The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival.

Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.

Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking.

Drug delivery systems (DDSs) that can overcome tumor heterogeneity and achieve deep tumor penetration are challenging to develop yet in high demand for cancer treatment. We report here a DDS based on self-assembling dendrimer nanomicelles for effective and deep tumor penetration via in situ tumor-secreted extracellular vesicles (EVs), an endogenous transport system that evolves with tumor microenvironment. Upon arrival at a tumor, these dendrimer nanomicelles had their payload repackaged by the cells into EVs, which were further transported and internalized by other cells for delivery "in relay." Using pancreatic and colorectal cancer-derived 2D, 3D, and xenograft models, we demonstrated that the in situ-generated EVs mediated intercellular delivery, propagating cargo from cell to cell and deep within the tumor. Our study provides a new perspective on exploiting the intrinsic features of tumors alongside dendrimer supramolecular chemistry to develop smart and effective DDSs to overcome tumor heterogeneity and their evolutive nature thereby improving cancer therapy.

HSP90ß prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53.

Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90ß (HSP90ß) plays a fundamental role in suppressing cataractogenesis. HSP90ß is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90ß is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90ß silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90ß can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90ß silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90ß and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90ß is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.

A genome-wide association study identifies a transporter for zinc uploading to maize kernels.

The Zn content in cereal seeds is an important trait for crop production as well as for human health. However, little is known about how Zn is loaded to plant seeds. Here, through a genome-wide association study (GWAS), we identify the Zn-NA (nicotianamine) transporter gene ZmYSL2 that is responsible for loading Zn to maize kernels. High promoter sequence variation in ZmYSL2 most likely drives the natural variation in Zn concentrations in maize kernels. ZmYSL2 is specifically localized on the plasma membrane facing the maternal tissue of the basal endosperm transfer cell layer (BETL) and functions in loading Zn-NA into the BETL. Overexpression of ZmYSL2 increases the Zn concentration in the kernels by 31.6%, which achieves the goal of Zn biofortification of maize. These findings resolve the mystery underlying the loading of Zn into plant seeds, providing an efficient strategy for breeding or engineering maize varieties with enriched Zn nutrition.

Broad-Range-Response Battery-Type All-in-one Self-Powered Stretchable Pressure-Sensitive Electronic Skin.

Highly sensitive self-powered stretchable electronic skins with the capability of detecting broad-range dynamic and static pressures are urgently needed with the increasing demands for miniaturized wearable electronics, robots, artificial intelligence, etc. However, it remains a great challenge to achieve this kind of electronic skins. Here, unprecedented battery-type all-in-one self-powered stretchable electronic skins with a novel structure composed of pressure-sensitive elastic vanadium pentoxide (V2 O5 ) nanowire-based porous cathode, elastic porous polyurethane /carbon nanotube/polypyrrole anode, and polyacrylamide ionic gel electrolyte are reported. A new battery-type self-powered pressure sensing mechanism involving the output current variation caused by the resistance variation of the electrodes and electrolytes under external pressure is revealed. The battery-type self-powered electronic skins combining high sensitivity, broad response range (1.8 Pa-1.5 MPa), high fatigue resistance, and excellent stability against stretching (50% tensile strain) are achieved for the first time. This work provides a new and versatile battery-type sensing strategy for the design of next-generation all-in-one self-powered miniaturized sensors and electronic skins.

Modulating the Coordination Environment of Carbon-Dot-Supported Fe Single-Atom Nanozymes for Enhanced Tumor Therapy.

