Xiangchun 37, a spring soybean variety with multiplexed traits of medium maturity period, high yield, and high seed oil content.

Soybean is an indispensable crop producing the majority of vegetative oils and proteins. China has been importing millions of ton of soy beans in recent years. Developing new varieties with favorable traits in both yield and resilience has great potential to meet the market needs in China. In this study, we bred a new variety (Xiangchun 37) which has been licensed by Ministry of Agriculture and Rural Affairs of the People's Republic of China in 2024. In the field tests, Xiangchun 37 showed medium maturity period (107.4 days from sowing to harvest), high yield (187.3 kg/667m2), and high seed oil content (22.19%). Overall assessment showed Xiangchun 37 had other favorable traits including the plant architecture and disease resistance. In conclusion, Xiangchun 37 is a new variety suitable for Hunan Province, China and has promising future for further genetic improvement as a germplasm with multiple favorable traits. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01505-5.

Phase I clinical trial of HC-1119: A deuterated form of enzalutamide.

The purpose of our study was to investigate the safety, pharmacokinetics (PK), and initial antitumor efficacy of HC-1119 in patients with metastatic castration-resistant prostate cancer (mCRPC). Eligible mCRPC patients were included in our study (NCT03774056) with two parts. Part A was a dose escalation study in which patients received a dose escalation of HC-1119 (40, 80, 160 and 200 mg/day). Part B was a dose expansion study in which patients received HC-1119 at the dose of 80 and 160 mg. Safety assessment and pharmacokinetic samplings were performed for all patients at the given time points; preliminary tumor response was also assessed. Twenty-four patients were enrolled in part A and 19 patients in part B, respectively. HC-1119 was safe, well tolerated and no dose-limiting toxicity was observed. Fatigue was the most common treatment-related adverse event and no seizures were observed. At the dose levels of 40, 80 and 160 mg, the AUC and Cmax of HC-1119 in plasma increased almost dose-proportionally at the steady state in mCRPC patients. Maximum prostate-specific antigen (PSA) response rates (≥50% reduction from the baseline) in dose escalation and dose expansion cohorts were 77% and 75%, respectively; the overall disease control rate (22 patients available for imaging analysis) was 72.7%, with PR in 4 patients, SD in 12 patients and PD in 6 patients; the 2-year overall survival rate in patients from Part B was 56.8%. HC-1119 was safe, well tolerated and efficacious and HC-1119 at 80 mg/day is recommended for further studies.

[A photothermal/chemotherapy injectable paclitaxel gel with irradiation stability].

The aim of this study is to construct an injectable gel with stable phototherapy and chemotherapy. Res-PTX@IR780 gel with phototherapy and chemotherapy property was prepared by introduction of photosensitizer IR780 and antioxidant resveratrol (Res) into the polyethylene glycol (PEG) solution of paclitaxel (PTX). The results showed that PTX, PTX@IR780 and Res-PTX@IR780 could form gels and the gels were injectable. ATR-FTIR results indicated not only components of the gels but also the formation of hydrogen bonding during the gelation. The results of UV showed instability of IR780 solution and stability improvement of Res-IR780 solution under infrared radiation (IR) irradiation. Photothermal tests showed that Res-PTX@IR780 displayed better photothermal conversion and photothermal stability under multiple irradiations than PTX@IR780. The results of in vivo exploration in mice showed that the skin site injected with Res-PTX@IR780 gel heated up from 35 ℃ to 64 ℃, and the temperature difference was up to 30 ℃. Res-PTX@IR780 gel is very promising as a combination agent of photothermal therapy and chemotherapy for the in situ treatment of tumors due to good photothermal conversion and photothermal stability under multiple irradiations.

Bevacizumab or fibronectin gene editing inhibits the osteoclastogenic effects of fibroblasts derived from human radicular cysts.

