Prevalence of physician-diagnosed asthma by occupational groupings in Manitoba,Canada

The objective of this research was to determine whether there are differences in the rate of physician-diagnosed asthma in various occupational groups. A prevalence survey using a population-based administrative database of a sample of the labor force in Manitoba, Canada was used. A sample of 22,561 individuals who were in the labor force at the time of the 1986 census were linked to the provincial administrative health database. The frequency of physician-diagnosed asthma and other obstructive respiratory conditions were measured. A case of asthma was defined as having at least three physician contacts for asthma between April 1, 1986, and March 31, 1990. Data on potential confounding factors such as age, gender, area of residence, income, and education were also available. The results showed that frequency of physician-diagnosed asthma by occupational grouping ranged from a low of 0.1/100 workers to a high of 4.8/100 workers. Three occupational groups, 1) other teaching and related occupations (SOC 279) (OR 2.54, 95% CI 1.18–5.44); 2) fabricating, installing, and repairing occupations of electrical electronic and related equipment (SOC 853) (OR 2.37, 95% CI 1.05–5.33); and 3) other occupations in laboring and other elemental work (SOC 992) (OR 2.51, 95% CI 1.21–5.24) were found to have elevated odds ratios for physician-diagnosed asthma. Datasets linking occupation and health care utilization may be useful tools for surveillance of work-related diseases in general, and for asthma in particular. However, further work should be done utilizing larger databases to determine the overall usefulness of this approach. Am. J. Ind. Med. 32:275-282, 1997. © 1997 Wiley-Liss, Inc.     

Who is an interventional cardiologist?

The following is a position statement from the Interventional Cardiology Committee of the Society for Cardiac Angiography and Interventions. Cathet. Cardiovasc. Diagn. 41:120–123, 1997. © 1997 Wiley-Liss, Inc.     

Selective averaging of rapidly presented individual trials using fMRI

A major limitation in conducting functional neuroimaging studies, particularly for cognitive experiments, has been the use of blocked task paradigms. Here we explored whether selective averaging techniques similar to those applied in event-related potential (ERP) experiments could be used to demonstrate functional magnetic resonance imaging (fMRI) responses to rapidly intermixed trials. In the first two experiments, we observed that for 1-sec trials of full-field visual checkerboard stimulation, the fMRI blood oxygenation level-dependent (BOLD) signal summated in a roughly linear fashion across successive trials even at very short (2 sec and 5 sec) intertrial intervals, although subtle departures from linearity were observed. In experiments 3 and 4, we observed that it is possible to obtain robust activation maps for rapidly presented randomly mixed trial types (left- and right-hemifield visual checkerboard stimulation) spaced as little as 2 sec apart. Taken collectively, these results suggest that selective averaging may enable fMRI experimental designs identical to those used in typical behavioral and ERP studies. The ability to analyze closely spaced single-trial, or event-related, signals provides for a class of experiments which cannot be conducted using blocked designs. Trial types can be randomly intermixed, and selective averaging based upon trial type and/or subject performance is possible. Hum. Brain Mapping 5:329–340, 1997. © 1997 Wiley-Liss, Inc.     

Three-Dimensional Reconstruction of Pulmonary Arteries in Plexiform Pulmonary Hypertension Using Cell-Specific Markers : Evidence for a Dynamic and Heterogeneous Process of Pulmonary Endothelial Cell Growth

The plexiform lesions of severe pulmonary hypertension (PH) are complex vascular structures composed primarily of endothelial cells. In this study, we use immunohistochemical markers to identify the various cell layers of pulmonary vessels and to identify different endothelial cell phenotypes in pulmonary arteries affected by severe PH. Our computerized three-dimensional reconstructions of nine vessels in five patients with severe PH demonstrate that plexiform (n = 14) and concentric-obliterative (n = 6) lesions occur distal to branch points of small pulmonary arteries. And, whereas plexiform lesions occur as solitary lesions, concentric-obliterative lesions appear to be only associated with, and proximal to, plexiform structures. The endothelial cells of plexiform lesions express intensely and uniformly the vascular endothelial growth factor (VEGF) receptor KDR and segregate phenotypically into cyclin-kinase inhibitor p27/kip1-negative cells in the central core of the plexiform lesion and p27/kip1-positive cells in peripheral areas adjacent to incipient blood vessel formation. Using immunohistochemistry and three-dimensional reconstruction techniques, we show that plexiform lesions are dynamic vascular structures characterized by at least two endothelial cell phenotypes. Plexiform arteriopathy is not merely an end stage or postthrombotic change--it may represent one stage in an ongoing, angiogenic endothelial cell growth process.     

Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site–specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell–based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.

