HRD effects on first-line adjuvant chemotherapy and PARPi maintenance therapy in Chinese ovarian cancer patients.

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large retrospectively collected Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526-0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423-0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs. 12 months; HR, 0.438; 95% CI, 0.201-0.957; P = 0.033) and OS (median, NA vs. NA months; HR, 0.12; 95% CI, 0.029-0.505; P = 0.001). Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.

Docosahexaenoic Acid Ester of Phloridzin Reduces Inflammation and Insulin Resistance via AMPK.

BACKGROUND: Docosahexaenoic acid-acylated phloridzin (PZ-DHA), a novel polyphenol fatty acid ester derivative, is synthesized through an acylation reaction of phloridzin (PZ) and docosahexaenoic acid (DHA). PZ-DHA is more stable than DHA and exhibits higher cellular uptake and bioavailability than PZ. OBJECTIVE: The study aims to investigate the effects of PZ-DHA on insulin resistance in the skeletal muscle and the related mechanisms; we used palmitic acid (PA)-treated C2C12 myotubes as an insulin resistance model. RESULTS: We found that PZ-DHA increased the activity of AMP-activated protein kinase (AMPK) and improved glucose uptake and mitochondrial function in an AMPK-dependent manner in untreated C2C12 myotubes. PZ-DHA treatment of the myotubes reversed PA-induced insulin resistance; this was indicated by increases in glucose uptake and the expression of membrane glucose transporter 4 (Glut4) and phosphorylated Akt. Moreover, PZ-DHA treatment reversed PA-induced inflammation and oxidative stress. These effects of PZ-DHA were mediated by AMPK. Furthermore, the increase in AMPK activity, improvement in insulin resistance, and decrease in inflammatory and oxidative responses after PZ-DHA treatment diminished upon co-treatment with a liver kinase B1 (LKB1) inhibitor, suggesting that PZ-DHA improved AMPK activity by regulating its upstream kinase, LKB1. CONCLUSION: The effects of PZ-DHA on insulin resistance in C2C12 myotubes may be mediated by the LKB1- AMPK signaling pathway. Hence, PZ-DHA is a promising therapeutic agent for insulin resistance in type 2 diabetes.

A General Synthesis Strategy for Hollow Metal Oxide Microspheres Enabled by Gel-Assisted Precipitation.

Hollow metal oxide microspheres (HMMs) have drawn enormous attention in different research fields. Reliable and scalable synthetic protocols applicable for a large variety of metal oxides are in emergent demand. Here we demonstrated that polymer hydrogel, such as the resorcinol formaldehyde (RF) one, existed as an efficient synthetic platform to build HMMs. Specifically, the RF gel forms stacked RF microspheres enlaced with its aqueous phase, where the following evaporation of the highly dispersed water leads to a gel-assisted precipitation (GAP) of the dissolved metal precursor onto the embedded polymeric solids suited for the creation of HMMs. By taking advantage of the structural features of hydrogel, this synthesis design avoids the delicate control on the usually necessitated coating process and provides a simple and effective synthetic process versatile for functional HMMs, particularly Nb2 O5 as a high-performance electrode material in Li-ion intercalation pseudocapacitor.

Early Interdisciplinary Supportive Care in Patients With Previously Untreated Metastatic Esophagogastric Cancer: A Phase III Randomized Controlled Trial.

PURPOSE: Effective interventions to improve prognosis in metastatic esophagogastric cancer (EGC) are urgently needed. We assessed the effect of the early integration of interdisciplinary supportive care for patients with metastatic EGC on overall survival (OS). PATIENTS AND METHODS: An open-label, phase III, randomized, controlled trial was conducted at Peking University Cancer Hospital & Institute. Patients with previously untreated metastatic EGC were enrolled. Patients were randomly assigned (2:1) to either early interdisciplinary supportive care (ESC) integrated into standard oncologic care or standard care (SC). ESC was provided by a team of GI medical oncologists, oncology nurse specialists, dietitians, and psychologists; patients in the SC group received standard oncologic care alone. The primary end point was OS in the intention-to-treat population. RESULTS: Between April 16, 2015, and December 29, 2017, 328 patients were enrolled: 214 in the ESC group and 114 in the SC group. At the data cutoff date of January 26, 2019, 15 (5%) patients were lost to follow-up. The median number of cycles of first-line chemotherapy was five (interquartile range [IQR], 4-7) in the ESC group and four (IQR, 2-6) in the SC group. The median OS was 14.8 months (95% CI, 13.3 to 16.3) in the ESC group and 11.9 months (95% CI, 9.6 to 13.6) in the SC group (hazard ratio, 0.68; 95% CI, 0.51 to 0.9; P = .021). CONCLUSION: The early integration of interdisciplinary supportive care is an effective intervention with survival benefits for patients with metastatic EGC. Further optimization and standardization are warranted.

