Miracle-dz/UniFAR-FTUs huggingface dataset:
Mast Cells Induce Migration of Dendritic Cells in a Murine Model of Acute Allergic Airway Disease

Background: The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway disease. Following activation, mast cells release a variety of stored or de novo-produced inflammatory mediators, several of them being capable of activating DCs. In this study, the role of mast cells on DC migration from the lungs to the thoracic lymph nodes was investigated in sensitized mice. Methods: Mast cell-deficient mice (KitW-sh/W-sh) and their wild-type counterparts were sensitized intraperitoneally with ovalbumine (OVA) in saline and challenged by a single intranasal administration of OVA labeled with a fluorescent dye (OVA-Alexa). Results: Following challenge, the relative and absolute amount of OVA- Alexa-positive DCs was clearly increased in sensitized wild-type mice compared to nonsensitized mice. In contrast, sensitized KitW-sh/W-sh showed no increase in OVA-Alexa-positive DCs compared to nonsensitized mast cell-deficient animals. In sensitized KitW-sh/W-sh mice reconstituted with bone marrow-derived mast cells (BMMCs), the number of OVA- Alexa-positive DCs was comparable to that in sensitized wild-type animals. However, transfer of allergen-exposed BMMCs to sensitized mice prior to airway challenge augmented airway inflammation similarly in wild-type and mast cell-deficient mice. In line with this, sensitization with allergen-pulsed DCs induced allergic airway disease independently of mast cells. Conclusions: This study shows an interaction between mast cells and DCs following allergen challenge in sensitized hosts. However, the function of mast cells can be bypassed in models utilizing activated allergen-exposed DCs to initiate the development of allergic airway disease.
Phosphonate analogues of carboxypeptidase A substrates are potent transition-state analogue inhibitors.

Analogues of tri- and tetrapeptide substrates of carboxypeptidase A in which the scissile peptide linkage is replaced with a phosphonate moiety (-PO2--O-) were synthesized and evaluated as inhibitors of the enzyme. The inhibitors terminated with either L-lactate or L-phenyllactate [designated (O) Ala and (O) Phe, respectively] in the P1' position. Transition-state analogy was shown for a series of 14 tri- and tetrapeptide derivatives containing the structure RCO-AlaP-(O)Ala [RCO-AP(O)A, AP indicates the phosphonic acid analogue of alanine] by the correlation of the Ki values for the inhibitors and the Km/kcat values for the corresponding amide substrates. This correlation supports a transition state for the enzymatic reaction that resembles the tetrahedral intermediate formed upon addition of water to the scissile carbonyl group. The inhibitors containing (O) Phe at the P1' position proved to be the most potent reversible inhibitors of carboxypeptidase A reported to date: the dissociation constants of ZAFP(O)F, ZAAP(O)F, and ZFAP(O)F are 4, 3, and 1 pM, respectively. Because of the high affinity of these inhibitors, their dissociation constants could not be determined by steady-state methods. Instead, the course of the association and dissociation processes was monitored for each inhibitor as its equilibrium with the enzyme was established in both the forward and reverse directions. A phosphonamidate analogue, ZAAPF, in which the peptide linkage is replaced with a -PO2-NH- moiety, was prepared and shown to hydrolyze rapidly at neutral pH (t1/2 = 20 min at pH 7.5). This inhibitor is bound an order of magnitude less tightly than the corresponding phosphonate, ZAAP(O)F, a result that contrasts with the 840-fold higher affinity of phosphonamidates for thermolysin [Bartlett, P. A. , & Marlowe, C. K. (1987) Science 235, 569-571], a zinc peptidase with a similar arrangement of active-site catalytic residues.
The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. DESIGN AND METHODS Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. RESULTS The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p < 0.001), mismatch in Epstein-Barr virus (EBV) serology (p < 0.001) and splenectomy (p = 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. INTERPRETATION AND CONCLUSIONS We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.
George William Sydney Fitzpatrick (1884-1948): An Australian Public Relations ‘pioneer’

Public relations scholarship has only briefly mentioned George Fitzpatrick, an Australian industry pioneer. This paper – based largely on archival material, contemporary articles, and other published primary sources – seeks to redress this gap in PR historiography. It examines Fitzpatrick’s family background, business networks, and diverse career, which included PR and government lobbying activities at a time when publicity practice in Australia was thought to be confined to the film sector. From journalist origins, Fitzpatrick moved into consultancy and pro bono PR work on behalf of governments, business, and charitable organisations. His PR campaigns, grounded in research trips to America and Europe in the 1930s, reflected considerable understanding of the ‘science of persuasion’ to influence public opinion. Fitzpatrick’s strategies included editorial, direct mail, advertising, events, and lobbying. In 1946 Fitzpatrick faced sensational allegations concerning his gambling businesses, from which he does not appear to have recovered. This paper concludes that although Fitzpatrick’s reputation was strongly damaged, his earlier charitable and political campaigns encapsulated PR practices well prior to the professional PR era in Australia.
Why Have We Failed to Cure Alzheimer's Disease?

