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Evaluation of FRalpha expression by tumor cell lines

Table of Patient Characteristics

IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen–specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcϵ receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127–41. ©2017 AACR.

Description of additional experiments and procedures carried out in this study

BackgroundInhaled corticosteroids (ICS) are frequently prescribedoutsideguidelines to COPD patients with mild or moderate airflow limitation and low exacerbation risk, despite little evidence of benefit and risk of adverse effects. This trial explored thefeasibilityof ICS withdrawalfrompatients with mild/moderate COPD in primary care.MethodsOpen, feasibility trial. Outcome measures included prevalence of suitable participants, sensitivity and specificity of their identification,their willingness to accept open randomisation to ICS withdrawal for up to 6 months or continuation with usual care.Results392 (13%) of 2967COPD patients from 20 practices (209,618 total population)identifiedas eligible for ICS withdrawalby algorithm electronic record search.Following individual record review, 243 (62%)deemedineligible because of (a)one severeor two moderate COPD exacerbations in previous year (86, 22%); (b)severe airflow limitation (65, 17%); (c) asthma (15, 4%); (d)other causes (77, 20%). Remainder (149)invited for assessment.61 attended and all agreed to randomisation to ICS withdrawal or usual care. At baseline assessment, 10 exhibitedairflow reversibility (forced expiratory volume (FEV)1 reversibility>12% and 200ml) which was a safety exclusion criterion, 2 had suffered ≥2 moderate exacerbations in prior year,7 had severe airflow limitation,2 had normal spirometry.40 were randomised.During ensuing 6 months, 1 patient died and another was lost to follow-up. 18 (45%) of the 38 (10 withdrawal, 8 usual care) exhibited previously undocumented FEV1variability consistent with asthma,supported bysignificant associations in ICS withdrawal group between FEV1 variability andelevated fractional exhaled nitric oxide (p=0.04), atopic history (p=0.01), elevated symptom score (p=0.04),poorerquality of life (p=0.04).ConclusionIdentifyingpatients with mild/moderate COPD suitable for ICS withdrawal was difficult because of poor recording of suitability criteria (undocumented exacerbations, unreliable lung function). Open, randomisation to ICS withdrawal or usual care was acceptableFollow-upretention at 6 months was excellent.Nearly 50% of participants with mild/moderate COPD and no previously recorded bronchodilator reversibility, demonstrated FEV1 variability during follow-up. In patients with mild/moderate COPD considered suitable for ICS withdrawal in primary care, surveillance of variability should be undertaken over at least 6 months. Trial registrationEudraCT Number: 2016-001876-31. Date registered: 5th August 2016.

BackgroundInhaled corticosteroids (ICS) are frequently prescribed outside guidelines to patients with chronic obstructive pulmonary disease (COPD) with mild/moderate airflow limitation and low exacerbation risk. This primary care trial explored the feasibility of identifying patients with mild/moderate COPD taking ICS, and the acceptability of ICS withdrawal.MethodsOpen feasibility trial. Outcome measures included prevalence of suitable participants, feasibility of their identification, their willingness-to-accept open randomisation to ICS withdrawal or continuation over 6 months follow-up.Results392 (13%) of 2967 patients with COPD from 20 practices (209 618 population) identified as eligible for ICS withdrawal by electronic search algorithm. After individual patient record review, 243 (62%) were excluded because of: severe airflow limitation (65, 17%); one or more severe or two or more moderate COPD exacerbations in the previous year (86, 22%); asthma (15, 4%); and severe comorbidities (77, 20%). After exclusion, 149 patients with COPD were invited to participate and 61 agreed to randomisation. At clinical assessment, 10 patients exhibited undocumented airflow reversibility (forced expiratory volume in 1 s (FEV1) reversibility >12% and >200 mL); 2 had suffered two or more undocumented, moderate exacerbations in the previous year; 7 had severe airflow limitation; and 2 had normal spirometry. Finally, 40 were randomised. One patient died and one was lost to follow-up. 18 (45%) of the 38 (10 withdrawal and 8 usual care) exhibited previously undocumented FEV1 variability suggestive of asthma, supported in the withdrawal group by significant associations with elevated fractional exhaled nitric oxide (p=0.04), elevated symptom score (p=0.04), poorer quality of life (p=0.04) and atopic status (p=0.01).ConclusionsIdentifying primary care patients with mild/moderate COPD suitable for ICS withdrawal is feasible but requires real-time verification because of unreliable recording of exacerbations and lung function. Suitable patients accepted randomisation to ICS withdrawal or continuation for the purposes of future studies. Follow-up compliance was high. Nearly 50% of participants with a diagnosis of mild/moderate COPD demonstrated previously undocumented FEV1 variability during follow-up, mandating monitoring for at least 6 months following withdrawal to exclude undiagnosed asthma.

