tbuckley/cabot-search huggingface dataset:
Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis
Authors: Brian W. Labadie, Riyue Bao, Jason J. Luke
Journal: Clinical Cancer Research (2018)

Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)-programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell-inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell-inflamed tumors is the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway. Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp-Kyn-AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.
Acoustic Methods for Pulmonary Diagnosis
Authors: Adam Rao, Emily Huynh, Thomas J. Royston, Aaron Kornblith, Shuvo Roy
Journal: IEEE Reviews in Biomedical Engineering (2018)

Recent developments in sensor technology and computational analysis methods enable new strategies to measure and interpret lung acoustic signals that originate internally, such as breathing or vocal sounds, or are externally introduced, such as in chest percussion or airway insonification. A better understanding of these sounds has resulted in a new instrumentation that allows for highly accurate as well as portable options for measurement in the hospital, in the clinic, and even at home. This review outlines the instrumentation for acoustic stimulation and measurement of the lungs. We first review the fundamentals of acoustic lung signals and the pathophysiology of the diseases that these signals are used to detect. Then, we focus on different methods of measuring and creating signals that have been used in recent research for pulmonary disease diagnosis. These new methods, combined with signal processing and modeling techniques, lead to a reduction in noise and allow improved feature extraction and signal classification. We conclude by presenting the results of human subject studies taking advantage of both the instrumentation and signal processing tools to accurately diagnose common lung diseases. This paper emphasizes the active areas of research within modern lung acoustics and encourages the standardization of future work in this field.
Abstract P173: Hypertension Clusters Across Time and Differential Risk of Mortality: National Health and Nutrition Examination Survey 1999 - 2012
Authors: Marcia P Jimenez, Mark A Green, Amol A Verma, S.V. Subramanian, Eric B Loucks, Fahad Razak
Journal: Circulation (2018)

Background: Blood pressure treatment strategies and targets are generally similar for most patients with hypertension, apart from individuals with certain specific comorbidities such as diabetes. We hypothesize that there is latent heterogeneity in the population of adults with hypertension and that this may be associated with differential risk of mortality and might suggest opportunities for more tailored treatment strategies. Our study of adults with hypertension in the US explores whether clusters of social and health-related characteristics exist, how trends in clusters have varied between 1999 and 2012, and how risk of mortality varies between clusters. Methods: In a nationally representative sample of adults (&amp;gt 18 years) with hypertension (physician diagnosed, systolic &amp;ge 140 mmHg or diastolic &amp;ge 90 mmHg, or taking hypertension -related medication) from the National Health and Nutrition Examination Survey from 1999 to 2012 (Total N=16,855), we used a hierarchical cluster analysis approach to identify hypertension sub-groups according to chronic diseases, social factors, and health behaviors. Results: We found significant heterogeneity among hypertensive participants across time, according to 7 distinct clusters: Young Mexican-Americans with good health (55% of sample); Low-income non-White elderly with good health behaviors (7%); Elderly obese who smoke (18%); Men with poor health who drink and smoke (1%); Normal weight individuals with high prevalence of cancer (16%); Low-income and fit individuals with poor health (1%); and Obese and morbidly obese with high prevalence of chronic conditions (2%). The prevalence of each of these clusters remained relatively constant throughout the last decade, although there was an increase in the “Elderly obese who smoke” cluster from 14% to 18%. Mortality risk varied by subgroup. For example, the odds of dying for “Obese and morbidly obese with high prevalence of chronic conditions” were 1.73 times higher compared to “Young Mexican-Americans with good health” (p-value&lt;0.001), adjusting for confounders over a 12 year follow-up interval. Conclusions: Sociodemographic and clinical clusters among hypertensive individuals in the U.S. remained stable over a decade, with higher risk of mortality associated with specific clusters. Recognizing these clinically-identifiable phenotypes may highlight opportunities to develop and evaluate targeted interventions that account for complex and inter-related clinical and social factors. Further, there is an opportunity through clinical trials to determine whether these clusters merit different blood pressure treatment strategies.
Abstract 13775: Increased Atherosclerosis in the Lack of IkBNS in LDL Receptor-deficient Mice is Associated With Increased Interleukin-6 Production by Macrophages
Authors: Koji Akita, Kikuo Isoda, Yayoi Sato-Okabayashi, Yuko Ishii, Kazunori Shimada, Hiroyuki Daida
Journal: Circulation (2015)