There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.
Clinically Significant Carbamazepine Drug Interactions: An Overview

Summary: Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug‐receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero‐order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug‐drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half‐life, and decreases serum concentrations; the clinician must reevaluate a patient's serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patient's drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug‐drug interactions are preventable. It is the responsibility of every physician to be alert to the potential for their occurrence whenever a change in the epileptic patient's drug regimen is made.
An Early Assessment of Start-Up Chile

In just two years and with no marketing budget, Start-Up Chile has generated remarkable buzz. Young entrepreneurs in Santiago—a city that until recently was not considered a major entrepreneurship hub, 1 often recognize the program’s name. Start-Up Chile has become the central convening force for a national entrepreneurial movement: although its collaborative office space is in the nation’s capital, its ripple effects are felt throughout the country, where entrepreneurs and local leaders have begun organizing meet-up events and conferences to promote discussions around innovation. The program has received even more attention internationally: plaudits have come from sources as wide-ranging as technology bloggers, 2 start-up hacker societies, 3 the Kauffman Foundation, 4 and The Economist. 5 In Chile, excitement around the program may stem mainly from the community and university events, new opportunities for aspiring entrepreneurs, and the program’s inspiring messaging, which conveys a vision for the country’s cultural transformation. The excitement abroad comes from less Chile-centric aspects of the program. For earlystage, location-independent foreign entrepreneurs—thus far, applying from over 70 countries globally—Start-Up Chile seems to be a proposition that cannot lose. Selected applicants receive an almost instantly deployed one-year working visa without having to work for another company, US$40,000 without having to give up an equity stake in their company, and a welcoming community of fellow founders from all around the world—and many more benefits. For proponents of entrepreneurship and innovation in the academic and foundation worlds, Start-Up Chile offers not only a new model to boost regional entrepreneurship but also the potential for a global movement of interconnected start-up networks. For Chileans, foreign applicant entrepreneurs, and hopeful influencers of policy alike, the project’s early successes seem to predict future ones. 6 However, it is important to discern
Characterization of Silicon Photomultipliers for PET Imaging

The Silicon Photomultiplier (SiPM) is a novel photodetector being developed for high energy physics applications. SiPM is attractive for PET imaging because it is compact; provides high gain at low voltage; is insensitive to magnetic fields; has a fast timing response; and is potentially inexpensive and CMOS-technology compatible. Researchers have characterized SiPM performance mostly in areas relevant to high-energy physics and astrophysics applications, with some findings demonstrating the potential usefulness of SiPM in positron emission tomography (PET) imaging. Using our photodetector characterization test-stand equipped with a 20 GSps sample rate and 6 GHz bandwidth oscilloscope, we have measured the gains in the range of 1-3 times 105 room temperature for SiPM samples obtained from different producers. We have measured the rising times and their standard deviations. Based on the measured dark-count rates at room temperature, we have also estimated the achievable energy resolution of SiPM in PET imaging when used with LSO and BGO scintillators.
Spectrum of gross deletions and insertions in the RB1 gene in patients with retinoblastoma and association with phenotypic expression

Quantitative multiplex PCR and genomic real‐time PCR were used to complete an RB1 mutation analysis in 57 of 433 and 72 of 262 patients with hereditary and isolated unilateral retinoblastoma, respectively. These patients were selected because in previous analyses, which focused mainly on the identification of point mutations, no RB1 mutation was found. We identified gross deletions and insertions in peripheral blood DNA from 26 of 57 patients (46%) with hereditary retinoblastoma, and in six of 72 patients (8.3%) with isolated unilateral disease. In addition, we identified 32 somatic mutations in tumor DNA from 31 of 72 patients (43%) with isolated unilateral retinoblastoma. Together with our previous results, we found that gross RB1 alterations were present in the peripheral blood DNA from 65 of 433 (15%) and 17 of 262 (6.5%) patients with bilateral or familial and isolated unilateral retinoblastoma, respectively. Including reported gross deletions, an analysis of the frequency of breakpoints per intron length shows higher densities in introns 13, 16, 23, and 24. Genotype–phenotype analyses showed that on the whole, carriers of gross deletions develop fewer retinoblastomas compared to patients who are heterozygous for other types of RB1 null mutations. Specifically, carriers of cytogenetic and submicroscopic whole gene deletions often have unilateral tumors only. By contrast, almost all patients with gross deletions with one breakpoint in RB1 have bilateral retinoblastoma. Hum Mutat, 26(5), 437–445, 2005. © 2005 Wiley‐Liss, Inc.
Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury

Carcinomas can overexpress brachyury, a transcription factor not expressed in most adult tissues. A therapeutic yeast vaccine targeting brachyury was tested in phase I clinical trials. It induced T-cell responses with no autoimmunity and showed preliminary clinical activity. The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. Cancer Immunol Res; 3(11); 1248–56. ©2015 AACR.
Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy

ObjectiveTo determine whether the peripheral fat wasting (lipodystrophy), which is seen in association with highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI), is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA (mtDNA) content or with large mtDNA deletions or insertions. DesignA four cohort cross-sectional study. MethodsThe mtDNA content of subcutaneous fat tissue from the neck, abdomen and thigh was determined by polymerase chain reaction utilizing the amplification of three different mtDNA fragments. The results from HIV-infected patients with peripheral fat wasting following more than 6 months of NRTI-containing HAART were compared with the results from three different control cohorts: HIV-infected patients with a similar treatment history without lipodystrophy; HIV-infected patients naive to antiretroviral therapy and HIV sero-negative participants. ResultsA decrease in mtDNA content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts. No large mitochondrial deletions or insertions were found. ConclusionsLipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.
A study of meandered microstrip coupler with high directivity

A novel design technique to improve the directivity of a microstrip direction coupler by a meandered structure is proposed in this paper. Increasing of even-mode phase velocity by the proposed meandering method is reported for the first time. An analytical method to obtain closed-form equations or even-mode phase velocity is developed. The proposed structure is verified by experiments. More than 40 dB measured directivity improvement comparing to conventional microstrip coupler is achieved.
Afferent connections of the parvocellular subparafascicular thalamic nucleus in the rat: Evidence for functional subdivisions

The parvocellular subparafascicular nucleus of the thalamus (SPFp) consists of separate subdivisions, i.e., a medial portion containing galanin‐immunoreactive (‐IR) axons and a lateral portion containing calcitonin gene related peptide (CGRP)‐IR neurons and fibers. These subdivisions appear to have distinct functional roles. In particular, ejaculation‐induced Fos expression is expressed in the medial SPFp. Hence, it was hypothesized that medial SPFp is involved in relay of copulation‐related information. In contrast, lateral SPFp is involved in the processing of auditory and visual signals involved in fear‐conditioned responses. Here we tested the hypothesis that medial and lateral subdivisions of SPFp receive different sets of afferents and that these differences contribute to the separate functional roles of the two subdivisions. Inputs to medial and lateral SPFp were identified following injections of FG restricted to either division in male rats. The medial SPFp receives unique inputs from lumbar spinothalamic cells and brain regions involved in processing of visceral stimuli, supporting the hypothesis that the medial SPFp is involved in the relay of genitosensory information critical for the expression of male sexual behavior. The afferents of the lateral SPFp include brain regions involved in processing of visual and auditory signals and support a role for this subdivision in relay of visual and auditory information. Thus, the two subdivisions of SPFp are anatomically and functionally distinctive. J. Comp. Neurol. 463:132–156, 2003. © 2003 Wiley‐Liss, Inc.
Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia

Abstract Background: Heparin-induced thrombocytopenia (HIT) is caused by platelet activating antibodies that recognize platelet factor 4/heparin (PF4/H) complexes. Laboratory testing plays a key role in the diagnosis of HIT. As functional assays are unfeasible for most clinical laboratories, antigen binding assays are commonly used in routine testing. However, their low specificity leads to overdiagnosis of HIT. Therefore, it is advisable to improve screening tests in this setting. Methods: Blood samples from 114 patients in whom HIT was suspected were investigated using a chemiluminescence test (HemosIL® AcuStar HIT-IgG), a PF4/H IgG enzyme immunoassay (Lifecodes PF4 IgG), an IgG-specific lateral flow immunoassay heparin-induced thrombocytopenia (LFI-HIT, STic Expert® HIT) and the heparin-induced platelet aggregation (HIPA) test. Results: Twenty-nine (25.4%) out of 114 subjects with suspected HIT had a positive HIPA test. None of patients with a 4Ts score <4 were positive at HIPA. HemosIL® AcuStar HIT-IgG showed the best performance in term of sensitivity and specificity when used as single test. Receiver operating characteristic (ROC) analysis showed optimization of sensitivity and specificity using a cut-off of 1.13 U/mL (0.95 and 0.98, respectively). As an alternative approach, a strategy based on screening samples by STic Expert® HIT and then retesting positive results by Lifecodes PF4 IgG (cut-off 1 OD) or HemosIL® AcuStar HIT-IgG (cut-off 1.3 U/mL) showed a performance compared to a single test approach by HemosIL® AcuStar HIT-IgG. Conclusions: The HemosIL® AcuStar HIT or a combinatorial approach with the STic Expert® HIT and the PF4/H IgG enzyme immunoassay provide an accurate diagnosis of immune HIT.