tbuckley/cabot-search huggingface dataset:
Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis
Authors: Uta Kiltz, Désirée van der Heijde, Annelies Boonen, Nurullah Akkoc, Wilson Bautista-Molano, Ruben Burgos-Vargas, James Cheng-Chung Wei, Praveena Chiowchanwisawakit, Maxime Dougados, M Tuncay Duruoz, Bassel Kamal Elzorkany, Inna Gaydukova, Lianne S Gensler, Michele Gilio, Simeon Grazio, Jieruo Gu, Robert D Inman, Tae-Jong Kim, Victoria Navarro-Compan, Helena Marzo-Ortega, Salih Ozgocmen, Fernando Pimentel dos Santos, Michael Schirmer, Simon Stebbings, Filip E Van den Bosch, Astrid van Tubergen, Juergen Braun
Journal: Annals of the Rheumatic Diseases (2018)

To evaluate construct validity, interpretability, reliability and responsiveness as well as determination of cut-off points for good and poor health within the original English version and the 18 translations of the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI) in 23 countries worldwide in patients with spondyloarthritis (SpA).A representative sample of patients with SpA fulfilling the ASAS classification criteria for axial (axSpA) or peripheral SpA was used. The construct validity of the ASAS HI was tested using Spearman correlation with several standard health outcomes for axSpA. Test-retest reliability was assessed by intraclass correlation coefficients (ICCs) in patients with stable disease (interval 4-7 days). In patients who required an escalation of therapy because of high disease activity, responsiveness was tested after 2-24weeks using standardised response mean (SRM).Among the 1548 patients, 64.9% were men, with a mean (SD) age 42.0 (13.4) years. Construct validity ranged from low (age: 0.10) to high (Bath AnkylosingSpondylitisFunctioning Index: 0.71). Internal consistency was high (Cronbach's α of 0.93). The reliability among 578 patients was good (ICC=0.87 (95% CI 0.84 to 0.89)). Responsiveness among 246 patients was moderate-large (SRM=-0.44 for non-steroidal anti-inflammatory drugs, -0.69 for conventional synthetic disease-modifying antirheumatic drug and -0.85 for tumour necrosis factor inhibitor). The smallest detectable change was 3.0. Values ≤5.0 have balanced specificity to distinguish good health as opposed to moderate health, and values ≥12.0 are specific to represent poor health as opposed to moderate health.The ASAS HI proved to be valid, reliable and responsive. It can be used to evaluate the impact of SpA and its treatment on functioning and health. Furthermore, comparison of disease impact between populations is possible.
Abstract #5347: The lung tumor suppressor GPRC5A inhibits activation of NF-\#954;B in human non-small cell lung adenocarcinoma cells
Authors: Jiong Deng, Junya Fujimoto, Xiao-Feng Ye, Tao-Yan Men, Xiao-Feng Lin, Yu-Long Chen, Dafna Lotan, Reuben Lotan
Journal: Cancer Research (2009)

G-protein coupled receptor family C, group 5, member A, (GPRC5A) is a seven trans-membrane protein. The expression pattern of the GPRC5A gene is unique, almost exclusively in lung tissue. GPRC5A expression is frequently suppressed in human lung cancers, including lung adenocarcinoma. This suggests that inactivation of this gene may contribute to lung tumorigenesis. Indeed, we have previously found that knockout of both alleles of the mouse Gprc5a gene enhances spontaneous lung carcinogenesis. Lung epithelial cells isolated from lungs of knockout mice had a constitutively activated nuclear factor kappa B (NF-\#954;B) and tumors that developed in this model were associated with inflammatory cells. Because chronic inflammation and aberrant NF-\#954;B activation have been implicated in human lung carcinogenesis as well, in this study we explored the relationship between GPRC5A expression and NF-\#954;B activation. We found that re-expression of GPRC5A in human adenocarcinoma H1792 cells, which express low level of GPRC5A, inhibits tumor necrosis factor alpha-induced NF-\#954;B activation and suppresses the transformed phenotype (anchorage-independent growth). GPRC5A-mediated NF-\#954;B inhibition was also observed in human colon cancer cell line HCT116 and human embryonic kidney (HEK) 293 cells immortalized with sheared fragments of adenovirus (Ad)5 DNA. Inhibition of NF-\#954;B activity by GPRC5A was correlated with loss of anchorage-independent growth and increased anoikis. The mechanism of NF-\#954;B inhibition was associated with GPRC5A-mediated inhibition of I\#954;B\#945; degradation. Over-expression of GPRC5A resulted in increased formation of a complex containing \#946;-arrestin 2, I\#954;B\#945; and the NF-\#954;B subunit p65. Depletion of \#946;-arrestin 2 by siRNA restored NF-\#954;B activation in GPRC5A stable transfectants evidenced by expression of TRAF1 a downstream target of NF-\#954;B. This result suggests that increased interaction of \#946;-arrestin 2 with I\#954;B\#945;/p65 complex is involved in GPRC5A-mediated inhibition of NF-\#954;B. An analysis of 150 cases of human lung adenocarcinoma by immunohistochemical staining revealed that increased nuclear localization of NF-\#954;B indicating activation correlated with suppressed expression of GPRC5A. These results have led to the conclusion that GPRC5A functions as a physiological inhibitor of NF-\#954;B activation in lung tissue and thereby suppress carcinogenesis. Further, we propose that GPRC5A function as a tumor suppressor in human lung tissue because its deletion or repression of its expression leads to aberrant activation of NF-\#954;B pathway and tumorigenesis.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5347.
A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease
Authors: Tanya M. Laidlaw, Katherine N. Cahill, Juan Carlos Cardet, Katherine Murphy, Jing Cui, Brittney Dioneda, Parul Kothari, Benjamin A. Raby, Elliot Israel, Joshua A. Boyce
Journal: Journal of Allergy and Clinical Immunology (2018)
Identifying vulnerable populations among breast cancer survivors.
Authors: Kit Yu Lu, Theresa M. Lee, Megan Lanigan, Beth Rudge, Yijin Wert, Lisa Torp
Journal: Journal of Clinical Oncology (2018)

