Expression of microRNAs can affect age of tumor onset and prognosis of cancer patients. However, nothing is known about the effects of microRNAs on altered age of cancer onset and disease‐specific ...survival of soft‐tissue sarcoma (STS) patients. The levels of miR‐210, also known as hypoxia‐regulated microRNA, were analyzed by quantitative real‐time (RT)‐PCR in the tumors of 78 STS patients. The patients were stratified according to their microRNA levels with low, intermediate and high expression levels and the association of microRNA expression and patients' survival was analyzed using multivariate Cox's regression hazard analyses. A significant correlation between an intermediate miR‐210 expression and disease‐specific death of STS patients relative risk (RR) = 3.19; p = 0.018 was observed compared with patients with high expression levels in their tumors. Interestingly, the association between an intermediate expression of miR‐210 and a poor prognosis was only significant in female STS patients (RR = 11.28; p = 0.010), but not observed in male individuals. Furthermore, the expression of miR‐210 showed a significant association with the age of tumor onset in a gender‐specific manner. Specifically, male patients with an intermediate expression of miR‐210 associated with a 9.6‐year later age of tumor onset (p = 0.017) compared with males with a low expression of miR‐210 in their tumors. However, no significant differences in the female patients were observed. This study provides the first evidence of a correlation of expression levels of a single microRNA (miR‐210) with the prognosis and age of tumor onset in a gender‐specific manner in STS patients.
Engineering change has grown steadily in prominence both as an important issue for industry and as an active academic research area. This paper provides a categorised overview and perspective on the ...published academic literature on engineering change. The aim is to give new researchers an understanding of the field’s breadth and depth, as well as pointers towards additional information, and established researchers a non-dogmatic summary perspective on the work accomplished in this area. Change is defined as an alteration made to parts, drawings or software that have already been released during the product design process and life cycle, regardless of the scale or the type of the change. A change may encompass any modification to the form, fit and/or function of the product as a whole or in part, and may alter the interactions and dependencies of the constituent elements of the product. Key aspects of the engineering change process are highlighted along with the tools and methods that are available to support the process. The nature of products (in terms of complexity, architecture and degree of innovation) and how that affects engineering change are covered. Important related areas such as organisational structure and employee attitudes are also highlighted. The paper concludes by discussing different strategies that have been proposed to cope with engineering change in today’s manufacturing environment.
Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although ...genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
Highly structured nursery habitats promote the survival of juvenile stages of many species by providing foraging opportunities and refuge from predators. Through integrated laboratory and field ...experiments, we demonstrate that nursery habitat structure affects survival and predator-prey interactions of red king crab Paralithodes camtschaticus. Crabs (<1 yr old Age 0; 8 to 10 mm carapace length CL) preferred complex biogenic habitats formed by structural invertebrates and macroalgae over structural mimics and sand in the absence of predators in laboratory experiments, yet they associated with any available structural habitat when fish predators were present. Survival was higher in the presence of complex habitat for Age 0 crabs (5 to 7.5 mm CL) with Pacific cod Gadus macrocephalus predators in the laboratory and for Age 0 (4 to 8 mm CL) and Age 1 (16 to 28 mm CL) crabs with fish and invertebrate predators in the field. Crab activity and refuge response behavior varied with crab stage and habitat. Age 0 crabs were cryptic, avoiding predators by associating with habitat structure or remaining motionless in the absence of structure, and were less likely to respond to an attack. In contrast, Age 1 crabs were more likely to respond to an attacking predator and were less likely to remain motionless in the absence of structural refuge, suggesting an ontogenetic shift in behavior. Complex habitats, cryptic behavior, and direct defense improve juvenile red king crab survival against certain predators, including demersal fishes.
Gravity-sensitive cellular responses are regularly observed in both specialized and nonspecialized cells. One potential mechanism for this sensitivity is a changing viscosity of the intracellular ...organelles. Here, we report a novel, to our knowledge, viscosity-sensitive molecular rotor based on mesosubstituted boron-dipyrrin used to investigate the response of viscosity of cellular membranes to hypergravity conditions created at the large diameter centrifuge at the European Space Agency Technology Centre. Mouse osteoblastic (MC3T3-E1) and endothelial (human umbilical vein endothelial cell) cell lines were tested, and an increase in viscosity was found with increasing hypergravity loading. This response is thought to be primarily biologically driven, with the potential for a small, instantaneous physical mechanism also contributing to the observed effect. This work provides the first, to our knowledge, quantitative data for cellular viscosity changes under hypergravity, up to 15 × g.
Our previous recordings from dorsal root ganglion and spinal lamina V neurons from TRPV1-mutant mice showed dramatic decreases in responses to temperatures near the activation threshold of this ...channel (43-49 degrees C). Somewhat unexpectedly, we only observed behavioral deficits in these mice at higher temperatures (50-58 degrees C). In the present study, we tested the hypothesis that the noxious heat-evoked pain behavior that persists in TRPV1-mutant mice reflects residual responsiveness of neurons in the superficial, but not deep, dorsal horn. To this end, we performed in vivo extracellular recordings of spinal nociresponsive neurons in laminae I and V in wild type (WT) and TRPV1 mutant mice. Neurons in WT and mutant mice from both laminae did not differ in their spontaneous activity or evoked responses to mechanical or cold stimuli. By contrast, most lamina I neurons from mutant mice responded to noxious heat with significantly higher thresholds than in WT mice. In contrast, lamina V neurons from mutant mice were virtually unresponsive to noxious heat before and after topical mustard oil-induced tissue injury. Interestingly, lamina I neurons in mutant mice displayed thermal sensitization following tissue injury, comparable in magnitude, but of shorter duration, than in WT mice. We conclude that TRPV1 is necessary for noxious heat-evoked responses of lamina V neurons, both before and after tissue injury. It is also an essential contributor to the normal activation threshold of lamina I neurons to noxious heat and for the full duration of thermal sensitization of lamina I neurons following injury. Finally, our results suggest that the processing of noxious thermal messages by neurons in lamina I involves convergent inputs from a heterogeneous population of primary afferent thermal nociceptors.
