RESUMEN
DP303c is a HER2-targeted ADC with a cleavable linker-MMAE payload. Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. This was a multicenter, dose escalation and dose expansion phase 1 study in China. Eligible patients were 18-75 years old with HER2-positive advanced solid tumors who were unable to benefit from standard therapy. DP303c was administered intravenously every 3 weeks, with accelerated titration at lower dose of 0.5 mg/kg and 3 + 3 design with dose levels of 1.0, 2.0, 3.0 or 4.0 mg/kg at dose escalation part, followed by the selected dose level at dose expansion part. The primary endpoints were safety and tolerability, as well as identification of recommended phase 2 dose. As of Feb 28, 2023, 94 patients were enrolled and received DP303c (dose escalation: n = 22; dose expansion: n = 72), of whom 68 patients had breast cancer. One dose limiting toxicity (Grade 3 eye pain) was observed at 4.0 mg/kg dose, and the maximum tolerated dose was not reached. The most common treatment-related adverse events at grade 3 or higher were blurred vison (16.0%), dry eye (6.4%), and peripheral neuropathy (5.3%). No treatment-related death occurred. Overall, among 91 efficacy evaluable patients, 39 patients (42.9%) achieved an objective response. Disease control was observed in 62 patients (68.1%). In 66 efficacy evaluable patients with breast cancer, 34 patients achieved an objective response (51.5%). Disease control was achieved in 51 patients (77.3%). Median PFS was 6.4 months. On a molar basis, DP303c Cmax at 3.0 mg/kg doses was 132-folder higher than that for free MMAE. DP303c demonstrated promising anti-tumor activity with acceptable safety in patients with pre-treated advanced HER2 positive solid tumors, especially in breast cancer. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610).
RESUMEN
Zinc finger protein 281 (ZNF281) has been shown to promote tumor progression. However, the underlying mechanism remains to be further elucidated. In this study, ZNF281 knockdown increased the expression of mitochondrial transcription factor A (TFAM) in hepatocellular carcinoma (HCC) cells, accompanied with increment of mitochondrial content, oxygen consumption rate (OCR) and levels of TCA cycle intermetabolites. Mechanistic investigation revealed that ZNF281 suppressed the transcription of TFAM, nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Furthermore, ZNF281 interacted with NRF1 and PGC-1α, and was recruited onto the promoter regions of TFAM, TFB1M and TFB2M repressing their expression. Knockdown of TFAM reversed ZNF281 depletion induced up-regulation of mitochondrial biogenesis and function, as well as impaired epithelial mesenchymal transition, invasion and metastasis of HCC cells. Our research uncovered a novel suppressive function of ZNF281 on mitochondrial biogenesis through inhibition of the NRF1/PGC-1α-TFAM axis, which may hold therapeutic potentials for HCC.
RESUMEN
Objective: To investigate the involvement and transcriptional targets of zinc finger protein 281 (ZNF281) in the progression of hepatocellular carcinoma (HCC). Methods: The expression of ZNF281 in HCC was detected in tissue microarray and cell lines. The role of ZNF281 in aggressiveness of HCC was examined using wound healing, matrigel transwell, pulmonary metastasis model and assays for expression of EMT markers. RNA-seq was used to find potential target gene of ZNF281. Chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (Co-IP) were employed to uncover the mechanism of the transcriptional regulation of ZNF281 on the target gene. Results: ZNF281 was increased in tumor tissues and positively correlated with vascular invasion in HCC. Knockdown of ZNF281 suppressed the migration and invasion with significant alteration of EMT marker expression in HLE and Huh7 HCC cell lines. RNA-seq screening showed that the tumor suppressor gene Annexin A10 (ANXA10) was a most up-regulated gene in response to ZNF281 depletion and responsible for the attenuation of aggressiveness. Mechanistically, ZNF281 interacted with the ANXA10 promoter region harboring ZNF281 recognition sites, and recruited components of nucleosome remodeling and deacetylation (NuRD) complex. By knocking down such components like HDAC1 or MTA1, ANXA10 was released from transcriptional repression by ZNF281/NuRD, and in turn reversed the EMT, invasion and metastasis driven by ZNF281. Conclusion: ZNF281 drives invasion and metastasis of HCC partially through transcriptional repression of tumor suppressor gene ANXA10 by recruiting NuRD complex.
RESUMEN
Anatase/rutile titanium dioxide (TiO2) with heterophase junction and large Brunauer-Emmett-Teller (BET) specific surface area (50.1 m2 g-1) is successfully synthesized by calcinating Materials of Institut Lavoisier-125(Ti) (MIL-125(Ti)) with 30% O2/Ar at the temperature of 600 °C (M-O-600). Several techniques are used to examine the physicochemical, photoelectrochemical and optical properties of samples, and their photocatalytic performances are evaluated by photodegradation of gaseous toluene and liquidus tetracycline (TC) under visible light illumination. It is found that the calcination temperature has significant influence on the crystal structure and physicochemical parameters of TiO2. The weight fractions of rutile and anatase TiO2 of M-O-600 are approximately 0.7 and 0.3, which displays outstanding photocatalytic activity. Through the construction of heterophase junction, M-O-600 has better oxygen adsorption and higher density of localized states, which effectively promotes the generation of superoxide radical (·O2-) and hydroxyl radical (·OH) species. In-situ infrared spectra indicate that toluene is oxidized to benzyl alcohol, benzaldehyde and benzoic acid in turn and then oxidized to formic acid and acetic acid before eventually degraded into H2O and CO2. Gas chromatography-mass spectrometry (GC-MS) is also used to further investigate the degradation pathway of toluene. Degradation pathway and mechanism of TC are studied by liquid chromatography-tandem mass spectrometry (LC-MS). Moreover, three-dimensional excitation-emission matrix fluorescence spectroscopy (3D EEMs) and total organic carbon (TOC) show that TC can be effectively mineralized through a series of reactions by M-O-600 during photocatalysis.
RESUMEN
The uniform tablet-like TiO2/C nanocomposites with two crystal types (rutile and anatase) and large specific surface area (438 m2 g-1) were successfully prepared by Materials of Institut Lavoisier-125(Ti) (MIL-125(Ti)) calcined at a suitable temperature and applied for photocatalytic tetracycline (TC). The nanocomposites were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM) and mapping, N2 adsorption-desorption isotherms, photoluminescence spectra (PL), photocurrent, and X-ray photoelectron spectroscopy (XPS). The changes of physicochemical parameters are discussed in detail. It is found that nanocomposite through suitable calcination temperature (M-A-800) with large surface area and appropriate micropore/mesopore ratio could strengthen separation and migration rates of photo-generated charge, resulting in the improvement of visible light photocatalytic activity of tetracycline, and exhibited about 2.0 times quicker than that of MIL-125(Ti). In addition, M-A-800 displayed favourable reusability and stability in four circulation tests. Finally, the reaction mechanism of photocatalyst and photodegradation pathway of tetracycline was also proposed. O2- was the most important active species, and dehydroxylation and decarboxylation were the main photodegradation pathway of tetracycline.