Background: IκBNS is a nuclear IκB protein which regulates nuclear factor-κB dependent interleukin (IL) -6 production. Although IL-6 is an important biomarker for cardiovascular diseases, the role of IκBNS in the development of atherosclerosis is poorly understood. Methods and Results: Mice that lacked IκBNS (IκBNS-/-) were crossed with LDL receptor-deficient (LDLr-/-) mice and formation of atherosclerotic lesion was analyzed after 16 weeks consumption of a high-fat diet. When compared with single LDLr-/- mice (n=6), the surface atherosclerotic lesions in aortas were significantly increased in IκBNS-/-LDLr-/- mice (n=6) (22.7 ± 3.0% vs. 6.2 ± 1.4 %; p &lt;0.001)(Figure). Immunostaining revealed significant increase in both Mac-3-positive (1.6-fold, p &lt;0.05) and α-SMA-positive (3.6-fold, p &lt;0.01) lesions in IκBNS-/-LDLr-/- mice compared with LDLr-/- mice. Furthermore, IL-6 expression (2.2-fold, p&lt;0.001), and percent phospho-STAT3-positive cell (1.9-fold, p&lt;0.05) were increased in IκBNS-/-LDLr-/- mice, indicating IκBNS deficiency promoted proliferation of both macrophage and smooth muscle cells via the IL-6-Stat3 signaling pathway. Then, we studied the function of macrophages. After LPS stimulation, the mRNA levels of both IL-6 (2.4-fold, p&lt;0.001) and IL-18 (1.4-fold, p&lt;0.05) were increased in the macrophages from IκBNS-/-LDLr-/- mice compared with LDLr-/- mice. Moreover, ELISA experiments revealed IκBNS-/-LDLr-/- macrophages produce much higher level of IL-6 in culture supernatants compared with LDL-/- macrophages (1.9-fold, p&lt;0.01). Conclusions: The present study shows that IκBNS gene deficiency in atherogenic mice led to the increase of IL-6 production and the development of atherosclerosis.
Vascularized 3D printed scaffolds for promoting bone regeneration
Authors: Yufei Yan, Hao Chen, Hongbo Zhang, Changjun Guo, Kai Yang, Kaizhe Chen, Ruoyu Cheng, Niandong Qian, Niklas Sandler, Yu Shrike Zhang, Haokai Shen, Jin Qi, Wenguo Cui, Lianfu Deng
Journal: Biomaterials (2018)
Eosinophilia in BP
Authors: K. Kridin
Journal: British Journal of Dermatology (2018)

Bullous pemphigoid (BP) is a skin condition that causes rashes and itchy blistering in the skin. 50‐60% of BP patients are also reported to have peripheral eosinophilia (PE), a painful disease caused by increased levels of disease‐fighting white blood cells called eosinophils. The objectives of this study, from Israel, were to learn more about which BP patients are affected by PE and to study the relationship between above‐average eosinophil levels in the blood (known as serum eosinophilia) and the symptoms of BP. To do this, 225 BP patients and 1125 control participants (control participants are healthy individuals used for comparison, in this case with 5 age, sex and ethnicity matched controls for each BP patient) were enrolled into the study. In total 113 (50.2%) BP patients and 49 (4.9%) control patients had PE. An independent association between eosinophil white blood cell count and diagnosis of BP was observed. BP patients with PE were generally significantly older than the other BP patients and had greater palmoplantar involvement (of the palms and soles of feet), whereas BP patients with normal eosinophil counts had greater involvement in mucosal surfaces (inside the nose, mouth, ears, genitals), the head and the neck. Patients with more severe BP were also noted to have significantly higher eosinophil counts than others with mild‐moderate BP. This study concludes that BP patients with severe peripheral eosinophilia were significantly older when their disease started, as well as proving the correlation between BP severity and PE.
Abstract 14700: Atorvastatin Safety and Pharmacokinetics in Acute Kawasaki Disease Patients With Coronary Artery Abnormalities
Authors: Adriana H Tremoulet, Sonia Jain, Pei-Ni Jone, Samuel R Dominguez, Marsha Anderson, Heather Heizer, Chisato Shimizu, Ming He, Elizabeth Duxbury, Brookie Best, Alessandra Franco, Negar Behnamfar, Feng He, John Whitin, Harvey Cohen, John Shyy, Beth Printz, Mary Glode, Jane C Burns
Journal: Circulation (2017)

Introduction: Despite therapy with intravenous immunoglobulin, 25% of children with Kawasaki disease (KD) develop coronary artery abnormalities (CAA) and endothelial cell (EC) dysfunction. Based on...
Phase 1b/2 study of binimetinib (BINI) in combination with nivolumab (NIVO) or NIVO plus ipilimumab (IPI) in patients (pts) with previously treated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with <i>RAS</i> mutation.
Authors: Johanna C. Bendell, Scott Kopetz, Mark R. Middleton, P. Taylor Eves, Viviana Bozon, Adam P. Boyd, Jan H.M. Schellens
Journal: Journal of Clinical Oncology (2018)

