Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.

Patients with urothelial carcinoma (UC) experience gemcitabine resistance is a critical issue. The role of hedgehog pathway in the problem was explored. The expressions of phospho-AKTser473, phospho-GSK3ßser9 and Gli2 were up-regulated in gemcitabine-resistant NTUB1 (NGR) cells. Without hedgehog ligands, Gli proteins can be phosphorylated by GSK3ß kinase to inhibit their downstream regulations. Furthermore, the GSK3ß kinase can be phosphorylated by AKT at its Ser9 residue to become an inactive kinase. Therefore, overexpression of AKT1, Flag-GSKS9D (constitutively inactive form) or active Gli2 (GLI2ΔN) in NTUB1 cells could activate Gli2 pathway to enhance migration/invasion ability and increase gemcitabine resistance, respectively. Conversely, overexpression of Flag-GSKS9A (constitutively active form) or knockdown of Gli2 could suppress Gli2 pathway, and then reduce gemcitabine resistance in NGR cells. Therefore, we suggest gemcitabine-activated AKT/GSK3ß pathway can elicit Gli2 activity, which leads to enhanced migration/invasion ability and resistance to gemcitabine therapy in UC patients. The non-canonical hedgehog pathway should be evaluated in the therapy to benefit UC patients.

Room Temperature Magnetoelectric Sensor Arrays For Application of Detecting Iron Profiles in Organs.

Noninvasive measurement of liver iron concentration (LIC) is clinically important. Yet, at the present time, it can only be achieved with SQUID technology. However, SQUID based BLS suffers high costs and cumbersome cryogenic requirements that prevent SQUID BLS from being adopted by clinical applications. Recently, we demonstrated that a single channel ME sensor with piezo-single crystals could detect LIC from only 3cc of mouse liver tissue without any magnetic field shielding. The results demonstrated not only the sensitivity of ME sensor system for LIC but also the feasibility for mapping LIC profiles spatially. This investigation further developed ME sensor arrays, exploiting the compact size and room temperature operation. A Dual-Channel 1-D ME sensor array along the vertical, Z-direction, was developed and shown to be sensitive to the skin-liver distance change which can be utilized to calibrate and eliminate the inter-subject variability of the LIC measurement due to skin-liver distance. With phantom having spatially dependent iron concentrations, the 1-D ME sensor array was capable of mapping the one-dimensional profile of the iron concentration in the horizontal X- and Y-directions. The results of the prototype sensor devices show the feasibility of an array ME-sensors for imaging iron profile.

A Novel Magnetoelectric Biomagnetic Susceptometer on Iron Level Detection with Mice Tissue in Vitro.

Iron plays a vital role in human body. Liver Iron Concentration (LIC) is directly correlated to total body iron and can be an important indicator to a variety of pathologies. Non-invasive methods to quantitatively assess tissue iron with low cost and high sensitivity have drawn vast interests and investments. Among various methods, the magnetoelectric (ME) sensor based biomagnetic liver susceptometer (BLS) is of great promise because it operates at room temperature but with the same principle as that of the well-developed SQUID (Superconducting Quantum Interference Device). Here, we report a magnetoelectric (ME) sensor based BLS system exploiting the recently developed PIN-PMN-PT piezoelectric single crystal. The newly developed ME BLS, which employs the horizontal scanning mechanism with a water bath interface to automatically eliminate the diamagnetic background of the tissues and irregular shape of torso, exhibits an overall sensitivity advancement (300X) to the sensor system previously reported. A linear correlation (R2 = 0.97) found between the system measurements and the biopsy data demonstrates the validity of the system. The ability to detect signals from only 3cc of mouse liver tissue samples suggests a high spatial resolution which could be used for finer scanning and enable magnetic distribution image and profiling.

A Room Temperature Ultrasensitive Magnetoelectric Susceptometer for Quantitative Tissue Iron Detection.

Iron is a trace mineral that plays a vital role in the human body. However, absorbing and accumulating excessive iron in body organs (iron overload) can damage or even destroy an organ. Even after many decades of research, progress on the development of noninvasive and low-cost tissue iron detection methods is very limited. Here we report a recent advance in a room-temperature ultrasensitive biomagnetic susceptometer for quantitative tissue iron detection. The biomagnetic susceptometer exploits recent advances in the magnetoelectric (ME) composite sensors that exhibit an ultrahigh AC magnetic sensitivity under the presence of a strong DC magnetic field. The first order gradiometer based on piezoelectric and magnetostrictive laminate (ME composite) structure shows an equivalent magnetic noise of 0.99 nT/rt Hz at 1 Hz in the presence of a DC magnetic field of 0.1 Tesla and a great common mode noise rejection ability. A prototype magnetoelectric liver susceptometry has been demonstrated with liver phantoms. The results indicate its output signals to be linearly responsive to iron concentrations from normal iron dose (0.05 mg Fe/g liver phantom) to 5 mg Fe/g liver phantom iron overload (100X overdose). The results here open up many innovative possibilities for compact-size, portable, cost-affordable, and room-temperature operated medical systems for quantitative determinations of tissue iron.

An Ultrasensitive Magnetoelectric Sensor System For the Quantitative Detection of Liver Iron.

Ultrasensitive magnetoelectric (ME) sensors have been developed using magnetostrictive/piezoelectric laminate heterostructures. This paper discusses a highly interdisciplinary design of a room temperature biomagnetic liver susceptometry system (BLS) based on the ME sensors. The ME-sensor based BLS maintains the ultrahigh sensitivity to detect the weak AC biomagnetic signals and introduces a low equivalent magnetic noise. The results reveal a "turning point" and successfully indicate the output signals to be linearly responsive to iron concentrations from normal iron level (0.05 mgFe/gliver phantom) to 5 mgFe/gliver phantom iron overload level (100X overdose). Further, the introduction of the water-bag technique shows the promise on the automatic deduction of the background (tissue) signal, enabling an even higher sensitivity and better signal-to-noise (SNR). With these improvements, it becomes feasible to get improved characterization flexibility and the field distribution mapping potential via signal processing from the correlations of multiple sensors in the system. Considering the wide presence of biomagnetic signals in human organs, the potential impact of such biomagnetic devices on medicine and health care could be enormous and far-reaching.