tbuckley/cabot-search huggingface dataset:
Adherence to Adding ICS to Rescue Therapy in a Pragmatic Trial with Adults with Asthma– a Pilot Study
Authors: Juan Carlos Cardet, Paula J. Busse, Jennifer K. Carroll, Thomas B. Casale, Tamera Coyne-Beasley, Maureen Fagan, Victoria E. Forth, Anne L. Fuhlbrigge, Michelle L. Hernandez, David Kaelber, Barbara Kaplan, Margarita Lorenzi, Suzanne Madison, Nancy E. Maher, Karen Majewski, Brian Manning, Melissa D. McKee, Sylvette Nazario, Wilson D. Pace, Michael J. Pencina, Cynthia S. Rand, Jacqueline Rodriguez-Louis, Lilin She, Joel Shields, Jessica E. Teng, Michael E. Wechsler, Juan P. Wisnivesky, Barbara P. Yawn, Elliot Israel
Journal: Journal of Allergy and Clinical Immunology (2018)
Response to Harreld re: “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”
Authors: Katherine E Warren, Gilbert Vezina, Tina Y Poussaint, Monika Warmuth-Metz, Roger J Packer, Mark W Kieran
Journal: Neuro-Oncology (2017)

Additional criteria apply.Please refer to protocol 14379-201 for full inclusion and exclusion criteria.† Patients can participate if they had some skin cancers, superficial bladder cancer (cancer that was only on the surface of the lining of the bladder), or carcinoma in situ (cancer that had not spread) of the cervix or breast that had been cured.
OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
Authors: Alix F. Leblanc, Jason A. Sprowl, Paola Alberti, Alessia Chiorazzi, W. David Arnold, Alice A. Gibson, Kristen W. Hong, Marissa S. Pioso, Mingqing Chen, Kevin M. Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H. Mathijssen, Raquel E. Reinbolt, Maryam B. Lustberg, Lara E. Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu
Journal: Journal of Clinical Investigation (2018)

Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion–transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
Assessment of the Tolerability and Safety in Humans of a New Adjuvanted Anti-allergic Therapeutic Vaccine
Authors: Mary C. Reyes Zamora, Raul L. Castro Almarales, Maytee Mateo Morejon, Wendy Ramirez González, Damaris Torralba Averoff, Mercedes Ronquillo Diaz, Alina C. González Paredes, Maria A. Tamayo Gutierrez, Mirta Álvarez Castelló, Jose S. Rodriguez Canosa, Oliver Perez, Alexis Labrada Rosado
Journal: Journal of Allergy and Clinical Immunology (2018)
Age is not a risk factor for complications after surgery in older patients, review finds
Authors: Susan Mayor
Journal: BMJ (2018)

Age is not a prognostic risk factor for complications after elective surgery in older patients, whereas frailty, cognitive impairment, and smoking are, a review has found.1

“Older adults are a diverse group of patients whose risk of postoperative complications is not solely defined by their age, comorbidities, or the type of surgical procedure they receive,” said the lead author, Jennifer Watt, from the University of Toronto in Ontario, Canada.

She added, “This study highlights how common postoperative complications are …
House dust mite impairs antiviral response in asthma exacerbation models through its effects on <scp>TLR</scp>3
Authors: H. Akbarshahi, M. Menzel, S. Ramu, I. Mahmutovic Persson, L. Bjermer, L. Uller
Journal: Allergy (2018)

Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral-induced asthma exacerbation, but little is known whether allergens may affect interferon responses.Our hypothesis is that house dust mite (HDM) impairs viral stimulus-induced antiviral signalling.Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response.HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN-β, IFN-λ, TLR3, RIG-I, MDA5, IRF-3 and IRF-7. Heat inactivation of HDM partially restored the TLR3-induced interferon response in vitro and in vivo. Our HBEC-data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level.Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients.
EML4-ALK is a new oncogene in non-small cell lung carcinoma showing wild-type EGFR and K-RAS from non-smokers
Authors: Daisy Wong, Kimpton So, Elaine Leung, Vicky Tin, Issan Tam, Lap Chung, Maria Wong
Journal: Cancer Research (2008)

