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In hadrontherapy centers, ion beams are accelerated by a cyclotron or synchrotron through electric and magnetic fields and, once the treatment energy is reached, ions interact with the patient. The interaction of the beam with magnets, other elements of particle accelerator or with the patient generates secondary radiation and the calculation for the design of the shielding is required. A first assessment of the shielding, generally made by concrete, can be performed by using Monte Carlo simulations, in which neutron yields and the ambient dose equivalent, H*(10), spatial distribution are obtained. The aim of this work is to evaluate, with a Monte Carlo approach, ambient dose equivalent values at various concrete depths generated by the secondary radiation. Simulations are performed considering helium, lithium, carbon, oxygen and iron primary beams. For existing facilities that already accelerates carbon ion, an equivalent carbon ratio is introduced to estimate the ion currents to get, in a given point, the same ambient dose equivalent as a carbon ion. Numerical results have been obtained simulating an ion beam that impinges on a thick iron or international commission on radiation units and measurements (ICRU) tissue, respectively, representing magnets and patient. The secondary radiation is transported through a large concrete shielding where ambient dose equivalent values are calculated as function of concrete thickness., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production., Methods: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes., Results: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production., Conclusions: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The human gut microbiota performs functions that are essential for the maintenance of the host physiology. However, characterizing the functioning of microbial communities in relation to the host remains challenging in reference-based metagenomic analyses. Indeed, as taxonomic and functional analyses are performed independently, the link between genes and species remains unclear. Although a first set of species-level bins was built by clustering co-abundant genes, no reference bin set is established on the most used gut microbiota catalog, the Integrated Gene Catalog (IGC). With the aim to identify the best suitable method to group the IGC genes, we benchmarked nine taxonomy-independent binners implementing abundance-based, hybrid and integrative approaches. To this purpose, we designed a simulated non-redundant gene catalog (SGC) and computed adapted assessment metrics. Overall, the best trade-off between the main metrics is reached by an integrative binner. For each approach, we then compared the results of the best-performing binner with our expected community structures and applied the method to the IGC. The three approaches are distinguished by specific advantages, and by inherent or scalability limitations. Hybrid and integrative binners show promising and potentially complementary results but require improvements to be used on the IGC to recover human gut microbial species., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68 + foamy Mϕs (or 'histiocytes'). Clinical manifestations arise from mass-forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK-kinase signaling pathway (BRAF V600E in more than half of the patients), and secrete abundant pro-inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine-blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up-regulated glycolysis, represent an additional, mutation-driven feature of ECD histiocytes, which sustains deregulated and protracted pro-inflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive Mϕ activation instructs the understanding of Mϕ dysfunction in other chronic inflammatory conditions., (©2020 Society for Leukocyte Biology.)

