Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction

Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.     

Hypersensitivity reactions to biological agents with special emphasis on tumor necrosis factor-alpha antagonists

PURPOSE OF REVIEW: Several biological agents have been introduced into the drug market and more are emerging. Adverse reactions to these agents have recently been classified into five different subtypes. Some of these reactions are frequent but without consequences for the patients. Others are less frequent but potentially life-threatening, and they include allergic reactions. RECENT FINDINGS: Hypersensitivity reactions are well described adverse drug reactions, corresponding to the ss-type of the newly proposed classification of adverse reactions induced by biological agents. We focus our search on tumor necrosis factor-alpha antagonists, as they represent a dramatic improvement in the therapy of both rheumatic and inflammatory bowel diseases and because adverse reactions have been closely scrutinized. We also add cases from our own experience. We found very few properly documented allergic reactions. SUMMARY: Hypersensitivity reactions to tumor necrosis factor-alpha antagonists are not rare. Whether these manifestations have to be considered type beta or type gamma reactions is still a matter of debate. There is a need for allergological tests in vivo and in vitro.     

Detecting human-to-human transmission of avian influenza A (H5N1)

Highly pathogenic avian influenza A (HPAI) subtype H5N1 has caused family case clusters, mostly in Southeast Asia, that could be due to human-to-human transmission. Should this virus, or another zoonotic influenza virus, gain the ability of sustained human-to-human transmission, an influenza pandemic could result. We used statistical methods to test whether observed clusters of HPAI (H5N1) illnesses in families in northern Sumatra, Indonesia, and eastern Turkey were due to human-to-human transmission. Given that human-to-human transmission occurs, we estimate the infection secondary attack rates (SARs) and the local basic reproductive number, R0. We find statistical evidence of human-to-human transmission (p = 0.009) in Sumatra but not in Turkey (p = 0.114). For Sumatra, the estimated household SAR was 29% (95% confidence interval [CI] 15%-51%). The estimated lower limit on the local R0 was 1.14 (95% CI 0.61-2.14). Effective HPAI (H5N1) surveillance, containment response, and field evaluation are essential to monitor and contain potential pandemic strains.     

Advanced head and neck cancer in older adults: Results of a short course accelerated radiotherapy trial

ObjectivesTo assess the feasibility and safety of a repeated SHort course Accelerated RadiatiON therapy (SHARON) regimen in the palliative setting of Head and Neck (H&N) cancer in older adults.Material and MethodsPatients with histological confirmed H&N cancers, age ≥ 80 years, expected survival >3 months, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 were enrolled. Patients were treated in cohorts of six patients: a total dose of 20 Gy was delivered in 2 consecutive days with a twice-daily fractionation (5 Gy per fraction) and at least 8-h interval. If no Grade 3 toxicity was registered, a second enrollment started with another cohort of six patients to whom were administered two cycles (total dose of 40 Gy). The primary endpoint was to evaluate the feasibility of the two cycles of treatment. Secondary endpoints were evaluation of symptoms control rate, symptoms-free survival (SFS), and Quality of Life (QoL) scores.ResultsSeventeen consecutive patients (median age: 85 years) were treated. Nine patients were treated with one cycle and 8 patients with two cycles. No G3 toxicity was reported in either cohort. With a median follow-up time of 4 months, 3-month SFS in the first and second cohorts was 83.3%, and 87.5%, respectively. The overall palliative response rate was 88%. Among 13 patients reporting pain, 8 (61.5%) showed an improvement or resolution of their pain.ConclusionRepeated short course accelerated radiotherapy in a palliative setting of H&N cancers is safe and well-tolerated in older adults.     

Heart–Brain Interactions in the MR Environment: Characterization of the Ballistocardiogram in EEG Signals Collected During Simultaneous fMRI

The ballistocardiographic (BCG) artifact is linked to cardiac activity and occurs in electroencephalographic (EEG) recordings acquired inside the magnetic resonance (MR) environment. Its variability in terms of amplitude, waveform shape and spatial distribution over subject’s scalp makes its attenuation a challenging task. In this study, we aimed to provide a detailed characterization of the BCG properties, including its temporal dependency on cardiac events and its spatio-temporal dynamics. To this end, we used high-density EEG data acquired during simultaneous functional MR imaging in six healthy volunteers. First, we investigated the relationship between cardiac activity and BCG occurrences in the EEG recordings. We observed large variability in the delay between ECG and subsequent BCG events (ECG–BCG delay) across subjects and non-negligible epoch-by-epoch variations at the single subject level. The inspection of spatial–temporal variations revealed a prominent non-stationarity of the BCG signal. We identified five main BCG waves, which were common across subjects. Principal component analysis revealed two spatially distinct patterns to explain most of the variance (85% in total). These components are possibly related to head rotation and pulse-driven scalp expansion, respectively. Our results may inspire the development of novel, more effective methods for the removal of the BCG, capable of isolating and attenuating artifact occurrences while preserving true neuronal activity.     