Fibronectin (FN) is a main component of extracellular matrix (ECM) in most adult tissues. Under pathological conditions, particularly inflammation, wound healing and tumors, an alternatively spliced exon extra domain A (EDA) is included in the FN protein (EDA+FN), which facilitates cellular proliferation, motility, and aggressiveness in different lesions. In this study we investigated the effects of EDA+FN on bone destruction in human radicular cysts and explored the possibility of editing FN gene or blocking the related paracrine signaling pathway to inhibit the osteoclastogenesis. The specimens of radicular cysts were obtained from 20 patients. We showed that the vessel density was positively associated with both the lesion size (R = 0.49, P = 0.001) and EDA+FN staining (R = 0.26, P = 0.022) in the specimens. We isolated fibroblasts from surgical specimens, and used the CRISPR/Cas system to knockout the EDA exon, or used IST-9 antibody and bevacizumab to block EDA+FN and VEGF, respectively. Compared to control fibroblasts, the fibroblasts from radicular cysts exhibited significantly more Trap+MNCs, the relative expression level of VEGF was positively associated with both the ratio of EDA+FN/total FN (R = 0.271, P = 0.019) and with the number of Trap+MNCs (R = 0.331, P = 0.008). The knockout of the EDA exon significantly decreased VEGF expression in the fibroblasts derived from radicular cysts, leading to significantly decreased osteoclastogenesis; similar results were observed using bevacizumab to block VEGF, but block of EDA+FN with IST-9 antibody had no effect. Furthermore, the inhibitory effects of gene editing on Trap+MNC development were restored by exogenous VEGF. These results suggest that EDA+FN facilitates osteoclastogenesis in the fibrous capsule of radicular cysts, through a mechanism mediated by VEGF via an autocrine effect on the fibroblasts. Bevacizumab inhibits osteoclastogenesis in radicular cysts as effectively as the exclusion of the EDA exon by gene editing.

The kinetic mechanism of bacterial ribosome recycling.

Bacterial ribosome recycling requires breakdown of the post-termination complex (PoTC), comprising a messenger RNA (mRNA) and an uncharged transfer RNA (tRNA) cognate to the terminal mRNA codon bound to the 70S ribosome. The translation factors, elongation factor G and ribosome recycling factor, are known to be required for recycling, but there is controversy concerning whether these factors act primarily to effect the release of mRNA and tRNA from the ribosome, with the splitting of the ribosome into subunits being somewhat dispensable, or whether their main function is to catalyze the splitting reaction, which necessarily precedes mRNA and tRNA release. Here, we utilize three assays directly measuring the rates of mRNA and tRNA release and of ribosome splitting in several model PoTCs. Our results largely reconcile these previously held views. We demonstrate that, in the absence of an upstream Shine-Dalgarno (SD) sequence, PoTC breakdown proceeds in the order: mRNA release followed by tRNA release and then by 70S splitting. By contrast, in the presence of an SD sequence all three processes proceed with identical apparent rates, with the splitting step likely being rate-determining. Our results are consistent with ribosome profiling results demonstrating the influence of upstream SD-like sequences on ribosome occupancy at or just before the mRNA stop codon.

Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties.

Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t1/2) and increased AUC0→∞. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.

Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles.

A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax), and nearly doubled its drug exposure in plasma (AUC0-∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.

Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors.

This letter presents synthesis and structure-activity relationship study of sulfonamide derivatives as inhibitors of Human Uric Acid Transporter 1 (hURAT1). Among all tested sulfonamide derivatives, compounds 9b, 16i and 19b exhibited excellent inhibition activity with IC50 value of 10, 2, and 83nM, respectively. In addition, compounds 9b and 19b demonstrated moderate PK profile in rats.

Effect of N-methyl deuteration on pharmacokinetics and pharmacodynamics of enzalutamide.

Enzalutamide, a second-generation antiandrogen, has been developed for the treatment of castration-resistance prostate cancer. We synthesized the deuterated analogues 6 and found that it showed higher drug exposure and thus stronger antitumor potency in preclinical settings. Compound 6 is being developed clinically for the potential to be differentiated from enzalutamide through reduced dosages and a higher safety margin.

MiR-540 as a novel adipogenic inhibitor impairs adipogenesis via suppression of PPARγ.

A better understanding of the molecular mechanisms in adipogenesis may provide new insights into adipose tissue-related diseases. Recently, microRNAs (miRNAs) have emerged as a class of epigenetic regulators of stem cell differentiation. In this study, we found that miR-540 was an essential negative regulator of adipogenic differentiation in adipose tissue-derived stromal cells (ADSCs). Lentivirus-mediated overexpression of miR-540 resulted in blockade of the expression of C/EBP-α and PPARγ, the two master transcription factors of adipogenesis, and deficient lipid accumulation, whereas inhibition of miR-540 promoted these processes. Target gene reporter assays showed that miR-540 directly targeted the 3'-untranslated region (3'UTR) of PPARγ, resulting in a decrease of PPARγ protein expression. Collectively, these data suggest that miR-540 represents a new adipogenic inhibitor by, at least in part, targeting PPARγ.

Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties.

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure.

Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties.

Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202.

A simple method for α-position deuterated carbonyl compounds with pyrrolidine as catalyst.