Glioblastoma (GBM) is the most common and deadliest malignant type of primary brain tumor (1). GBM patients are poorly responsive to traditional treatments, resulting in a grim prognosis that has only modestly improved over the past several decades, motivating the hunt for new treatment approaches (2). So far, chimeric antigen receptor (CAR)-engineered natural killer (NK) cells targeting single GBM antigens—EGFR, EGFRvIII, or ErbB2/HER2—have been limited to the use of NK cell lines, and the overall response rates have been disappointingly low and inconsistent (3–5). These responses appear to mirror the clinical hurdles of single antigen-targeted CAR-T therapies for GBM (6–9). CAR-T cells, administered to target single GBM antigens via intracavitary, intraventricular, or intravenous routes, have so far resulted in inconclusive durable responses (8).Preclinical and patient data have pointed to the heterogeneity of the GBM tumor microenvironment (TME) as a uniquely complex obstacle to overcome ( 10). This is reflected in immunotherapies tested so far having struggled to improve GBM patient overall survival (OS) in phase III clinical trials (11, 12). GBM induces localized lymphopenia to drive disease progression and resist treatment (13). In addition, the tumor’s heterogeneity is broad, with each of the known GBM subtypes—classical, mesenchymal, neural, and proneural—displaying diverse genetic and epigenetic signatures associated with distinct and variable cell plasticities (14). Not surprisingly, the outgrowth of antigen escape variants has been recorded clinically with most GBM-associated antigens to date, resulting in immune evasion and resistance to treatment (7, 15). And though strategies including dual antigen-targeting or programmable tumor-sensing CARs—so far primarily in the context of adoptive T cell therapy—have been evaluated preclinically to combat such evasion, GBM employs mechanisms beyond antigen escape to avoid targeting. Treatment evasion by GBM is fueled by a heavily immunosuppressive, hypoxic TME, which provides a niche unfavorable to NK cell effector function (16). A subset of GBM cells, glioma stem-like cells (GSCs), contribute to treatment resistance and are poorly recapitulated by conventional GBM model cell lines, including U87MG (17). Metabolic and functional pathways, moreover, converge to fuel the tumor’s invasiveness by driving exhaustion of immune cells (18). For instance, immunometabolic dysregulation of NK cell function in GBM is driven in part by the activity of ecto-5′-nucleotidase (CD73). CD73 is a hypoxic ectoenzyme that we and others have found to be associated with a negative prognosis and has emerged as an attractive clinical target (19, 20). In addition, we have previously shown that the CD73-driven accumulation of extracellular adenosine (ADO) leads to significant purinergic signaling–mediated impairment of NK cell activity (21, 22).Although they are among the most abundant lymphocytes found within the GBM TME, NK cells are still present in insufficient amounts in these tumors and exhibit a highly dysfunctional phenotype (23, 24). The need to recapitulate NK cell function lost to multiple complex mechanisms not only presents a significant challenge to traditional CAR-NK therapy but requires a greater presence specifically within the tumor tissue to mount meaningful clinical responses.Here, we describe an example of a multifunctional, engineered human NK cell–based therapy for glioblastoma developed around the programmed targeting of three clinically recognized pathways of GBM progression: antigen escape, immunometabolic suppression, and poor intratumoral NK cell presence. We achieved dual antigen recognition by modifying NK cells with multi-CARs to target disialoganglioside (GD2) and ligands to NK group 2D (NKG2D), which are widely expressed on human GBM (25, 26). Within the same NK cells, we engineered the concomitant local release of an antibody fragment that impairs immunosuppressive purinergic signaling by blocking the activity of CD73 via the cleavage of a tumor-specific linker. This cleavage is dependent on the activity of proteases that are up-regulated in the tumor microenvironment (27). Such local release is able to avoid systemic toxicities owing to its tumor-specific activation that occurs independently of CAR-based signaling.We report the homing of such multifunctional NK cells was enhanced when administered in conjunction with autophagy inhibitors in patient-derived GBM xenografts. Disabling autophagy further revealed a sophisticated and complex reorganization of anti-GBM immunological responses which could contribute to enhanced CAR-NK effector function. The clinical efficacy of adding an autophagy inhibitor to GBM therapy has shown that such treatments are clinically safe and well tolerated (28). We reveal a nuanced and potentially important role for autophagy inhibitors in adoptive human NK therapy.These studies aim to expand the repertoire of GBM-targeting NK cell–based immunotherapy and describe a first example of addressing, simultaneously, the challenge of tumor antigen heterogeneity, an immunosuppressive TME, and insufficient intratumoral trafficking of NK cells.     

Genetic linkage study of bipolar disorder and the serotonin transporter

The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Old Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter. © 1996 Wiley-Liss, Inc.