Noninvasive detection of tumor-infiltrating T cells by PET reporter imaging

Adoptive transfer of tumor-reactive T cells can successfully reduce tumor burden; however, in rare cases, lethal on-target/off-tumor effects have been reported. A noninvasive method to track engineered cells with high sensitivity and resolution would allow observation of correct cell homing and/or identification of dangerous off-target locations in preclinical and clinical applications. Human deoxycytidine kinase triple mutant (hdCK3mut) is a nonimmunogenic PET reporter that was previously shown to be an effective tool to monitor whole-body hematopoiesis. Here, we engineered a construct in which hdCK3mut is coexpressed with the anti-melanoma T cell receptor F5, introduced this construct into human CD34 cells or PBMCs, and evaluated this approach in multiple immunotherapy models. Expression of hdCK3mut allowed engrafted cells to be visualized within recipient bone marrow, while accumulation of [¹⁸F]-L-FMAU in hdCK3mut-expressing T cells permitted detection of intratumoral homing. Animals that received T cells coexpressing hdCK3mut and the anti-melanoma T cell receptor had demonstrably higher signals in HLA-matched tumors compared with those in animals that received cells solely expressing hdCK3mut. Engineered T cells caused cytotoxicity in HLA/antigen-matched tumors and induced IFN-γ production and activation. Moreover, hdCK3mut permitted simultaneous monitoring of engraftment and tumor infiltration, without affecting T cell function. Our findings suggest that hdCK3mut reporter imaging can be applied in clinical immunotherapies for whole-body detection of engineered cell locations.     

Interest of tumor necrosis factor-alpha -308 G/A and interleukin-10 -592 C/A polymorphisms in human African trypanosomiasis.

This study aimed to determine whether single nucleotide polymorphisms (SNPs) within tumour necrosis factor-alpha (TNF) and interleukin-10 (IL10) promoters and genes are associated with human African trypanosomiasis (HAT). The polymorphisms used in the analysis were TNF(-308G/A), TNF(-238G/A), TNF(-1031T/C), TNF(+488G/A), IL10(-1082G/A) and IL10(-592C/A). A familial case-control sample of 277 individuals (102 cases and 175 parents) and a matched case-control group of 225 subjects (88 cases and 137 unrelated controls) were gathered together in this study. A conditional logistic regression was used to test for association. We carried out this analysis in the overall population and after stratification by time of exposure, age and ethnic group. Our results show that in the overall population, and after stratification by time of exposure, the IL10(-592A) allele is associated with a lower risk of disease, suggesting the possibility of a protective effect. After stratification by time of exposure, individuals homozygous for the SNP located in the TNF(-308) promoter were shown to present a higher risk of developing the disease early after exposure. Our study shows that TNF(-308G/A) and IL10(-592C/A) SNPs are polymorphisms of interest in the investigation of the genetic susceptibility to human African trypanosomiasis. Larger studies are currently underway to confirm these results.     

Low back pain in physical education teachers

The purpose of this study was to investigate the factors related to occupational low back pain (LBP) occurring in male physical education teachers (PET). The location was set in Athens and we used questionnaires to collect information. Analysis revealed that the prevalence of LBP during the survey was 63%. The correlation of personal factors and LBP showed that the prevalence of LBP was significantly higher in those PET (odds ratio, 2.5) who answered yes to the item "no personal training" than in the PET who did not. Moreover, many occupational factors are related to LBP. These were the items "lifting gym instruments" (odds ratio, 2.6) and "helping students into flexing posture" (odds ratio, 3.0). From the working conditions it was confirmed that the PET (odds ratio, 2.5) who "spent more than 35 hours per week in teaching physical education" were correlated with LBP. Our results suggest that PET, under the current working condition, are vulnerable to low back pain. An improvement of these conditions must be taken into account in order to prevent LBP.     

Does the antimigraine action of flunarizine involve the dopaminergic system? A clinical-neuroendocrinological study

We have investigated the prolactin response to bromocriptine (BRC), a D2 dopamine receptor agonist in migrainous women before and after treatment with flunarizine. We evaluated whether this test was predictive of therapeutic efficacy of flunarizine treatment and whether the therapeutic response to flunarizine treatment was related to its effect on dopaminergic system at tuberoinfundibular level. Ten migrainous women underwent a BRC test in the late follicular phase before and after 1 and 3 months of treatment with flunarizine 10 mg at bedtime. Blood samples of prolactin (PRL), growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone were taken at basal condition. PRL was also evaluated 1 and 2 h after BRC (2.5 mg) administration. Each patient kept a daily headache diary for 1 month prior to the test and throughout the study. The level of PRL inhibition after BRC administration, observed before flunarizine treatment, was not predictive of the therapeutic response observed after 1 and 3 months of treatment. The effect of flunarizine on PRL level was not related to the therapeutic efficacy of the drug. These data suggest that flunarizine does not attenuate the activity of dopaminergic neurons in migrainous patients, and that the antimigraine effect of flunarizine does not seem related to its action on dopaminergic system at least at tuberoinfundibular level.     