Herein, carbon dot (CD)-supported Fe single-atom nanozymes with high content of pyrrolic N and ultrasmall size (ph-CDs-Fe SAzyme) are fabricated by a phenanthroline-mediated ligand-assisted strategy. Compared with phenanthroline-free nanozymes (CDs-Fe SAzyme), ph-CDs-Fe SAzyme exhibit higher peroxidase (POD)-like activity due to their structure similar to that of ferriporphyrin in natural POD. Aberration-corrected high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and X-ray absorption fine structure spectroscopy (XAFS) analyses show that metal Fe is dispersed in ph-CDs-Fe SAzyme as single atoms. Steady-state kinetic studies show that the maximum velocity (Vmax ) and turnover number (kcat ) of H2 O2  homolytic cleavage catalyzed by ph-CDs-Fe SAzyme are 3.0 and 6.2 more than those of the reaction catalyzed by CDs-Fe SAzyme. Density functional theory (DFT) calculations show that the energy barrier of the reaction catalyzed by ph-CDs-Fe SAzyme is lower than that catalyzed by CDs-Fe SAzyme. Antitumor efficacy experiments show that ph-CDs-Fe SAzyme can efficiently inhibit the growth of tumor cells both in vitro and in vivo by synergistic chemodynamic and photothermal effects. Here a new paradigm is provided for the development of efficient antitumor therapeutic approaches based on SAzyme with POD-like activity.

Biomimetic Transparent Layered Tough Aerogels for Thermal Superinsulation and Triboelectric Nanogenerator.

Transparent aerogels are ideal candidates for thermally insulating windows, solar thermal receivers, electronics, etc. However, they are usually prepared via energy-consuming supercritical drying and show brittleness and low tensile strength, significantly restricting their practical applications. It remains a great challenge to prepare transparent aerogels with high tensile strength and toughness. Herein, biomimetic transparent tough cellulose nanofiber-based nanocomposite aerogels with a layered nanofibrous structure are achieved by vacuum-assisted self-assembly combined with ambient pressure drying. The nacre-like layered homogeneous nanoporous structures can reduce light scattering and effectively transfer stress and prevent stress concentration under external forces. The aerogels exhibit an attractive combination of excellent transparency and hydrophobicity, high compressive and tensile strengths, high toughness, excellent machinability, thermal superinsulation, and wide working temperature range (-196 to 230 °C). It is demonstrated that they can be used for superinsulating windows of buildings and high-efficient thermal management for electronics and human bodies. In addition, a prototype of transparent flexible aerogel-based triboelectric nanogenerator is developed. This work provides a promising pathway toward transparent tough porous materials for energy saving/harvesting, thermal management, electronics, sensors, etc.

Overcoming Pharmaceutical Bottlenecks for Nucleic Acid Drug Development.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic and swift approval of two mRNA vaccines have put nucleic acid therapeutics in the spotlight of both the scientific community and the general public. Actually, in addition to mRNAs, multiple nucleic acid therapeutics have been successively commercialized over the past few years. The rapid development of nucleic acid drugs not only demonstrates their superior potency but also marks a new era of the field. Compared with conventional treatments targeting proteins rather than the root causes of diseases at the genetic level, nucleic acids are capable of achieving long-standing or even curative effects against undruggable disorders by modulating gene expression via inhibition, editing, addition, or replacement. This offers a terrific arsenal for expanding therapeutic access to diseases lacking current treatment options and developing vaccines to provide swift responses to emerging global health threats.Despite the stunning success and recent resurgence of interest in the field, the unfavorable physicochemical characteristics (i.e., the negative charge, large molecular weight, and hydrophilicity), susceptibility to nuclease degradation, off-target toxicity, and immunogenicity are a brake for moving nucleic acid therapeutics from bench to bedside. Currently, developing technologies to improve the circulation stability, targeting affinity, cellular entry, endolysosomal escape, efficacy, and safety of nucleic acid drugs still remains a major pharmaceutical bottleneck.In this Account, we outline the research efforts from our group on the development of technology platforms to overcome the pharmaceutical bottlenecks for nucleic acid therapeutics. We have engineered a variety of intelligent delivery platforms such as synthetic nanomaterials (i.e., lipid nanoparticles, polymers, and inorganic nanoparticles), physical delivery methods (i.e., electroporation), and naturally derived vehicles (i.e., extracellular vesicles), aiming at endowing nucleic acids with improved circulation stability, targeting affinity, and cellular internalization (Get in) and stimuli responsive endolysosomal escape capability (Get out). Moreover, we will discuss our progress in developing a series of modification strategies for sequence engineering of nucleic acids to endow them with enhanced nuclease resistance, translation efficiency, and potency while alleviating their off-target toxicity and immunogenicity (Sequence engineering). Integrating these technologies may promote the development of nucleic acid therapeutics with potent efficacy and improved safety (Efficacy & safety). With this Account, we hope to offer insights into rational design of cutting-edge nucleic acid therapeutic platforms. We believe that the continuing advances in nucleic acid technologies together with academic-industry collaborations in the clinic, will promise to usher in more clinically translatable nucleic acid therapeutics in the foreseeable future.

Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

A Class of Activatable NIR-II Photoacoustic Dyes for High-Contrast Bioimaging.

Photoacoustic (PA) imaging is emerging as one of the important non-invasive imaging techniques in biomedical research. Small molecule- second near-infrared window (NIR-II) PA dyes combined with imaging data can provide comprehensive and in-depth in vivo physiological and pathological information. However, the NIR-II PA dyes usually exhibit "always-on" properties due to the lack of a readily optically tunable group, which hinders the further applications in vivo. Herein, a novel class of dyes GX have been designed and synthesized as an activatable NIR-II PA platform, in which the absorption/emission wavelength of GX-5 extends up to 1082/1360 nm. Importantly, the GX dyes have a strong tissue penetration depth and high-resolution for the mouse vasculature structures in NIR-II PA 3D imaging and high signal-to-noise ratio in NIR-II fluorescence (FL) imaging. Furthermore, to demonstrate the applicability of GX dyes, the first NIR-II PA probe GX-5-CO activated by carbon monoxide (CO) was engineered and employed to reveal the enhancement of the CO levels in the hypertensive mice by high-contrast NIR-II PA and FL imaging. We expect that many derivatives of GX dyes will be developed to afford versatile NIR-II PA platforms for designing a wide variety activatable NIR-II PA probes as biomedical tools.

Revisiting the Hetero-Interface of Electrolyte/2D Materials in an Electric Double Layer Device.

Electric double layer (EDL) devices based on 2D materials have made great achievements for versatile electronic and opto-electronic applications; however, the ion dynamics and electric field distribution of the EDL at the electrolyte/2D material interface and their influence on the physical properties of 2D materials have not been clearly clarified. In this work, by using Kelvin probe force microscope and steady/transient optical techniques, the character of the EDL and its influence on the optical properties of monolayer transition metal dichalcogenides (TMDs) are probed. The potential drop, unscreened EDL potential distribution, and accumulated carriers at the electrolyte/TMD interface are revealed, which can be explained by nonlinear Thomas-Fermi theory. By monitoring the potential distribution along the channel, the evolution of the electric field-induced lateral junction in the TMD EDL transistor is accessed, giving rise to the better exploration of EDL device physics. More importantly, EDL gate-dependent carrier recombination and exciton-exciton annihilation in monolayer TMDs on lithium-ion solid state electrolyte (Li2 Al2 SiP2 TiO13 ) are evaluated for the first time, benefiting from the understanding of the interaction between ions, carriers, and excitons. The work will deepen the understanding of the EDL for the exploitation of functional device applications.

A long-acting recombinant FSH supports high-quality mouse follicle development and oocyte maturation in vitro by coordinating somatic and germ cell transcriptomes.

Strategies to maximize individual fertility chances are constant requirements of ART. In vitro folliculogenesis may represent a valid option to create a large source of immature ovarian follicles in ART. Efforts are being made to set up mammalian follicle culture protocols with suitable FSH stimuli. In this study, a new type of recombinant FSH (KN015) with a prolonged half-life is proposed as an alternative to canonical FSH. KN015 supports the in vitro development of mouse follicles from primary to preovulatory stage with higher efficiency than canonical FSH and enhanced post-fertilization development rates of the ovulated oocytes. The use of KN015 also allows us to compare the dynamic transcriptome changes in oocytes and granulosa cells at different stages, in vivo and in vitro. In particular, KN015 facilitates mRNA accumulation in growing mouse oocytes and prevents spontaneous luteinization of granulosa cells in vitro. Novel analyses of transcriptome changes in this study reveal that the in vivo oocytes were more efficient than in vitro oocytes in terms of maternal mRNA clearing during meiotic maturation. KN015 promotes the degradation of maternal mRNA during in vitro oocyte maturation, improves cytoplasmic maturation and, therefore, enhances embryonic developmental potential. These findings establish new transcriptome data for oocyte and granulosa cells at the key stages of follicle development, and should help to widen the use of KN015 as a valid and commercially available hormonal support enabling optimized in vitro development of follicles and oocytes.

