The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

Cancer is a disease exhibiting uncontrollable cell growth and spreading to other parts of the organism. It is a heavy, worldwide burden for mankind with high morbidity and mortality. Therefore, groundbreaking research and innovations are necessary. Research in space under microgravity (µg) conditions is a novel approach with the potential to fight cancer and develop future cancer therapies. Space travel is accompanied by adverse effects on our health, and there is a need to counteract these health problems. On the cellular level, studies have shown that real (r-) and simulated (s-) µg impact survival, apoptosis, proliferation, migration, and adhesion as well as the cytoskeleton, the extracellular matrix, focal adhesion, and growth factors in cancer cells. Moreover, the µg-environment induces in vitro 3D tumor models (multicellular spheroids and organoids) with a high potential for preclinical drug targeting, cancer drug development, and studying the processes of cancer progression and metastasis on a molecular level. This review focuses on the effects of r- and s-µg on different types of cells deriving from thyroid, breast, lung, skin, and prostate cancer, as well as tumors of the gastrointestinal tract. In addition, we summarize the current knowledge of the impact of µg on cancerous stem cells. The information demonstrates that µg has become an important new technology for increasing current knowledge of cancer biology.     

Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.     

"Milk makes me sick but my body needs it": conflict and contradiction in the establishment of authoritative knowledge

This article takes lactose intolerance as a topic for exploring clashes of power, authority, and knowledge in clinical interactions and interpretations of laywomen. In clinics providing maternal and child care, staff and clients jointly produced authoritative knowledge, most often a version of biomedicine. The Euroamerican staff tended to give advice that was biologically appropriate for them but not for many of their patients, a process reflecting what we refer to as biocentrism. Resulting information given to pregnant and lactating women and diagnoses of children's growth patterns were inappropriate in some cases, with potentially serious legal and health implications. Clinic staff often unwittingly ignored the efforts of their clients to begin a discussion of discrepancies between their bodily knowledge and clinic advice. Some women created their own syntheses, which supported the ascendancy of biomedical knowledge but were not in the interests of their own health.     

Role of endoproteolytic dibasic proprotein processing in maturation of secretory proteins in Trichoderma reesei

Cell extracts of Trichoderma reesei exhibited dibasic endopeptidase activity toward the carboxylic side of KR, RR, and PR sequences. This activity was stimulated by the presence of Ca2+ ions and localized in vesicles of low bouyant density; it therefore exhibited some similarity to yeast Kex2. Analytical chromatofocusing revealed a single peak of activity. The dibasic endopeptidase activity was strongly and irreversibly inhibited in vitro as well as in vivo by 1 mM p-amidinophenylmethylsulfonyl fluoride (pAPMSF) but not by PMSF at concentrations up to 5 mM. We therefore used pAPMSF to study the role of the dibasic endopeptidase in the secretion of protein by T. reesei. Secretion of xylanase I (proprotein processing sequence -R-R- downward arrow-R- downward arrow-A-) and xylanase II (-K-R- downward arrow-Q-) was strongly inhibited by 1 mM pAPMSF, and a larger, unprocessed enzyme form was detected intracellularly under these conditions. Secretion of cellobiohydrolase II (CBH II; -E-R- downward arrow-Q-) was only slightly inhibited by pAPMSF, and no accumulation of unprocessed precursors was detected. In contrast, secretion of CBH I (-R-A- downward arrow-Q-) was stimulated by pAPMSF addition, and a simultaneous decrease in the concentration of intracellular CBH I was detected. Similar experiments were also carried out with a single heterologous protein, ShBLE, the phleomycin-binding protein from Streptoalloteichus hindustanus, fused to a series of model proprotein-processing sequences downstream of the expression signals of the Aspergillus nidulans gpdA promoter. Consistent with the results obtained with homologous proteins, pAPMSF inhibited the secretion of ShBLE with fusions containing dibasic (RK and KR) target sequences, but it even stimulated secretion in fusions to LR, NHA, and EHA target sequences. Addition of 5 mM PMSF, a nonspecific inhibitor of serine protease, nonspecifically inhibited the secretion of heterologous proteins from fusions bearing the NHA and LR targets. These data point to the existence of different endoproteolytic proprotein processing enzymes in T. reesei and demonstrate that dibasic processing is obligatory for the secretion of the proproteins containing this target.     