Metachronous early gastric adenocarcinoma presenting coinstantaneously with complete remission of stage IV gastric MALT lymphoma

Adenocarcinoma and lymphoma represent the two most common malignant tumours of the stomach, with both neoplasms being associated with infection by Helicobacter pylori. However, the presence of lymphoma and adenocarcinoma in the same patient is a rare entity with synchronous neoplasms being more common than metachronous types. We report a case of stage IV gastric MALT lymphoma of the gastric angle with infiltration of the bone marrow successfully treated with chemotherapy and the occurrence of metachronous early gastric adenocarcinoma of the fundus presenting 1 year after the diagnosis of the lymphoma.     

A quantitative study of growth cone filopodial extension

The extension of filopodia from growth cones of regenerating neurites from rat superior cervical ganglion neurons in tissue culture was studied. Cultures were grown on a thin layer of fibrous collagen and maintained in a medium containing serum and nerve growth factor. Time-lapse cinematography and computer-assisted morphometry were used to observe and measure the kinetics of extension of individual filopodia. Filopodia extended from the growth cone margin, trailing neurite, or from each other. Frequently, extension was preceded by the appearance at the cone margin of a nodule of cytoplasm which appeared dense in phase-contrast optics. Branch points between adjacent extending filopodia remained fixed with respect to the growth cone while the filopodia lengthened. The rate of extension was maximum just after initiation (0.12 +/- 0.4 micron/sec; mean +/- SD; n = 36) and declined thereafter until the filopodium collapsed. This initial rate of extension was directly correlated with the eventual length of the filopodium (r = 0.67). Filopodia of growth cones arising from embryonic neurons exhibited higher initial extension rates (range: 0.07 to 0.20 micron/sec; mean = 0.13 micron/sec) than those of postnatal neurons (range: 0.01 to 0.13 micron/sec; mean = 0.09 micron/sec). These data are discussed in relation to a model proposed by Tilney and Inoue [1982] for the extension, by distal addition of G-actin to growing filaments, of another type of elongating process filled with microfilaments, the acrosomal process of Thyone sperm.     

Audiovisual synchrony perception for speech and music assessed using a temporal order judgment task

This study investigated people's sensitivity to audiovisual asynchrony in briefly-presented speech and musical videos. A series of speech (letters and syllables) and guitar and piano music (single and double notes) video clips were presented randomly at a range of stimulus onset asynchronies (SOAs) using the method of constant stimuli. Participants made unspeeded temporal order judgments (TOJs) regarding which stream (auditory or visual) appeared to have been presented first. The accuracy of participants' TOJ performance (measured in terms of the just noticeable difference; JND) was significantly better for the speech than for either the guitar or piano music video clips, suggesting that people are more sensitive to asynchrony for speech than for music stimuli. The visual stream had to lead the auditory stream for the point of subjective simultaneity (PSS) to be achieved in the piano music clips while auditory leads were typically required for the guitar music clips. The PSS values obtained for the speech stimuli varied substantially as a function of the particular speech sound presented. These results provide the first empirical evidence regarding people's sensitivity to audiovisual asynchrony for musical stimuli. Our results also demonstrate that people's sensitivity to asynchrony in speech stimuli is better than has been suggested on the basis of previous research using continuous speech streams as stimuli.     

Temporal order judgments for audiovisual targets embedded in unimodal and bimodal distractor streams

We investigated whether the presence of unimodal or bimodal (synchronous) distractors would affect temporal order judgments (TOJs) for pairs of asynchronous audiovisual target stimuli. Participants made unspeeded TOJs regarding which of a pair of auditory and visual stimuli, presented at different stimulus onset asynchronies using the method of constant stimuli, occurred first. These asynchronous target stimuli were presented in a fixed position amongst a stream of three (auditory, visual, or audiovisual) distractors in each block of trials. The largest just noticeable differences (JNDs) were reported when the target stimuli were presented in the middle (position 3) of the distractor stream. Importantly, audiovisual distractors were shown to interfere with TOJ performance far more than unimodal (auditory or visual) distractors. The point of subjective simultaneity (PSS) was also influenced by the modality of the distractors, and by the position of the target within the distractor stream. These results confirm the existence of a specifically bimodal crowding effect, with audiovisual TOJs being impaired far more by the presence of audiovisual distractors that by unimodal auditory or visual distractors.