176 Background: Long term survival is common after breast cancer treatment with 5-year survival rate reaching almost 90%. Many breast cancer survivors (BCS) face varying degrees of quality of life (QOL) issues depending on their age of diagnosis, severity of their disease, and treatment course. This is a retrospective analysis to describe demographics, QOL concerns, and to identify vulnerable populations among the BCS. Methods: This is a retrospective analysis of BCS seen at our Breast Cancer Survivorship Program from Oct 2016 to Oct 2017. Patients were given a comprehensive survey to assess self-reported symptoms and concerns following their treatment. Chi-square test was used to analyze group differences. The Fisher exact test was employed when any of the expected frequencies was five or less. Results: 252 patients (age 26-93; median 60) were seen. Characteristics are listed in the Table. Most common self-reported concerns affecting BCS were: fatigue (40%), insomnia (38%), hot flashes (29%), night sweats (26%), pain (26%), trouble concentrating (26%), and neuropathy (25%). Majority(87%) reported having a happy outlook and felt that they have a sense of purpose (85%), but about 12% of BCS felt isolated at least 50% of their time. Young cancer survivors (age ≤45) (p&lt;0.0001), higher stage BCS (Stage 2-3) (p=0.0023), and those who had chemotherapy either alone or as part of their multi-modality treatment (p=0.0061) were significantly more likely to worry about their cancer post treatment. The same populations were significantly less likely to return back to at least 50% of their pre-treatment baseline (young cancer survivors p=0.0049; higher stage p=0.0011; chemo+/-other treatments p=0.0012). Conclusions: Majority of BCS report a happy and optimistic outlook post treatment, but some may experience significant QOL issues. Identifying common concerns after treatments and vulnerable populations are especially important to deliver quality care and to optimize interventions. [Table: see text]
Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death
Authors: Tsadik Habtetsion, Zhi-Chun Ding, Wenhu Pi, Tao Li, Chunwan Lu, Tingting Chen, Caixia Xi, Helena Spartz, Kebin Liu, Zhonglin Hao, Nahid Mivechi, Yuqing Huo, Bruce R. Blazar, David H. Munn, Gang Zhou
Journal: Cell Metabolism (2018)
Enzyme-Responsive Hydrogels May Help Treat Arthritis
Authors: Tracy Hampton
Journal: JAMA (2018)

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Wobbling Forth and Drifting Back: The Evolutionary History and Impact of Bacterial tRNA Modifications
Authors: Gaurav D Diwan, Deepa Agashe
Journal: Molecular Biology and Evolution (2018)