Bacterial resistance to antibiotics is a global public health problem. Its association with bloodstream infections is even more severe and may easily evolve to sepsis. To improve our response to these bacteria, it is essential to gather thorough knowledge on the main pathogens along with the main mechanisms of resistance they carry. In this paper, we performed a large meta-analysis of 3872 bacterial genomes isolated from blood samples, from which we identified 71 745 antibiotic resistance genes (ARGs). Taxonomic analysis showed that Proteobacteria and Firmicutes phyla, and the species Klebsiella pneumoniae and Staphylococcus aureus were the most represented. Comparison of ARGs with the Resfams database showed that the main mechanism of antibiotic resistance is mediated by efflux pumps. Clustering analysis between resistome of blood and soil-isolated bacteria showed that there is low identity between transport and efflux proteins between bacteria from these environments. Furthermore, a correlation analysis among all features showed that K. pneumoniae and S. aureus formed two well-defined clusters related to the resistance mechanisms, proteins and antibiotics. A retrospective analysis has shown that the average number of ARGs per genome has gradually increased. The results demonstrate the importance of comprehensive studies to understand the antibiotic resistance phenomenon., (© The Author(s) 2019. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Objectives: The aim of this meta-analysis was to compare outcomes of patients undergoing transcatheter aortic valve implantation (TAVI) with those undergoing surgical aortic valve replacement using sutureless valves., Methods: A systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was performed., Results: No randomized controlled trials were identified. Six comparative studies using propensity score matching met the inclusion criteria. This meta-analysis identified 1462 patients in that 731 patients underwent surgical aortic valve replacement using sutureless valves (SU) and 731 patients underwent a TAVI. The 30-day or in-hospital mortality was lower in the SU group [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.36-0.80; P = 0.003]. In the TAVI group, the incidence of postoperative stroke was higher (OR 0.36, 95% CI 0.17-0.79; P = 0.01). The incidence of moderate or severe paravalvular regurgitation was higher in the TAVI group (OR 0.22, 95% CI 0.14-0.35; P = 0.001). There were neither differences in the postoperative renal failure (OR 1.44, 95% CI 0.46-4.58; P = 0.53) nor in the number of patients requiring postoperative pacemaker implantation (OR 1.06, 95% CI 0.54-2.08; P = 0.86). Patients in the SU group required more transfusions (OR 4.47, 95% CI 2.77-7.21; P = 0.0001), whereas those in the TAVI group had higher major vascular complications (OR 0.06, 95% CI 0.01-0.25; P = 0.0001). Intensive care unit stay was not different (mean difference 0.99, 95% CI - 1.22 to 1.40; P = 0.53). One-year survival was better in the SU group (Peto OR 0.35, 95% CI 0.18-0.67; P = 0.001), as was the 2-year survival (Peto OR 0.38, 95% CI 0.17-0.86; P = 0.001)., Conclusions: Surgical aortic valve replacement using sutureless valves is associated with better early and mid-term outcomes compared with TAVI in high- or intermediate-risk patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

