[Contribution of central motion conduction time to the assessment of corticospinal tract lesions and its clinical significance].

Objective: To investigate the association of central motion conduction time (CMCT) with corticospinal tract lesions and its clinical application. Methods: Patients who completed transcranial magnetic stimulation-motor evoked potentials were included from Department of Neurology, Xuanwu Hospital between June 2020 and June 2021. The differences of CMCT values between corticospinal tract sign-positive group and tendon reflex-positive group and the relevant negative groups were compared. The consistency between increased CMCT values and the positive signs of corticospinal tract damage, as well as the significance of CMCT in different neurological diseases were further evaluated. Results: A total of 271 patients were included in the study, aged 12-86 (49±16) years, with 137 males (50.55%) and 134 females (49.45%). The CMCT valuesï¼»M（Q1，Q3）］from Hoffmann's sign-positive group [9.52 (8.54, 10.99) ms vs 9.03 (8.30, 9.53) ms], Babinski's sign-positive group [19.54 (16.97, 24.43) ms vs 16.85(15.63, 18.55) ms] and tendon reflex-positive group [15.38 (9.27, 19.28) ms vs 10.49(8.79, 16.60) ms] were larger than those of relevant negative groups (all P<0.01). In the Babinski sign-positive group, 78.01%(181/232) of the patients had increased CMCT, while in the Hoffmann's sign-positive group, only 26.03%(19/73) of the patients had increased CMCT, indicating that the contribution of CMCT from the lower extremities to the assessment of corticospinal tract lesions was better than that of the upper extremities. With the increase of CMCT values in lower limbs, Babinski sign positive rate increased, the difference was statistically significant(P<0.001). In nervous system diseases, the consistency between CMCT and pathological signs was 75.65% (205/271). Conclusions: The contribution of CMCT from the lower extremities to the assessment of corticospinal tract lesions is superior to that of upper limbs. The higher increase of CMCT values are more reliable for corticospinal tract damage. CMCT has a good concordance with corticospinal tract lesions in some neurological diseases, which can be used to assist clinical diagnosis.

Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy.

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin ß3 is another potential target for combination treatment with SAIT301. Suppression of integrin ß3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin ß3 are resistant to crizotinib treatment, suggesting that FGFR and integrin ß3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody.

The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.

RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression.

PURPOSE: Previously, we reported a causal relationship between RUNX3 methylation and bladder tumor development. Thus, in order to clarify its role in tumorigenesis, this study aims to identify the function of RUNX3 methylation in normal adjacent urothelium of patients with non-muscle invasive bladder cancer (NMIBC). METHODS: Tumor tissue and donor-matched normal adjacent tissue from 55 patients who underwent transurethral resection (TUR) were selected for the study, and RUNX3 promoter methylation was assessed using methylation-specific polymerase chain reaction (MS-PCR). RESULTS: RUNX3 promoter methylation occurred more frequently in tumor samples than in histologically normal urothelium in patients with NMIBC (P = 0.02). The methylation rates for the RUNX3 promoter in normal adjacent urothelium and tumor tissue were 47% and 69%, respectively. Interestingly, RUNX3 methylation in normal adjacent urothelium was associated with tumor number (P = 0.022) and progression (P = 0.035). Kaplan-Meier estimates revealed that RUNX3 methylation in normal urothelium showed a significant association with time to progression (P = 0.017) in NMIBC patients. Stratifying the patients into 'both methylation', 'one methylation' and 'no methylation' groups for tumors and normal urothelium revealed that no progression occurred in the 'no methylation' group during follow-up. Multivariate Cox regression analysis demonstrated that RUNX3 methylation in normal urothelium [hazards ratio (HR): 5.692, P = 0.042] was an independent predictor of progression. CONCLUSIONS: RUNX3 methylation was associated with transition from normal urothelium to bladder tumor. More importantly, RUNX3 methylation in normal adjacent urothelium may predict progression in NMIBC patients who have undergone TUR.

Using a three-dimension head mounted displayer in audio-visual sexual stimulation aids in differential diagnosis of psychogenic from organic erectile dysfunction.

