Resistance to TRAIL and how to surmount it

Development of resistance to TRAIL-induced toxicity is one of the strategies used from tumor cells to escape destruction from the immune system. This process may occur through aberrant expression of functional receptors, overexpression of decoy receptors on tumor cell membrane, or malfunctioning of downstream signals triggered by specific ligation of TRAIL. Numerous cytostatic, but also noncytostatic, drugs like protease inhibitors and NO-hybridized molecules have been shown to revert sensitivity of neoplastic cells to TRAIL by means of different mechanisms. This paper will review the possible routes of reconstitution of sensitivity to TRAIL-mediated immune response by specific modulation of different signals responsible for the development of resistance at both the membrane and the intracellular levels. Moreover, we will review and suggest novel strategies, aimed at resetting immune cell efficiency in cancer treatment.     

Baker's asthma due to xylanase and cellulase without sensitization to alpha-amylase and only weak sensitization to flour

BACKGROUND: The baking additives xylanase and cellulase were described as baking additives causing baker's asthma. It is not known whether monosensitization to these enzymes may occur. METHODS: We present a case report of a baker with work-related asthma evaluated by skin prick test (SPT), enzyme-linked immunosorbent assay (EAST), immunoblot, EAST and immunoblot inhibition, and specific bronchial challenge. Fungal xylanase and alpha-amylase were measured by two-site enzyme immunoassays in products used by the patient at work. RESULTS: Allergy to xylanase and cellulase was demonstrated by SPT, EAST, immunoblot and specific bronchial challenge (for xylanase only). No sensitization to alpha-amylase could be demonstrated, but there was a weak flour allergy as documented by EAST and immunoblot and a positive occupational-type challenge with high concentrations of rye flour. Four baking additives contained measurable amounts of fungal alpha-amylase and xylanase, without a correlation between these enzymes. CONCLUSIONS: We conclude that occupational asthma due to the baking additives xylanase and cellulase may occur without concomitant sensitization to alpha-amylase and only weak sensitization to flour.     

Exposure to bright light and darkness to treat physiologic maladaptation to night work

Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.     

Models and analyses to understand threats to polio eradication

To achieve complete polio eradication, the live oral poliovirus vaccine (OPV) currently used must be phased out after the end of wild poliovirus transmission. However, poorly understood threats may arise when OPV use is stopped. To counter these threats, better models than those currently available are needed. Two articles recently published in BMC Medicine address these issues. Mercer et al. (BMC Med 15:180, 2017) developed a statistical model analysis of polio case data and characteristics of cases occurring in several districts in Pakistan to inform resource allocation decisions. Nevertheless, despite having the potential to accelerate the elimination of polio cases, their analyses are unlikely to advance our understanding OPV cessation threats. McCarthy et al. (BMC Med 15:175, 2017) explored one such threat, namely the emergence and transmission of serotype 2 circulating vaccine derived poliovirus (cVDPV2) after OPV2 cessation, and found that the risk of persistent spread of cVDPV2 to new areas increases rapidly 1–5 years after OPV2 cessation. Thus, recently developed models and analysis methods have the potential to guide the required steps to surpass these threats. ‘Big data’ scientists could help with this; however, datasets covering all eradication efforts should be made readily available.Please see related articles: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0937-y and https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0941-2.     

Baylor's program to attract minority students and others to science and medicine

To attract minority students and others to careers in medical practice and biomedical research and to prepare them for such careers, Baylor College of Medicine conducts a variety of summer enrichment programs and other programs to improve how science is presented to students in their preprofessional years from elementary grades through college. These efforts aim to increase the number of competitive candidates for medical school, particularly those from minority groups underrepresented in medicine. They entail close collaboration between the Baylor administration and faculty from Texas public schools and two-year and four-year colleges and universities. The authors discuss the rationale for these programs and comment about the need for institutional commitments of faculty and financial support. They note that these programs are an investment in the future and that longitudinal assessment is needed to determine their ultimate success.     

The ECG changes due to altitude and to catecholamines

Summary In order to distinguish the effects of beta-receptor stimulation on the ECG from other factors during short-term adjustment to hypoxic aerohypoxia, the ECG of 19 volunteers were compared during moderately acute, stepwise exposure to high altitude (6,000 m) in a low pressure chamber, once with and once without beta-receptor blockade (propranolol), and after isoprenaline inhalation at ground level. The results show that beta-receptor stimulation accounts mainly for most ECG changes during altitude exposure, i.e., for the shortening of R-R interval, the lengthening of Q-T and in particular for the ST-T flattening, the latter therefore being only an indirect sign of hypoxia. After exclusion of the catecholamines, the minor but still significant ECG changes at altitude (shortening of R-R interval, increase of P wave, prolongation of P-Q, deviation of the R vector, T wave flattening in the left precordial leads) may be attributed to other, so far undefined factors, such as cardiac hypoxia, vagal withdrawal, or increase of pulmonary resistance.Dedicated to Prof. O. A. M. Wyss on the occasion of his 80th birthdayThe study was supported in part by a grant from the Stiftung für wissenschaftliche Forschung an der UniversitÄt Zürich     