A semi-rigid complete ring including a chordal sizing system has been introduced with the aim of standardizing neochordae implantation. Instructions for use of this ring suggest to pass the neochordae through the free margin of mitral leaflets. We introduce a modification of this technique in the presence of myxomatous leaflets., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Few experiences exist in minimally invasive cardiac surgery for the treatment of double-valve disease. We report our early experience in 69 patients, describing postoperative results. The introduction of sutureless aortic prostheses has implemented this treatment option, with a significant reduction of cardiopulmonary bypass and cross-clamp times., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The aim of this study was to compare early outcomes and mid-term survival of high-risk patients undergoing minimally invasive aortic valve replacement through right anterior mini-thoracotomy (RT) with sutureless valves versus patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis., Methods: From October 2008 to March 2013, 269 patients with severe aortic stenosis underwent either RT with perceval S sutureless valves (n = 178 patients, 66.2%) or TAVI (n = 91, 33.8%: 44 transapical and 47 trans-femoral). Of these, 37 patients undergoing RT with the perceval S valve were matched to a TAVI group by the propensity score., Results: Baseline characteristics were similar in both groups (mean age 79 ± 6 years) and the median logistic EuroSCORE was 14% (range 9-20%). In the matched group, the in-hospital mortality rate was 8.1% (n = 3) in the TAVI group and 0% in the RT group (P = 0.25). The incidence rate of stroke was 5.4% (n = 2) versus 0% in the TAVI and RT groups (P = 0.3). In the TAVI group, 37.8% (n = 14) had mild paravalvular leakage (PVL) and 27% (n = 10) had moderate PVL, whereas 2.7% (n = 1) had mild PVL in the RT group (P < 0.001). One- and 2-year survival rates were 91.6 vs 78.6% and 91.6 vs 66.2% in patients undergoing RT with the perceval S sutureless valve compared with those undergoing TAVI, respectively (P = 0.1)., Conclusions: Minimally invasive aortic valve replacement with perceval S sutureless valves through an RT is associated with a trend of better early outcomes and mid-term survival compared with TAVI., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: After a panel process, recommendations on the use of sutureless and rapid deployment valves in aortic valve replacement were given with special respect as an alternative to stented valves., Methods: Thirty-one international experts in both sutureless, rapid deployment valves and stented bioprostheses constituted the panel. After a thorough literature review, evidence-based recommendations were rated in a three-step modified Delphi approach by the experts., Results: Literature research could identify 67 clinical trials, 4 guidelines and 10 systematic reviews for detailed text analysis to obtain a total of 28 recommendations. After rating by the experts, 12 recommendations were identified and degree of consensus for each was determined. Proctoring and education are necessary for the introduction of sutureless valves on an institutional basis as well as for the individual training of surgeons. Sutureless and rapid deployment should be considered as the valve prosthesis of first choice for isolated procedures in patients with comorbidities, old age, delicate aortic wall conditions such as calcified root, porcelain aorta or prior implantation of aortic homograft and stentless valves as well as for concomitant procedures and small aortic roots to reduce cross-clamp time. Intraoperative transoesophageal echocardiography is highly recommended, and in case of right anterior thoracotomy, preoperative computer tomography is strongly recommended. Suitable annular sizes are 19-27 mm. There is a contraindication for bicuspid valves only for Type 0 and for annular abscess or destruction due to infective endocarditis. Careful but complete decalcification of the aortic root is recommended to avoid paravalvular leakage; extensive decalcification should be avoided not to create annular defects. Proximal anastomoses of concomitant coronary artery bypass grafting should be placed during a single aortic cross-clamp period or alternatively with careful side clamping. Available evidence suggests that the use of sutureless and rapid deployment valve is associated with (can translate into) reduced early complications such as prolonged ventilation, blood transfusion, atrial fibrillation, pleural effusions and renal replacement therapy, respectively, and may result in reduced intensive care unit and hospital stay in comparison with traditional valves., Conclusion: The international experts recommend various benefits of sutureless and rapid deployment technology, which may represent a helpful tool in aortic valve replacement for patients requiring a biological valve. However, further evidence will be needed to reaffirm the benefit of sutureless and rapid deployment valves., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In this article, the in vivo study performed to evaluate the uniformity of biological doses within an hypothetical target volume and calculate the values of relative biological effectiveness (RBE) at different depths in the spread-out Bragg peak (SOBP) of the new CNAO (National Centre for Oncological Hadrontherapy) carbon beams is presented, in the framework of a typical radiobiological beam calibration procedure. The RBE values (relative to (60)Co γ rays) of the CNAO active scanning carbon ion beams were determined using jejunal crypt regeneration in mice as biological system at the entrance, centre and distal end of a 6-cm SOBP. The RBE values calculated from the iso-effective doses to reduce crypt survival per circumference to 10, ranged from 1.52 at the middle of the SOBP to 1.75 at the distal position and are in agreement with those previously reported from other carbon ion facilities. In conclusion, this first set of in vivo experiments shows that the CNAO carbon beam is radiobiologically comparable with the NIRS (National Institute of Radiological Sciences, Chiba, Japan) and GSI (Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany) ones., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Surgical aortic valve replacement (AVR) is increasingly performed in elderly patients with good perioperative outcomes and long-term survival, resulting in significant health-related quality-of-life benefits. This study aimed to evaluate the outcome of patients aged ≥ 80 years undergoing isolated AVR through