Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma.

Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments. Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide. Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model. Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.

Ascending aorta dilatation reduces the influence of elevated pulse pressure on left ventricular hypertrophy: findings from a Chinese elderly hypertensive population.

OBJECTIVE: To determine the role of ascending aorta dilatation in the relationship between pulse pressure (PP) and left ventricular (LV) hypertrophy. METHODS: A total of 1556 Chinese elderly hypertensive patients were retrospectively studied. Transthoracic echocardiography was used to obtain the aortic and cardiac structure measurements. In addition, brachial blood pressure was measured, and total arterial compliance, systemic vascular resistance, arterial elastance, and end-systolic LV elastance were calculated. The participants were divided into four groups according to the status of ascending aortic diameter and PP. RESULTS: LV mass index increased in succession in the four groups, i.e., the group with the normal aorta and lower PP, with the normal aorta and higher PP, with aortic dilatation and lower PP, and with aortic dilatation and higher PP (P trend < 0.001). Total arterial compliance-1, arterial elastance, and end-systolic LV elastance were slightly higher in the individuals with normal aorta compared to those with aortic dilatation, regardless of PP being lower or higher (P < 0.01). Compared to the group with the normal aorta and lower PP, individuals with aortic dilatation had a significantly increased multivariable adjusted risk of LV hypertrophy, and higher PP further exacerbated this risk [aortic dilatation with lower PP (OR = 1.75, 95% CI: 1.01-3.04) and aortic dilatation with higher PP (OR = 3.42, 95% CI: 2.03-5.77)]. In the relation between PP and LV mass index (ß = 0.095, P < 0.001), -41.3% of the total effect was attributable to mediation by ascending aortic diameter (P < 0.0001). CONCLUSIONS: In Chinese elderly patients with hypertension, ascending aorta dilatation could reduce the influence of elevated PP on LV hypertrophy.

Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 drug transport.

Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR). There is an immense demand for development of novel agents that can overcome the MDR in cancer. A group of transmembrane proteins called ATP-binding cassette transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR. An analysis of structural congeners among a group of compounds led to the discovery of CCTA-1523 that could selectively reverse ABCG2-mediated MDR in cancer cells in vitro and in vivo. CCTA-1523 (5µM) sensitized the ABCG2 overexpressing cancer cells and ABCG2 transfected cells to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the efflux function of ABCG2; also there was no change in the protein expression or the localization of the ABCG2 in the presence of CCTA-1523. The reversal effect of CCTA-1523 was reversible. Importantly, co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts. Taken together, our findings indicate that CCTA-1523 is a potent, selective and reversible modulator of ABCG2 that may offer therapeutic promise for multidrug- resistant malignancies.

Multi-substituted N-phenyl-2, 2-dichloroacetamide analogues as anti-cancer drugs: design, synthesis and biological evaluation.

Our earlier research has shown that mono-substituted N-phenyl-2, 2-dichloroacetamide exhibited much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this paper, a variety of multi-substituted N-phenyl-2, 2-dichloroacetamides were synthesized and biologically evaluated. The results showed that 3, 5-disubstituted N-phenyl-2, 2-dichloroacetamide analogues had satisfactory potency. Among them, N-(3, 5-diiodophenyl)-2, 2-dichloroacetamide had an IC50 of 2.84 micromol x L(-1) against non-small cell lung cancer cell line A549 and could induce cancer cell apoptosis.