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Chlorogenic acid (CGA) has incredible potential for various pharmaceutical, nutraceutical, and agricultural applications. However, the traditional extraction approach from plants is time-consuming, further limiting its production. Herein, we design and construct the de novo biosynthesis pathway of CGA using modular coculture engineering in Escherichia coli, which is composed of MG09 and BD07 strains. To accomplish this, the phenylalanine-deficient MG09 strain was engineered to utilize xylose preferentially and to overproduce precursor caffeic acid, while the tyrosine-deficient BD07 strain was constructed to consume glucose exclusively to enhance another precursor quinic acid availability for the biosynthesis of CGA. Further pathway modularization and balancing in the context of syntrophic cocultures resulted in additional production improvement. The coculture strategy avoids metabolic flux competition in the biosynthesis of two CGA precursors, caffeic acid and quinic acid, and allows for production improvement by balancing module proportions. Finally, the optimized coculture based on the aforementioned efforts produced 131.31 ± 7.89 mg/L CGA. Overall, the modular coculture engineering strategy in this study provides a reference for constructing microbial cell factories that can efficiently biomanufacture complex natural products.

Ground moving target detection is one of the foremost tasks for multichannel synthetic aperture radar (SAR) system. The traditional robust principal component analysis (RPCA) method is capable of separating low-rank and sparse components from mixed echo signals, and it has been widely applied in SAR ground moving target indication (GMTI). However, it suffers from sensitivity to channel mismatch, high computational complexity, and excessively high false alarm rates. To address these issues, a novel method that combines adaptive multichannel data reconstruction (DR) with improved pseudo-skeleton decomposition (IPSD) is proposed. First, the iterative weighted approach is presented to precisely reconstruct the multichannel data vector with the joint-pixel model. After that, IPSD is presented to achieve the moving target detection, in which the row and column index sets are selected using the generalized inner product (GIP) and the amplitude histogram distribution criterion. Compared to the existing algorithms, the proposed algorithm effectively addresses the challenge of improving local region coherence in multichannel image sequences. In addition, compared to previous RPCA methods, the proposed algorithm significantly reduces false alarm rates in strong clutter backgrounds while achieving higher efficiency. Simulation results and real SAR data experiments validate the effectiveness of the proposed algorithm.

Study Design: Retrospective case series.Objectives: To present outcomes concerning patients with early-onset mixed-type congenital scoliosis (EOMTCS) treated with the traditional single growing rod (TSGR), focusing on the growth of unsegmented levels (USLs).Methods: Patients with EOMTCS who underwent TSGR and had a minimum of 4 USLs, 4 distractions, and 3-year follow-up were enrolled. Spine radiographs before and after index surgery and at the latest follow-up were evaluated. The length of the concave and convex side of USLs and thoracic parameters were measured. The absolute value and percentage of growth were calculated.Results: Fourteen patients (mean age, 7.3 ± 2.8 years) were enrolled. The average follow-up duration was 4.9 ± 1.2 years, during which time 84 distractions and 8 final fusions were performed. The average number of USLs was 6.3 ± 2.2. The total and annual percent growth of concave side of USLs was significantly higher than convex side (32.2 ± 13.3% vs. 23.9 ± 9.5%, p = 0.007; 6.8 ± 2.7%/year vs. 5.1% ± 2.2%/year, p = 0.007, respectively). The concave-to-convex ratio of USLs increased from 58.6 ± 6.4 ± 7.6% at baseline to 68.8 ± 9.3% at the latest follow-up (p < 0.001). The Campbell’s space available for lung ratio increased from 74.9 ± 11.1% at baseline to 89.6 ± 7.0% at the latest follow-up (p < 0.001).Conclusions: In patients with EOMTCS, unilateral repetitive lengthening with TSGR can accelerate the growth of the concave side of USLs and improve the symmetry of the thorax.

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this “transformer”-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

Patients with cancer have reduced immune function and are susceptible to bacterial infection after surgery, chemotherapy, or radiotherapy. Spherical nanoparticles formed by the self-assembled peptide V6K3can be used as carriers for poorly soluble antitumor drugs to effectively deliver drugs into tumor cells. V6K3was designed to achieve nanoparticle-to-nanofiber geometric transformation under induction by plasma amine oxidase (PAO). PAO is commercially available and functionally similar to lysyl oxidase (LO), which is widely present in serum. After the addition of fetal bovine serum (FBS) or PAO, the secondary structure of the peptide changed, while the spherical nanoparticles stretched and transformed into nanofibers. The conversion of the self-assembled morphology reveals the susceptibility of this amphiphilic peptide to subtle chemical modifications and may lead to promising strategies to control self-assembled architecture via enzyme induction. Enzymatically self-assembled V6K3had bactericidal properties after PAO addition that were surprisingly superior to those before PAO addition, enabling this peptide to be used to prevent infection. The amphiphilic peptide V6K3displayed antitumor properties and low toxicity in mammalian cells, demonstrating good biocompatibility, as well as bactericidal properties, to prevent bacterial contamination. These advantages indicate that enzymatically self-assembled V6K3has great biomedical application potential in cancer therapy.