a right anterior minithoracotomy (RAMT) and compare it with a full sternotomy (FS)., Methods: Two hundred and eighty-three elderly patients aged 80 years or more underwent isolated AVR between February 2001 and September 2013. With propensity score matching (1 : 1), the outcomes of patients having minimally invasive surgery (RAMT) were compared with those in whom the FS approach had been employed (100 vs 100 patients). TAVRs and partial sternotomy cases were excluded from the analysis., Results: There were two conversions in the RAMT group. Operative times did not significantly differ in the two groups. Patients in the RAMT group received a larger-sized prosthesis (P < 0.001) and were more likely to receive sutureless valves (P < 0.001). Shorter time for extubation (P < 0.001) and shorter hospital length of stay (P = 0.005) were observed in the RAMT group. Zero vs 4 (4.0%) (P = 0.043) patients had postoperative stroke and 2 (2.0%) vs zero (P = 0.16) had a transient ischaemic attack in the RAMT versus FS group, respectively. We registered the same rate of permanent pacemaker implant (P = 0.47) and that of new-onset atrial fibrillation (P = 0.28) for both groups. Six patients died, with no significant difference for in-hospital mortality (P = 0.68). No variable had a statistically significant predictive value for in-hospital mortality. RAMT patients were more likely to be discharged home directly or via rehabilitation (P = 0.031). FS, along with four other factors, independently predicted longer hospital stay. Though the median follow-up duration was longer in the FS group (59 vs 24 months, P < 0.001), the two groups had similar survival rates at 5 years (80 vs 81%, P = 0.37). Ten factors were associated with long-term survival by Cox regression analysis, and RAMT had no statistical impact (P = 0.38)., Conclusions: Minimally invasive AVR through right anterior minithoracotomy can be safely performed in patients aged ≥80 years with acceptable morbidity and mortality rates. It is an expeditious and effective alternative to full sternotomy AVR and might be associated with lower postoperative stroke incidence, earlier extubation and shorter hospital stay., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Triple valve surgery (TVS) is still a challenge for surgeons because of prolonged cardiopulmonary bypass (CPB) and myocardial ischaemic times. The reported operative mortality rate for TVS ranges between 2.5 and 25%; long-term survival is also diminished, with reported survival rates at 5 and 10 years of 75-82 and 61-75%, respectively. The objective of our study is to define early and late clinical outcomes, reporting the initial experience in the treatment of triple valve disease through a minimally invasive approach., Methods: A retrospective, observational, cohort study was undertaken of prospectively collected data on 106 patients who underwent TVS at our institution between October 2001 and June 2013. A total of 101 procedures were done through the standard median sternotomy; however, in 5 patients, the surgical procedure was carried out through a right minithoracotomy. Univariate analysis was performed to identify predictors of early and late survival., Results: The in-hospital mortality rate was 5.6% (6 of 107 patients). Predictors of early mortality were: previous cardiac surgery [odds ratio (OR) 4, 95% confidence interval (CI) 1.08-5.2, P = 0.04], preoperative left ventricular ejection fraction (LVEF) (OR 0.9, 95% CI 0.8-1.1, P = 0.003), prolonged CPB time (OR 1.02, 95% CI 1.01-1.04, P = 0.01) and postoperative pulmonary complications (OR 8, 95% CI 5.8-41, P = 0.0001). Five- and 10-year survival rates were 85 ± 3 and 65 ± 9%, respectively. In univariate analysis, diabetes [hazard ratio (HR) 2.5, 95% CI 1-6.2, P = 0.045], preoperative dialysis (HR 3, 95% CI 2-4.7, P = 0.001), unstable angina (HR 4.8, 95% CI 1-18, P = 0.03), preoperative LVEF (HR 0.9, 95% CI 0.8-1.1, P = 0.02), concomitant coronary artery bypass grafting (CABG) (HR 2.5, 95% CI 1.5-5.7, P = 0.006), prolonged CPB time (HR 1.02, 95% CI 1.01-1.13, P = 0.006), postoperative pacemaker (PMK) implantation (HR 6.2, 95% CI 1.3-18, P = 0.01) and postoperative pulmonary complications (HR 3.3, 95% CI 2.1-7.3, P = 0.002) were found to be significant predictors of late mortality following TVS. The freedom rates from valve-related complications and reoperation at 10 years were 95 ± 2 and 97 ± 2%, respectively. The 10-year freedom rates from thromboembolism and anticoagulation-related haemorrhage were 88 ± 5 and 88 ± 4%, respectively., Conclusions: TVS offers encouraging short-term and long-term patient survival; these good results after TVS in patients with advanced valvular heart disease justify aggressive surgical therapy in these patients. TVS with a minimally invasive approach is feasible and could be another treatment option., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In this paper, the evaluation of the dosimetric capability of a detector based on a CR-39 solid-state nuclear track detector coupled to a 1 cm thickness of PMMA radiator was made with the aim of understanding the applicability of this technique to personal and environmental neutron dosimetry. The dosemeter has been exposed to monoenergetic and quasi-monoenergetic neutron beams at PTB in Braunschweig, Germany and at Ithemba Laboratories, in Faure, South Africa, with peak energies ranging from 0.565 to 100 MeV. The results showed a response that is almost independent of the neutron energy in the whole energy range., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Within the framework of the EURADOS Working Group 11, a comparison of passive neutron dosemeters in high-energy neutron fields was organised in 2011. The aim of the exercise was to evaluate the response of poly-allyl-glycol-carbonate neutron dosemeters from various European dosimetry laboratories to high-energy neutron fields. Irradiations were performed at the iThemba LABS facility in South Africa with neutrons having energies up to 66 and 100 MeV., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Bonner sphere spectrometers (BSS) are being used widely in neutron spectrometry since 1960. The response to neutrons of these moderating detectors spans over a broad energy range. This work discusses the measurement of the sensitivity of an extended range BSS hosting a CR39 nuclear track detector coupled to a boron converter. Two kinds of boron converters were tested, the first made by natural boron and a second one enriched in (10)B. The BSS response functions were calculated with Monte Carlo simulation using the MCNPX 2.4.0. and the FLUKA codes.

