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Abstract The prevention of blindness from glaucoma requires multiple treatments to lower intraocular pressure. Here, human contact lenses are modified with highly porous metal‐organic frameworks with sustained release of brimonidine for prolonged glaucoma treatment. Various metal‐organic frameworks were screened for their attachment to lenses, loading with brimonidine, and drug‐release properties. Optimized therapeutic ocular lenses conjugated with MIL‐101(Cr) frameworks maintain optical transparency and power. Coating of lenses with MIL‐101(Cr) nanoparticles reduced brimonidine washout with tears and ensured a gradual and localized release of the drug into the eyeball through the cornea. The hybrid lenses provided a 4.5‐fold better decrease in eye pressure, compared by area under the curve (AUC) value to a commercially available brimonidine tartrate solution. Therapeutic lenses did not induce any notable eye irritation or corneal damage in vivo. The newly developed hybrid lenses are expected to provide a robust platform for the therapy and prevention of various ocular diseases.

Abstract The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e−)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field.

Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.

Alternate partial root-zone drip fertigation (ADF) is a combination of alternating irrigation and drip fertigation, with the potential to save water and increase nitrogen (N) fertilizer efficiency. A 2-year greenhouse experiment was conducted to evaluate the effect of different fertigation frequencies on the distribution of soil moisture and nutrients and tomato yield under ADF. The treatments included three ADF frequencies with intervals of 3 days (F3), 6 days (F6) and 12 days (F12), and conventional drip fertigation as a control (CK), which was fertilized once every 6 days. For the ADF treatments, two drip tapes were placed 10 cm away on each side of the tomato row, and alternate drip irrigation was realized using a manual valve on the distribution tapes. For the CK treatment, a drip tape was located close to the roots of the tomato plants. The total N application rate of all treatments was 180 kg ha−1. The total irrigation amounts applied to the CK treatment were 450.6 and 446.1 mm in 2019 and 2020, respectively; and the irrigation amounts applied to the ADF treatments were 60% of those of the CK treatment. The F3 treatment resulted in water and N being distributed mainly in the 0–40-cm soil layer with less water and N being distributed in the 40–60-cm soil layer. The F6 treatment led to 21.0 and 29.0% higher 2-year average concentration of mineral N in the 0–20 and 20–40-cm soil layer, respectively and a 23.0% lower N concentration in the 40–60-cm soil layer than in the CK treatment. The 2-year average tomato yields of the F3, F6, F12, and CK treatments were 107.5, 102.6, 87.2, and 98.7 t ha−1, respectively. The tomato yield of F3 was significantly higher (23.3%) than that in the F12 treatment, whereas there was no significant difference between the F3 and F6 treatment. The F6 treatment resulted in yield similar to the CK treatment, indicating that ADF could maintain tomato yield with a 40% saving in water use. Based on the distribution of water and N, and tomato yield, a fertigation frequency of 6 days under ADF should be considered as a water-saving strategy for greenhouse tomato production.

Abstract PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin‐proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano‐PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano‐PROTACs are developed by encapsulating PROTACs in glutathione (GSH)‐responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano‐PROTAC, nanoengineered BRD4 degrader ARV‐771, improves BRD4 protein degradation and decreases the downstream oncogene c‐Myc expression. Benefiting from the GSH‐scavenging ability to amply the c‐Myc‐related ferroptosis and cell cycle arrest, this ARV@PDSA Nano‐PROTACs strategy shows superior anti‐tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano‐PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

Abstract Early-stage brain metastasis of breast cancer (BMBC), due to the existence of an intact blood–brain barrier (BBB), is one of the deadliest neurologic complications. To improve the efficacy of chemotherapy for BMBC, a Trojan horse strategy-based nanocarrier has been developed by integrating the cell membrane of a brain-homing cancer cell and a polymeric drug depot. With the camouflage of a MDA-MB-231/Br cell membrane, doxorubicin-loaded poly (D, L-lactic-co-glycolic acid) nanoparticle (DOX-PLGA@CM) shows enhanced cellular uptake and boosted killing potency for MDA-MB-231/Br cells. Furthermore, DOX-PLGA@CM is equipped with naturally selected molecules for BBB penetration, as evidenced by its boosted capacity in entering the brain of both healthy and early-stage BMBC mouse models. Consequently, DOX-PLGA@CM effectively reaches the metastatic tumor lesions in the brain, slows down cancer progression, reduces tumor burden, and extends the survival time for the BMBC animal. Furthermore, the simplicity and easy scale-up of the design opens a new window for the treatment of BMBC and other brain metastatic cancers.

