Breast cancer is the second cause of cancer mortality in women globally. Early detection, treatment, and metastasis monitoring are of great importance to favorable prognosis. Although conventional ...diagnostic methods, such as breast X-ray mammography and image positioning biopsy, are accurate, they could cause radioactive or invasive damage to patients. Liquid biopsy as a noninvasive method is convenient for repeated sampling in clinical cancer prognostic, metastatic evaluation, and relapse monitoring. MicroRNAs encased in exosomes circulating in biofluids are promising candidate cancer biomarkers because of their cancer-specific expression profiles. Here, we report an in situ detection of microRNA-1246 (miR-1246) in human plasma exosomes as breast cancer biomarker by a nucleic acid functionalized Au nanoflare probe. Needing neither time-consuming and costly isolation of exosomes from the plasma sample nor transfection means, the Au nanoflare probe can directly enter the plasma exosomes to generate fluorescent signal quantitatively by specifically targeting miR-1246. Only 40 μL of plasma is needed to incubate 4 h with the probe, giving signal sensitive enough to distinguish samples of breast cancer to normal control. Using plasma miR-1246 level detected by our assay as a marker, we differentiated 46 breast cancer patients from 28 healthy controls with 100% sensitivity and 92.9% specificity at the best cutoff. This simple, accurate, sensitive, and cost-effective liquid biopsy by the Au nanoflare probe is potent to be developed as a noninvasive breast cancer diagnostic assay for clinical adaption.
Seasonal influenza still greatly threatens public health worldwide, leading to significant morbidity and mortality. Antiviral medications for influenza treatment are limited and accompanied by ...increased drug resistance. In severe influenza virus infection, hyperinflammation and hypoxia may be the significant threats associated with mortality, so the development of effective therapeutic methods to alleviate excessive inflammation while reducing viral damage is highly pursued. Here, a multifunctional MOF‐based nanohybrid of Cu─TCPP@Mn3O4 as a novel drug against influenza A virus infection (MOF = metal−organic framework; TCPP = tetrakis (4‐carboxyphenyl) porphyrin) is designed. Cu─TCPP@Mn3O4 exhibits potent inhibitory capability against influenza A virus infection in vitro and in vivo. The mechanism study reveals that Cu─TCPP@Mn3O4 inhibits the virus entry by binding to the HA2 subunit of influenza A virus hemagglutinin. In addition, the nanoparticles of Mn3O4 in Cu─TCPP@Mn3O4 can scavenge intracellular ROS with O2 generation to downregulate inflammatory factors and effectively inhibit cytokines production. By reconstructing the antioxidant microenvironment, Cu─TCPP@Mn3O4 features as a promising nanomedicine with anti‐inflammatory and anti‐viral synergistic effects.
A multifunctional MOF‐based nanohybrid of Cu─TCPP@Mn3O4 as a novel drug against influenza A virus infection is designed. Cu─TCPP@Mn3O4 exhibits potent inhibitory capability against influenza A virus infection in vitro and in vivo. By reconstructing the antioxidant microenvironment, Cu─TCPP@Mn3O4 features as a promising nanomedicine with anti‐viral, anti‐inflammatory, and anti‐oxidant synergistic effects.
Chemoresistance and migration represent major obstacles in the therapy of non‐small‐cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present ...study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase‐9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti‐migration and anti‐proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti‐NSCLC agent, especially for chemotherapy‐resistant NSCLC treatment.
•Adaptive Kriging-based reliability estimation for multiple responses in a single run.•New learning scheme is proposed for simultaneously addressing multiple responses.•Generalized Subset simulation ...is adopted to accelerate convergence of the simulation.•Potential repeated calculation of the original ways is avoided by the proposed one.
Many systems have multiple stochastic responses, which correspond to multiple Limit-State Functions (LSFs). Over the past decade, researches on adaptive Kriging-based failure probability estimation have been focused on enhancing its performance for single response, whereas few efforts have been devoted to simultaneously coping with multiple responses of a system. Those methods have to estimate multiple responses in the same system one by one, potential repeated calculation is inevitable. This paper proposes a novel methodology for multiple responses within a single run, which includes an Adaptive Kriging-Monte Carlo Simulation for multiple responses (AK-MCS-m) and an Adaptive Kriging-Generalized Subset Simulation (AK-GSS). Once the surrogate for a certain LSF meets the requirement, the others are kept updating until the accuracy of ones for all are accepted. Two learning schemes considering the optimal effect and the averaging effect for all the LSFs are proposed. A heuristic comparative study on learning schemes for simultaneously constructing the Kriging models for multiple responses are conducted on AK-MCS-m. GSS is adopted to simultaneously estimate all the failure probabilities upon the constructed Kriging models and hence accelerate convergence for the outer loop of the simulation. Four examples are used to demonstrate the performance of the methodology.