Background:While recognition and documentation of true drug allergy is critically important, most physicians acknowledge that its prevalence is likely overestimated, often on the basis of historical, sometimes anecdotal evidence. Correct or not, once applied, drug allergy labels may result in altered, potentially inferior therapy, increased costs and prolonged hospitalisation. Objective:Estimate the point prevalence, accuracy and symptomatology of self-reported drug allergy in a typical, large NHS Acute Trust adult inpatient population. In the subset with penicillin allergy (PA), estimate additional management costs from the use of alternative antibiotics and readmission rates in the previous 5 years. Methods:Data on self-reported drug allergies were extracted from 440 adult inpatient prescription charts over a 4 month period. Where penicillin allergy (PA) was reported, alternative antibiotic regimens were recorded and their additional costs calculated. Hospital electronic records were used to assess readmission rates of PA patients. Results:194/440 inpatients (44.5%) reported at least one drug allergy. Antibiotic allergy was most commonly reported (51%), followed by analgesic (23%) and antiemetic (12%) allergy. PA accounted for 76% of reported antibiotic allergy. The commonest reported symptoms were cutaneous (42%) and gastrointestinal (18%). Where antibiotic therapy was required for patients with PA to manage acute infections, Ciprofloxacin, Clarithromycin, Teicoplanin, Clindamycin and Cefuroxime were the most commonly employed alternatives. Extrapolation of these figures to include the entire Trust inpatient population suggested that the use of alternative antibiotics in PA patients incurred additional annual expenditure of £268,000. Further, 87% of PA patients had been admitted more than once in the preceding 5 years, with 74% requiring further courses of antibiotics during these admissions. Conclusion:Self-reported drug allergy, and in particular PA, is common in hospital inpatient populations and, in addition to the potentially unnecessary hazards to individual patients resulting from the use of alternative antibiotics, results in a considerable additional financial burden to the healthcare system. This problem could be eliminated by the provision of a nationwide and equitable tertiary Allergy service.

Background: Immunoglobulin E is a signalling molecule within the environment of the respiratory tract, the high affinity receptor for which, FceRI, is expressed by dendritic cells (DC). Little is known, however, of the expression and function of FceRI on DC in the human respiratory tract. Methods: CD1c+ DC were purified from surgically resected nasal turbinates of 11 atopic and 12 nonatopic patients with chronic rhinosinusitis. Expression of FceRI was determined by flow cytometry. Cytokine production by DC was determined by cytometric bead array. Results: Expression of FceRI was significantly elevated on respiratory tract dendritic cells (RTDC) from atopic as compared to nonatopic patients. Activation of RTDC through FceRI induced production of the pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokine IL-10. The production of IL-6 and TNF-α was elevated in atopic compared to nonatopic patients studied. Conversely IL-10 production was elevated in nonatopic patients. Concomitant activation of FceRI and stimulation of RTDC with IL-4 inhibited production of IL-10 by RTDC. Neutralization experiments with anti-IL-10 Ab enhanced whereas addition of exogenous IL-10 to RTDC inhibited FceRI-mediated inflammatory cytokine production. Conclusion: The function of FceRI on RTDC from patients with rhinosinusitis is susceptible to counter regulation by IL-4 and IL-10.

Atopic allergic asthma is characterized by activation of Th2-type T cells in the bronchial mucosa. Previous reports have suggested an important role for costimulation through the CD28/CTLA4-CD80/CD86 pathway in allergen activation of T cells in animal models of inhaled allergen challenge. However, human allergen-specific lines and clones were reported to be costimulation independent. We therefore examined CD80 and CD86 dependence of allergen-induced T cell proliferation and cytokine production in peripheral blood and bronchoalveolar lavage from atopic asthmatic subjects and controls. Both allergen-induced proliferation and IL-5 production from PBMC were inhibited by CTLA4-Ig fusion protein and anti-CD86, but not anti-CD80 mAbs. When allergen-specific CD4+ T cell lines from peripheral blood were examined, proliferation and cytokine production were found to be independent of CD80 or CD86 costimulation. However, when cells obtained directly from the airways were examined, allergen-induced proliferation of bronchoalveolar lavage T cells from atopic asthmatic subjects was inhibited by anti-CD86 but not anti-CD80. In addition, bronchoalveolar lavage-adherent cells from asthmatic, but not control subjects showed APC activity to autologous T cells. This was also inhibited by anti-CD86 but not anti-CD80. Thus allergen-induced T cell activation and IL-5 production in the airway in asthmatic subjects is susceptible to blockade by agents interfering with costimulation via CD86, and this may hold therapeutic potential in asthma.