Prostate cancer risk prediction models in Eastern Asian populations: current status, racial difference, and future directions.

Prostate cancer (PCa) risk calculators (RCs) with prostate-specific antigen (PSA) and other risk factors can greatly improve the accurate prediction of potential risk of PCa compared to PSA. The European Randomized Study of Screening for PCa Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) are developed on the Western population. However, the Western RCs showed limited diagnostic efficacy in the Eastern Asian population, mainly due to racial differences between the two populations. We aimed to review the application of Western RCs and Eastern Asian RCs in Eastern Asian cohorts and to identify the characteristics and efficacy of these RCs.

A facile synthetic strategy for the creation of hollow noble metal/transition metal oxide nanocomposites.

We have reported an efficient synthetic protocol to build different hollow hybrid nanocomposites with tunable compositions, such as Au/TiO2, Pt/ZrO2, and Au/CexTi1-xO2. The noble metal nanoparticles were well encapsulated in a wall composed of the designated transition metal oxides, showing promising potential as stable catalysts as demonstrated by Pt/ZrO2 for methane combustion.

Construction of uniform ZrO2 nanoshells by buffer solutions.

We identified that the growth kinetics of ZrO2 could be well-tuned in a CH3COOH-CH3COONa based buffer solution, which provided an efficient way to build uniform ZrO2 nanoshells on various substrates. Using this synthetic strategy, yolk-shell structured Pd@ZrO2 is demonstrated as a promising catalyst for methane oxidation.

Characterization of a mannose utilization system in Bacillus subtilis.

The mannose operon of Bacillus subtilis consists of three genes, manP, manA, and yjdF, which are responsible for the transport and utilization of mannose. Upstream and in the same orientation as the mannose operon a regulatory gene, manR, codes for a transcription activator of the mannose operon, as shown in this study. Both mannose operon transcription and manR transcription are inducible by mannose. The presence of mannose resulted in a 4- to 7-fold increase in expression of lacZ from the manP promoter (P(manP)) and in a 3-fold increase in expression of lacZ from the manR promoter (P(manR)). The transcription start sites of manPA-yjdF and manR were determined to be a single A residue and a single G residue, respectively, preceded by -10 and -35 boxes resembling a vegetative sigma(A) promoter structure. Through deletion analysis the target sequences of ManR upstream of P(manP) and P(manR) were identified between bp -80 and -35 with respect to the transcriptional start site of both promoters. Deletion of manP (mannose transporter) resulted in constitutive expression from both the P(manP) and P(manR) promoters, indicating that the phosphotransferase system (PTS) component EII(Man) has a negative effect on regulation of the mannose operon and manR. Moreover, both P(manP) and P(manR) are subject to carbon catabolite repression (CCR). By constructing protein sequence alignments a DNA binding motif at the N-terminal end, two PTS regulation domains (PRDs), and an EIIA- and EIIB-like domain were identified in the ManR sequence, indicating that ManR is a PRD-containing transcription activator. Like findings for other PRD regulators, the phosphoenolpyruvate (PEP)-dependent phosphorylation by the histidine protein HPr via His15 plays an essential role in transcriptional activation of P(manP) and P(manR). Phosphorylation of Ser46 of HPr or of the homologous Crh protein by HPr kinase and formation of a repressor complex with CcpA are parts of the B. subtilis CCR system. Only in the double mutant with an HPr Ser46Ala mutation and a crh knockout mutation was CCR strongly reduced. In contrast, P(manR) and P(manP) were not inducible in a ccpA deletion mutant.

Optimization of an E. coli L-rhamnose-inducible expression vector: test of various genetic module combinations.

BACKGROUND: A capable expression vector is mainly characterized by its production efficiency, stability and induction response. These features can be influenced by a variation of modifications and versatile genetic modules. RESULTS: We examined miscellaneous variations of a rhaPBAD expression vector. The introduction of a stem loop into the translation initiation region of the rhaPBAD promoter resulted in the most significant improvement of eGFP expression. Starting from this plasmid, we constructed a set of expression vectors bearing different genetic modules like rop, ccdAB, cer and combinations thereof, and tested the efficiency of expression and plasmid stability. The plasmid pWA21, containing the stem loop, one cer site and rop, attained high expression levels accompanied by a good stability, and on that score seems to be a well-balanced choice. CONCLUSION: We report the generation of variations of the rhaPBAD expression vector and characterization hereof. The genetic modules showed a complex interplay, therefore two positive effects combined sometimes resulted in a disadvantage.