (BHR) and peak expiratory flow (PEF) variability are associated expressions of airway lability, yet probably reflect different underlying pathophysiologic mechanisms. We investigated whether both measures can be used interchangeably to identify subjects who are susceptible to ambient air pollution. Data on BHR ( ⩾ 20% fall in FEV1), PEF variability (ampl%mean PEF > 5% on any day during an 8-d period with low air pollution levels) and diary data on upper and lower respiratory symptoms, cough, and phlegm were collected in 189 subjects (48–73 yr). The acute effects (lag0) of particulate matter with a diameter less than 10 μ m (PM10), black smoke, SO2 and NO2 on the prevalence of symptoms were estimated with logistic regression. In subjects with airway lability, both when expressed as PEF variability (69%) and BHR (28%), the prevalence of symptoms increased significantly with increasing levels of air pollution, especially in those with the greater PEF variability (n = 55, 29%). We found no such consistent positive associations in adults without airway lability. PEF variability, and to a smaller extent BHR, can be used to identify adults who are susceptible to air pollution. Though odds ratios were rather low (ranging from 1.13 to 1.41), the impact on public health can be substantial because it applies to large populations.
Topical fulvestrant solution has no effect on male and postmenopausal female androgenetic alopecia: results from two randomized, proof-of-concept studies
Authors: J. Gassmueller, R. Hoffmann, A. Webster
Journal: British Journal of Dermatology (2007)

Background Androgenetic alopecia (pattern baldness) affects approximately half of all white-skinned men and women over the age of 40 years. Based on preclinical studies in mice in which topical fulvestrant (ICI182,780, an anti-oestrogen) caused telogen hair follicles to enter anagen, thereby causing hair growth, a topical formulation of fulvestrant was developed for the potential treatment of androgenetic alopecia. Objectives To evaluate the efficacy of fulvestrant solution in stimulating hair growth in men and postmenopausal women with androgenetic alopecia in two randomized, phase II, minoxidil- and/or vehicle-controlled studies. Methods One hundred and two white-skinned men aged 18–50 years with Norwood/Hamilton grades III, IIIv, IV, V or Va androgenetic alopecia received topical fulvestrant 70 mg mL−1 solution, vehicle or minoxidil 2% solution twice daily for 16 weeks. Seventy postmenopausal women with Ludwig grade 1 or 2 androgenetic alopecia received topical fulvestrant 70 mg mL−1 solution or vehicle twice daily for 16 weeks. The endpoints in both studies were hair density, cumulative hair thickness and hair growth rate, measured by TrichoScan analysis of digital images. Results There were no statistically significant differences favouring fulvestrant over vehicle at study end (day 113) for any of the efficacy parameters in men or women. Statistically significant differences in favour of minoxidil over fulvestrant were seen from day 57 onwards for hair density, cumulative hair thickness and hair growth rate in men. Conclusions These results indicate a lack of effect of topical fulvestrant in the treatment of subjects with androgenetic alopecia. The reasons for this lack of effect remain unclear.
Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis
Authors: Saskia C.A. de Jager, Beatriz Bermúdez, Ilze Bot, Rory R. Koenen, Martine Bot, Annemieke Kavelaars, Vivian de Waard, Cobi J. Heijnen, Francisco J.G. Muriana, Christian Weber, Theo J.C. van Berkel, Johan Kuiper, Se-Jin Lee, Rocio Abia, Erik A.L. Biessen
Journal: The Journal of Experimental Medicine (2011)

Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor−/− mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15−/− chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15−/− macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein–coupled receptor kinase 2+/− macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.
Autoantibodies to the extracellular and intracellular domain of bullous pemphigoid 180, the putative key autoantigen in bullous pemphigoid, belong predominantly to the IgG1 and IgG4 subclasses
Authors: E. Laffitte, M. Skaria, F. Jaunin, K. Tamm, J-H. Saurat, B. Favre, L. Borradori
Journal: British Journal of Dermatology (2001)