Confirmation of the human-pathogenic microsporidia Enterocytozoon bieneusi, Encephalitozoon intestinalis, and Vittaforma corneae in water

Microsporidia, as a group, cause a wide range of infections, though two species of microsporidia in particular, Enterocytozoon bieneusi and Encephalitozoon intestinalis, are associated with gastrointestinal disease in humans. To date, the mode of transmission and environmental occurrence of microsporidia have not been elucidated due to lack of sensitive and specific screening methods. The present study was undertaken with recently developed methods to screen several significant water sources. Water concentrates were subjected to community DNA extraction followed by microsporidium-specific PCR amplification, PCR sequencing, and database homology comparison. A total of 14 water concentrates were screened; 7 of these contained human-pathogenic microsporidia. The presence of Encephalitozoon intestinalis was confirmed in tertiary sewage effluent, surface water, and groundwater; the presence of Enterocytozoon bieneusi was confirmed in surface water; and the presence of Vittaforma corneae was confirmed in tertiary effluent. Thus, this study represents the first confirmation, to the species level, of human-pathogenic microsporidia in water, indicating that these human-pathogenic microsporidia may be waterborne pathogens.     

A simplified modeling approach using microbial growth kinetics for predicting exposure concentrations of organic chemicals in treated wastewater effluents

Various mathematical relationships have been used to assess exposure concentrations of organic chemicals when emissions occur via wastewater treatment. These relationships range from a simple removal factor calculation to more sophisticated approaches using kinetic based mathematical models. While these existing approaches have been used by decision makers to screen new chemicals for exposure assessments, they all have limitations in the predictive capabilities. Thus, a simplified modeling approach grounded in sound scientific fundamentals that utilizes relatively easy to obtain input parameters is needed. In this paper a simplified modeling approach that utilizes microbial growth kinetics was developed for predicting effluent concentrations in secondary biological wastewater treatment systems. Receiving water predicted exposure concentrations (PEC) are assessed by using a dilution factor. One advantage of this approach is that it allows for wastewater treatment plant effluent concentrations, and therefore receiving water exposure levels, to be predicted with a minimum amount of experimental data. It also provides quantitative data that can be used to assess the relative biodegradability of different chemicals for use in regulatory and risk assessment activities.     

Prognostic value of plasma fibrinogen concentration in patients with unstable angina and non-Q-wave myocardial infarction (TIMI IIIB Trial)

The records of 60 patients with gallbladder carcinoma (GBC) operatively treated between 1966 and 1993 at Belen Hospital, Trujillo, Perú, were retrospectively reviewed. The ratio of men to women was 1:7.5 and the average of age was 61 years. The accuracy of ultrasonography and oral cholecystograms for the specific diagnosis was 21% and 0% respectively. The surgical procedures employed were simple cholecystectomy (n = 56), right hepatectomy (n = 2). Whipple operation (n = 1) and extended cholecystectomy (n = 1), and our resectability rate for GBC is currently 50%. Simple cholecystectomy was a potentially curative surgical procedure in patients with in situ cancer (stage O) and early GBC (stage 1). In hospital mortality was 11.6% and 5-year survival rate for the total series was 15%. Gallstones were present in 95% of patients and most tumors (58%) had grown by diffuse infiltration or were associated with empyema (38%). Tumor stage, depth of invasion, tumor grade histologic type were all predictive of patient outcome. This report reinforces the difficulty in diagnosis and the poor prognosis for patients with GBC. We hold the view that more radical approaches for invasive cancers will enhance the operative results.