In recent years uncertainty evaluation in measurements has achieved great importance. National and international standards offer guidelines to evaluate uncertainties, but these procedures are, until now, not well understood by the operators. This is because of the fact that a detailed uncertainty evaluation is not an easy operation and a standard rule to apply in all cases is not available. Every measurement procedure has its own uncertainty evaluation. In this work, attention is focused upon the electret ion chambers (EIC), widely used in radon concentration measurements. Measurements of gamma radiation sensitivity are performed in a secondary standard calibration laboratory and measurement of radon concentration sensitivity is performed in a radon chamber 0.8 m3 in volume. Raw data are analysed to evaluate the calibration factors and the combined uncertainties are determined. The aim of the work is to give a practical method to assess the uncertainty of a radon measurement.

LR115 cellulose nitrate films efficiency is strongly dependent on the conditions of etching. In this paper a new method to evaluate a correction factor for this effect is given. The film is scanned with an high-resolution scanner, the diameter of the tracks is measured, and the correction factor is calculated from the average diameter of the tracks. The sensitivity of the film is found to have a linear dependence on the average diameter, and the classical correction, based on the residual thickness, can be substituted by a method based on average track diameter.

To evaluate the uncertainties for nuclear track detectors used in radon measurements, a full understanding is required of the physical phenomena involved and the behaviour of the instruments utilised in the measuring process. As it concerns the LR115 nuclear track detector, an overall evaluation of uncertainty was given. It was assessed taking into account different contributions and determining their relative weights. Since such detectors are often read by a spark counter device, a model to describe its behaviour was developed and a saturation factor was estimated. Its expression and its associated uncertainty are given. Hence, it has been possible to draw a calibration curve, in which all the uncertainty sources have been considered.