The surface evolution of fibers has been attracting great attention in many areas. In this work, we demonstrated the feasibility of directly electrospinning grooved and porous polyvinylidene fluoride ...fibers by varying polymer concentration and using both single/binary solvent systems. We discovered that grooved fibers can be generated from a variety of binary solvent systems, whereas porous fibers can be achieved using low boiling point solvent (LBPS) systems. The results indicated that the key factors for the formation of grooved fibers are the polymer concentration, the difference of evaporation rate (the difference of boiling points between each of the two studied solvents) between the two solvents, and the solvent ratio. While the polymer concentration, the presence of LBPS, and the solvent ratio are the decisive factors for the formation of porous structures. The formation mechanism of grooved fibers was attributed to void-based elongation, wrinkle-based elongation, and collapsed jet-based elongation. The mechanism for the formation of porous fibers was ascribed to the coexistence of both thermally induced phase separation and vapor induced phase separation. These structures can be used in different applications, such as harvesting energy and filtration. Importantly, we believe our work can serve as guidelines for the preparation of grooved and porous nanofibers through electrospinning.
Coordination reaction of a known three-dimensional (3D) polymer precursor {Na3Na9(Cbdcp)6(H2O)18}n (A, Cbdcp = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium) with Zn(NO3)2·6H2O in H2O or H2O/DMF at ...100 °C and in the presence of aspirin, 5-fluorouracil (5-FU) as modulators, trans-1,2-bis(4-pyridyl)ethylene (bpe) or 1,2-bis(4-pyridyl)ethane (bpea) as ancillary ligands afforded six novel Zn(II)-based metal-organic frameworks (MOFs), that is, {Zn(Cbdcp)(H2O)3·H2O}n (1, 1D zigzag chain), {Zn(HCbdcp)2·H2O}n (2, 2D sheet), {Zn(Cbdcp)(bpe)1/2·2H2O}n (3, 3D polymer), {Zn(Cbdcp)(bpe)1/2·2H2O}n (4, 2D network), {Zn(Cbdcp)(bpea)1/2·2H2O}n (5, 3D polymer) and {Zn(Cbdcp)(bpea)1/2·2H2O}n (6, 2D network). Among them, compound 2 contains aromatic rings, positively charged pyridinium, Zn2+ cation centers and carboxylic acid groups lined up on the 2D sheet structure with a certain extended surface exposure. The unique structure of 2 facilitates effective association with carboxyfluorescein (FAM) labeled probe single stranded DNA (probe ss-DNA, delineates as P-DNA) to yield a P-DNA@2 system, and leads to fluorescence quenching of FAM via a photoinduced electron transfer process. The P-DNA@2 system is effective and reliable for the detection of human immunodeficiency virus 1 ds-DNA (HIV ds-DNA) sequences and capable of distinguishing complementary HIV ds-DNA from mismatched target sequences with the detection limit as low as 10 pM (S/N = 3).
Six water-stable zinc(II) zwitterionic carboxylate compounds with 1D chain, 2D and 3D networks were synthesized. Compound 2 can interact with the probe DNA through noncovalent bonds to form P-DNA@2 system. This system can be used as an effective, fluorescent sensing platform for the detection of HIV ds-DNA with the detection limit as low as 10 pM. Display omitted
•Six water-stable zinc(II) zwitterionic carboxylate compounds with 1D chain, 2D and 3D networks were synthesized.•Compound 2 can interact with the probe DNA through noncovalent bonds to form P-DNA@2 system.•A Zinc(II)-based MOF can interact with the probe DNA to form a system, which can be used for the detection of HIV ds-DNA.
We designed and synthesized three new berberine-based compounds, namely, pyridine-2,6-dimethyl-/2,2'-bipyridine-3,3'-dimethyl-tethered berberine dimers BD1 and BD2, and a tetrakis(4-benzyl)ethylene ...linked berberine tetramer BD4. We identified that the dimer BD2 and tetramer BD4, as well as 1,10-phenanthroline-2,9-dimethyl-linked berberine dimer BD3 previously reported by us, showed remarkable aggregation-induced emission (AIE) properties which endowed them with higher singlet oxygen (
O
) production ability than berberine. Of the four compounds, BD3 exhibits the lowest Δ
energy with the highest
O
generation ability and thus was selected for further construction of AuNSs-BD3@HA (denoted as ABH, AuNSs = gold nanostars; HA = hyaluronic acid). The nanosystem of ABH shows a remarkable therapeutic effect toward breast cancer by combining photodynamic therapy (PDT) from BD3, photothermal therapy (PTT) from AuNSs, and the CD44-targeting capability of HA. The synergistically enhanced PDT and PTT induce superior cancer cell apoptosis/necrosis
and anti-breast cancer activity
. This study provides a new concept for PDT using natural product derivatives and their combination with PTT for efficient treatment of tumors.
