Background: Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive. Methods: With the goal to investigate the molecular basis of MET amplification (MET amp ) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET amp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo. Results: We find that cancer cells driven by MET amp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In MET amp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit MET amp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors. Conclusions: Our results demonstrate that MET amp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring MET amp , a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.

Background: This study, the first of its kind, originated with the need for a brace (an ankle foot orthosis), to constrain ankle plantarflexion and dorsiflexion within a motion threshold of <5°. A conventional thermoplastic, solid brace failed during a quasi-static loading study, informing the investigation and development of an experimental carbon composite brace, maximizing stiffness and proximity of shank and foot cylindrical shells to provide the required degree of control. Methods: Two experiments were conducted: a quasi-static loading study, using cadaveric limbs (n = 2), and a gait study with healthy subjects (n = 14). Conditions tested were STOP, FREE, and CONTROL. Data for all studies were collected using six motion-capture cameras (Vicon, Oxford, UK; 120 Hz) tracking bone-anchored markers (cadaveric limbs) and skin-anchored markers (subjects). In the quasi-static loading study, loading conditions were congruent with the gait study. Study 1 involved a quasi-static loading analysis using cadaveric limbs, compared motion data from a conventional thermoplastic solid brace and the experimental brace. Study 2 involved quantifying ankle plantarflexion and dorsiflexion in subjects during treadmill walking, in brace STOP, FREE, and CONTROL conditions. Findings: The experimental brace in STOP condition consistently constrained ankle plantarflexion and dorsiflexion below the motion threshold of <5°, across all studies. Interpretation: Collectively, these findings demonstrate (1) that a conventional thermoplastic, solid brace was ineffective for clinical applications that required significant motion control, and (2) that ankle motion control is most effective when considered as a relationship between the brace, the ankle-foot complex, and the external forces that affect them both.

No description available.

No description available.

Utilization of potential synergistic interactions among different bioactive agents is a promising approach to inhibit complex diseases such as cancer. Nobiletin (NBT) and tangeretin (TAN) are major polymethoxyflavones (PMFs) found in citrus fruits. Herein, we studied NBT and TAN in combination with atorvastatin (ATST, Lipitor, a cholesterol-lowering drug) in MDAMB231 and MCF-7 human breast cancer cells. Both NBT/ATST and TAN/ATST combinations at low doses produced much stronger inhibitory effect on cancer cell viability in comparison to those produced by NBT, TAN, or ATST alone at much higher doses. Isobologram analysis confirmed that both NBT/ATST and TAN/ATST combinations produced strong synergy in inhibiting the growth of two breast cancer cell lines. Flow cytometry analysis showed that both NBT/ATST and TAN/ATST combinations caused significant cell cycle arrest at G0/G1 phase in MDAMB231 cells (ER+). Consistent with these results, PMFs and ATST combinations decreased expression levels of phospho Rb, cyclin D1, and CDK4. Further experiments showed that the combination treatment induced autophagy and late apoptosis in MDA-MB-231 cells. Meanwhile, co-treatment of PMFs and ATST induce G2/M phase in MCF-7 (ER+) cells.. The combination of PMFs and ATST also caused autophagy in MCF-7 cells, which was evidenced by activation of LC3B and P62. In conclusion, our result demonstrated strong synergy between two major citrus PMFs (NBT and TAN) and ATST in inhibiting human breast cancer cell growth.

No description available.

