Anticancer Activity of Sunitinib Analogues in Human Pancreatic Cancer Cell Cultures under Normoxia and Hypoxia

Pancreatic cancer remains one of the deadliest cancer types. It is usually characterized by high resistance to chemotherapy. However, cancer-targeted drugs, such as sunitinib, recently have shown beneficial effects in pancreatic in vitro and in vivo models. Therefore, we chose to study a series of sunitinib derivatives developed by us, that were proven to be promising compounds for cancer treatment. The aim of our research was to evaluate the anticancer activity of sunitinib derivatives in human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 under normoxia and hypoxia. The effect on cell viability was determined by the MTT assay. The compound effect on cell colony formation and growth was established by clonogenic assay and the activity on cell migration was estimated using a 'wound healing' assay. Six out of 17 tested compounds at 1 mu M after 72 h of incubation reduced cell viability by 90% and were more active than sunitinib. Compounds for more detailed experiments were chosen based on their activity and selectivity towards cancer cells compared to fibroblasts. The most promising compound EMAC4001 was 24 and 35 times more active than sunitinib against MIA PaCa-2 cells, and 36 to 47 times more active against the PANC-1 cell line in normoxia and hypoxia. It also inhibited MIA PaCa-2 and PANC-1 cell colony formation. Four tested compounds inhibited MIA PaCa-2 and PANC-1 cell migration under hypoxia, but none was more active than sunitinib. In conclusion, sunitinib derivatives possess anticancer activity in human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cell lines, and they are promising for further research

Interferometric length metrology for the dimensional control of ultra-stable Ring Laser Gyroscopes

We present the experimental test of a method for controlling the absolute length of the diagonals of square ring laser gyroscopes. The purpose is to actively stabilize the ring cavity geometry and to enhance the rotation sensor stability in order to reach the requirements for the detection of the relativistic Lense-Thirring effect with a ground-based array of optical gyroscopes. The test apparatus consists of two optical cavities 1.32 m in length, reproducing the features of the ring cavity diagonal resonators of large frame He-Ne ring laser gyroscopes. The proposed measurement technique is based on the use of a single diode laser, injection locked to a frequency stabilized He-Ne/Iodine frequency standard, and a single electro-optic modulator. The laser is modulated with a combination of three frequencies allowing to lock the two cavities to the same resonance frequency and, at the same time, to determine the cavity Free Spectral Range (FSR). We obtain a stable lock of the two cavities to the same optical frequency reference, providing a length stabilization at the level of 1 part in $10^{11}$, and the determination of the two FSRs with a relative precision of 0.2 ppm. This is equivalent to an error of 500 nm on the absolute length difference between the two cavities

Rotational sensitivity of the "G-Pisa" gyrolaser

G-Pisa is an experiment investigating the possibility to operate a high sensitivity laser gyroscope with area less than $1 \rm m^2$ for improving the performances of the mirrors suspensions of the gravitational wave antenna Virgo. The experimental set-up consists in a He-Ne ring laser with a 4 mirrors square cavity. The laser is pumped by an RF discharge where the RF oscillator includes the laser plasma in order to reach a better stability. The contrast of the Sagnac fringes is typically above 50% and a stable regime has been reached with the laser operating both single mode or multimode. The effect of hydrogen contamination on the laser was also checked. A low-frequency sensitivity, below $1 \rm Hz$, in the range of $10^{-8} \rm {(rad / s)/ \sqrt{Hz}}$ has been measured.Comment: 6 pages, 6 figures, presented at the EFTF-IFCS joint conference 200

Developing fiber lasers with Bragg reflectors as deep sea hydrophones

The present paper will discuss the work in progress at the Department of Physics of the University of Pisa in collaboration with the IFAC laboratory of CNR in Florence to develop pressure sensors with outstanding sensitivity in the acoustic and ultrasonic ranges. These devices are based on optically-pumped fiber lasers, where the mirrors are Bragg gratings written into the fiber core

A high sensitivity tool for geophysical applications: A geometrically locked Ring Laser Gyroscope

This work demonstrates that a middle size ring laser gyroscope (RLG) can be a very sensitive and robust instrument for rotational seismology, even if it operates in a quite noisy environment. The RLG has a square cavity, $1.60\times 1.60$ m$^2$, and it lies in a plane orthogonal to the Earth rotational axis. The Fabry-Perot optical cavities along the diagonals of the square were accessed and their lengths were locked to a reference laser. Through a quite simple locking circuit, we were able to keep the sensor fully operative for 14 days. The obtained long term stability is of the order of 3~nanorad/s and the short term sensitivity close is to 2~nanorad/s$\cdot$Hz$^{-1/2}$. These results are limited only by the noisy environment, our laboratory is located in a building downtown.Comment: 9 pages, 4 figures, 25 reference

5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action

In the effort to identify and develop new HIV-1 inhibitors endowed with innovative mechanisms, we focused our attention on the possibility to target more than one viral encoded enzymatic function with a single molecule. In this respect, we have previously identified by virtual screening a new indolinone-based scaffold for dual allosteric inhibitors targeting both reverse transcriptase-associated functions: polymerase and RNase H. Pursuing with the structural optimization of these dual inhibitors, we synthesized a series of 35 new 3-[2-(4-aryl-1,3-thiazol-2-ylidene)hydrazin-1-ylidene]1-indol-2-one and 3-[3-methyl-4-arylthiazol-2-ylidene)hydrazine-1-ylidene)indolin-2-one derivatives, which maintain their dual inhibitory activity in the low micromolar range. Interestingly, compounds 1a, 3a, 10a, and 9b are able to block HIV-1 replication with EC50 < 20 µM. Mechanism of action studies showed that such compounds could block HIV-1 integrase. In particular, compound 10a is the most promising for further multitarget compound development

Length measurement and stabilization of the diagonals of a square area laser gyroscope

Large frame ring laser gyroscopes are top sensitivity inertial sensors able to measure absolute angular rotation rate below prad s-1 in few seconds. The GINGER project is aiming at directly measuring the Lense-Thirring effect with an 1% precision on an Earth based experiment. GINGER is based on an array of large frame ring laser gyroscopes. The mechanical design of this apparatus requires a micrometric precision in the construction and the geometry must be stabilized in order to keep constant the scale factor of the instrument. The proposed control is based on square cavities, and relies on the length stabilization of the two diagonals, which must be equal at micrometric level. GP2 is the prototype devoted to the scale factor control test. As a first step, the lengths of the diagonals of the ring cavity have been measured through an interferometric technique with a statistical accuracy of some tens of nanometers, and they have been locked to the wavelength of a reference optical standard. Continuous operation has been obtained over more than 12 h, without loss of sensitivity. GP2 is located in a laboratory with standard temperature stabilization, with residual fluctuations of the order of 1 C. Besides the demonstration of the control effectiveness, the analysis of the Sagnac frequency demonstrates that relative small and low-cost ring lasers (around one meter of side) can also achieve a sensitivity of the order of nrad s-1 in the range 0.01-10 Hz in a standard environment, which is the target sensitivity in many different applications, such as rotational seismology and next generation gravitational waves detectors