LB-62  Lung cancers that develop in chronic smokers result from tobacco carcinogenesis but the etiology of those in non-smokers remain unclear. Although environmental tobacco smoke from passive smoking is recognized to be a causative factor, genetic evidences suggest distinct carcinogenic pathways in the two cancer populations. Mutations involving the epidermal growth factor receptor (EGFR) prevail in non-smokers, particularly those of East Asian descent, while various genes, e.g. K-RAS, are involved in lung cancers of smokers. Genetic translocation with gene fusion is mainly found in lympho-haematological and connective tissue malignancies, but in recent years, its role in epithelial cancers such as prostate carcinoma is beginning to be recognized. The echinoderm microtubule-associated protein-like 4 (2p21) - anaplastic lymphoma kinase (2p23) (EML4-ALK) fusion gene that results from chromosome 2 inversion has been identified recently in non-small cell lung cancers (NSCLC) from Japan. Its transforming power has been demonstrated in cultured mouse fibroblasts and its oncogenic potential in nude mice. We investigated the frequency, genetics and clinicopathological profile of EML4-ALK in 240 resected primary NSCLC (192 adenocarcinomas [AD], 30 squamous cell carcinoma [SCC], 18 other types) from 117 men, 123 women. Using reverse-transcription polymerase chain reaction, 13 (5.42%) cases were found involving 4 variants of fusion transcripts in which a variable length of EML4 is fused to exon 20 of ALK. This included 2 cases of variant 1 (V1) (EML4 exon 13), 2 of V2 (exon 20), 8 of V3 (exon 6) and 1 of V4 (exon 18). The genomic breakpoints of all the variants were identified by direct DNA sequencing and were consistent with the results of the fusion transcripts. The cases showing EML4-ALK included 11 AD and 2 SCC. There were statistically significant association with never (10/115) and passive (2/17) smokers together, compared to current smokers (1/74) (Chi square test, P = 0.013). Patients with EML4-ALK were apparently younger (mean 56.8±10.9 years) compared to those without the fusion gene(mean 62.8±10.2 years) (t test, P = 0.039). No significant association was found between the fusion gene and patient gender, tumour size, grade, lymph node or pathological stages. All patients harboring the fusion gene showed wild-type EGFR (13/123) and K-RAS (13/216). The association between EML4-ALK and wild-type EGFR was statistically significant (Chi square test, P
Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa
Authors: Patrick T. McGann, Thomas N. Williams, Peter Olupot‐Olupot, George A. Tomlinson, Adam Lane, José Luís Reis da Fonseca, Robert Kitenge, George Mochamah, Ham Wabwire, Susan Stuber, Thad A. Howard, Kathryn McElhinney, Banu Aygun, Teresa Latham, Brígida Santos, Léon Tshilolo, Russell E. Ware
Journal: American Journal of Hematology (2018)

Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.
Trust may reduce or delay chemotherapy because of staff shortages
Authors: Abi Rimmer
Journal: BMJ (2018)

An Oxford hospital has said that it may reduce or delay courses of chemotherapy because it is struggling to recruit specialist nurses.

Andrew Weaver, head of chemotherapy at the Churchill Hospital, was reported by the Times newspaper to have emailed colleagues to outline proposals for the future of chemotherapy at the hospital.

“Currently we are down approximately 40% on the establishment of nurses on DTU [day treatment unit] and as a consequence we are having to delay chemotherapy patients’ starting times to 4 weeks,” said the memo, quoted in the Times report on 10 January.

Weaver warned that the current level of chemotherapy care was “unsustainable” given the limited number of staff, …
Abstract 23: Visceral Adiposity is Associated with Persistently High and Less Variable Blood Pressure: Results From the Dallas Heart Study
Authors: Yuichiro Yano, Wanpen Vongpatanasin, Colby Ayers, Aslan Turer, Aslan Turer, Alvin Chandra, Mercedes Carnethon, Philip Greenland, James de Lemos, Ian Neeland
Journal: Circulation (2016)

