Efficacy of c-Met inhibitor for advanced prostate cancer

<p>Abstract</p> <p>Background</p> <p>Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.</p> <p>Methods</p> <p>We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.</p> <p>Results</p> <p>We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.</p> <p>Conclusions</p> <p>The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.</p

Application of Triboelectric Nanogenerator in Fluid Dynamics Sensing: Past and Future

The triboelectric nanogenerator (TENG) developed by Z. L. Wang’s team to harvest random mechanical energy is a promising new energy source for distributed sensing systems in the new era of the internet of things (IoT) and artificial intelligence (AI) for a smart world. TENG has many advantages that make it suitable for a wide range of applications, including energy harvesting, environmental protection, wearable electronics, robotics, and self-powered sensors. Sensing as an important part of TENG applications is gradually expanding, with the in-depth study of TENG sensing in its working principle, material selection, processing technology, system integration, surface treatment, and back-end algorithms by researchers. In industry and academia, fluid dynamics sensing for liquid and air is urgently needed but lacking. In particular, local fluid sensing is difficult and limited to traditional sensors. Fortunately, with advantages for ordinary TENGs and TENGs as fluid dynamics sensors, fluid dynamics sensing can be better realized. Therefore, the paper summarizes the up-to-date work on TENGs as fluid dynamics sensors, discusses the advantages of TENGs as fluid dynamics sensors in-depth, and, most importantly, aims to explore possible new key areas to help guide the future direction of TENG in fluid dynamics sensing by addressing the key challenges

Phrenic nerve neurotization of the musculocutaneous nerve with end-to-side neurorrhaphy: A short report in a rabbit model

This experimental study was performed to evaluate the efficacy of end-to-side coaptation between the musculocutaneous nerve and the phrenic nerve for brachial plexus injuries with nerve-root avulsions. In an experimental rabbit model, neurotization of the musculocutaneous nerve with the phrenic nerve was compared using end-to-end and end-to-side neurorrhaphy. Preliminary results from electrophysiologic and histologic examinations indicate that end-to-side neurotization of the musculocutaneous nerve with the phrenic nerve is an effective means for musculocutaneous nerve repair. The effectiveness of the phrenic nerve is attributed to its large number of motor axons. (c) 2006 Wiley-Liss, Inc

Long-term evaluation of rabbit peripheral nerve repair with end-to-side neurorrhaphy in rabbits

This study was designed to quantitatively assess long-term end-to-side neurorrhaphy in rabbits. The cut right ulnar nerve was repaired and sutured to the median nerve, in which a perineurial window was created in an end-to-side fashion 3 cm above the elbow joint. Both the extent of the reinnervation and the integrity of the intact donor nerve were evaluated in 36 rabbits randomly treated with fresh or delayed nerve repair. Evaluations included motor nerve conduction velocity (MNCV), dry muscle weight (DMW), and histological examinations at 9 and 12 months postoperatively. The recovery rates of MNCV were 90.1% and 92.8% for the ulnar nerve, and 95.7% and 96.8% for the median nerve, compared to intact contralateral nerves at 9 and 12 months, respectively. MNCV was not detectable for the ulnar nerve in control animals, while it was normal for the median nerve. Recoveries of flexor carpi ulnaris dry muscle weight of about 90.7% and 94.5% were observed at 9 and 12 months postoperatively, respectively. However, muscle mass measurements revealed a recovery of only 31.3% and 27% for control groups at 9 and 12 months postoperatively. The differences between experimental groups and control groups were statistically significant (P &lt; 0.01). Neurofilament and silver stains showed numerous sprouting axons originating from the median nerve to the ulnar nerve. The results indicate that end-to-side neurorrhaphy could induce axonal sprouting from the main nerve trunk of upper limbs in rabbits, leading to useful functional recovery. (c) 2006 Wiley-Liss, Inc

Repair of the main nerve trunk of the upper limb with end-to-side neurorrhaphy: An experimental study in rabbits