Background: Incidents of severe and fatal anaphylaxis to accidentally ingested food allergens are increasing. Individuals are more likely to encounter difficulties when eating away from home. In restaurants, front-of-house and kitchen staff may be called upon to provide information about ingredients or ensure certain food allergens are excluded from dishes. Following a series of reactions related to the accidental ingestion of peanuts in curries we assessed food allergy awareness and allergen avoidance practices amongst the staff of Asian-Indian restaurants. Methods: A questionnaire survey was administered by telephone to one member of staff in each restaurant. Results: Fifty percent (40/80) of restaurants participated. Responders included managers, owners, waiters and chefs. Most (90%) had received food hygiene training, but only 15% food allergy training. 25% could name three common food allergens. 3 in 4 listed nuts, but less than 1in 5 mentioned peanuts. Common misunderstandings included 60% of staff believing an individual experiencing an allergic reaction should drink water to dilute the allergen. A less prevalent, but perhaps more concerning, was the misunderstanding that cooking food would prevent it causing an allergic reaction (25%). Despite poor knowledge, all respondents were comfortable and 65% were “very comfortable” with providing a “safe” meal for a customer with a food allergy. 60% expressed interest in future food allergy training. Conclusions: Despite high confidence in their own understanding of allergy, many staff lacked the knowledge to provide “safe” meals for food allergic customers. Traditionally tree nuts are a common ingredient in Asian-Indian dishes cuisine and there was widespread, but not universal, awareness of tree nuts as a common allergen. Peanuts were less commonly recognised as a common allergen, an observation of extreme concern as peanuts are being substituted for tree nuts as they are cheaper and avoid having to inflate meal prices. Our data highlights the need for greater training of restaurant staff. In parallel, food allergic customers need to exercise vigilance when making meal choices and develop skills to order a safe meal. The management of allergy is multifaceted, and this study indicates the importance of health professionals working beyond the clinical setting to collaborate with colleagues in the hospitality industry, public health and environmental health in coordinated endeavours to improve patient safety.

The type I (CD4 + Th1, CD8 + Tc1) and type II (CD4 + Th2, CD8 + Tc2) paradigm of cytokine-secreting T cell subsets has advanced considerably in recent years. CD4 + Th2 cells have been closely associated with initiation and maintenance of allergic inflammation and new signals, such as OX40, TSLP and IL-25 that promote this lineage in disease have been identified. More recently, invariant natural killer cells (iNKT) have been proposed as a source of type II cytokines in severe disease, although debate regarding the relative importance of this cell type is ongoing. An additional CD4 + T cell subset that secretes the pro-inflammatory mediator IL-17 has been described and its role in allergic disease is under active investigation. Conversely, the importance of cells that inhibit disease-promoting adaptive immune responses has been increasingly recognised. Suppressor or regulatory T cells (Treg) play an important role in controlling immune responses in the periphery and include both naturally occurring and adaptive or inducible Treg that secrete inhibitory cytokines such as IL-10 and TGF . These cells appear important in the maintenance of health, are impaired in active allergic or asthmatic disease and appear to be induced or restored following certain successful disease therapies. Our increased understanding of T cell biology in allergic disease has provided a clearer understanding of the mechanisms of well-established and relatively successful therapies such as corticosteroids and allergen immunotherapy. This provides the impetus for the development of novel, better tolerated and better targeted immunotherapeutic interventions in allergic diseases.

This MBA project analyzes the benefit of integrating Radio Frequency Identification (RFID) technology into the Department of Defense supply chain management infrastructure. The project confirms the existence of an inherent value in logistics information used as a resource in Department of Defense supply chain management applications. Also identified is the value of comprehensive and real time logistics information to the warfighter and what he or she is willing to pay for that information. For example, the average value the warfighter is willing to pay on a deployed aircraft carrier is 2.46% of the carrier's average annual budget, or $856,775. To determine these values, the project uses the results of a survey distributed to Naval Supply Corps Officers who were used as survey respondents due to their positioning as a logistics and financial choke point between the man in the foxhole and their commanding officers. Using the value that Supply Officers are willing to pay for comprehensive and real time information, a value added figure is determined for the inclusion of RFID technology in the Department of Defense supply chain management infrastructure. Continuing with the aircraft carrier example, the value added figure is $11.28 per requisition.