A simple, cost-effective method for deuteration of carbonyl compounds employing pyrrolidine as catalyst and D2O as deuterium source was described. High degree of deuterium incorporation (up to 99%) and extensive functional group tolerance were achieved. It is the first time that secondary amines are used as catalysts for H/D exchange of carbonyl compounds, which also allow the deuteration of complex pharmaceutically interesting substrates. A possible catalytic mechanism, based on the hydrolysis of 1-pyrrolidino-1-cyclohexene, for this pyrrolidine-catalyzed H/D exchange reaction has been proposed.

Evaluation of intramural hematoma: a novel use of 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging.

BACKGROUND: Aortic intramural hematoma (IMH) is one of the typical entities of acute aortic syndrome and probably accounts for 5-25% of all cases. The ulcer-like projections (ULP), which are described as a focal, blood-filled pouch protruding into the hematoma of the aortic wall, are regarded as one of the high-risk imaging features of IMH and may cause initial medical treatment failure and death. CASE PRESENTATION: We present a case report of an acute type B IMH patient with impaired renal function and newly developed ULP in the acute phase. The 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MR) was performed to evaluate the condition of aortic hematoma. The 18F-FDG focal uptake along the aortic wall of the hematoma was normal compared to the background (SUVmax 2.17; SUVSVC 1.6; TBR 1.35). We considered the IMH stable in such cases and opted for medical treatment and watchful observation. Six months after discharge, the patient's recovery was satisfactory, and aortic remodeling was ideal. CONCLUSIONS: The 18F-FDG PET/MR is a novel tool to evaluate the risk of IMH patients and thus provides information for therapy selection.

Population Pharmacokinetics Modeling and Simulation of Deutenzalutamide, A Novel Androgen Receptor Antagonist, in Patients With Metastatic Castration-Resistant Prostate Cancer.

Deutenzalutamide is a new molecular entity androgen receptor antagonist. The primary aim of this study was to develop a population pharmacokinetic model of deutenzalutamide and evaluate effects of intrinsic and extrinsic factors on pharmacokinetics. A nonlinear mixed-effects modeling approach was performed to develop the population pharmacokinetic of deutenzalutamide using data from 1 Phase I trial of deutenzalutamide. Goodness-of-fit plots, prediction-corrected visual predictive check, and bootstrap analysis were carried out to evaluate the final model. Simulation for the developed model was used to evaluate the covariate effects on the pharmacokinetics of deutenzalutamide. A 2-compartment model with first-order absorption and elimination from the central compartment was established for deutenzalutamide. The final covariate included body weight on peripheral compartment volume. This is the first research developing the population pharmacokinetic model of deutenzalutamide in patients with metastatic castration-resistant prostate cancer, and it is expected to support the future clinical administration of deutenzalutamide.

How forage grain ratoon rice improves the grain yield during the ratoon season.

Introduction: In recent years, with the rapid expansion of ratoon rice production in Hunan, a unique ratoon rice-based production system, forage-grain ratoon rice (FG-RR), has been newly developed. Ratooning rice is a season of rice harvested by utilizing the dormant buds on the rice stubble left after harvesting the first season of rice to sprout and grow. Therefore, the characteristics of stalks themselves are crucial for the production of ratoon rice. The cutting period and higher stubble height directly affect the characteristics of ratoon rice stubbles. Based on this, we conducted the following research. Methods: In 2021 and 2022, field experiments were conducted in central China to study the effects of different cutting periods and stubble height on the regeneration rate and nutrient content of ratoon crops. The treatments included two cutting periods (10 days after heading in the first season and 30 days after heading in the first season, respectively referred to as T10 and T30) and two stubble heights (10 cm and 30 cm, respectively referred to as H10 and H30). Results: Compared with the T30H30 treatment, T10H10 and T10H30 increased grain yield by 48.1%, 41.7%, 73.1%, and 65.2% in the two-year ratoon seasons, while T30H10 reduced grain yield by 30.9% and 19.5% in the two years, respectively. Early cutting increased the panicles, spikelets per panicle, and filled grain rate to varying increase, while higher stubble height increased panicles but decreased spikelet panicle. On the one hand, early cutting and higher stubble height increased the dry and fresh weight, nonstructural carbohydrates (NSCs), organic carbon (C), and nitrogen content of rice stalks, thereby improving the regeneration rate of ratoon rice. On the other hand, early cutting and higher stubble height retention increased the accumulation of nitrogen in rice stubble throughout the entire growth period and facilitated the transport of nitrogen to the mature panicles. Discussion: Therefore, appropriate early cutting and higher stubble height retention are the keys to improving the grain yield and stability of ratoon rice.