Incidence rates for CNS tumours in children of age 0-14 years in the Region of Lombardy, Italy, during the period 1988-93 were analysed; survival probability updated to December 1995 was also estimated. CNS tumours defined according to the International Classification of Diseases for Oncology codes were actively searched for. CNS tumours were diagnosed in 296 children. The age-standardized rates were 40.0 per million child years for both sexes together, and 45.3 for boys and 34.4 for girls. In all age groups, boys had a higher incidence than girls. The annual incidences were 13.7, 7.0, 5.8 for astrocytoma, medulloblastoma and ependymoma, respectively. The overall survival percentages at 5 and 8 years after diagnosis were 68 and 66, respectively. Prognosis was good for astrocytoma (5-year survival, 81%), and declined in the order: other gliomas (5-year survival, 76%); ependymoma (5-year survival, 62%), and medulloblastoma (5-year survival, 43%). The histological type of the tumour was the most powerful independent predictor of survival in children with a CNS tumour. Medulloblastoma/primitive neuroectodermal tumours appeared to have the highest risk of a poor prognosis compared with astrocytoma (relative risk, 3.27; 95% confidence interval, 1.81-5.91). Age at diagnosis and sex had no significant effect on survival. The incidence of childhood CNS tumours found in this study is higher than previously reported in Italy, and is one of the highest in the world from population-based data. Survival of children with brain tumours has improved greatly in recent years. These results suggest that children in Lombardy with CNS tumours had a good survival experience compatible with high quality of care.

Background: The monomeric laminin receptor, a 67-kd high-affinity laminin-binding protein, is expressed by a variety of normal cell types. Overexpression and abnormal surface distribution of this receptor have been demonstrated in tumor cells where it appears to promote tumor invasion and metastasis. Previously, we reported the existence of an association between laminin receptor overexpression by lung cancer cells and the presence of tumor-infiltrating lymphocytes (TILs) bearing gammadelta T-cell receptors. Gammadelta(+) lymphocytes represents a sizable fraction of the TILs in approximately one fourth of lung cancers analyzed thus far., Purpose: The aim of this study was to determine whether gammadelta(+) TILs might participate in the immune response against lung cancer through recognition of monomeric laminin receptors expressed by tumor cells., Methods: Tumor cells from 11 lung cancer specimens exhibiting sizable gammadelta(+) T-cell infiltrates and from 11 other specimens infiltrated predominantly by lymphocytes bearing alphabeta(+) T-cell receptors were analyzed for expression of the monomeric laminin receptor by use of the monoclonal antibody (MAb) MLuC5. Gammadalta TILs and chibeta+ TILs derived from four tumors were each examined for cytotoxic activity toward lung cancer target cells by use of a standard 51Cr-release assay and lung tumor cell lines expressing different levels of surface monomeric laminin receptor. The ability of MAbs directed against the laminin receptor (i.e., MLuC5) or against gammadelta T-cell receptors (i.e., TigammaA and A13) as well as laminin peptides known to bind to the laminin receptor to inhibit TIL-mediated target cells lysis was also determined., Results: We confirmed that the association between overexpression of the monomeric laminin receptor by lung tumor cells and the presence of gammadeltadelta+ TILs is statistically significant (two sided P = .003; Fisher's exact test). We also observed a relationship between the levels of laminin receptor expression on cultured lung cancer cells and their susceptibility to specific lysis by gammadelta(+), but not alphabeta+, TILs. This specific cell killing was not T-cell receptor mediated, but it was inhibited by addition of the anti-monomeric laminin receptor MAb MLuC5 and by a synthetic peptide corresponding to amino acids 2091-2108 of the laminin A chain., Conclusion and Implications: Our results indicate gammadelta(+) TILs localized at human lung cancer sites can kill tumor cells in a process that involves interaction with the monomeric laminin receptor. The infiltration of gammadelta(+) TILs at lung tumor sites may represent a first line of defense against cells undergoing malignant transformation.