Abstract Background Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. Methods NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. Results Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. Conclusions The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy. Graphical Abstract

Highlights Small-sized trastuzumab-targeted micelles (T-MP) were engineered using a surfactant-stripping approach that yielded concentrated phthalocyanines with strong near infrared absorption. T-MP accumulated more in the lymph node (LN) metastases of orthotopic colorectal cancer compared to the micelles conjugated with control IgG. Following surgical resection of the primary tumor, minimally invasive photothermal treatment of the metastatic LN with T-MP, but not the control micelles, extended mouse survival. Abstract Tumor lymph node (LN) metastasis seriously affects the treatment prognosis. Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration. Here, we speculate through introducing targeting capacity, the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy. Trastuzumab-targeted micelles (

AIM: To observe the efficacy of two conbercept regimens in the treatment of polypoid choroidal angiopathy.METHODS: Twenty-one patients with polypoidal choroidal vasculopathy who met the inclusion criteria and were treated in our hospital were randomly divided into two groups. The group A(9 patients and 9 eyes)was treated with 3+Q12W scheme, namely, 0.5mg conbercept ophthalmic injection was intravitreally injected every 4wk for 3 consecutive times, and then 1 time every 12wk. In the group B(12 patients and 12 eyes), 3+TAE scheme was carried out, that is 0.5mg conbercept ophthalmic injection was intravitreally injected every 4wks for 3 consecutive times. The time of next injection was determined according to the evaluation results of each visit. The interval to the next visit/treatment was ≥ 4wk and ≤ 12wk. The best corrected visual acuity(BCVA), central retinal thickness(CRT)and the frequency of injection were compared between the two groups at 12 and 48wk after treatment, respectively.RESULTS: BCVA of the group A was 74.78±11.23 letters and 74.67±13.94 letters at 12 and 48wk after treatment, which increased by 7.00±4.21 letters and 6.89±4.48 letters at the baseline before treatment, respectively. BCVA in the group B was 77.83±5.46 letters and 77.58±8.59 letters respectively at 12 and 48wk after treatment, which were 8.75±7.54 letters and 8.50±5.60 letters higher than the baseline before treatment. At the 12 and 48wk after injection, the average CRT in the group A was 276.33±44.34μm and 240.56±40.11μm, respectively, which were 43.22±42.21μm and 79.00±53.64μm lower than the baseline before treatment. At the 12 and 48wk after injection, the average CRT in the group B was 271.58±63.08μm and 241.00±43.91 μm, which were 57.42±45.33μm and 88.00±61.16μm lower than the baseline before treatment, respectively. The average times of intravitreal injection of conbercept were 6.00±0.00 and 7.75±1.14 times in the 3+Q12W group and the 3+TAE group, respectively.CONCLUSION: Two different regimens of conbercept could reduce the CRT and improve the visual acuity of the patients with polypoidal choroidal vasculopathy. And the times of intravitreal injection in the 3+Q12W administration group were less than those in the3+TAE administration group.

Abstract Background Identifying genotype-phenotype links and causative genes from quantitative trait loci (QTL) is challenging for complex agronomically important traits. To accelerate maize gene discovery and breeding, we present the Complete-diallel design plus Unbalanced Breeding-like Inter-Cross (CUBIC) population, consisting of 1404 individuals created by extensively inter-crossing 24 widely used Chinese maize founders. Results Hundreds of QTL for 23 agronomic traits are uncovered with 14 million high-quality SNPs and a high-resolution identity-by-descent map, which account for an average of 75% of the heritability for each trait. We find epistasis contributes to phenotypic variance widely. Integrative cross-population analysis and cross-omics mapping allow effective and rapid discovery of underlying genes, validated here with a case study on leaf width. Conclusions Through the integration of experimental genetics and genomics, our study provides useful resources and gene mining strategies to explore complex quantitative traits.

