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Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

The strong oxide–metal interaction makes inverse oxide–metal configurations more active than conventional bulk systems. An atomic-scale understanding of the growth mechanism and structural properties of these metal oxides on noble metal substrates is essential for the design and improvement of inverse catalysts. Here, using two-dimensional iron oxide (FeO) thin films on the Au(111) surface as a model system, we investigated the growth mechanism of the first and second layer FeO on Au(111) by high-resolution scanning tunneling microscopy. Fe atoms embed in the subsurface of Au(111) at low coverage and squeeze out the surrounding Au atoms. Assisted by oxidation to generate FeO, the islands move to the surface and finally cover the Au(111) surface to form a Moiré superstructure. Density functional theory calculations reveal the formation of the strong interfacial Fe–Au bonds and remarkable charge transfer. The second layer of FeO exhibits a modulated ellipsoidal Moiré pattern because of the strong Fe–Fe bonds along with the variation of interlayer distance at different sites. This study on the growth mechanism and surface structures of mono- and bilayer FeO on Au(111) promotes future research on the metal oxide–substrate interactions in the field of catalysis.

Granulomatous lobular mastitis (GLM) is an idiopathic inflammatory breast disease that tends to recur on the same side. With the accumulation of clinical cases, it has been observed that GLM can also occur contralaterally. Currently, most studies on GLM focus on treatment methods and risk factors for ipsilateral recurrence, and there are few reports on bilateral GLM. The study aimed to summarize the clinical characteristics of patients with bilateral GLM by reviewing their clinical data, and to discuss the risk factors affecting the occurrence of bilateral GLM. A retrospective study of the medical records database of patients with GLM admitted between May 2019 and August 2022 was performed. Patients were divided into bilateral GLM group (bilateral GLM group) and unilateral GLM patients (unilateral GLM group). Demographic and clinical characteristics, treatment, and follow-up were collected and analyzed. In this study, by reviewing the clinical data of 59 cases of bilateral GLM, we found that the median time between the onset of bilateral GLM on both sides was 6.63 (0–18) months. Additionally, because of the simultaneous or interval onset on both sides, the duration of the disease was longer compared to unilateral cases. Regarding the history of external hospital treatment, it was found that about 57.63% of patients with bilateral GLM received 2 or more treatment modalities, with a higher involvement of herbal medicine. Meanwhile, by counting the clinical data of the 2 groups of patients with bilateral GLM and unilateral GLM, it was shown by univariate analysis that fertility, nipple development, absolute CD4 value, and CD4/CD8 ratio were associated with contralateral onset of GLM in both groups, with inverted nipple being an independent risk factor.

An efficient theranostic nanoplatform responding to tumour microenvironments with characters of simple and flexible combinations owns great potential in cancer diagnosis and therapy. Herein, a series of triblock copolymers, mPEG-b-PDPA-b-P(nBMA-r-cystamine) (EPB), were synthesized and among them, the structure of EPB-3 was optimized for both fluorescence imaging-guided cancer diagnosis and multi-modal therapy with good biocompatibility. (1) The self-assembled nanoparticles of EPB-3-ICG1obtained by conjugating one ICG on EPB-3 viaS–S bonds effectively performed reduction-sensitive OFF/ON fluorescence signal transition, thus inducing tumour cell-specific amplified fluorescence imaging in vitroand in vivo. (2) By entrapping Au nanorods into the co-assembled NPs of EPB-3 and EPB-3-ICG1, EPB-3-ICG1@Au NPs could synchronously induce strong tumour fluorescence imaging and high local photothermal effect, indicating the potential of imagine-guided photothermal therapy. (3) EPB-3 NPs could efficiently co-load paclitaxel (PTX) and ICG to form stable EPB-3@PTX@ICG NPs, which provided long periods of intracellular pH-sensitive sustainable drug release and highly enhanced apoptosis of 4T1 cells in vitroby the chemo-photothermal effect. Excitingly, a single intravenous injection of EPB-3@PTX@ICG NPs followed by a one-time local near-infrared light (NIR, 808 nm) irradiation treatment for 10 min could lead to significant inhibition of tumour growth, avoiding tumor metastasis and extending the survival of mice. All the above-mentioned results suggest that EPB-3 provides a nanoplatform with the characters of simple structure, convenience of use and flexible combination, holding potential for multi-modal diagnosis and therapy.