Platelet factors ameliorate thoracic aortic aneurysm and dissection by inhibiting the FGF-FGFR cascade activation in aortic-endothelial cell.

Thoracic aortic aneurysm and dissection (TAAD) is closely associated with vascular endothelial dysfunction. Platelet factor 4 (PF4) is crucial for maintaining vascular endothelial cell homeostasis. However, whether PF4 can influence the progression of TAAD remains unknown. In the present study, we constructed a liposome-encapsulated PF4 nanomedicine and verified its effect on BAPN-induced TAAD in vivo. We found that liposome PF4 nanoparticles (Lipo-PF4), more effectively than PF4 alone, inhibited the formation of TAAD. In vitro, PF4 improved endothelial cell function under pathological conditions by inhibiting migratory and angiogenic abilities of human aortic endothelial cells (HAECs). Mechanically, PF4 inhibited the development of TAAD and improved HAECs function by combining with heparin sulfate and blocking fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling. Taken together, we developed a nano-drug (Lipo-PF4) that effectively ameliorates the progression of TAAD by improving endothelial function. Lipo-PF4 is expected to be a therapeutic option for TAAD in the future.

Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers.

Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC50 = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC50 = 3.11 ± 0.08 nM vs IC50 = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC50 = 52.82 nM vs IC50 = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies.

Cutting time & height improve carbon and energy use efficiency of the forage-food dual-purpose ratoon rice cropping.

Forage-food dual-purpose ratoon rice cropping (FFRR) is used to balance forage demands with ratoon rice grain yields, that is whole plant (stem and sheath, panicles) cuttings in the main season are used as forage, and rice in the regeneration season is used as food. In this study, the local ratoon rice production system as the control, we were carried out the field experiment of cultivation practices (cutting time and cutting height), and investigated the system productivity, economic benefits, carbon footprints and energy use efficiency. The energy use efficiency, energy productivity and energy profitability increased with cutting time delay, and cutting height decreased. Significant differences of these index were observed among the treatments for cutting time and cutting height (p < 0.05). Carbon efficiency and carbon sustainability index was increase with cutting time delay, and there was significant difference among the treatment of cutting time in 2018 (p < 0.05), the minimum carbon footprint of FFRR was 78.6 kgCO2 t-1 averagely at the cutting time of 30 days after the flowering stage. In 2018, the maximum net income of FFRR was 30,577 CNY hm-2 at a cutting time of 30 days after the flowering stage while the stubble height was 10 cm, and dependent on the forage yield of the main crop; in 2019, the maximum net income of FFRR was 27,326 CNY hm-2 at a cutting time of 10 days after the flowering stage while the stubble height was 10 cm, and dependent on the grain yield of the ratoon crop. Therefore, the optimal cultivation practice of the FFRR (cutting at 30 days after the flowering stage and with a stubble height of 10 cm) showed higher carbon and energy use efficiency, economic benefits of the FFRR were fluctuated with the price of forage of the main crop and rice grain of the ratoon crop.

Development of a novel patient-reported outcome measure for orthognathic surgery.

OBJECTIVES: This study aimed to develop a new patient-reported outcome measure (PROM) to systematically and scientifically evaluate patients' subjective feelings after orthognathic surgery. METHODS: A literature review and semi-structured interviews were conducted to construct a conceptual framework and an item pool, followed by expert and patient surveys for measure construction. We conducted a clinical investigation to test the feasibility, reliability, and content validity of this measure. RESULTS: The conceptual framework included four domains: psychological health, physiological health, social function, and satisfaction, and 33 items were included in the survey. Following the expert analysis, 31 items remained in the draft. The clinical investigation showed a 100% recovery and completion rate and good reliability, with Cronman-Brown formula coefficients of 0.893 and 0.944, respectively. CONCLUSIONS: A new outcome measure to evaluate patients' subjective feelings after orthognathic surgery was successfully developed, and the clinical investigation demonstrated that the PROM had satisfactory feasibility, reliability, and validity. Further studies are possible based on our PROM, and data on a larger scale may reveal more information on patients' subjective feelings about orthognathic surgery. CLINICAL SIGNIFICANCE: The novel PROM provides a systematic and scientific way to evaluate the patient's subjective feelings to help surgeons obtain complete patient-reported information after orthognathic surgery. Additionally, standardised multicentre research on patients' subjective feelings using our PROM is possible and could improve the effectiveness of the evaluation and help maintain treatment quality.