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Tingjie Yin,* Lihui Dong,* Bei Cui, Lei Wang, Lifang Yin, Jianping Zhou, Meirong Huo State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China *These authors contributed equally tothis work Abstract: Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol®) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane™, nab™ relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery. Keywords: human serum albumin, nanosuspension, paclitaxel, polyethylene glycol, solid-dispersion technology

A genetic map including three avirulence (Avr) genes, AvrPik, AvrPiz, and AvrPiz-t, was constructed in a genetic cross of two rice field isolates, 84R-62B and Y93-245c-2. The chromosomal locations of the Avr genes were determined by using selected markers to probe Southern blots of the parental chromosomes that had been separated by contour-clamped homogenous electric fields electrophoresis. Electrophoretic karyotyping showed that both parental isolates 84R-62B and Y93-245c-2 contained seven chromosomes greater than 3.5 megabases (Mb) in size and 84R-62B possessed a small chromosome of approximately equal to 1.6 Mb. The linkage groups containing AvrPiz and AvrPiz-t were assigned to chromosomes 3 and 7, respectively. Some markers from the linkage group that contained AvrPik hybridized with chromosome 1 and the 1.6-Mb chromosome, yet all of the cloned RAPD markers that were closely linked to AvrPik hybridized exclusively to the 1.6-Mb chromosome in 84R-62B, the parent that possesses AvrPik. Thus, we conclude that AvrPik is located on the 1.6-Mb chromosome in 84R-62B.

Background: There is an increasing prevalence of ischemic nephropathy in the aging population of the world. However, the exact incidence of ischemic nephropathy in the Chinese population is still uncertain. The present study investigated the incidence of renal artery stenosis (RAS) in patients with suspected coronary artery disease (CAD) using renal angiography. Methods: Renal angiography was performed immediately after coronary artery angiography in 141 patients with suspected CAD, including 59 males and 82 females whose mean ages were 59 ± 10 years. Comorbidities included hypertension (n = 69), diabetes mellitus (n = 21), hyperlipidemia (n = 19), hypokalemia (n = 7) and preoperative renal insufficiency (Cr >132 µmol/l; n = 14). The patients were divided into CAD (luminal narrowing of ≧50%) and non-CAD (luminal narrowing of <50%) subgroups, and RAS (luminal narrowing of ≧50%) and non-RAS subgroups. In the RAS group, there were 11 patients (5 males, 6 females) in whom percutaneous transluminal renal angioplasty was performed in conjunction with stent implantation due to refractory hypertension. Results: The incidence of RAS was 18.4% (26/141) in all cases and 30.8% (16/52) in patients with CAD identified by coronary artery angiography. Ten cases with RAS were found among the 89 cases with normal coronary arteries (11.2%). The incidence of RAS in patients with CAD was higher than that in patients without CAD (30.8 vs. 11.2%, p< 0.05). In 52 cases with CAD, the incidence of RAS with three vessel lesions was significantly higher than that with one or two vessel lesions. Hypertension, CAD, renal insufficiency, hyperlipidemia and hypokalemia were associated with a higher risk of RAS. Conclusions: This study suggests that RAS is very common in the elderly Chinese population, specifically for those with three vessel lesions in CAD. For early detection of potential ischemic nephropathy, renal angiography is necessary in patients who receive coronary artery angiography.

Elective single embryo transfer (eSET) has been increasingly advocated, but concerns about the lower pregnancy rate after reducing the number of embryos transferred have encouraged transfer of multiple embryos. Extended embryo culture combined with electively freezing all embryos and undertaking a deferred frozen embryo transfer might increase pregnancy rate after eSET. We aimed to establish whether elective frozen single blastocyst transfer improved singleton livebirth rate compared with fresh single blastocyst transfer. This multicentre, non-blinded, randomised controlled trial was undertaken in 21 academic fertility centres in China. 1650 women with regular menstrual cycles undergoing their first cycle of in-vitro fertilisation were enrolled from Aug 1, 2016, to June 3, 2017. Eligible women were randomly assigned to either fresh or frozen single blastocyst transfer. The randomisation sequence was computer generated, with block sizes of two, four, or six, stratified by study site. For those assigned to frozen blastocyst transfer, all blastocysts were cryopreserved and a delayed frozen-thawed single blastocyst transfer was done. The primary outcome was singleton livebirth rate. Analysis was by intention to treat. This trial is registered at the Chinese Clinical Trial Registry, number ChiCTR-IOR-14005405. 825 women were assigned to each group and included in analyses. Frozen single blastocyst transfer resulted in higher rates of singleton livebirth than did fresh single blastocyst transfer (416 [50%] vs 329 [40%]; relative risk [RR] 1·26, 95% CI 1·14–1·41, p<0·0001). The risks of moderate or severe ovarian hyperstimulation syndrome (four of 825 [0·5%] in frozen single blastocyst transfer vs nine of 825 [1·1%] in fresh single blastocyst transfer; p=0·16), pregnancy loss (134 of 583 [23·0%] vs 124 of 481 [25·8%]; p=0·29), other obstetric complications, and neonatal morbidity were similar between the two groups. Frozen single blastocyst transfer was associated with a higher risk of pre-eclampsia (16 of 512 [3·1%] vs four of 401 [1·0%]; RR 3·13, 95% CI 1·06–9·30, p=0·029). Frozen single blastocyst transfer resulted in a higher singleton livebirth rate than did fresh single blastocyst transfer in ovulatory women with good prognosis. The increased risk of pre-eclampsia after frozen blastocyst transfer warrants further studies. The National Key Research and Development Program of China.

