tbuckley/cabot-search huggingface dataset:
Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus
Authors: A. Salem, S. Rozov, A. Al-Samadi, V. Stegajev, D. Listyarifah, V.-P. Kouri, X. Han, D. Nordström, J. Hagström, K.K. Eklund
Journal: British Journal of Dermatology (2016)

Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high‐affinity histamine H4 receptor (H4R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4R pattern, which is deranged in oral lichen planus (OLP). To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP. Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real‐time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high‐performance liquid chromatography. l‐histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N‐methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate‐to‐high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon‐γ upregulated HDC‐gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor‐α. LPS induced a dose‐dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins. HOKs are histamine‐producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low‐affinity H1R and H2R, but high enough to stimulate the high‐affinity H4R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.
Adding tests to risk based guidelines: evaluating improvements in prediction for an intermediate risk group
Authors: Nina P Paynter, Nancy R Cook
Journal: BMJ (2016)

Using an additional test in patients who are not at high enough risk of developing disease to confidently treat, or low enough risk to confidently not treat would seem to be a straightforward way to resolve the clinical equipoise and is recommended by many guidelines. However, clear methods for evaluating the population utility of additional tests in this group have not been established. This paper includes worked examples and simulation data to show that focus on the intermediate risk group alone can be misleading and that population utility is best evaluated across the full range of risk.
Results of a german noninterventional study (NIS) of cetuximab-based therapy in pretreated-patients (pts) with metastatic colorectal cancer (mCRC).
Authors: C. Jehn, K. Stenzel, L. Böning, H. Kröning, K. Possinger, D. Lueftner
Journal: Journal of Clinical Oncology (2010)

3632 Background: Clinical trials may have a selection bias caused by an underrepresentation of pts older than 65 years (y) and of ECOG performance status > 1. Post-marketing NIS are a helpful tool to evaluate approved therapies in daily practice in the general patient population. The aim of this subgroup analysis of this german NIS was to evaluate the efficacy and safety profile of cetuximab in combination with chemotherapy in irinotecan pretreated mCRC patients aged > 65 y and < 65 y. Methods: Between 04/2005 and 11/2007 the data of 497 irinotecan-pretreated pts with mCRC (out of 657 pts documented) were entered in the database of this NIS. We analyzed both patient groups applying descriptive statistics and χ2- or Fishers exact test. Results: Median age was 66 y (30-88) with 247 and 250 pts of age < 65 and age > 65, respectively. 17.4% and 21.6% of pts in both groups showed an ECOG-Status of 2-3. Pts had 1-4 lines of previous chemotherapy: 26% and 17% 1 line, 43% and 43% 2 lines, 19% and 25% 3 lines, and 13% and 15% 4 lines (p = 0.55). Cetuximab was mainly combined with irinotecan in a weekly regimen (71% and 73%) and also combined with 5-FU in 20% and 19% of pts, respectively. Severe cetuximab-related toxicity occurred in 2% (6 and 4 pts, respectively). The median duration of any grade of skin reaction (35 d) was in pts age < 65 significantly longer (42 d), than in patients age > 65 (31 d); (p = 0.04). However, there was a trend towards higher grade (≥ 2) skin toxicity in pts age > 65. Skin toxicity led to discontinuation of therapy in 2.6% (6 pts in both groups), but in 22% and 31% to a dose modification and in 6% and 11% to a treatment pause. The objective response rates were similar for both groups: 38.1% for age < 65 vs. 36.4% for age > 65 (p = 0.57). The rates for secondary resectability of metastases after cetuximab-based therapy were 4.4% for both groups. Time to tumor progression was similar for both age groups: 4 months (range: 1.0-19.0) and 5 months (1.0-17.0) (p = 0.79). Conclusions: Cetuximab has a similar efficacy and safety profile for pts age > 65 and < 65 y. Therefore these results add valuable information to the clinical trials. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono
Association between rosacea and gastrointestinal disorders
Authors: A. Alexoudi, I. Alexoudi, S. Gatzonis
Journal: British Journal of Dermatology (2016)

We read with great interest the results of a nationwide cohort study published by Egeberg et al.1 demonstrating that the prevalence of coeliac disease, Crohn disease, ulcerative colitis, irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO) and Helicobacter pylori infection was higher among patients with rosacea when compared with controls. Recently, with regard to the same cohort, the authors indicated that rosacea constitutes an independent risk factor for Parkinson disease (PD).2

The entire gastrointestinal tract (GIT) is affected in PD and motility disorders are included in the most common nonmotor manifestations in these patients. Additionally, increasing evidence suggests that GIT might be the site of initiation of PD. Persistent gastric or intestinal infection with H. pylori and SIBO deteriorates motor fluctuations.