Cancer presents a significant health threat, necessitating the development of more precise, efficient, and less damaging treatment approaches. To address this challenge, we employed the 1-ethyl-(3-dimethyl aminopropyl) carbodiimide/N-hydroxy succinimide (EDC/NHS) catalytic system and utilized quaternized chitosan oligosaccharide (HTCOSC) as a drug carrier to construct a nanoparticle delivery system termed HTCOSC-cRGD-ES2-MTX (CREM). This system specifically targets integrin αvβ3 on tumor cell surfaces and enables simultaneous loading of the antiangiogenic agent ES2 (IVRRADRAAVP) and the chemotherapy drug methotrexate (MTX). Due to its amphiphilic properties, CREM self-assembles into nanoparticles in aqueous solution, exhibiting an average diameter of 179.47 nm. Comparative studies demonstrated that CREM, in contrast to free ES2 and MTX-free nanoparticles (CRE), significantly suppressed the proliferation of EAhy926 endothelial cells and B16 melanoma cells in vitro, resulting in inhibition rates of 71.18 and 82.25%, respectively. Furthermore, CREM exhibited a hemolysis rate below 2%, indicating excellent in vitroantiangiogenic and antitumor activity as well as favorable blood compatibility. Additionally, both CRE and CREM demonstrated favorable tumor targeting capabilities through the specific binding action of cyclic RGD (cRGD) to integrin αvβ3. Further in vivoinvestigations revealed that CREM induced apoptosis in tumor cells via the mitochondrial apoptotic pathway and reduced the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), thereby inhibiting tumor angiogenesis. This potent antitumor effect was evident through a tumor suppression rate of 80.19%. Importantly, histopathological staining (HE staining) demonstrated the absence of significant toxic side effects of CREM on various organs compared to MTX. In conclusion, the CREM nano drug delivery system synergistically enhances the therapeutic efficacy of antiangiogenic drugs and chemotherapeutic agents, thus offering a novel targeted approach for cancer treatment.

The combined use of unilateral biportal endoscopy and selective nerve root block can successfully accomplish precise decompression for elderly patients with radiologically multi-segmental LSS.

Background: Endostatin (ES) is a promising anti-angiogenesis protein and has been approved for the treatment of non-small cell lung cancer, but short half-life, poor stability and nonspecific delivery caused great pain to patients and produced unsatisfactory treatment effectiveness. Objective: In this work, in order to overcome these disadvantages, ES was covalently modified by polysulfated heparin (PSH) with the expectancy of longer half-life, higher anti-angiogenesis activity and better cellular uptake. Methods: To characterize the cellular uptake, flow cytometry and confocal laser scanning microscopy were used to study the intracellular localization of fluorescein isothiocyanate-labeled ES and PSH-ES in EAhy926 endothelial cells. Zebrafish model was used to study the anti-angiogenesis activities of ES and its derivatives in vivo. The 125I-radiolabeled ES and PSH-ES were administered to healthy BALC/c mice for the pharmacokinetics study. Results: Compared with ES, better cellular uptake effects were detected in PSH-ES group. Both ES and PSH-ES showed inhibition on the intersegmental vessels formation, while PSH-ES displayed a higher one. The half-life of PSH-ES was lengthened and area under the curve (AUC) was increased. At the same time, ES and PSH-ES were both widely and rapidly distributed in the lungs, livers, kidneys and hearts with little difference. Conclusion: The results indicated that PSH displayed good properties as a novel glyco-modifier for protein and peptide. The results also showed that PSH-ES displayed better cellular uptake, higher antiangiogenesis activity and prolonged half-life, which would lead to better anti-tumour effects.

Background: Endostatin (ES) is a promising anti-angiogenesis protein and has been approved for the treatment of non-small cell lung cancer, but short half-life, poor stability and nonspecific delivery caused great pain to patients and produced unsatisfactory treatment effectiveness. Objective: In this work, in order to overcome these disadvantages, ES was covalently modified by polysulfated heparin (PSH) with the expectancy of longer half-life, higher anti-angiogenesis activity and better cellular uptake. Methods: To characterize the cellular uptake, flow cytometry and confocal laser scanning microscopy were used to study the intracellular localization of fluorescein isothiocyanate-labeled ES and PSH-ES in EAhy926 endothelial cells. Zebrafish model was used to study the anti-angiogenesis activities of ES and its derivatives in vivo. The 125I-radiolabeled ES and PSH-ES were administered to healthy BALC/c mice for the pharmacokinetics study. Results: Compared with ES, better cellular uptake effects were detected in PSH-ES group. Both ES and PSH-ES showed inhibition on the intersegmental vessels formation, while PSH-ES displayed a higher one. The half-life of PSH-ES was lengthened and area under the curve (AUC) was increased. At the same time, ES and PSH-ES were both widely and rapidly distributed in the lungs, livers, kidneys and hearts with little difference. Conclusion: The results indicated that PSH displayed good properties as a novel glyco-modifier for protein and peptide. The results also showed that PSH-ES displayed better cellular uptake, higher antiangiogenesis activity and prolonged half-life, which would lead to better anti-tumour effects.

Paclitaxel (PTX) is one of the natural products used as first- or second-line treatment of cancer. It has a wide spectrum of activity against various cancer types, but low solubility in water, and toxicity to normal tissues such as hypersensitivity reaction and neuropathy limited its applications. The serious endeavors have been made to design and fabricate a more favorable nanoformulation lowering the inherent toxicity and side effects of PTX. The polymer-drug conjugates as a class of polymer-based nanomedicines have been reported to reduce adverse effects, enhance uptake and accumulation in tumor cells, potentiate therapeutic efficacy and improve patient compliance compared to polymer-encapsulated drugs. Collectively, very “old” PTX as cytotoxic drug bound to polymer has enormous potential and broad prospects. In this review, we mainly pay attention to summarize progress in the polymer-PTX conjugates designed and evaluated in recent decades to potentiate the therapeutic efficacy and tackle adverse effects of PTX.