Background The mechanisms of abscisic acid (ABA) and auxin (IAA) in inducing adventitious root (AR) formation, biomass accumulation, and plant development under long-term waterlogging (LT-WL) conditions are largely unexplored. This study aimed to determine the roles of exogenous application of ABA and IAA in two woody plants ( Cleistocalyx operculatus and Syzygium jambos ) under LT-WL conditions. A pot experiment was conducted using a complete randomized design with two factors: (i) LT-WL and (ii) application of exogenous phytohormones (ABA and IAA) for 120 d. Results Results revealed that exogenous ABA and IAA promoted LT-WL tolerance in both species. In C. operculatus and S. jambos , plant height, the number of blades, leaf area, and fresh shoot weight were increased by exogenous IAA under LT-WL. However, exogenous ABA affected more the adventitious and primary root in C. operculatus compared to S. jambos . LT-WL decreased drastically the photosynthetic activities in both species, but adding moderate amounts of exogenous ABA or IAA protected the photosynthesis apparatus under LT-WL. Exogenous phytohormones at certain levels decreased the superoxide anion level and malondialdehyde accumulation in plants under LT-WL. Also, the increase of the peroxidases and superoxide dismutase activities by exogenous phytohormones was more marked in C. operculatus compared to S. jambos . Meanwhile, the catalase activity was down-regulated in both species by exogenous phytohormones. Exogenous ABA or IAA positively regulated the jasmonic acid content in ARs under LT-WL. Moderate application of exogenous ABA or IAA in plants under LT-WL decreased the ABA content in the leaves. Lower accumulation of IAA and ABA in the leaves of C. operculatus under LT-WL was positively correlated with a decrease in antioxidant activity. Conclusions Lastly, C. operculatus which has greater morphology indexes was more tolerant to waterlogging than S. jambos . Moreover, the adaptive strategies via exogenous ABA were more built around the below-ground biomass indexes particularly in C. operculatus , while exogenous IAA backed the above-ground biomass in both species. Overall, the exogenous hormones applied (spraying or watering) influenced differentially the plant’s responses to LT-WL. The phytohormonal profile of plants exposed to waterlogging stress varied depending on the species’ tolerance level.

Recently, the therapeutic potential of immune-modulation during the progression of chronic obstructive pulmonary disease (COPD) has been attracting increasing interest. However, chronic inflammatory response has been over-simplified in descriptions of the mechanism of COPD progression. As a form of first-line airway defense, epithelial cells exhibit phenotypic alteration, and participate in epithelial layer disorganization, mucus hypersecretion, and extracellular matrix deposition. Dendritic cells (DCs) exhibit attenuated antigen-presenting capacity in patients with advanced COPD. Immature DCs migrate into small airways, where they promote a pro-inflammatory microenvironment and bacterial colonization. In response to damage-associated molecular patterns (DAMPs) in lung tissue affected by COPD, neutrophils are excessively recruited and activated, where they promote a proteolytic microenvironment and fibrotic repair in small airways. Macrophages exhibit decreased phagocytosis in the large airways, while they demonstrate high pro-inflammatory potential in the small airways, and mediate alveolar destruction and chronic airway inflammation. Natural killer T (NKT) cells, eosinophils, and mast cells also play supplementary roles in COPD progression; however, their cellular activities are not yet entirely clear. Overall, during COPD progression, \"exhausted\" innate immune responses can be observed in the large airways. On the other hand, the innate immune response is enhanced in the small airways. Approaches that inhibit the inflammatory cascade, chemotaxis, or the activation of inflammatory cells could possibly delay the progression of airway remodeling in COPD, and may thus have potential clinical significance.