This article is protected by copyright. All rights reserved.
Allergen-specific immunotherapy: is it vaccination against toxins after all?
Authors: M. F. Bachmann, T. M. Kündig
Journal: Allergy (2016)

IgE-mediated allergies, in particular allergic rhinoconjunctivitis and asthma, have reached epidemic proportions, affecting about one-third of the population in developed countries. The most effective treatment for allergies is specific immunotherapy (SIT), which involves the injection of increasing doses of an allergen extract to allergic individuals. The current form of SIT was first introduced in 1911 and recently celebrated its 100th birthday for the treatment of hay fever. The concept of this therapy at the time was straightforward, as it was believed that pollen contained toxins against which the patient could be vaccinated. However, the understanding became blurred with the discovery that IgE antibodies were the effector molecules of the allergic response. Subsequent research focused on the idea that SIT should induce tolerance keeping the IgE antibodies at bay. In this review, we will discuss the various hypotheses for the mechanism of SIT and we will put forward the concept that allergens may be viewed as 'protoxins' which need to be activated by IgE antibodies. Within this framework, protoxin-neutralizing antibodies are the key effector molecules while a shift to Th1 or Treg cells mainly contributes to the efficacy of SIT by helping B cells to produce neutralizing IgG antibodies.
National prostate cancer screening rates following the 2012 United States Preventive Services Task Force recommendation discouraging prostate-specific antigen (PSA)-based screening.
Authors: Michael William Drazer, Dezheng Huo, Scott E. Eggener
Journal: Journal of Clinical Oncology (2015)

5026 Background: The prostate cancer screening debate intensified following the 2012 United States Preventive Task Force (USPSTF) recommendation discouraging prostate specific antigen (PSA) testing-based screening. Previously published USPSTF recommendations did not appreciably reduce screening among groups at high risk for over-diagnosis and over-treatment. The effects of the 2012 guidelines on screening are unknown. Methods: We used the National Health Interview Survey (NHIS), a nationally representative survey, to estimate the proportion of men age 40 and older screened for prostate cancer in 2010 and 2013. We utilized an externally validated nine-year mortality index to analyze screening rates based on remaining life expectancy. We used logistic regression to compare screening rates from 2010 to 2013 and explored which subgroups had significant changes in PSA screening. Results: Screening significantly declined from 2010 to 2013 among all men over 50. Men ages 60-74 were most heavily tested, with 51.2% screened in 2010 and 43.6% in 2013 (P < 0.01). Screening significantly declined for men ages 50-59 (P < 0.01) and over 75 (P = 0.03) but not among 40-49 year olds (P= 0.4). A large percentage of men with a high predicted likelihood ( > 52%) of 9 year mortality were screened for prostate cancer, including approximately 32.2% of men over 75. Interestingly, college-educated men had higher screening rates than less college educated men but also had a larger screening decline from 2010 (62.7%) to 2013 (50.2%). Conclusions: Prostate cancer screening significantly declined among men over 50 following the 2012 USPSTF guideline discouraging PSA-based screening. A large proportion of men continue to be screened despite a high risk ( > 52%) of nine-year mortality, including 32.2% of men age 75 and older.
David Oliver: Consultant contracts and seven day services
Authors: David Oliver
Journal: BMJ (2016)

It’s a year since England’s health secretary, Jeremy Hunt, gave a speech linking his government’s promise of “truly seven day” NHS services with changes to contracts for the junior doctors and consultants supposed to enable this.1

He has suggested that a need for more “senior decision makers” (consultants) at evenings and weekends justified changes to trainees’ contracts. Meanwhile, however, the consultant contract has been on the back burner.2