Neurospora mutants sensitive both to mutagens and to histidine

Summary Previous work in this and other laboratories showed that histidine strongly inhibits growth of mutants at ten out of 20 known mutagen-sensitivity loci in Neurospora, and that nine of the histidine-sensitive mutants disturb meiosis when homozygous. These and other results suggested that histidine affects recombination or DNA repair. Current work with the histidine-sensitive mutant uvs-6 shows that it is also inhibited by several other metabolites but none of them is as effective as histidine. On minimal medium without histidine or other inhibitors, uvs-6 first grows normally, then slows drastically and begins stop-start growth. Conidia from stop-start uvs-6 mycelia produce rejuvenated cultures. The stop-start growth, UV-sensitivity, histidine-sensitivity, and recessive meiotic characters of uvs-6 segregated together in crosses, and reverted together. In tests on other mutagen-sensitive mutants, sensitivity to histidine was strongly correlated with stop-start growth and with sensitivity to other metabolites. Histidine induces premature stop-start growth in at least two mutants. Several possible explanations for the histidine-sensitivity have been excluded.     

When to switch and what to switch to: strategic use of antiretroviral therapy

Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.     

Vestibular and somatosensory contributions to responses to head and body displacements in stance

The relative contribution of vestibular and somatosensory information to triggering postural responses to external body displacements may depend on the task and on the availability of sensory information in each system. To separate the contribution of vestibular and neck mechanisms to the stabilization of upright stance from that of lower body somatosensory mechanisms, responses to displacements of the head alone were compared with responses to displacements of the head and body, in both healthy subjects and in patients with profound bilateral vestibular loss. Head displacements were induced by translating two 1-kg weights suspended on either side of the head at the level of the mastoid bone, and body displacements were induced translating the support surface. Head displacements resulted in maximum forward and backward head accelerations similar to those resulting from body displacements, but were not accompanied by significant center of body mass, ankle, knee, or hip motions. We tested the effect of disrupting somatosensory information from the legs on postural responses to head or body displacements by sway-referencing the support surface. The subjects' eyes were closed during all testing to eliminate the effects of vision. Results showed that head displacements alone can trigger medium latency (48–84 ms) responses in the same leg and trunk muscles as body displacements. Nevertheless, it is unlikely that vestibular signals alone normally trigger directionally specific postural responses to support surface translations in standing humans because: (1) initial head accelerations resulting from body and head displacements were in opposite directions, but were associated with activation of the same leg and trunk postural muscles; (2) muscle responses to displacements of the head alone were only one third of the amplitude of responses to body displacements with equivalent maximum head accelerations; and (3) patients with profound bilateral vestibular loss showed patterns and latencies of leg and trunk muscle responses to body displacements similar to those of healthy subjects. Altering somatosensory information, by sway-referencing the support surface, increased the amplitude of ankle muscle activation to head displacements and reduced the amplitude of ankle muscle activation to body displacements, suggesting context-specific reweighting of vestibular and somatosensory inputs for posture. In contrast to responses to body displacements, responses to direct head displacements appear to depend upon a vestibulospinal trigger, since trunk and leg muscle responses to head displacements were absent in patients who had lost vestibular function as adults. Patients who lost vestibular function as infants, however, had near normal trunk and leg response to head displacements, suggesting a substitution of upper trunk and neck somatosensory inputs for missing vestibular inputs during development.     

Allergenic extracts to diagnose and treat sensitivity to insect venoms and inhaled allergens

Objective

To review allergenic extracts used to diagnose or treat insect allergies, including how the extracts are manufactured and their measurements of potency or concentration.

Range Correction Applied to Heart Rate and to GSR Data

The utility of the range correction, in which each individual autonomic level or response measure is expressed in terms of estimates of that S's maximum and minimum level or response amplitude, was evaluated in terms of the apparent reduction in error variance indicated by larger or more significant treatment effects. The data analyzed were from an experiment in which 48 Ss received 12 painful shocks in each of four conditions of shock predictability. A reduction in error variance resulted from correcting, for individual differences in tonic range, measures of tonic SC (a replication of previous findings) and measures of tonic HR (a new finding). A reduction in error variance also resulted from dividing each SCR to shock by that S's largest SCR, i.e., by correcting phasic SCR measures for individual differences in range of SCR. No marked improvement resulted from a similar correction of phasic HRR data.     

Lipid transport to avian oocytes and to the developing embryo

Studies of receptor-mediated lipoprotein metabolic pathways in avian species have revealed that physiological intricacies of specific cell types are highly analogous to those in mammals. A prime example for the power of comparative studies across different animal kingdoms, elucidated in the chicken, is that the expression of different lipoprotein receptors in somatic cells and oocytes are the key to oocyte growth. In avian species, yolk precursor transport from the hen's liver to rapidly growing oocytes and the subsequent transfer of yolk nutrients via the yolk sac to the developing embryo are highly efficient processes. Oocytes grow from a diameter of 5 mm to 2.5-3 cm in only 7 days, and the yolk sac transfers nutrients from the yolk stored in the mature oocyte to the embryo within just 2 weeks. The underlying key transport mechanism is receptor-mediated endocytosis of macromolecules, i.e., of hepatically synthesized yolk precursors for oocyte growth, and of mature yolk components for embryo nutrition, respectively. Recently, the receptors involved, as well as the role of lipoprotein synthesis in the yolk sac have been identified. As outlined here, lipoprotein degradation/resynthesis cycles and the expression of lipoprotein receptors are not only coordinated with the establishment of the follicular architecture embedding the oocyte, but also with the generation of the yolk sac vasculature essential for nutrient transfer to the embryo.