Autoantibodies to the extracellular domain (ECD) of bullous pemphigoid (BP) antigen 180 (BP180) are thought to play a crucial part in the pathophysiology of BP.As the various IgG subclasses have different biological properties, we have sought to assess the relative isotype distribution of IgG to BP180 and their reactivity against the ECD and intracellular domain (ICD) of BP180.The reactivity of 27 sera from patients with BP was assayed by immunoblotting against recombinant proteins covering the ECD and ICD of BP180.Twenty-seven (100%) and 21 (77%) of 27 BP sera, respectively, contained IgG1 and IgG4 autoantibodies binding to the ECD of BP180. Fourteen (82%) and six (35%) of the 17 BP sera that were reactive with the ICD of BP180 had autoantibodies of the IgG1 and IgG4 subclass, respectively. The profile of the isotype restriction appeared to be similar when the response to the ECD vs. that to the ICD was compared. IgG2 and IgG3 reactivity with BP180 was found less frequently. Patients with BP of longer duration showed a tendency to have, in addition to IgG1, an IgG4 response.Consistent with prior evidence indicating that subepidermal blister formation in BP is dependent upon complement activation, the frequent finding of complement-fixing IgG1 autoantibodies to both the ECD and ICD of BP180 might have pathogenic relevance in BP. These findings provide new insights relevant for our understanding of the immune response to BP180, the putative key autoantigen in BP.
Predictive factors for survival of patients with inoperable malignant distal biliary strictures: a practical management guideline
Authors: F Prat, O Chapat, B Ducot, T Ponchon, J Fritsch, A D Choury, G Pelletier, C Buffet
Journal: Gut (1998)

Background —Stenting is the treatment of choice for inoperable malignant strictures of the common bile duct. Criteria for the choice of stents (plastic versus metallic) remain controversial because predicting survival is difficult. Aims —To define prognostic factors in order to improve the cost effectiveness of endoscopic palliation. Patients —One hundred and one patients were included in a prospective trial. Seven prognostic variables for survival were analysed (age, sex, bilirubinaemia, weight loss, presence of liver metastases, and tumour histology and size). All patients were followed until death or at least one year after inclusion. By the end of the study, 81 (80.2%) patients had died. Results —In univariate analysis, the variables associated with survival were weight loss (p&lt;0.05) and tumour size (p&lt;0.01). By multivariate analysis, tumour size was the only independent prognostic factor (p&lt;0.05). A threshold of 30 mm at diagnosis distinguished two survival profiles: the median survival of patients with a tumour greater than 30 mm was 3.2 months, whereas it was 6.6 months for patients with a tumour less than 30 mm (p&lt;0.001). Conclusions —A practical strategy could be based on tumour size at diagnosis: a metal stent should be systematically chosen for patients with an inoperable tumour smaller than 30 mm, while larger tumours are efficiently palliated by a plastic stent.
Comparing LCZ696 With Enalapril According to Baseline Risk Using the MAGGIC and EMPHASIS-HF Risk Scores
Authors: Joanne Simpson, Pardeep S. Jhund, Jose Silva Cardoso, Felipe Martinez, Arend Mosterd, Felix Ramires, Adel R. Rizkala, Michele Senni, Iain Squire, Jianjian Gong, Martin P. Lefkowitz, Victor C. Shi, Akshay S. Desai, Jean L. Rouleau, Karl Swedberg, Michael R. Zile, John J.V. McMurray, Milton Packer, Scott D. Solomon
Journal: Journal of the American College of Cardiology (2015)
A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes
Authors: M Stadler, U Germing, K-O Kliche, K M Josten, R Kuse, W-K Hofmann, H Schrezenmeier, J Novotny, O Anders, H Eimermacher, W Verbeek, H-H Kreipe, H Heimpel, C Aul, A Ganser
Journal: Leukemia (2004)