As the NHS’s medical director, Bruce Keogh, has stated, Hunt further conflated issues by suggesting that contract changes were essential for delivering seven day services.3 More confusion …
P209 The Burden of Hospital Acquired Pneumonia: A cohort study: Abstract P209 Table 1
Authors: V Navaratnam, E O’Dowd, H Staniforth, L Haynes, J Lacey, A Gummow, RB Hubbard, T Bewick
Journal: Thorax (2015)

<h3>Background</h3> Hospital acquired pneumonia (HAP) is a common nosocomial condition, especially in the elderly population. We aimed to describe clinical and demographic features of patients diagnosed with HAP (excluding ventilator associated pneumonia) in a large teaching hospital and investigate the association of these features with 30 day mortality. <h3>Methods</h3> We used electronic medical records to identify all individuals with a physician diagnosis of HAP between 1/11/2014 and 31/4/2015. We extracted information on demographics, radiographic and laboratory findings, antibiotic prescriptions and mortality. HAP was defined as either diagnosis of pneumonia after 48 h of admission or hospital admission within the preceding 10 days. 30 day mortality was defined as death within 30 days of first being prescribed antibiotics for HAP. Logistic regression was used to generate odds ratios for death at 30 days, stratified by clinical and demographic features. White cell count and C Reactive Protein (CRP) levels were divided into quartiles. <h3>Results</h3> There were 790 people with a diagnosis of HAP during the study period. 396 (50.1%) were male and mean age at admission was 78.0 years (standard deviation [SD] 13.1). 56 (7.1%) people were admitted from a nursing home. 706 (89.4%) patients were admitted under medical specialities. 186 (23.5%) had a Charlson Index Score of 0, and 62 (7.9%) had dementia coded as a co-morbid illness. 48.9% of patients were reported to have consolidation on chest radiograph, whilst 19.9% were reported to have clear lungs. 598 (75.7%) patients had been admitted to hospital for at least 48 h prior to starting antibiotics for HAP, with a median stay of 5 days in hospital prior to starting antibiotics for HAP (Interquartile range [IQR]: 2 to 11). 240 (30.4%) patients died within 30 days of first being prescribed antibiotics for HAP. Features strongly associated with increased mortality at 30 days were older age, higher Charlson Index Score and high CRP (see Table 1). <h3>Conclusion</h3> Our findings suggest that HAP poses a substantial burden to secondary care services and carries a high mortality rate.
The Absolute Lymphocyte to Monocyte Ratio at Diagnosis Further Stratifies Survival Based on Cell of Origin in Diffuse Large B-Cell Lymphoma
Authors: Sumana Devata, Nicholas Herrman, Robert Briski, Farahk Keyoumarsi, Daniel F Boyer, Megan S Lim, Nathanael G. Bailey, Ryan A. Wilcox
Journal: Blood (2014)
New Drug Targets All 6 HCV Types
Authors: Rebecca Voelker
Journal: JAMA (2016)

Joining the wave of recently approved hepatitis C virus (HCV) drugs that act directly on the virus is a tablet containing sofosbuvir, which was approved in 2013, and velpatasvir—the first drug to treat all 6 major forms of HCV infection (http://bit.ly/290Hwgp).
Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors
Authors: Stephanie L. Ham, Ramila Joshi, Gary D. Luker, Hossein Tavana
Journal: Advanced Healthcare Materials (2016)

Solid tumors develop as 3D tissue constructs. As tumors grow larger, spatial gradients of nutrients and oxygen and inadequate diffusive supply to cells distant from vasculature develops. Hypoxia initiates signaling and transcriptional alterations to promote survival of cancer cells and generation of cancer stem cells (CSCs) that have self-renewal and tumor-initiation capabilities. Both hypoxia and CSCs are associated with resistance to therapies and tumor relapse. This study demonstrates that 3D cancer cell models, known as tumor spheroids, generated with a polymeric aqueous two-phase system (ATPS) technology capture these important biological processes. Similar to solid tumors, spheroids of triple negative breast cancer cells deposit major extracellular matrix proteins. The molecular analysis establishes presence of hypoxic cells in the core region and expression of CSC gene and protein markers including CD24, CD133, and Nanog. Importantly, these spheroids resist treatment with chemotherapy drugs. A combination treatment approach using a hypoxia-activated prodrug, TH-302, and a chemotherapy drug, doxorubicin, successfully targets drug resistant spheroids. This study demonstrates that ATPS spheroids recapitulate important biological and functional properties of solid tumors and provide a unique model for studies in cancer research.
Iodine Supplements During and After Pregnancy—Reply
Authors: Alex Stagnaro-Green, Scott Sullivan, Elizabeth N. Pearce
Journal: JAMA (2013)