Aberrant SUMO2/3 modification of RUNX1 upon SENP1 inhibition is linked to the development of diabetic retinopathy in mice.

Our previous report established that RUNX family transcription factor 1 (RUNX1) promotes proliferation of mouse retinal microvascular endothelial cells (mRMECs) and exacerbates diabetic retinopathy (DR). However, the mechanism behind the upregulation of RUNX1 remains unclear. This study aims to investigate the possible correlation between histone SUMOylation and RUNX1 in DR, as well as the involved molecules. A mouse model of diabetes was induced by streptozotocin (STZ). These mice had increased retinal thickness and elevated production of inflammatory cytokines. Additionally, they showed elevated levels of SUMO1 and SUMO2/3, but reduced levels of SUMO specific peptidase 1 (SENP1) in retinal tissues. Co-immunoprecipitation and Western blot assays revealed that the RUNX1 protein was primarily modified by SUMO2/3, and SENP1 inhibited SUMO2/3 modification, thereby reducing RUNX1 expression. Overexpression of SENP1 alleviated symptoms in mice and alleviated inflammation. In vitro experiments demonstrated that the SENP1 overexpression suppressed the proliferation, migration, and angiogenesis of high-glucose-induced mRMECs. However, further overexpression of RUNX1 counteracted the alleviating effects of SENP1 both in vivo and in vitro. In conclusion, this study demonstrates that the downregulation of SENP1 in DR leads to SUMO2/3-dependent activation of RUNX1. This activation promotes proliferation of mRMECs and exacerbates DR symptoms in mice.

Comparison of the effects of buffalo LIF and mouse LIF on the in vitro culture of buffalo spermatogonia.

Leukemia inhibitory factor (LIF) is an important growth factor that supports the culture and maintenance of spermatogonial stem cells (SSCs) by suppressing spontaneous differentiation. Different LIF sequences may lead to differences in function. The protein sequences of buffalo LIF and mouse LIF differed by 65.5% according to MEGA software analysis. The PB-LIF-GFP-Puro vector was constructed, and the CHO-K1 cell line was established. The final LIF protein concentration in the CHO-K1 cell culture medium was approximately 4.268 ng/mL. Here, we report that buffalo LIF effectively maintains the self-renewal of buffalo spermatogonia during culture. Buffalo spermatogonia were cultured in conditioned medium containing no LIF (0 ng/mL), mouse LIF (1 ng/mL), mouse LIF (10 ng/mL), or buffalo LIF (1 ng/mL). Furthermore, the effects of mouse LIF and buffalo LIF culture on the maintenance of buffalo spermatogonia were determined by analyzing cell colony formation, quantitative real-time polymerase chain reaction, cell immunofluorescence, and cell counting. The buffalo LIF (1 ng/mL) group showed similar maintenance of the proliferation of buffalo spermatogonia to that in the mouse LIF (10 ng/mL) group. These results demonstrated that the proliferation of buffalo spermatogonia can be maintained in vitro by adding a low dose of buffalo LIF. This study provides a foundation for the further optimization of in vitro buffalo SSC culture systems.

TsOH-catalyzed acyl migration reaction of the Bz-group: innovative assembly of various building blocks for the synthesis of saccharides.