In this study we have investigated the ability of human B lymphocytes to produce granulocyte-macrophage colony stimulating factor (GM-CSF) and, in preliminary experiments, granulocyte CSF (G-CSF). The sources of human B cells were surgically removed tonsils from normal individuals and peripheral blood from patients with B cell chronic lymphocytic leukemia (B-CLL). Tonsil B lymphocytes were purified by E rosetting and complement-mediated cytotoxicity with selected monoclonal antibodies and subsequently fractionated by a Percoll density gradient into in vivo activated and resting cells. The latter cell fractions were subsequently cultured with or without stimuli. GM-CSF was detected by a bioassay, G-CSF by an enzyme-linked immunoassay. In vivo and in vitro activated B cells produced GM-CSF, whereas in vivo activated, but not in vitro activated, B lymphocytes produced G-CSF. These results were confirmed by Northern blot experiments with cDNA probes specific for GM-CSF and G-CSF genes. Many B cell suspensions from B-CLL patients produced GM-CSF or G-CSF only following Staphylococcus Aureus Cowan I (SAC) stimulation; in some cases, a spontaneous production or no production at all of the two cytokines was detected. The possible implications of these results for B cell physiology and for the pathogenesis of immunologically mediated diseases will be discussed.

In order to define the signal requirements for leukaemic T cell activation, the proliferation and interleukin-2 (IL-2) production of peripheral lymphocytes from a patient with a HTLV-I-, CD4+, CD45RA+ CD45RO+ CD25- T-CLL were evaluated after the delivery of different stimuli. Unlike resting CD4+ normal T lymphocytes that can be activated only by a two-signal stimulation, T-CLL cells proliferated and released IL-2 in response to a pair of anti-CD2 monoclonal antibodies (MoAbs) or concanavalin A (Con A) in the absence of both accessory cells (AC) and phorbol myristate acetate (PMA). The two stimuli were also able to induce CD25 expression within 12-20 h on the majority of T-CLL cells. A response to anti-CD3 and anti-CD28 MoAbs was detected only in the presence of PMA, similar to that observed in normal resting T lymphocytes matched for phenotype. Both Con A- and CD2-induced proliferation were strongly inhibited by the addition of anti-CD25 MoAb. Furthermore, T-CLL lymphocytes acquired anti-tumour lytic activity after culture in the presence of PMA and ionomycin. We conclude that HTLV1- CD25- T-CLL can be characterized not only by morphological and phenotypical studies but also on the basis of signal requirements for cell activation.

Activated T lymphocytes often accumulate in the lower dermis of patients with systemic sclerosis (scleroderma) and may play a role in the development of dermal fibrosis. We propagated and cloned these cells directly from skin biopsies in four of eight cases of early, untreated systemic sclerosis with diffuse scleroderma. The cloning frequency estimates were f = 0.20 and f = 0.48 for T cells derived from the skin of two patients versus f = 0.68 and f = 0.96 for autologous blood T lymphocytes. All but one of 24 skin-derived scleroderma clones were CD4+. Clonal analyses performed with CD4+ clones from patients and normal controls showed that all but one skin-derived clones synthesized either interferon-gamma (60%), glycosaminoglycan-stimulatory factor (26%) or both (9%) when induced in vitro by a mitogen, concanavalin A, but not by autologous dermal fibroblasts. In contrast, blood-derived clones had a different functional phenotype. All skin-derived clones produced tumour necrosis factor-alpha. Our results demonstrate that T lymphocytes obtained from the skin of patients with systemic sclerosis synthesized cytokines which could modulate functions of human dermal fibroblasts.

Serum IgD concentrations have been determined in twenty-one patients with Hodgkin's disease, in eight patients with non-Hodgkin's lymphomas and in twenty-eight normal (control) individuals by both a solidphase radio-immuno-assay and radial-immunodiffusion. Fourteen of the Hodgkin's patients displayed three to forty-five-fold increased serum IgD levels as compared to control individuals, while in the remaining seven patients IgD concentrations were practically normal. Patients with non-Hodgkin's lymphomas had decreased IgD concentrations.