Although combination inhaled corticosteroids (ICs) are known to cause voice disorders in otherwise vocally healthy individuals, it is unknown whether those adverse effects can be reversed by the cessation of treatment. Quantitative aerodynamic measures such as phonation threshold pressure (PTP) and phonation threshold flow (PTF) can be used to identify the development of, and recovery from, vocal pathologies. We examined the effects and reversibility of ICs on laryngeal aerodynamics. This study was a mid-project investigation as part of a larger ongoing project. The 18 larynges were from rabbits that received ICs, a control condition, or no treatment. Experimental group rabbits received ICs twice per day until inflammatory changes (e.g., erythema, edema) became visible through endoscopic observation. One experimental group (i.e., the induction group) received treatment until symptoms were observed and then larynges were harvested. The other experimental group (i.e., the reversibility group) had ICs withdrawn once visible changes were detected via endoscopy; larynges were harvested only after these changes no longer differed from baseline. Both experimental groups had corresponding control rabbits that received twice-daily nebulized saline and followed the same withdrawal and larynx harvest schedule. A final group received no treatment. During benchtop phonation trials, PTP and PTF values were determined. All data were analyzed using descriptive and parametric statistics. No significant between-group differences were observed. Descriptively, however, average PTP and PTF values for the reversibility group were lower than the induction group. Additionally, average PTP and PTF values for the reversibility group were slightly lower than the induction group. Both experimental groups had higher PTP and PTF values than the control larynges. The results of this study indicate a trend in recovery for larynges afforded a recovery period from ICs. Further testing is needed to substantiate these preliminary findings.

No description available.

No description available.

Vid tunneldrivning inom infrastrukturprojekt i Sverige är den mest förekommande bergbulten för permanenta förstärkningar den konventionella kamstålsbulten. En ingjuten bult utan förspänning. Montaget sker genom att med handkraft pressa in bulten i ett cementfyllt borrhål. Detta ger upphov till spill av cement och stor fysisk ansträngning, när tusentals bultar monteras i varje projekt. Den permanenta bergssäkringen uppnås först när den omslutande cementen har härdat. Detta medför ett moment i bergförstärkningsskedet där entreprenören måste säkra tunneln med temporära driftbultar.   För att undvika temporärbultning kan en förspänd ingjuten bult användas som permanent bult. Exemplet på en sådan bult är PC-bulten. Vid montage ger den en omedelbar driftsäkring och en permanent förstärkning genom injektering via det inre röret. Bulten blir då helt ingjuten av cement.  Syftet med studien är att jämföra PC-bulten med kamstålsbulten. Studien undersöker den förmodade nyttan i belastningsergonomi och ekonomi av att använda PC-bulten som permanent förstärkningsbult. Genom att utföra en styrd observation på ett studiebesök där tunneldrivning med bergförstärkning skedde har de båda bultarnas montagearbete jämförts ur belastningsergonomisk synpunkt. För att utreda skillnader i arbetsvolym och tidsåtgång utfördes beräkningar på ett sammanställt bultprotokoll. Beräkningarna visar vilken förstärkningsbult som medför den lägsta kostnaden för bultförstärkning.  Av resultatet i studien framgår det att det finns en stor potential i ett framtida användande av PC-bulten som permanent bult vid tunnelförstärkning. Potentialen ligger i en klart förbättrad arbetsmiljö i avseendet belastningsergonomi och i den tidsvinst framtida projekt kan nyttja. / The conventional rebar bolt, a grouted bolt with no pre-stress, is the most commonly used rock reinforcement bolt for tunneling in Swedish infrastructural projects. The assembly takes place by manually pushing the bolt into a borehole filled with grout. This gives rise to spillage and great physical exertion when thousands of bolts are mounted in each project.   Permanent safety is only achieved when the surrounding cement has cured. This entails a moment in the rock reinforcement stage where the contractor must secure the tunnel with temporary operating bolts.  To avoid temporary bolting, a pre-stressed bolt can be used as a permanent bolt. An example of such a bolt is the PC-bolt. When assembled, it provides immediate operational safety and permanent reinforcement by injection through the inner pipe. The bolt is then completely sealed with grout.  The purpose of the study is to compare the PC-bolt with the rebar bolt. The study explores the supposed benefit of economics and load ergonomics of using the PC-bolt as a permanent reinforcement bolt. By conducting a controlled observation on a field study to a site where tunneling with rock reinforcement occurred. The assembly of the two bolts has been compared out of a load ergonomic view point. In order to investigate differences in work volume and time, calculations were made on a compiled bolt protocol. The calculations show which reinforcement bolt results in the lowest cost of the assembly.  The result of the study shows that there is a great potential in the future use of the PC-bolt as a permanent bolt for tunneling. The potential lies in a clearly improved work environment regarding ergonomic loads and more time efficient installation that can be utilized in future projects.