Along with tRNAs, enzymes that modify anticodon bases are a key aspect of translation across the tree of life. tRNA modifications extend wobble pairing, allowing specific ("target") tRNAs to recognize multiple codons and cover for other ("nontarget") tRNAs, often improving translation efficiency and accuracy. However, the detailed evolutionary history and impact of tRNA modifying enzymes has not been analyzed. Using ancestral reconstruction of five tRNA modifications across 1093 bacteria, we show that most modifications were ancestral to eubacteria, but were repeatedly lost in many lineages. Most modification losses coincided with evolutionary shifts in nontarget tRNAs, often driven by increased bias in genomic GC and associated codon use, or by genome reduction. In turn, the loss of tRNA modifications stabilized otherwise highly dynamic tRNA gene repertoires. Our work thus traces the complex history of bacterial tRNA modifications, providing the first clear evidence for their role in the evolution of bacterial translation.
An open label, single arm, prospective phase II study to evaluate the efficacy and safety of bevacizumab with gemcitabine and carboplatin as first-line treatment for metastatic triple negative breast cancer patients.
Authors: Sudeep Gupta, Govind K. Babu, Raju Titus Chacko, Dinesh Doval, Chirag Desai, Nalini Kilara, Shona Milon Nag, Chirag A. Shah, SVS Deo, Smruti B. Koppikar, Binay Swarup, Anil Arjundas Kukreja, Vinod Raina
Journal: Journal of Clinical Oncology (2018)

1098 Background: There is a higher burden (29.2%-46%) of TNBC patients in India. This single arm, phase II trial evaluated the efficacy and safety of bevacizumab in combination with gemcitabine and carboplatin as first line treatment in Indian patients with metastatic TNBC. Methods: TNBC patients with prior adjuvant anthracycline and taxane therapy and no prior treatment for metastatic disease received bevacizumab (15mg/kg) with gemcitabine and carboplatin, every three weeks until disease progression or unacceptable toxicity. Results: Forty patients were accrued at 10 Indian centers between February 2011 to April 2013. At median follow-up of 12 (0.5 –59.3) months there were 27 disease progressions and 23 deaths. Using EORTC QLQ-30 questionnaire, improvements were observed in physical function (P = 0.0435), emotional function (P = 0.002) and pain perception (P = 0.0243) domains from baseline to cycle 6. Median duration of study treatment was 4.6 (0.3 – 18.4) months. Overall, 24 (60%) patients reported 133 adverse events (99 non-serious, 34 serious) including proteinuria, rectal hemorrhage (grade 3) and fatigue (grade 4) in 1 patient each. A total of 34 serious adverse events were reported in 17 (42.5%) patients. No new safety signals were identified and bevacizumab was found to be well tolerated by Indian patients. Conclusions: Bevacizumab in combination with gemcitabine and carboplatin as first line treatment in metastatic TNBC, resulted in favorable survival outcomes with acceptable toxicity. The patients also experienced significant improvement in several domains of health related QoL during the first 6 cycles of this treatment. Efficacy results Clinical trial information: NCT01201265.Primary Endpoint N = 40 Median PFS 8.5 months (95% CI: 5.2 – 15.3) Secondary Endpoints N = 40 Median OS (protocol-defined end of study) 15.8 months (95% CI: 11.8 – 24.9) Updated Median OS (additional 14.5 months follow-up) 23.1 months (95% CI: 9.6 – 36.0) TTP 8.9 months (95% CI: 6.0 – 18.1) Complete Response (CR) 2 (5%) Partial Response (PR) 18 (45%) Stable Disease (SD) 17 (42.5%) Overall Response Rate (CR+PR) 20 (50%) Clinical Benefit Rate (CR+PR+SD) 37 (92.5%)
Geriatric communication skills training: Shared decision making and care planning for the older cancer patient and the caregiver.
Authors: Ruth Manna, Smita C. Banerjee, Megan Johnson Shen, Beatriz Korc-Grodzicki, Yesne Alici, Natalie Gangai, Koshy Alexander, Jimmie Holland, Patricia A. Parker, Christian J Nelson
Journal: Journal of Clinical Oncology (2018)

