Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.

Solvent-driven biotoxin into nano-units as a versatile and sensitive SERS strategy.

In recent years, marine biotoxins have posed a great threat to fishermen, human security and military prevention and control due to their diverse, complex, toxic and widespread nature, and the development of rapid and sensitive methods is essential. Surface-enhanced Raman spectroscopy (SERS) is a promising technique for the rapid and sensitive in situ detection of marine biotoxins due to its advantages of rapid, high sensitivity, and fingerprinting information. However, the complex structure of toxin molecules, small Raman scattering cross-section and low affinity to conventional substrates make it difficult to achieve direct and sensitive SERS detection. Here, we generate a large number of active hotspot structures by constructing monolayer nanoparticle films with high density hotspots, which have good target molecules that can actively access the hotspot structures using nanocapillaries. In addition, the efficient and stable signal can be achieved during dynamic detection, increasing the practicality and operability of the method. This versatile SERS method achieves highly sensitive detection of marine biotoxins GTX and NOD, providing good prospects for convenient, rapid and sensitive SERS detection of marine biotoxins.

Intelligent and robust DNA robots capable of swarming into leakless nonlinear amplification in response to a trigger.

Nonlinear DNA signal amplification with an enzyme-free isothermal self-assembly process is uniquely useful in nanotechnology and nanomedicine. However, progress in this direction is hampered by the lack of effective design models of leak-resistant DNA building blocks. Here, we propose two conceptual models of intelligent and robust DNA robots to perform a leakless nonlinear signal amplification in response to a trigger. Two conceptual models are based on super-hairpin nanostructures, which are designed by innovating novel principles in methodology and codifying them into embedded programs. The dynamical and thermodynamical analyses reveal the critical elements and leak-resistant mechanisms of the designed models, and the leak-resistant behaviors of the intelligent DNA robots and morphologies of swarming into nonlinear amplification are separately verified. The applications of the designed models are also illustrated in specific signal amplification and targeted payload enrichment via integration with an aptamer, a fluorescent molecule and surface-enhanced Raman spectroscopy. This work has the potential to serve as design guidelines of intelligent and robust DNA robots and leakless nonlinear DNA amplification, and also as the design blueprint of cargo delivery robots with the performance of swarming into nonlinear amplification in response to a target automatically, facilitating their future applications in biosensing, bioimaging and biomedicine.

Construction of Optimal SERS Hotspots Based on Capturing the Spike Receptor-Binding Domain (RBD) of SARS-CoV-2 for Highly Sensitive and Specific Detection by a Fish Model.

It is highly challenging to construct the best SERS hotspots for the detection of proteins by surface-enhanced Raman spectroscopy (SERS). Using its own characteristics to construct hotspots can achieve the effect of sensitivity and specificity. In this study, we built a fishing mode device to detect the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at low concentrations in different detection environments and obtained a sensitive SERS signal response. Based on the spatial resolution of proteins and their protein-specific recognition functions, SERS hotspots were constructed using aptamers and small molecules that can specifically bind to RBD and cooperate with Au nanoparticles (NPs) to detect RBD in the environment using SERS signals of beacon molecules. Therefore, two kinds of AuNPs modified with aptamers and small molecules were used in the fishing mode device, which can specifically recognize and bind RBD to form a stable hotspot to achieve high sensitivity and specificity for RBD detection. The fishing mode device can detect the presence of RBD at concentrations as low as 0.625 ng/mL and can produce a good SERS signal response within 15 min. Meanwhile, we can detect an RBD of 0.625 ng/mL in the mixed solution with various proteins, and the concentration of RBD in the complex environment of urine and blood can be as low as 1.25 ng/mL. This provides a research basis for SERS in practical applications for protein detection work.

In-situ SERS readout strategy to improve the reliability of beta-galactosidase activity assay based on X-gal staining in shortening incubation times.

Beta-galactosidase (ß-gal) activity is closed related with senescence cells and aging-associated diseases, however, the traditional readout of ß-gal activity based on X-gal staining was limited to low sensitivity in short incubation times and false positives in long incubation times. Here, we expose the potential role of insoluble X-gal hydrolysates in causing false positives by diffusion pollution depending on organic medium and then propose the in-situ Surface-enhanced Raman spectroscopy (SERS) readout strategy to identify and locate ß-gal positive cells. By building the blue-white screening model and fabricating SERS-active needle sensor, the sensitive detection of ß-gal has been realized with the detection limit of less than 1 nmol L-1. The in-situ SERS readout strategy is proved to be necessary and feasible to improve the reliability of X-gal staining assay through shortening the time to a few hours. Moreover, its application was also preliminarily evaluated to analyse individual cells and tissues, which showed the well consistency for judgement of ß-gal activity cells at different times. Consequently, by improving reliability and reducing time consumption, this SERS readout strategy may be of great significance to promote the application of X-gal staining assay in biology and biomedicine.