We designed this study to compare the efficacy of using a three-dimension head mounted displayer (3-D HMD) and a conventional monitor in audio-visual sexual stimulation (AVSS) in differential diagnosis of psychogenic from organic erectile dysfunction (ED). Three groups of subjects such as psychogenic ED, organic ED, and healthy control received the evaluation. The change of penile tumescence in AVSS was monitored with Nocturnal Electrobioimpedance Volumetric Assessment and sexual arousal after AVSS was assessed by a simple question as being good, fair, or poor. Both the group of healthy control and psychogenic ED demonstrated a significantly higher rate of normal response in penile tumescence (P<0.05) and a significantly higher level of sexual arousal (P<0.05) if stimulated with 3-D HMD than conventional monitor. In the group of organic ED, even using 3-D HMD in AVSS could not give rise to a better response in both assessments. Therefore, we conclude that using a 3-D HMD in AVSS helps more to differentiate psychogenic from organic ED than a conventional monitor in AVSS.

Quantum computing of quantum chaos and imperfection effects.

We study numerically the imperfection effects in the quantum computing of the kicked rotator model in the regime of quantum chaos. It is shown that there are two types of physical characteristics: for one of them the quantum computation errors grow exponentially with the number of qubits in the computer, while for the other the growth is polynomial. A certain similarity between classical and quantum computing errors is also discussed.

Hepatitis D virus infection in liver tissues of patients with hepatitis B in China.

2,346 liver samples from 17 cities of China for intrahepatic hepatitis D antigen (HDAg) were studied by direct enzyme-labelled technique. HDAg was detected in 167 out of 1,764 samples of HBsAg positive individuals making a detection rate of 9.47%. Hepatitis D virus (HDV) infection existed in all the examined districts with no significant difference in the HDAg detection rate. It was found that the intrahepatic HDAg detection rate was related to the pathologic type of the liver disease. The HDAg detection rate in chronic liver diseases and severe hepatitis was higher than in other liver diseases. It suggests that HDV infection is associated with the progression and chronicity of the liver disease. Studies on the relationship between HDV infection and HBV replication showed that HBV replication might be suppressed by HDV infection. Both HDV and HBV, however, could replicate in the same hepatocyte simultaneously.

Analysis of antigenic polypeptides of Dane particles and antibody response ability of HBV infected subjects to PreS1 polypeptides.

We demonstrated the constitutive polypeptides (PP) of Dane particles employing Western Blot and investigated the antibody response ability of HBV infected subjects to PreS1 PP in comparison with other serum markers from HBV infected individuals. The results indicated that 1) the major reason for discrepant results may be related to the detergents used in the sample solutions and the degree of denaturation the samples had undergone; 2) there are 12 bands in the PAGE-graph of Dane particles. By Western Blot it was confirmed that 5 PP (P24, P27, P36, P39, P42) are derived from S-open reading frame (S-ORF), P21 is associated with C-ORF, P24-25 possesses some epitopes of Pol protein, and P45 and P76 express similar epitopes to human IgG and IgM; and 3) the prevalence of anti-PreS1 PP was 17.24% in the group of healthy persons following latent HBV infection, much higher than that of HBV infected patients (1.21%). The above findings imply that antibody response ability of the host to PreS1 PP is attributing to the outcome of HBV infection. It may play an important role in the elimination of the virus.

A study on hepatitis D virus infection in liver tissues of patients with hepatitis B in China.

2346 liver samples from 17 areas in China were investigated for intrahepatic hepatitis D antigen (HDAg) by direct enzyme-labelled technique. HDAg was detected in 167 out of 1764 samples of HBsAg positive individuals with the detection rate of 9.47%. Hepatitis D virus (HDV) infection existed in all the examined areas without any significant difference regarding HDAg detection rate. A relationship of intrahepatic HDAg to the pathologic type of the liver disease was observed. The HDAg detection rate in chronic liver diseases and severe hepatitis was higher than in other liver diseases. It suggested that HDV infection was associated with the progression and chronicity of the liver disease. Studies on the relationship between HDV infection and HBV replication showed that HBV replication might be suppressed by HDV infection. Both HDV and HBV, however, could replicate in the same hepatocyte simultaneously.