TPS870 Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.
Injection of Adipose-Derived Stromal Cells in the Knee of Patients with Severe Osteoarthritis has a Systemic Effect and Promotes an Anti-Inflammatory Phenotype of Circulating Immune Cells
Authors: Yves-Marie Pers, Julie Quentin, Rosanna Feirreira, Francisco Espinoza, Naoill Abdellaoui, Nejla Erkilic, Maïlys Cren, Emilie Dufourcq-Lopez, Oliver Pullig, Ulrich Nöth, Christian Jorgensen, Pascale Louis-Plence
Journal: Theranostics (2018)

come from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Short contact with nickel causes allergic contact dermatitis
Authors: M. G. Ahlström, J. P. Thyssen, T. Menné, K. Midander, A. Julander, C. Lidén, C. R. Johnsen, J. D. Johansen
Journal: British Journal of Dermatology (2018)

Allergic contact dermatitis is a common type of eczema that causes inflammation when skin comes into contact with certain substances. Although it is well accepted that long term skin contact can cause nickel allergy and dermatitis, the significance of relatively short and repeated nickel exposure in relation to induction and elicitation (i.e. first triggering) of nickel allergy has been less explored, and it has been proposed that short skin contact with nickel is safe. A study conducted in Denmark and Sweden attempted to test this proposition by examining whether repeated skin contact with nickel over short time periods would elicit allergic contact dermatitis. 16 adults who were known to have nickel allergy were tested along with a further 10 non‐allergic control subjects (a control subject is a healthy individual used for comparison). The subjects were exposed to nickel and aluminium discs on each forearm and each earlobe for 3 x 10 minutes. Also, one arm would be treated for 24 hours beforehand with 0.5% sodium lauryl sulfate (SLS) under occlusion (meaning the solution was applied then wrapped up with plastic wrap or cloth). SLS is added to bath products and detergents to make them foam and is a common cause of skin reactions. The purpose of this was to monitor differences in reactions to nickel in skin that was either normal or already irritated (by the SLS). Each nickel and aluminium site was evaluated and blood flow measured, as increased blood flow can show that skin is reacting to nickel. 62.5% of nickel allergic subjects reacted to nickel on the SLS treated arm. The nickel exposed skin also caused significantly more blood flow than aluminium exposed skin. No change in reactivity or blood flow was seen in any non‐SLS nickel exposed arms in nickel allergic patients, or in any control subjects. This study shows that relatively short repeated contact with nickel can elicit allergic contact dermatitis in irritated skin in people who already have a nickel allergy. The results support the restrictions in current nickel regulation.
Abstract 17780: The Impact of Neurogenic Stunned Myocardium on Cardiovascular Events During Hospitalization in Patients With Acute Ischemic Stroke
Authors: Kaho Shibata, Takahiro Nakashima, Shoji Kawakami, Kazuhiro Nakao, Fumiyuki Otsuka, Masashi Fujino, Kensaku Nishihira, Tetsuo Arakawa, Yoshio Tahara, Yu Kataoka, Yasuhide Asaumi, Teruo Noguchi, Satoshi Yasuda, Tomotaka Tanaka, Masafumi Ihara, Kazunori Toyoda
Journal: Circulation (2017)

Introduction: Neurologic Disorders are known to be associated to transient left ventricular (LV) dysfunction mainly on subarachnoid hemorrhage, namely “neurogenic stunned myocardium” (NSM). However...
What We Can Do about Maternal Mortality — And How to Do It Quickly
Authors: Susan Mann, Lisa M. Hollier, Kimberlee McKay, Haywood Brown
Journal: New England Journal of Medicine (2018)

Interview with Dr. Susan Mann on steps that hospitals can take to keep women safe during and after childbirth. (08:46)Download Every U.S. hospital providing obstetrical care can take four key actions to help curb the tragic trend of increasing maternal mortality. And an additional year of training could be offered for family medicine physicians who want to practice obstetrics in rural areas.
Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension
Authors: Maelíosa T.C. Mc Crudden, Eneko Larrañeta, Annie Clark, Courtney Jarrahian, Annie Rein-Weston, Sophie Lachau-Durand, Nico Niemeijer, Peter Williams, Clement Haeck, Helen O. McCarthy, Darin Zehrung, Ryan F. Donnelly
Journal: Journal of Controlled Release (2018)