Exploring the utility of Au@PVP-polyamide-Triton X-114 for SERS tracking of extracellular senescence associated-beta-galactosidase activity.

A compound with enrichment and SERS enhancement was successfully developed, which could rapidly adsorb X-gal hydrolysates from a liquid matrix in 5 minutes and further be used for SERS analysis with a detection limit of less than 1 × 10-9 mol L-1. This novel strategy will facilitate the development of an analytical approach for cellular senescence.

Donafenib in Progressive Locally Advanced or Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Results of a Randomized, Multicenter Phase II Trial.

Background: An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. Methods: This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. Results: The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% (p = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) (p = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month, p = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Conclusions: Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.

Elucidation of leak-resistance DNA hybridization chain reaction with universality and extensibility.

Hybridization chain reaction (HCR) was a significant discovery for the development of nanoscale materials and devices. One key challenge for HCR is the vulnerability to background leakage in the absence of the initiator. Here, we systematically analyze the sources of leakage and refine leak-resistant rule by using molecular thermodynamics and dynamics, biochemical and biophysical methods. Transient melting of DNA hairpin is revealed to be the underlying cause of leakage and that this can be mitigated through careful consideration of the sequence thermodynamics. The transition threshold of the energy barrier is proposed as a testing benchmark of leak-resistance DNA hairpins. The universal design of DNA hairpins is illustrated by the analysis of hsa-miR-21-5p as biomarker when used in conjunction with surface-enhanced Raman spectroscopy. We further extend the strategy for specific signal amplification of miRNA homologs. Significantly, it possibly provides a practical route to improve the accuracy of DNA self-assembly for signal amplification, and that could facilitate the development of sensors for the sensitive detection of interest molecules in biotechnology and clinical medicine.

Evaluation of chemiluminescent immunoassay quantitative detection for pro-gastrin-releasing peptide (ProGRP) in serum and plasma.

OBJECTIVE: To evaluate a newly developed Hybiome ProGRP chemiluminescent assay. METHODS: Analytical sensitivity, precision, recovery, and equivalency of serum and plasma, serum stability, and complement interference of the Hybiome ProGRP assay were evaluated. Serum specimens from 318 individuals including 38 small cell lung cancer (SCLC), 65 non-small cell lung cancer (NSCLC), 53 benign lung diseases, and 162 healthy controls were assessed using the Hybiome ProGRP assay and Roche Elecsys ProGRP assay, and the results were compared. RESULTS: The Hybiome ProGRP assay showed good analytical sensitivity, precision, and accuracy, and it showed equivalence between serum and plasma and serum stability. The methodological comparison results showed good correlation between the Hybiome and Roche assays (slope, 0.9889; intercept, 1.28). Both the Hybiome and Roche assays showed good ability to distinguish between SCLC and NSCLC. Based on 95% specificity in the NSCLC cohort, a clinical differentiation cut-off for separating SCLC from NSCLC patients was 114 pg/mL for the Hybiome assay and 117 pg/mL for the Roche assay; the AUC was 0.9166 and the sensitivity was 71.05% for Hybiome and 0.9045 and 76.32% for Roche, respectively. CONCLUSION: The Hybiome ProGRP chemiluminescent assay shows good analytical performance and good correlation with the Roche Elecsys ProGRP assay.

Increased 131I Accumulation in the Gallbladder and High-grade Serous Ovarian Adenocarcinoma.

It is unusual to observe I accumulation in the gallbladder and high-grade serous ovarian adenocarcinoma during posttherapeutic I scan. We report the case of a 55-year-old woman with papillary thyroid cancer, who received total thyroidectomy and then 3 courses of I therapy. The posttherapeutic whole-body scan after the third dose of I therapy revealed abnormal I uptake in the right upper abdomen, overlapping the liver, and the pelvis. Further SPECT/CT imaging found that they were from an enlarged gallbladder and a large pelvic complex solid and cystic mass, which was pathologically confirmed as bilateral high-grade serous ovarian adenocarcinoma.