Background This study aimed to assess the efficacy and safety of transarterial chemoembolization (TACE) in combination with apatinib (TACE-apatinib) for patients with unresectable hepatocellular carcinoma (HCC). Methods This study was a multicenter, randomized, open-label, prospective, phase III trial. Patients with unresectable HCC were randomly assigned in a 1:1 ratio to receive either TACE-apatinib or TACE-alone treatment. Patients in the TACE-apatinib group began with a dosage of 500 mg/day of oral apatinib administered 4 days after the first TACE. The primary endpoint of this study was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to untreatable (unTACEable) progression (TTUP), and safety assessment. Results From November 1, 2018 to November 18, 2021, a total of 196 patients were randomly assigned to either the TACE-apatinib ( n  = 86) or TACE-alone ( n  = 92) group. The median PFS in the TACE-apatinib group was significantly longer than that of in the TACE-alone group (6.1 months vs. 3.4 months, p  < 0.0001). The median OS was significantly prolonged in the TACE-apatinib group compared to the TACE-alone group (28.9 months vs. 24.0 months, p  = 0.0005). The median TTUP in the TACE-apatinib group was 26.8 months, which was significantly longer than that of 20.1 months in the TACE-alone group ( p  = 0.0003). A significantly higher ORR and DCR were observed in the TACE-apatinib group compared to the TACE-alone group (ORR: 58.1% vs. 31.5%, p  < 0.001; DCR: 87.2% vs. 69.6%, p  = 0.004). Most of the treatment-related adverse events were grades 1–2, and no treatment-related deaths were observed. Conclusions Apatinib significantly improved the treatment effects of TACE for patients with unresectable HCC. TACE-apatinib could serve as a promising treatment option for this patient population, offering notable survival benefits while maintaining an acceptable safety profile. Trial registration Chinese Clinical Trial Register, No. ChiCTR1800018621.

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV. SARS-CoV-2 variants with immune escape capability highlight the need for the development of cross-neutralising vaccines and regimens. Here, the authors assess the immunogenicity and safety of NVSI-06-08, that integrates antigens from multiple SARS-CoV-2 strains into a single immunogen, as a heterologous booster in adults previously vaccinated with the inactivated vaccine.

BACKGROUND:Cervical collars are used after laminoplasty to protect the hinge opening, reduce risks of hinge fractures, and avoid spring-back phenomena. However, their use may lead to reduced range of motion and worse neck pain. OBJECTIVE:To investigate the clinical, radiological, and functional outcomes of patients undergoing single-door laminoplasty with or without collar immobilization. METHODS:This was a prospective, parallel, single-blinded randomized controlled trial. Patients underwent standardized single-door laminoplasty with mini-plates for cervical myelopathy and were randomly allocated into 2 groups based on the use of collar postoperatively. Clinical assessments included cervical range of motion, axial neck pain (VAS [visual analogue scale]), and objective scores (short-form 36-item, neck disability index, and modified Japanese Orthopaedic Association). All assessments were performed preoperatively and at postoperative 1, 2, 3, and 6 wk, and 3, 6, and 12 mo. Comparative analysis was performed via analysis of variance adjusted by baseline scores, sex, and age as covariates. RESULTS:A total of 35 patients were recruited and randomized to collar use (n = 16) and without (n = 19). There were no dropouts or complications. There were no differences between groups at baseline. Subjects had comparable objective scores and range of motion at postoperative time-points. Patients without collar use had higher VAS at postoperative 1 wk (5.4 vs 3.5; P = .038) and 2 wk (3.5 vs 1.5; P = .028) but subsequently follow-up revealed no differences between the 2 groups. CONCLUSION:The use of a rigid collar after laminoplasty leads to less axial neck pain in the first 2 wk after surgery. However, there is no additional benefit with regards to range of motion, quality of life, and complication risk.

Disease resistance (R) genes in plants encode products that specifically recognise incompatible pathogens and trigger a cascade of events leading to disease resistance in the host plant. R-gene specificity is dictated by both host R genes and cognate avirulence (avr) genes in pathogens. However, the basis of gene-for-gene specificity is not well understood. Here, we report the cloning of the R gene Xa27 from rice and the cognate avr gene avrXa27 from Xanthomonas oryzae pv. oryzae. Resistant and susceptible alleles of Xa27 encode identical proteins. However, expression of only the resistant allele occurs when a rice plant is challenged by bacteria harbouring avrXa27, whose product is a nuclear localized type-III effector. Induction of Xa27 occurs only in the immediate vicinity of infected tissue, whereas ectopic expression of Xa27 resulted in resistance to otherwise compatible strains of the pathogen. Thus Xa27 specificity towards incompatible pathogens involves the differential expression of the R gene in the presence of the AvrXa27 effector.