We developed an efficient method to achieve the regioselective acyl migration of benzoyl ester. In all the cases, the reactions required only the commercially available organic acid catalyst TsOH·H2O. This method enables the benzoyl group to migrate from secondary groups to primary hydroxyl groups, or from equatorial secondary hydroxyl groups to axial hydroxyl groups. The 1,2 or 1,3 acyl migration would potentially occur via five- and six-membered cyclic ortho acid intermediates. A wide range of orthogonally protected monosaccharides, which are useful intermediates for the synthesis of natural oligosaccharides, were synthesized. Finally, to demonstrate the utility of the method, a tetrasaccharide portion from a mycobacterial cell wall polysaccharide was assembled.

PLAGL1 is associated with prognosis and cell proliferation in pancreatic adenocarcinoma.

BACKGROUND: Emerging evidence has shown the crucial roles of pleomorphic adenoma gene (PLAG) family genes in multiple cancers. However, their functions and mechanisms in pancreatic adenocarcinoma (PAAD) remain poorly understood. METHODS: We analyzed the expression levels of PLAG family genes in both The Cancer Genome Atlas (TCGA) database and a Gene Expression Omnibus (GEO) database, and confirmed the results in our three independent cohorts of 382 PAAD tissues and 362 adjacent nontumor pancreatic tissues. Integrated analyses were carried out to explore the function, mechanism and prognostic value of the selected PLAG family gene in PAAD patients. RESULTS: By analyzing the TCGA and GEO databases, PLAGL1 was identified to be downregulated in PAAD tissues, and its decreasing levels of both mRNA and protein were verified in our three independent PAAD cohorts. PLAGL1 expression was inversely correlated with clinicopathological factors including the Ki67+ cell rate and pathologic stage. Further GSEA of the TCGA-PAAD cohort demonstrated that multiple signaling pathways implicated in cell proliferation were enriched in the lower PLAGL1 expressing PAAD group. Moreover, we demonstrated that PLAGL1 expression was obviously negatively associated with patients' overall survival outcome in both the TCGA-PAAD cohort and our verification cohorts. Additionally, through MTS and BrdU assays, we further demonstrated in vitro that PLAGL1 had the impact of preventing the proliferation of pancreatic cancer cells. CONCLUSIONS: Our present study suggested that downregulated PLAGL1 might act as a biomarker in predicts poor prognosis and one of important factors in increasing cell proliferation in PAAD. This study provides us with a novel prognostic marker and therapeutic strategy for PAAD, which deserves further study.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Highly hydrophilic and dispersed TiO2 nano-system with enhanced photocatalytic antibacterial activities and accelerated tissue regeneration under visible light.

Titanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.

Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy.

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF- and PTX-derived prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug-nanocarrier compatibility and exhibited greatly improved pharmacokinetic profiles and high tumor accumulation. HF nanomedicine pretreatment restored stromal homeostasis and considerably facilitated the distribution of PTX nanomedicine and its penetration into carcinoma cells, leading to positive modulation of the infiltration of cytotoxic T cells and significant regression of tumor growth in two PDAC models. Our nanomedicine-based stromal remodeling strategy appears promising for treating desmoplastic malignancies.

Systematic review of artificial intelligence tack in preventive orthopaedics: is the land coming soon?

PURPOSE: This study aims to describe and assess the current stage of the artificial intelligence (AI) technology integration in preventive orthopaedics of the knee and hip joints. MATERIALS AND METHODS: The study was conducted in strict compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Literature databases were searched for articles describing the development and validation of AI models aimed at diagnosing knee or hip joint pathologies or predicting their development or course in patients. The quality of the included articles was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and QUADAS-AI tools. RESULTS: 56 articles were found that meet all the inclusion criteria. We identified two problems that block the full integration of AI into the routine of an orthopaedic physician. The first of them is related to the insufficient amount, variety and quality of data for training, and validation and testing of AI models. The second problem is the rarity of rational evaluation of models, which is why their real quality cannot always be evaluated. CONCLUSION: The vastness and relevance of the studied topic are beyond doubt. Qualitative and optimally validated models exist in all four scopes considered. Additional optimization and confirmation of the models' quality on various datasets are the last technical stumbling blocks for creating usable software and integrating them into the routine of an orthopaedic physician.