Dr Bath and colleagues from the United Kingdom question our assertion that an RCT of iodine supplementation in pregnant and lactating women is unethical. Our statement relates to the United States where multiple medical societies recommend supplementation. We stand by this statement. However, geographic differences do exist. The lack of a national policy on iodine supplementation in the United Kingdom is perplexing, especially in light of the 2011 study documenting iodine insufficiency in school-aged girls
NICE recommends dropping two drugs from Cancer Drugs Fund
Authors: Nigel Hawkes
Journal: BMJ (2016)

Two drugs currently provided under the Cancer Drugs Fund (CDF) should cease to be available because they are not cost effective, the National Institute for Health and Care Excellence (NICE) has concluded.

Everolimus for breast cancer (Afinitor, Novartis) and ibrutinib for mantle cell lymphoma (Imbruvica, Janssen) do not meet the grade, says NICE in draft guidance now open for consultation.1 2

Under its new operating model the CDF acts as a gateway fund for new cancer drugs, with NICE calling the shots. In the former model the fund made its own decisions …
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Authors: Adriano Maida, Annika Zota, Kim A. Sjøberg, Jonas Schumacher, Tjeerd P. Sijmonsma, Anja Pfenninger, Marie M. Christensen, Thomas Gantert, Jessica Fuhrmeister, Ulrike Rothermel, Dieter Schmoll, Mathias Heikenwälder, Juan L. Iovanna, Kerstin Stemmer, Bente Kiens, Stephan Herzig, Adam J. Rose
Journal: Journal of Clinical Investigation (2016)

Dietary protein intake is linked to an increased incidence of type 2 diabetes (T2D). Although dietary protein dilution (DPD) can slow the progression of some aging-related disorders, whether this strategy affects the development and risk for obesity-associated metabolic disease such as T2D is unclear. Here, we determined that DPD in mice and humans increases serum markers of metabolic health. In lean mice, DPD promoted metabolic inefficiency by increasing carbohydrate and fat oxidation. In nutritional and polygenic murine models of obesity, DPD prevented and curtailed the development of impaired glucose homeostasis independently of obesity and food intake. DPD-mediated metabolic inefficiency and improvement of glucose homeostasis were independent of uncoupling protein 1 (UCP1), but required expression of liver-derived fibroblast growth factor 21 (FGF21) in both lean and obese mice. FGF21 expression and secretion as well as the associated metabolic remodeling induced by DPD also required induction of liver-integrated stress response-driven nuclear protein 1 (NUPR1). Insufficiency of select nonessential amino acids (NEAAs) was necessary and adequate for NUPR1 and subsequent FGF21 induction and secretion in hepatocytes in vitro and in vivo. Taken together, these data indicate that DPD promotes improved glucose homeostasis through an NEAA insufficiency-induced liver NUPR1/FGF21 axis.
Tip of the Tongue
Authors: Benjamin L. Lampson, Stacy W. Gray, Edmund S. Cibas, Bruce D. Levy, Joseph Loscalzo
Journal: New England Journal of Medicine (2016)