Introduction: Hypertension is strongly linked to obesity. Blood pressure variability (BPV), a novel BP phenotype with potential clinical significance, may also be associated with increased adiposity. We aimed to investigate the relationship between body fat distribution and average BP and BPV in the short- and long-term. Methods: Using data from the Dallas Heart Study, we assessed within-visit (short-term) and visit-to-visit (long-term) BPV (average real variability [ARV], defined as the average of absolute differences of BP between successive BP measures) during a 5-month follow-up period (2000-2002). Five BP measures were taken at each of the 3 visits (two in-office and one in-home survey). The associations of visceral (VAT) and abdominal subcutaneous adipose tissue (SAT) quantified by MRI and lower body subcutaneous fat (LBF) by DEXA with BP phenotypes were assessed using multivariable-adjusted linear regression. Results: 2595 participants with mean age 44 years; 54 % women; 68 % non-White; mean BMI 29 kg/m2, mean SBP 127 mmHg and DBP 79 mmHg were included. The short-term ARV of SBP at home and office, and long-term ARV of SBP over 3 visits were 4.0±2.4 mm Hg, 4.1±2.5 mmHg, and 9.8±7.1 mmHg, respectively. VAT, SAT, and LBF were not associated with short-term ARV of SBP, while higher VAT was associated with lower long-term ARV of SBP (Table). VAT was strongly associated with average SBP in the short- and long-term, while higher LBF was associated with lower average SBP in the short- and long-term. Conclusions: Greater VAT is associated with persistently higher short- and long-term average BP with lower variability over visits. The presence of persistently elevated BP, coupled with lower BPV, associated with visceral adiposity may impose higher cardiac workload and consequently increase cardiac hypertrophy and risk for heart failure.
Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility
Authors: Chen Li, Wanqing Sun, Chunhu Gu, Zheng Yang, Nanhu Quan, Jingrun Yang, Zhaoling Shi, Lu Yu, Heng Ma
Journal: Theranostics (2018)

Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive.Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance.The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress.Methods: Chronic pain was induced by chronic compression of the dorsal root ganglion (CCD).After 2 weeks CCD, aldehyde dehydrogenase (ALDH2) KO or wild-type (WT) littermate mice were then subjected to in vivo MI/R.Results: In CCD-WT mice, heightened nociception paralleled circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation.Mechanistically, CCD-induced 4-HNE overload provoked cardiac Sirtuin 1 (SIRT1) carbonylative inactivation and inhibited Liver kinase B1 (LKB1) -AMP-activated protein kinase (LKB1-AMPK) interaction, which resulted in exacerbated MI/R injury and higher mortality compared with non-CCD WT mice.ALDH2 deficiency further aggravated CCD-induced susceptibility to MI/R injury.Exogenous 4-HNE exposure in peripheral tissue mimicked chronic pain-induced aldehyde overload, elicited sustained allodynia and increased MI/R injury.However, cardiac-specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly ameliorated chronic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and improved cardiac function).Conclusion: Collectively, chronic pain-enhanced carbonyl stress promotes myocardial ischemic intolerance by SIRT1 carbonylative inactivation and impairment of LKB1-AMPK interaction.ALDH2 activation and prevention of protein carbonylation may be a potential therapeutic target for myocardial ischemic vulnerability in chronic pain patients.Our results newly provided overlapping cellular mechanisms of chronic pain and myocardial dysfunction interplay.
A Targeted Agent Rectifies the Impaired Glucose Tolerance Associated with a Calcium-Sensing Receptor Gain-of-Function Mouse Model
Authors: V N Babinsky, F M Hannan, M A Nesbit, A Hough, L Bentley, T A Hough, E Joynson, M Stewart, S Wells, D Richards, R D Cox, R V Thakker
Journal: Endocrine Reviews (2014)
A Canadian genome-wide association study and meta-analysis confirm HLA as a risk factor for peanut allergy independent of asthma
Authors: Yuka Asai, Aida Eslami, C. Dorien van Ginkel, Loubna Akhabir, Ming Wan, David Yin, George Ellis, Moshe Ben-Shoshan, Ingo Marenholz, David Martino, Manuel A. Ferreira, Katrina Allen, Bruce Mazer, Hans de Groot, Nicolette W. de Jong, Roy Gerth van Wijk, Anthony E.J. Dubois, Sarah Grosche, Sarah Ashley, Franz Rüschendorf, Birgit Kalb, Kirsten Beyer, Markus M. Nöthen, Young-Ae Lee, Rick Chin, Stephen Cheuk, Joshua Hoffman, Eric Jorgensen, John S. Witte, Ronald B. Melles, Xiumei Hong, Xiaobin Wang, Jennie Hui, Arthur W. (Bill) Musk, Michael Hunter, Alan L. James, Gerard H. Koppelman, Andrew J. Sandford, Ann E. Clarke, Denise Daley
Journal: Journal of Allergy and Clinical Immunology (2018)
Cell cycle stop during neutrophil differentiation in vivo does not involve p21cip1 but is accompagnied by a simultaneous downregulation of CDK2, CDK4, and CDK6
Authors: Yuko M. Mishima, Yuji Mishima, Yasuhito Terui, Takuma Sakurai, Muneo Yamada, Kiyohiko Hatake
Journal: Blood (2003)
Early Genetic Diagnosis of Neurofibromatosis Type 2 From Skin Plaque Plexiform Schwannomas in Childhood
Authors: Elisabeth Castellanos, Adrià Plana, Cristina Carrato, Meritxell Carrió, Inma Rosas, Emilio Amilibia, Francesc Roca-Ribas, Cristina Hostalot, Alicia Castillo, Andrea Ros, Ariadna Quer, Juan Luis Becerra, Hector Salvador, Conxi Lázaro, Ignacio Blanco, Eduard Serra, Isabel Bielsa
Journal: JAMA Dermatology (2018)

Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing.To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2.Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses.Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed.In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype.This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.
Pfizer abandons research into Alzheimer’s and Parkinson’s diseases
Authors: Nigel Hawkes
Journal: BMJ (2018)

The drug giant Pfizer has announced that it is pulling out of early stage research into Alzheimer’s and Parkinson’s diseases, with the loss of 300 jobs.

Its money can be more productively invested elsewhere, the company said. “This was an exercise to reallocate spend across our portfolio, to focus on those areas where our pipeline, and our scientific expertise, is strongest,” it said. The job losses will be at sites in the US.

Mikael Dolsten, president of worldwide research and development for the company, told a conference in San Francisco on 8 January …
Abstract 16280: Long-Term Outcomes of Percutaneous Coronary Intervention in Patients With Cirrhosis or End-Stage Liver Disease
Authors: Daniel Y Lu, Matthew D Saybolt, Daniel H Kiss, William H Matthai, Kimberly A Forde, Jay Giri, Robert L Wilensky
Journal: Circulation (2016)

Introduction:  Patients with cirrhosis and coronary artery disease (CAD) are at high risk for surgical revascularization and are often referred for percutaneous coronary intervention (PCI). If not adequately revascularized, patients may be denied listing for liver transplantation. PCI in the cirrhotic population has inherent risks, including but not limited to bleeding and acute kidney injury (AKI) due to coagulopathies, cytopenias, varices, and dynamic renal perfusion. Data on long term outcomes of PCI in cirrhotics are lacking.   Hypothesis:  PCI in cirrhotics is associated with a high risk of long term complications.   Methods:  A single-institution retrospective cohort study was performed. Patients with angiographically significant CAD and cirrhosis were identified from a database of left heart catheterizations (LHC) in the University of Pennsylvania Health System between 1/1/2007-12/31/2015. Short and long term outcomes were obtained from the electronic medical record. Patients or families were contacted directly if they were lost to follow up.   Results:  There were 51 successful PCI events in 43 patients, and 34 LHCs in 27 patients identifying significant CAD ultimately treated with medical management alone. Eleven out of 43 patients in the PCI group were listed for liver transplant, of which 4 received transplant. Eight out of 27 in the medical management group were listed, of which 6 received transplant. Complete revascularization occurred in only 3 patients, but there were no peri-transplant cardiovascular events in either group. Overall PCI-related complication rates during up to 1 year of followup were high (53%), including major bleeding (32%) on dual antiplatelet therapy (DAPT), post-PCI AKI (29%), and hematoma (4%). The medical management group had significantly fewer events (23% vs. 53%, p    Conclusions:  PCI in patients with cirrhosis is associated with a high risk of complications related to severity of liver disease and use of DAPT. Transplantation was successfully accomplished even in the absence of complete revascularization.
Erratum to: Effect of an immune-enhancing diet on lymphocyte in head-injured rats: What is the role of arginine?
Authors: Djamel Hamani, Christine Charrueau, Marie-José Butel, Valérie Besson, Linda Belabed, Ioannis Nicolis, Servane Le Plénier, Catherine Marchand-Leroux, Jean-Claude Chaumeil, Luc Cynober, Christophe Moinard
Journal: Intensive Care Medicine (2007)