Abstract Background Atrial fibrillation (AF) is a common complication after radical surgery of esophageal cancer. The aim of this study was to explore AF risk factors after radical surgery of esophageal carcinoma. Method The data of 335 patients with esophageal cancer who were admitted in our hospital from January 2014 to August 2016 for the first time were retrospectively analyzed. We retrieved the papers in some data banks using the search terms including English and Chinese search terms, and obtained 13 factors which were mentioned in more than 6 papers. The 13 factors including age, gender, history of smoking, history of hypertension, history of peripheral vascular disease, history of cardiac stents or angina pectoris, preoperative pulmonary infection, preoperative brain natriuretic peptide (BNP) level, preoperative left ventricular diastolic dysfunction, operative method, lesion location, intraoperative blood transfusion, adhesion between lymph nodes and pericardium, underwent univariate and multivariate analyses. Results Of the 335 patients with esophageal cancer, 48 had AF within one week after operation. Univariate analysis indicated that the age (OR: 4.89; CI: 2.53–9.47, P: 0.000), gender (OR: 2.26; CI: 1.17–4.37, P: 0.013), history of peripheral vascular disease (OR: 2.29; CI: 1.06–4.92, P: 0.030), history of cardiac stents or angina pectoris (OR: 27.30; CI: 12.44–59.91, P: 0.000), preoperative BNP level (OR: 27.13; CI: 10.97–67.06, P: 0.000), preoperative left ventricular diastolic dysfunction (OR: 2.22; CI: 1.19–4.14, P: 0.012), operative method (OR: 2.09; CI: 1.002–4.380, P: 0.046), intraoperative blood transfusion (OR: 20.24; CI: 8.39–48.82, P: 0.000), and adhesion between lymph nodes and pericardium were risk factors (OR: 2.05; CI: 1.08–3.87, P: 0.024). Furthermore, multivariate analysis displayed that advanced age (OR: 5.044; CI: 1.748–14.554, P: 0.003), male (OR: 6.161; CI: 2.143–17.715, P: 0.001), history of cardiac stents or angina pectoris (OR: 48.813; CI: 13.674–174.246, P: 0.000), preoperative BNP > 100 (OR: 41.515; CI: 9.380–183.732, P: 0.000), open surgery (OR: 3.357; CI: 1.026–10.983, P: 0.045), intraoperative blood transfusion (OR: 58.404; CI: 10.777–316.509, P: 0.000), and adhesion between lymph nodes and pericardium (OR: 3.954; CI: 1.364–11.459, P: 0.011) were risk factors which could increase the incidence of postoperative AF. Conclusion We should pay attention to the above risk factors in order to reduce the incidence of postoperative AF.

In the current study, the effects of cracks in source field plates (SFPs) on the electrical performance of AlGaN/GaN high electron mobility transistors (HEMTs) are investigated systematically using numerical simulation. In detail, the influence of crack width and junction angle in SFPs on device performance is studied. The results indicate that the SFP structure increases the breakdown voltage of a device, but the occurrence of cracks causes premature breakdown, which is confirmed experimentally by the structural analysis of these devices after breakdown. With an increase in crack width, the electrical performance becomes worse. A beveled SFP architecture is proposed by increasing the angle at the SFP junction to reduce the probability of cracking and enhance the reliability of the device. However, with an increase in bevel angle, the modulation effect of the SFP on the channel electric field is gradually weakened. Therefore, it is necessary to balance the relationship between electrical performance and bevel angle according to the actual demands. This work provides potential support for SFP structural optimization design for AlGaN/GaN HEMTs.

Abstract Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano‐Pt) as a catalase‐like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano‐Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano‐Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed “nano‐Pt/VP@MLipo,” is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the VP‐mediated PDT, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano‐Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.

Long noncoding RNA SPRY4‐IT1 has been reported to promote melanoma cell growth and invasion, and to block apoptosis. The purpose of this study was to investigate the clinical significance of SPRY4‐IT1 in patients with malignant melanoma. The relative expression levels of SPRY4‐IT1 were measured in plasma samples from 70 patients and 79 healthy controls by quantitative reverse transcriptase polymerase chain reaction. SPRY4‐IT1 expression is high in melanoma patients but low in healthy controls, and is closely associated with tumor site and tumor stage. Elevated SPRY4‐IT1 significantly reduces overall survival rates of patients and is considered as an independent prognostic factor in patients with melanoma. The prognostic nomogram shows a good prediction of the probability of 5‐year overall survival of patients with melanoma (c‐index: 0.72). The calibration curve for the probability of survival presents good agreement between actual outcomes and predictive consequences. In summary, SPRY4‐IT1 may be a potential prognostic marker and a potential therapeutic target.