We know of no current published data on the prevalence of craniosynostosis in Germany, so our objective in this study was to contribute to the limited knowledge of its epidemiology by assessing time ...trends, the frequency of prenatal diagnosis, and the timing of diagnosis and treatment. Data were collected in Saxony-Anhalt during the period 2000–17, and we designed a retrospective multicentre cohort study. The prevalence was 4.8 cases of craniosynostosis/10 000 births, and did not increase during that time. We compared the data of 91 patients with those of 273 controls. There were 75 boys and 16 girls (ratio 4.7:1). Fifty-one children had isolated craniosynostosis, consisting of 46 with a single-suture, and five with a multisuture, synostosis. Twenty-nine were associated with other congenital malformations, and 11 were syndromic. Three cases had been diagnosed prenatally, and 34 had skull deformities diagnosed immediately after birth at a mean (SD) age of 3.4 (4.7) months. The mean (SD) age at the time of first admission to hospital in one of the three surgical centres of Saxony-Anhalt was 5.9 (5.5) months, and 65 patients were operated on at a mean age of 9.1 (6.3) months. In contrast to published reports we found a prevalence of 4.8 cases of craniosynostosis/10 000 births that did not increase during the period 2000–16. Although we found a low prenatal detection rate, the diagnosis and treatment in this cohort study seemed timely.
Cells sense and react on changes of the mechanical properties of their environment and, likewise, respond to external mechanical stress applied to them. However, whether the gravitational field as ...overall body force modulates cellular behavior is unclear. Different studies demonstrated that micro- and hypergravity influences the shape and elasticity of cells, initiate cytoskeleton reorganization, and influence cell motility. All these cellular properties are interconnected and contribute to forces that cells apply on their surrounding microenvironment. Yet, studies that investigated changes of cell traction forces under hypergravity conditions are scarce. Here, we performed hypergravity experiments on 3T3 fibroblast cells using the large-diameter centrifuge at the European Space Agency - European Space Research and Technology Centre. Cells were exposed to hypergravity of up to 19.5 g for 16 h in both the upright and the inverted orientation with respect to the g-force vector. We observed a decrease in cellular traction forces when the gravitational field was increased up to 5.4 g, followed by an increase of traction forces for higher gravity fields up to 19.5 g independent of the orientation of the gravity vector. We attribute the switch in cellular response to shear thinning at low g-forces, followed by significant rearrangement and enforcement of the cytoskeleton at high g-forces.
Objectives
The purpose of this prospective clinical study was to identify the bacterial spectra on the surface of oral squamous cell carcinomas (OSCC) in comparison to oral mucosa of patients with a ...higher risk to emerge an OSCC and a control group to determine their susceptibility to various common antibiotics.
Material and methods
Swabs from 90 patients, 30 patients of each group, were cultured on media for aerobes and anaerobes and tested with agar diffusion and Etest.
Results
The predominant pathogens of the normal healthy oral mucosa were aerobes. The ratio between aerobes and anaerobes was 2:1, balanced in risk patients and inverted in the OSCC group. Altogether, 1,006 isolates were cultured. The most frequent strains were 47 viridans streptococci, 30 S
taphylococcus
species, 14
Enterococcus faecalis
, 36
Neisseria
species, 14
Escherichia coli
, and 23 other aerobes, 66
Peptostreptococcus
species, 39
Fusobacterium
species, and 34
Prevotella
species. The resistance rates in the OSCC group were penicillin 40 %, ampicillin 57 %, doxycycline 23 %, clindamycin 47 %, and amoxicillin/clavulanic acid 20 %, but up to 100 % of pathogens were susceptible to azithromycin, telithromycin, levofloxacin, and moxifloxacin.
Conclusion
Gram-negative anaerobes play a decisive role in the development of postoperative infections in patients with OSCC. This tumor special type of colonization does not agree with the normal flora of the oral cavity. Clinical relevance: Biofilms on OSCC surfaces provide an important reservoir for anaerobic bacteria. As a consequence, a proposal for an antibiotic prophylactic regime should be given.
Oral squamous cell carcinoma (OSCC) is among the tenth most common human cancers worldwide with evidence of an increase in incidence rate and mortality. Despite advances in treatment modalities, the ...prognosis of this cancer is still very poor and has not changed over the past two decades. This study is based on samples collected from 42 patients with a primary OSCC. Immunohistochemical staining for Glut-1 was carried out and compared with the clinicopathological data. Thirty-two patients showed in their tumors a weak or undetectable Glut-1 expression, whereas in tumors of 10 patients a moderate to strong Glut-1 expression was detected. In multivariate Cox's regression hazard analysis, patients whose tumors had a moderate to strong Glut-1 expression possessed a 4.9-fold increased risk of tumor-related death compared to the other patients. Our results suggest that Glut-1 expression is an independent prognostic marker for routine assessment of OSCC.
PDF