Designing and developing nanomedicine based on the tumor microenvironment (TME) for effective cancer treatment is highly desirable. In this work, polyvinyl pyrrolidone (PVP) dispersed nanoscale ...metal-organic framework (NMOF) of Fe-TCPP (TCPP = tetrakis (4-carboxyphenyl) porphyrin) loaded with hypoxia-activable prodrug tirapazamine (TPZ) and coated by the cancer cell membrane (CM) is constructed (the formed nanocomposite denoted as PFTT@CM). Due to the functionalization with the homologous cancer cell membrane, PFTT@CM is camouflaged to evade the immune clearance and preferentially accumulates at the tumor site. Once internalized by cancer cells, PFTT@CM is activated by the TME through redox reaction and Fenton reaction between Fe3+ in nano-platform and endogenous glutathione (GSH) and hydrogen peroxide (H2O2) to promote GSH exhausting as well as •OH and O2 production, which triggers ferroptosis and dramatically enhances photodynamic therapy (PDT) efficacy. Subsequently, the PDT process mediated by TCPP and light would consume oxygen and aggravate tumor hypoxia to further activate the prodrug TPZ for cancer chemotherapy. As a consequence, the TME-driven PFTT@CM nano-platform not only demonstrated its TME modulation ability but also showed a sequential synergistic therapy, which eventually inhibited the cancer cell proliferation. This multimodal nano-platform is expected to shed light on the design of TME-activatable reaction to reinforce the synergistic therapeutic outcome and facilitate the development of effective cancer nanomedicine.
Background:
Due to the highly organized tissue and avascular nature of the rotator cuff, rotator cuff tears have limited ability to heal after the tendon is reinserted directly on the greater ...tubercle of the humerus. Consequently, retears are among the most common complications after rotator cuff repair. Augmentation of rotator cuff repairs with patches has been an active area of research in recent years to reduce retear rate.
Hypothesis:
Graft augmentation with 3D collagen could prevent retears of the repaired tendon and improve tendon-bone healing in moderate to large rotator cuff tears.
Study Design:
Randomized controlled study; Level of evidence, 2.
Methods:
A prospective, randomized controlled study was performed in a consecutive series of 112 patients age 50 to 85 years who underwent rotator cuff repair with the suture-bridge technique (58 patients, control group) or the suture-bridge technique augmented with 3-dimensional (3D) collagen (54 patients, study group). All patients were followed for 28.2 months (range, 24-36 months). Visual analog scale score for pain, University of California Los Angeles (UCLA) shoulder score, and Constant score were determined. Magnetic resonance imaging was performed pre- and postoperatively (at a minimum of 24 months) to evaluate the integrity of the rotator cuff and the retear rate of the repaired tendon. Three patients in each group had biopsies at nearly 24 months after surgery with histological assessment and transmission electron microscopy.
Results:
A total of 104 patients completed the final follow-up. At the 12-month follow-up, the UCLA shoulder score was 28.1 ± 1.9 in the study group, which was significantly better than that in the control group (26.9 ± 2.1, P = .002). The Constant score was also significantly better in the study group (87.1 ± 3.2) than in the control group (84.9 ± 4.2, P = .003). However, at the final follow-up, no significant differences were found in the UCLA shoulder scores (29.4 ± 1.9 in the control group and 30.0 ± 1.6 in the study group, P = .052) or Constant scores (89.9 ± 3.2 in the control group and 90.8 ± 3.5 in the study group, P = .18). In terms of structural integrity, more patients in the study group had a favorable type I retear grade (18/51) than in the control group (10/53) (P = .06). The postoperative retear rate was 34.0% in the control group and 13.7% in the study group, thus indicating a significantly lower retear rate in the study group (P = .02). Biopsy specimens of the tendon-bone interface in 6 patients revealed more bone formation and more aligned fibers with larger diameters in the study group than in the control group. No intraoperative or postoperative complications were noted in either group.
Conclusion:
3D collagen augmentation could provide effective treatment of moderate to large rotator cuff tears, providing substantial functional improvement, and could reduce the retear rate. This technique could also promote new tendon-bone formation, thus exerting a prominent effect on tendon-bone healing.
Development of versatile sensing methods for sensitive and specific detection of clinically relevant nucleic acids and proteins is of great value for disease monitoring and diagnosis. In this work, ...we propose a novel isothermal Self-primer EXPonential Amplification Reaction (SPEXPAR) strategy based on a rationally engineered structure-switchable Metastable Hairpin template (MH-template). The MH-template initially keeps inactive with its self-primer overhanging a part of target recognition region to inhibit polymerization. The present targets can specifically compel the MH-template to transform into an “activate” conformation that primes a target-recyclable EXPAR. The method is simple and sensitive, can accurately and facilely detect long-chain single-stranded nucleic acids or proteins without the need of exogenous primer probes, and has a high amplification efficiency theoretically more than 2 n . For a proof-of-concept demonstration, the SPEXPAR method was used to sensitively detect the characteristic sequence of the typical swine fever virus (CSFV) RNA and thrombin, as nucleic acid and protein models, with limits of detection down to 43 aM and 39 fM, respectively, and even the CSFV RNA in attenuated vaccine samples and thrombin in diluted serum samples. The SPEXPAR method may serve as a powerful technique for the biological research of single-stranded nucleic acids and proteins.
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