Background: Rheumatoid Arthritis (RA) is a systemic autoimmune disease leading to joint destruction. The prevention of bone and cartilage destruction has received increased attention in recent years.Objective: To evaluate the current evidences regarding the bone-protecting efficacy of Chinese medicine or the combination of Chinese medicine and Western medicine for RA.Methods: We comprehensively searched PubMed, Embase, the Cochrane Library (www.thecochranelibrary.com), the China National Knowledge Infrastructure (CNKI), the Database for Chinese Technical Periodicals (VIP), and SinoMed. We then performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) assessing the two therapy methods.Results: Sixteen studies including 1,171 patients were included in the final analysis. The results showed that Chinese medicine could significantly improve the bone mineral density (BMD) (mean difference [MD] = 0.05 /g·cm−2, 95% CI [0.03, 0.08], P < 0.00001), and decrease the serum matrix metalloproteinase 3 (MMP-3) ([SMD] = −2.84, 95% CI [−4.22, −1.47], P < 0.0001).Conclusions: Chinese medicine may provide an efficiently alternative choice for the treatment of RA in terms of the bone-protecting efficiency. Given the inherent limitations of the included studies, future well-designed RCTs are required to confirm and update the findings of this analysis.

Linhe National Meteorological Station, a representative weather station in the Hetao Irrigation District of China, was selected as the research site for the present study. Changes in climatic variables and reference evapotranspiration (ET0) (estimated by the Penman-Monteith method) were detected using Mann-Kendall tests and Sen's slope estimator, respectively. The authors analyzed the relationship between the ET0 change and each climatic variable's change. From 1954 to 2012, the air temperature showed a significant increasing trend, whereas relative humidity and wind speed decreased dramatically. These changes resulted in a slight increase in ET0. The radiative component of total ET0 increased from 50% to 57%, indicating that this component made a greater contribution to the increase in total ET0 than the aerodynamic component, especially during the crop growing season (from April to October). The sensitivity analysis showed that ET0 in Hetao is most sensitive to mean daily air temperature (11.8%), followed by wind speed (−7.3%) and relative humidity (4.8%). Changes in sunshine duration had only a minor effect on ET0 over the past 59 years.

Mesoporous silica nanoparticles (MSN) have attracted a lot of attention during the past decade which is attributable to their versatile and high loading capacity, easy surface functionalization, excellent biocompatibility, and great physicochemical and thermal stability. In this review, we discuss the factors affecting the loading of protein into MSN and general strategies for targeted delivery and controlled release of proteins with MSN. Additionally, we also give an outlook for the remaining challenges in the clinical translation of protein-loaded MSNs.

We consider split panel design efficiency in analysis of variance models, that is, the determination of the cross-sections series optimal proportion in all samples, to minimize parametric best linear unbiased estimators of linear combination variances. An orthogonal matrix is constructed to obtain manageable expression of variances. On this basis, we derive a theorem for analyzing split panel design efficiency irrespective of interest and budget parameters. Additionally, relative estimator efficiency based on the split panel to an estimator based on a pure panel or a pure cross-section is present. The analysis shows that the gains from split panel can be quite substantial. We further consider the efficiency of split panel design, given a budget, and transform it to a constrained nonlinear integer programming. Specifically, an efficient algorithm is designed to solve the constrained nonlinear integer programming. Moreover, we combine one at time designs and factorial designs to illustrate the algorithm's efficiency with an empirical example concerning monthly consumer expenditure on food in 1985, in the Netherlands, and the efficient ranges of the algorithm parameters are given to ensure a good solution.

AIM: To evaluate the efficacy and safety of vitrectomy combined with internal limiting membrane(ILM)peeling for treating foveoschisis in high myopia.METHODS: Thirty high-myopia patients(30 eyes)with foveoschisis from March 2011 to March 2013 were divided two groups: the treatment group(16 eyes)was treated with vitrectomy combined with ILM peeling, and the control group(14 eyes)was treated only with vitrectomy. The foveoschisis reattachment and and best spectacle-correction were measured preoperatively and 2mo after surgery.RESULTS: The improvement of foveoschisis reattachment and best spectacle-correction in the treatment group was significantly better than those in the control group(P<0.05).CONCLUSION: Vitrectomy combined with ILM peeling is a safe and effective treatment for foveoschisis in high myopia.