A 65-year-old woman with a history of HIV infection, hypertension, and hyperlipidemia had a 1-week history of cough with pink sputum and mild shortness of breath on exertion, but no fever, chills, night sweats, rhinorrhea, or nasal congestion.
<i>Notes from the Field:</i>Cluster of Lymphogranuloma Venereum Cases Among Men Who Have Sex with Men — Michigan, August 2015–April 2016
Authors: Alex de Voux, James B. Kent, Kathryn Macomber, Karen Krzanowski, Dawn Jackson, Tayneata Starr, Sandra Johnson, Deborah Richmond, Lawrence R. Crane, Jonathan Cohn, Christopher Finch, Jevon McFadden, Allan Pillay, Cheng Chen, Laurie Anderson, Ellen N. Kersh
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Lymphogranuloma venereum (LGV) is a sexually transmitted disease (STD) caused by infection with invasive Chlamydia trachomatis serovars L1-L3 (1). LGV is characterized by inguinal and/or femoral lymphadenopathy, typically following a transient, self-limited genital ulcer or papule that might go unnoticed. Rectal infection can result in proctocolitis that can present with mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and tenesmus, and signs of granulomas and/or ulcerations on anoscopy (1,2). LGV can be an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic colorectal fistulas and strictures (2). In Europe, outbreaks of LGV have been reported among men who have sex with men (MSM), often in association with human immunodeficiency virus (HIV) coinfection (3-5). The prevalence of LGV in the United States is unknown (1), because diagnostic tests to differentiate LGV from non-LGV Chlamydia trachomatis are not widely available (6), and providers might not know that they should report cases that are presumptively treated.
Allogeneic HSCT for Patients Aged More Than 55 Years with Myeloid Malignancies: Results of 171 Patients
Authors: Tamim Alsuliman, Samia Harbi, Raynier Devillier, Sabine Furst, Catherine Faucher, Angela Granata, Jean ElCheikh, Christian Chabannon, Luca Castagna, Norbert Vey, Didier Blaise
Journal: Blood (2015)
Hemorrhagic Myocardial Infarction
Authors: Michał Hawranek, Michał Wróbel, Jerzy Nożyński, Damian Pres, Marek Gierlotka, Przemysław Trzeciak, Krzysztof Dyrbuś, Jacek Piegza, Andrzej Lekston, Mariusz Gąsior
Journal: Journal of the American College of Cardiology (2016)
First-line single agent of gefitinib in patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase II study
Authors: S. Niho, K. Kubota, K. Goto, K. Yoh, H. Ohmatsu, R. Kakinuma, Y. Nishiwaki
Journal: Journal of Clinical Oncology (2004)

7059 Background: Gefitinib is active for recurrent NSCLC after platinum-based chemotherapy (Fukuoka M, et al. J Clin Oncol 21:2237, 2003. Kris MG, et al. JAMA 290:2149, 2003). However, efficacy of gefitinib as first-line chemotherapy remains unknown. We conducted a phase II study of single agent of gefitinib in chemonaïve pts with advanced NSCLC. Methods: Eligibility criteria: stage IIIB (malignant pleural or pericardial effusion and/or metastasis in the same lobe) or IV NSCLC without previous chemotherapy, measurable lesion, 20≤age≤74, ECOG PS 0 or 1, PaO2≥60 torr, and adequate bone marrow, renal, and hepatic functions. Patients with interstitial pneumonia, pulmonary fibrosis, paralytic ileus, symptomatic brain metastases, or infection, were excluded. Treatment: Pts received 250mg doses of gefitinib every day. Administration of gefitinib was terminated, if partial response was not achieved within eight weeks or no tumor reduction was observed within four weeks. In these cases, platinum-based doublet chemotherapy was performed as salvage. Results: Forty-two pts were enrolled between March and November 2003, and 40 of them were eligible. To date, thirty-seven pts were evaluable. Patient characteristics: male/female = 24/13, median age = 61 (range 44–74), ECOG PS 0/1 = 14/23, stage IIIB/IV = 3/34, and adenocarcinoma / squamous / large cell = 27/3/7. Ten pts achieved partial response. The response rate was 27% (95% CI: 18–44%). The most common toxicity included grade 1 or 2 acne-like eruption (46%) and grade 1 diarrhea (19%). Grade 2 hepatic toxicity was observed in 3%. Four pts developed grade 5 interstitial lung disease (ILD). Conclusions: Single agent of gefitinib is active in chemonaïve pts with advanced NSCLC, but produces unacceptable frequnet ILD. No significant financial relationships to disclose.