80 Background: Medical decision-making is the process of shared understanding of a patient’s personal values and subsequent negotiation to reach a treatment decision. Discussing options and engaging patients in decision-making remains a challenge for many clinicians. The challenge is greater when treating older patients, who may be cognitively impaired, and may have family members or caregivers playing significant roles in their care. The geriatric communication skills training (CST) guides clinicians in effectively communicating with older cancer patients and their caregivers around pivotal cancer care decisions. Methods: A multidisciplinary team from a Comprehensive Cancer Center collaborated on the development of a one-day training program, consisting of three geriatric specific CST modules: Geriatrics 101, Cognitive Syndromes and Shared Decision Making. Each module included a brief didactic (30 min) with exemplary videos, followed by experiential role play (90 min) with standardized patients (SP), co-led by multi-disciplinary facilitators. These sessions were video recorded to enable reflective learning, group discussion, and feedback. We examined preliminary efficacy of the intervention on multiple outcomes, including participant course evaluations, self-efficacy and coded SP assessments. Results: 28 clinicians, including mental health professionals, oncologists, family practitioners, physician assistants, nurse practitioners, and social workers participated in the training. All participants reported strong satisfaction results with the workshop. Self-efficacy ratings increased significantly across all three modules, t(21) = -4.58, p &lt; .001 between pre-training (M = 3.39, SD = .66) and post-training (M = 4.13, SD = .59). In SP assessments, participants also demonstrated significant uptake of agenda setting skills and increased responsiveness to caregiver concerns from pre to post training. Conclusions: The geriatric CST program was well received and demonstrated improvements in knowledge. Interdisciplinary training groups present for excellent case discussion and modeling opportunities for a variety of communication challenges.
Efficacy of an Inhaled IL-13 Antibody Fragment in a Model of Chronic Asthma
Authors: Daniel Lightwood, Markus Tservistas, Monique Zehentleitner, Kaushik Sarkar, Alison Turner, Marguerite Bracher, Bryan Smith, Sabrina Lamour, Tim Bourne, Stevan Shaw, Neil Gozzard, Roger T. Palframan
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: IL-13 is an important cytokine implicated in the pathogenesis of allergic asthma and is an attractive target for an inhaled therapeutic.Objective: To investigate the efficacy of CDP7766, a nebulized inhaled anti–IL-13 monoclonal antibody Fab fragment, in a model of allergic asthma in cynomolgus macaques naturally sensitized to Ascaris suum.Methods: CDP7766 was nebulized using a vibrating-membrane nebulizer on the basis of eFlow technology. The aerosol generated was analyzed to determine the particle size profile and the biophysical and functional properties of CDP7766. Nebulized CDP7766 (0.1–60 mg/animal, once daily for 5 d) was delivered via the inhaled route.Measurements and Main Results: The investigational eFlow nebulizer used in this study generated a respirable aerosol of CDP7766 with no evidence of degradation, loss of potency, aggregation, or formation of particulates. Inhaled CDP7766 was well tolerated in the model (no adverse effects related to local irritation) and significantly inhibited BAL allergen-induced cytokine and chemokine upregulation (60 mg vs. vehicle: eotaxin-3, P < 0.0008; MIP [macrophage inflammatory protein]-1β, IL-8, IFN-γ, P ≤ 0.01). CDP7766 significantly inhibited the increase in pulmonary resistance stimulated by inhaled allergen, measured 15 minutes and 24 hours after allergen challenge.Conclusion: Inhaled CDP7766 potently inhibited the function of IL-13 generated during the airway response to inhaled allergen in cynomolgus macaques, demonstrating the potential of inhaled anti–IL-13 therapeutics for the treatment of allergic asthma.
A new allergic rhinitis therapy (MP29-02) is more effective than current first line monotherapies in providing allergic rhinitis patients relief from their nasal and ocular symptoms (rTNSS, rT5SS, rT7SS)
Authors: G Canonica, J Bousquet, J Mullol, JC Virchow, U Munzel, Claus Bachert
Journal: Allergy (2013)
Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma
Authors: Inan Olmez, Ying Zhang, Laryssa Manigat, Mouadh Benamar, Breanna Brenneman, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Jeongwu Lee, Tarek Abbas, Roger Abounader, Benjamin Purow
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB–mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials. Significance: CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-κB and can be reversed by a dual c-Met/Trk inhibitor. Cancer Res; 78(15); 4360–9. ©2018 AACR.
Altitude sickness and acetazolamide
Authors: Jonathan Williamson, Pippa Oakeshott, Jon Dallimore
Journal: BMJ (2018)

### What you need to know

A 25 year old man plans to trek to Everest Base Camp (5545 m) in Nepal for charity. He asks you for a prescription of acetazolamide to prevent mountain sickness. 

For most people, mountain sickness is a self limiting illness, but it can become life threatening. It is estimated that more than 100 million people per year travel to the hypoxic environments found at altitudes above 2500 m,1 and at least 10% to 20% of unacclimatised individuals develop acute mountain sickness at this height.2 Acclimatisation to altitude involves multiple physiological changes, occurring over days to weeks, which enable individuals to function better in these hypoxic environments. If this natural adaptation is surpassed by the rate of exposure to altitude, acute mountain sickness can occur. Acetazolamide can help to prevent acute mountain sickness developing and has fewer side effects than alternative drugs such as dexamethasone, which can mask symptoms and therefore carries greater risks.2345 Acetazolamide causes mild diuresis and increases renal excretion of bicarbonate, causing a mild metabolic acidosis which in turn increases respiratory rate (improving oxygenation).

In the UK, prescribing acetazolamide for travel is an optional service, not included in the general practitioner’s contract. Some GPs may decide not to prescribe acetazolamide on this basis, or because they feel it is outside the scope of their practice.

This article is an approach to discussing travel and activity at high altitude, prevention of sickness, and acetazolamide prescription for non-specialists.

### History

#### What does the person know about acute mountain sickness?

Symptoms of acute mountain sickness …