The platelet-activating factor receptor activates the extracellular signal-regulated kinase mitogen-activated protein kinase and induces proliferation of epidermal cells through an epidermal growth factor-receptor-dependent pathway

Platelet-activating factor (PAF) is a lipid mediator that has been implicated in a variety of keratinocyte functions. Keratinocytes express the specific receptor for PAF (PAF-R), a seven-transmembrane G-protein-coupled receptor. Although PAF-R-dependent stimulation of numerous signal transduction pathways has been shown in a variety of cell types, to date there has been no analysis of PAF-R signal transduction in human epidermal cells. There is also contradictory evidence that PAF acts as either a suppressor or activator of keratinocyte proliferation. Using a model system created by retroviral-mediated transduction of the PAF-R into the PAF-R-negative epidermal cell line KB, we now demonstrate that the activation of the epidermal PAF-R results in the activation of both the extracellular signal-regulated kinase (ERK) and p38, but not the jun N-terminal kinase mitogen-activated protein (MAP) kinase pathways. Additionally, we show that the activation of the PAF-R stimulates the replication of epidermal cells. The activation of the ERK signal transduction pathway, as well as the PAF-dependent increase in cell proliferation, was dependent on the transactivation of the epidermal growth factor receptor (EGF-R). PAF-R-induced transactivation of the EGF-R was blocked by pharmacologic inhibitors of matrix metalloproteinases, of heparin-binding epidermal growth factor (HB-EGF), and specific inhibitors of the EGF-R tyrosine kinase. Activation of p38 MAP kinase by the PAF-R was not dependent on EGF-R activation and represents a distinct pathway of PAF-R-mediated signal transduction. In summary, these studies provide a mechanism whereby the PAF-R can exert proliferative effects through the activation of the EGF-R.     

Endocrine pancreatic dysfunction in HIV-infected children: association with growth alterations

BACKGROUND: The pancreatic endocrine system normally guarantees a quick and efficient response to daily metabolic perturbations, but associated data for human immunodeficiency virus (HIV)-infected patients are lacking. A prospective study was performed to evaluate pancreatic endocrine secretion and its possible association with failure to thrive among HIV-infected children. METHODS: Fourteen well-nourished, prepubertal, HIV-infected children (6 boys and 8 girls; age range, 5-11 years), none of whom were receiving protease inhibitors, and 16 clinically healthy sex- and age-matched children formed the patient group and the control group, respectively. At yearly follow-up examinations, insulin, glucagon, C-peptide, and glucose levels were measured; the ratio of insulin to glucose, the ratio of insulin to glucagon, and the homeostasis model assessment (HOMA) index were calculated; the glucagon test was administered; and growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, cortisol, and lipid patterns were evaluated. RESULTS: Insulin, glucagon, C-peptide, glucose, and HOMA measurements were significantly higher among patients, compared with control subjects, at all 3 follow-ups performed to date. The glucagon test revealed a normal glycemic response in all the healthy control subjects and a significantly impaired response in 11 patients. A significant correlation emerged between the ratio of insulin to glucagon and the growth velocity of HIV-infected children. CONCLUSION: To our knowledge, the present study provides the first evidence of altered pancreatic endocrine secretion and its association with growth failure among HIV-infected children.     

Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature

Thrombotic events in congenital hypo‐afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo‐afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio‐CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low‐dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti‐thrombotic management in this peculiar setting.     

Robustness of two different methods of monitoring respiratory system compliance during mechanical ventilation

Robustness measures the performance of estimation methods when they work under non-ideal conditions. We compared the robustness of artificial neural networks (ANNs) and multilinear fitting (MLF) methods in estimating respiratory system compliance (C _RS) during mechanical ventilation (MV). Twenty-four anaesthetized pigs underwent MV. Airway pressure, flow and volume were recorded at fixed intervals after the induction of acute lung injury. After consecutive mechanical breaths, an inspiratory pause (BIP) was applied in order to calculate C_RS using the interrupter technique. From the breath preceding the BIP, ANN and MLF had to compute C_RS in the presence of two types of perturbations: transient sensor disconnection (TD) and random noise (RN). Performance of the two methods was assessed according to Bland and Altman. The ANN presented a higher bias and scatter than MLF during the application of RN, except when RN was lower than 2% of peak airway pressure. During TD, MLF algorithm showed a higher bias and scatter than ANN. After the application of RN, ANN and MLF maintain a stable performance, although MLF shows better results. ANNs have a more stable performance and yield a more robust estimation of C _RS than MLF in conditions of transient sensor disconnection.