One means of combating the spread of human immunodeficiency virus (HIV) is through the delivery of long-acting, antiretroviral (ARV) drugs for prevention and treatment. The development of a discreet, self-administered and self-disabling delivery vehicle to deliver such ARV drugs could obviate compliance issues with daily oral regimens. Alternatives in development, such as long-acting intramuscular (IM) injections, require regular access to health care facilities and disposal facilities for sharps. Consequently, this proof of concept study was developed to evaluate the use of dissolving microarray patches (MAPs) containing a long-acting (LA) nanosuspension of the candidate ARV drug, rilpivirine (RPV). MAPs were mechanically strong and penetrated skin in vitro, delivering RPV intradermally. In in vivo studies, the mean plasma concentration of RPV in rats (431 ng/ml at the Day 7 time point) was approximately ten-fold greater than the trough concentration observed after a single-dose in previous clinical studies. These results are the first to indicate, by the determination of relative exposures between IM and MAP administration, that larger multi-array dissolving MAPs could potentially be used to effectively deliver human doses of RPV LA. Importantly, RPV was also detected in the lymph nodes, indicating the potential to deliver this ARV agent into one of the primary sites of HIV replication over extended durations. These MAPs could potentially improve patient acceptability and adherence to HIV prevention and treatment regimens and combat instances of needle-stick injury and the transmission of blood-borne diseases, which would have far-reaching benefits, particularly to those in the developing world.
Thijs Bleiker: “the guru of tuberculin research”
Authors: Tony Sheldon
Journal: BMJ (2018)

On returning to a remote village soon after setting up a tuberculosis (TB) project, Matthijs Adriaan Bleiker (“Thijs”) was dismayed to find the bicycle—provided so a nurse could supervise drug regimens in outlying communities—in bits, its tyres flat. It had a puncture; no one knew how to mend it, and so the project had collapsed.

Such frustrations of fieldwork were, however, familiar to Bleiker, working in the 1960s and 70s in bush areas of Mali, Malawi, Suriname, and Tanzania, often for months at a time. They never shook his ambition to eradicate tuberculosis by 2000. He told his two daughters—Eveline Kruijf-Bleiker, a professor in the psychology of clinical genetics, and Jacqueline van Bekkum-Bleiker, a general practitioner—“If we don’t do it, no one will.”

First at the Dutch organisation for applied scientific research, TNO, and later as director of the Netherlands TB Foundation (KNCV), Bleiker spent his career fighting TB. He worked in research laboratories, television studios, and international conference centres; photographed one day when he presented Queen Juliana of the Netherlands with the latest edition of the TB textbook (figure 2), the next day with the chief of a Suriname village, reachable only by canoe.



Thijs Bleiker presenting Queen Juliana with the latest edition of the tuberculosis textbook

His major achievement is considered …
Clostridium difficile associated disease
Authors: Ali Hassoun
Journal: BMJ (2018)

### What you need to know

Clostridium difficile associated disease (CDAD) is an infection of the colon caused by the bacteria Clostridium difficile . It occurs in patients whose normal bowel flora have been disrupted, commonly by recent antibiotic use. It is often, but not always, acquired in healthcare facilities and often presents as acute onset diarrhoea. Recurrences are relatively common.

C difficile are Gram positive, anaerobic, spore forming rods that produce toxins A and B. These toxins cause an inflammatory response in the large intestine, leading to increased vascular permeability and pseudomembrane formation.1 The condition is also known as pseudomembranous colitis, CDI, or Clostridioides difficile. 

C difficile is responsible for 48% of healthcare associated gastrointestinal infections in acute care hospitals across Europe,2 and has become one of the most common causes of healthcare associated infections in US hospitals. In one US study, C difficile infection accounted for 10% of patients presenting to the emergency department with diarrhoea and no vomiting.3

Guidance from the US published in March 2018 details important updates in diagnosis and treatment.4

Common symptoms include diarrhoea, abdominal pain and tenderness, and fever. Severity varies from isolated mild diarrhoea to copious watery diarrhoea with severe abdominal …
Asilomar survey: researcher perspectives on ethical principles and guidelines for BCI research
Authors: Michelle Pham, Sara Goering, Matthew Sample, Jane E. Huggins, Eran Klein
Journal: Brain-Computer Interfaces (2018)

Brain-computer Interface (BCI) research is rapidly expanding, and it engages domains of human experience that many find central to our current understanding of ourselves. Ethical principles or guidelines can provide researchers with tools to engage in ethical reflection and to address practical problems in research. Though researchers have called for clearer ethical principles or guidelines, there is little existing data on what form these should take. We developed a prospective set of ethical principles for BCI research with specific guidelines and shared them, via a survey, to participants at the 6th International BCI Meeting at the Asilomar Conference Center in 2016. Respondents were broadly supportive of principles of Care for Subjects, Modesty, Participation, Inclusivity, Relationality, Justice, and Social Impact. Principles more traditionally aligned with responsible conduct of research showed higher levels of endorsement. Researcher support for specific principle-based ethical guidelines varied with respect to stringency of researcher obligations.