The aim of this study was to assess the effectiveness of reinnervation using end-to-side neurorrhaphy in the upper extremity of the rabbit. The cut right ulnar nerve was repaired and sutured to the side of the median nerve about 3 cm above the elbow joint. The extent of reinnervation was quantitatively evaluated, as well as the integrity of the intact donor nerve in 36 rabbits randomly treated with fresh or delayed nerve repair with or without perineurotomy. Evaluations included nerve conduction velocity (NCV) of both the ulnar and medial nerves, dry muscle weight, and histologic examination (neurofilament stain and morphometric assessment) at 3 and 6 months postoperatively. NCV recovery rates were 79% and 87% for the ulnar nerve, and 89% and 94% for the median nerve compared to contralateral intact nerves, at 3 and 6 months, respectively Flexor carpi ulnaris muscle mass measurements revealed a recovery in dry muscle weight of about 81% and 88% at 3 and 6 months, respectively, compared to the intact contralateral flexor carpi ulnaris. Histologic studies with neurofilament staining reveal numerous axonal sprouts at the distal end of the median nerve, indicative of myelinated axonal regeneration. Morphometric analysis demonstrated no difference between fresh and delayed repairs. These results indicate that in the upper extremity of rabbits, end-to-side neurorrhaphy permits axonal regeneration from the intact donor nerve, and is associated with satisfactory recovery. The effect of the procedure on the donor nerve was negligible. (c) 2006 Wiley-Liss, Inc

Current treatment concepts for neuromas-in-continuity

A neuroma-in-continuity is a neuroma that results from failure of the regenerating nerve growth cone to reach peripheral targets. It occurs within an intact nerve in response to internally damaged fascicles, resulting in a distal portion of the nerve that no longer functions property. Management of neuromas-in-continuity is challenging. Chemical methods, and microsurgical techniques including fascicular ligation, and burying into muscle and bone have been reported to prevent neuroma-in-continuity formation. The purpose of this article is to present novel techniques for neuroma-in-continuity management, and to discuss the related literature. (C) 2008 Elsevier Ltd. All rights reserved

Unraveling the Rich Fragmentation Dynamics Associated with S–H Bond Fission Following Photoexcitation of H₂S at Wavelengths ∼129.1 nm

H2S is being detected in the atmospheres of ever more interstellar bodies, and photolysis is an important mechanism by which it is processed. Here, we report H Rydberg atom time-of-flight measurements following the excitation of H2S molecules to selected rotational (JKaKc′) levels of the 1B1 Rydberg state associated with the strong absorption feature at wavelengths of λ ∼ 129.1 nm. Analysis of the total kinetic energy release spectra derived from these data reveals that all levels predissociate to yield H atoms in conjunction with both SH(A) and SH(X) partners and that the primary SH(A)/SH(X) product branching ratio increases steeply with ⟨Jb2⟩, the square of the rotational angular momentum about the b-inertial axis in the excited state. These products arise via competing homogeneous (vibronic) and heterogeneous (Coriolis-induced) predissociation pathways that involve coupling to dissociative potential energy surfaces (PES(s)) of, respectively, 1A″ and 1A′ symmetries. The present data also show H + SH(A) product formation when exciting the JKaKc′ = 000 and 111 levels, for which ⟨Jb2⟩ = 0 and Coriolis coupling to the 1A′ PES(s) is symmetry forbidden, implying the operation of another, hitherto unrecognized, route to forming H + SH(A) products following excitation of H2S at energies above ∼9 eV. These data can be expected to stimulate future ab initio molecular dynamic studies that test, refine, and define the currently inferred predissociation pathways available to photoexcited H2S molecules

Molecular and Serological Surveillance for Mycobacterium leprae and Mycobacterium lepromatosis in Wild Red Squirrels (Sciurus vulgaris) from Scotland and Northern England

Leprosy is a poverty-associated infectious disease in humans caused by Mycobacterium leprae or M. lepromatosis, often resulting in skin and peripheral nerve damage, which remains a significant public health concern in isolated areas of low- and middle-income countries. Previous studies reported leprosy in red squirrels in the British Isles, despite the fact that autochthonous human cases have been absent for centuries in this region. To investigate the extent of M. leprae and M. lepromatosis presence in wild red squirrels in the northern UK, we analyzed 220 blood/body cavity fluid samples from opportunistically sampled red squirrels (2004–2023) for specific antibodies against phenolic glycolipid-I, a cell wall component specific for these leprosy bacilli. Additionally, we assessed bacillus-derived DNA by real-time PCR (qPCR) in 250 pinnae from the same cohort. M. lepromatosis and M. leprae DNA were detected by qPCR in 20.4% and 0.8% of the squirrels, respectively. No cases of co-detection were observed. Detectable levels of anti-PGL-I antibodies by UCP-LFA were observed in 52.9% of animals with the presence of M. lepromatosis determined by qPCR, and overall in 15.5% of all animals. In total, 22.6% (n = 296) of this UK cohort had at least some exposure to leprosy bacilli. Our study shows that leprosy bacilli persist in red squirrels in the northern UK, emphasizing the necessity for ongoing molecular and serological monitoring to study leprosy ecology in red squirrels, gain insight into potential zoonotic transmission, and to determine whether the disease has a conservation impact on this endangered species