The colony-forming capacity of peripheral blood T-cells isolated from B-cell chronic lymphocytic leukemia patients was studied and compared with that of peripheral blood T-cells isolated from 2 groups of normal controls (young and aged healthy donors). Upon stimulation with phytohemagglutinin or pokeweed mitogen. T-cells from both the patients and the controls developed into colonies but only in the presence of the appropriate conditioned media. When the responses of the 3 groups were compared, no statistically significant differences were detected. However, the number of patients who failed to respond to phytohemagglutinin was larger than that of normal controls. Studies on a selected group of patients demonstrated that such unresponsiveness was unrelated to the presence of suppressor cells or to inadequate conditions used for stimulation in culture. Rather, this unresponsiveness may be connected with an intrinsic T-cell defect present in certain B-cell chronic lymphocytic leukemia patients.

Peripheral blood mononuclear cells from atopic donors were stimulated in vitro with allergens (Rye group I or Dermatophagoides pteronyssinus). T cell lines were originated and maintained in long term culture using IL-2 and periodical restimulations with allergen. The lines were antigen specific (i.e. responded to the allergen used to raise them and not to other antigens) and required that the antigen was presented by autologous cells (i.e. they were restricted). The restriction elements were probably at the level of HLA-DR antigens since the proliferative response was specifically blocked by anti-HLA-DR antibodies. Surface marker analysis revealed that the lines comprised mainly cells with an helper/inducer phenotype, although cells with markers of the suppressor/cytotoxic T cells were also present. The lines could be cloned by limiting dilution and clones with the same restriction and specificity as the parental line were isolated. These studies demonstrate the possibility of obtaining a large number of allergen specific human T cells that can be used for further in vitro studies on the regulation of the IgE response.

Six different immune complex test systems for the detection of IgG Fc receptors were applied to the study of various human lymphocyte populations. The extent of binding varied widely according to the system and the cell type employed. Two systems bound preferentially to a high proportion of B lymphocytes from peripheral blood or tonsils, one of which bound with only a very few T cells. In contrast, four other test systems which bound well with the Fc receptors on T lymphocytes gave weaker reactions with Fc receptors on B cells. The reactivity of Fc receptors on null or third population lymphocytes was similar to that of the Fc-positive T cells. Pronase digestion experiments showed a graded selective loss of reactivity with the different Fc reagents. No one system was optimal for all of the lymphocyte populations, although aggregated IgG exhibited the broadest spectrum of reactivity. A pronounced effect of temperature was evident on the binding reactions, and native IgG showed strong binding at 4 degrees C, particularly to the Fc receptors on T cells.

The lymphocyte surface phenotype of lymph nodes from patients with larynx or urinary bladder carcinoma was investigated by using a panel of monoclonal antibodies. The phenotype pattern of lymphocytes from lymph nodes invaded by malignant cells (as assessed by histopathology) was different from that of the cells from noninvaded or normal control nodes. Although the proportion of natural killer cells or macrophages was similar in the 3 groups of lymph nodes, invaded lymph nodes contained a higher proportion of T-cells and a lower B-cell percentage. Furthermore, cells from invaded nodes comprised 15-20% of T3+ T8+ cells that coexpressed the M1 marker and, to some extent, also the Leu 7 marker. A large proportion of cells with multiple markers were activated, as shown by the expression of Tac and HLA-DR antigens. In 2 patients activated T8+ cells expressing also M1 and Leu 7 markers infiltrated the tumor site. The presence of these activated cells both in involved nodes and tumor mass may indicate that they originate in response to cancer.

Rosettes with ox erythrocytes coated with purified IgG antibody were used to detect Fc receptors on neutrophils from 60 patients with solid neoplasias and from 55 normal controls. The mean average of the rosettes in the patients was 48.10%, and that in normal controls was 79.42%, with a highly significant difference according to the Wilcoxon test [negative probability, P(w)-4.47 . 10(-5)]. The low proportion of patients' rosettes ws related to the presence of a serum factor, which also inhibited normal neutrophil rosette formation. Patient neutrophils (or normal neutrophils treated with patient sera) recovered their rosetting capacity when cultured in vitro. No correlation was found between low percentages of rosette-forming cells and the level of circulating immune complexes of the individual patients. Additional evidence also supported the finding that IC and the serum factor are probably unrelated.