High locoregional recurrence of breast cancer after surgery remains a clinically appealing challenge. Local chemotherapy, especially sustainable delivery of chemotherapeutics at tumor sites by implantable hydrogels, has shown great potential to prevent cancer recurrence. However, the applications of conventional hydrogels are often limited by their intrinsic poor drug penetration into solid tumors and nonspecific drug accumulation in adjacent normal tissues. Herein, we developed a novel modular coassembly strategy to prepare a kind of pH-sensitive, tumor-specific targeting, and penetrating peptide (CRGDK)-modified doxorubicin-based prodrug nanoparticles (PDNPs), whose aqueous dispersion can undergo sol–gel transition after in vivo injection by thermo-induced self-aggregation to in situ form biodegradable hydrogel depot (PDNPs-gel), anchoring high amounts of PDNPs at tumor sites. Because of CRGDK-mediated targeting to overexpressed neuropilin-1 receptors on tumor vessels and tumor cells, PDNPs released from PDNPs-gel can effectively penetrate into tumor tissues, specifically enter tumor cells and finally realize intracellular acid-triggered drug release. In an in vivo incomplete resection of breast cancer model, a single peritumoral administration of PDNP-gel can achieve high inhibition efficacy against tumor recurrence. In addition, the administration of PDNP-gel only involves simple redispersion of PDNPs in water without any pretreatment for gelation, providing great convenience for storage, dosage, and prescription in practical use. Collectively, the reported multifunctional nanoparticles self-aggregated hydrogel system possesses great potential for efficient postsurgical prevention of tumor recurrence.

Context:Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support.Objective:This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC).Methods:This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33–56 y) and median follow-up time of 37 months (interquartile range, 15–82 mo).Results:The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P< .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66–132.26) and 24.61 (12.31–49.21), 34.46 (30.71–38.66), and 5.87 (4.37–7.88), and 24.73 (18.34–33.35) and 1.68 (0.54–5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07–11.11) and 14.96 (95% CI, 3.93–56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old.Conclusion:This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.

Central sensitivity of thyroid hormone refers to the sensitivity of hypothalamic–pituitary–thyroid (HPT) axis to the change in circulating free thyroxine (fT4). A complex relationship exists between thyroxine levels and iodine nutritional status. To explore the relationship between thyroid hormone sensitivity and iodine nutritional status in elevated thyrotropin (TSH), we used national data to assess the relationship between thyroid hormone sensitivity and iodine nutritional status with contrasting demographic characteristics in China.We enrolled 12,197 participants with TSH > 4.2 mIU/L from China. Serum and urine samples were collected, and we measured serum fT4, TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels and urinary iodine concentration (UIC). The thyroid hormone sensitivity indices were calculated based on fT4 and TSH. The thyroid feedback quantile-based index (TFQI) is a new index to reflect thyroid hormone sensitivity. Higher TFQI quartiles indicated lower thyroid hormone sensitivity.The odds ratios (ORs) for the fourth versus first TFQI quartile were 0.84 (95% CI 0.72–0.99) for iodine deficiency, 1.24 (95% CI 1.05–1.47) for TPOAb+, and 0.44 (95% CI 0.40–0.50) for females. The OR of the fourth and first TFQI quartiles for age <30 years and >60 years was 2.09 (95% CI 1.82–2.41) and 1.19 (95% CI 1.05–1.36), respectively (P  < 0.05). Other thyroid sensitivity indices also yielded similar results.Thyroid hormone sensitivity and age have a U-shaped association in individuals with elevated TSH. Increased thyroid hormone sensitivity is associated with iodine deficiency and the female gender. Decreased thyroid hormone sensitivity is associated with TPOAb+. These findings are interesting and potentially useful for understanding the interaction between iodine nutrition and the hypothalamic–pituitary–thyroid axis.

The authors argue that China has moved beyond the Open Door Period of university reform to a new era described as the Global Ambition Period. In this new era of university reform, the nation’s policy makers focus a good deal of their attention on developing world-class universities. Evidence is drawn from national initiatives implemented by the Ministry of Education, in the form of Projects 211 and 985, as well as from case studies of three leading research universities. Findings from Peking University are used to highlight the significance of academic personnel reform as a key step in fostering a more competitive environment for promoting faculty productivity. The case of Tsinghua University is used to focus attention on the growing importance of university-industry relations as part of establishing the economic development potential of leading research universities. Finally, the case of Renmin University is used to highlight the growing importance of internationalization. Together, these three case studies highlight the ambitious character of China’s 21st century vision for its leading research universities.

Emerging clustered regularly interspaced short palindromic repeat/associated protein (CRISPR/Cas) genome editing technology shows great potential in gene therapy. However, proteins and nucleic acids suffer from enzymatic degradation in the physiological environment and low permeability into cells. Exploiting carriers to protect the CRISPR system from degradation, enhance its targeting of specific tissues and cells, and reduce its immunogenicity is essential to stimulate its clinical applications. Here, the authors review the state‐of‐the‐art CRISPR delivery systems and their applications, and describe strategies to improve the safety and efficacy of CRISPR mediated genome editing, categorized by three types of cargo formats, that is, Cas: single‐guide RNA ribonucleoprotein, Cas mRNA and single‐guide RNA, and Cas plasmid expressing CRISPR/Cas systems. The authors hope this review will help develop safe and efficient nanomaterial‐based carriers for CRISPR tools. This review mainly focuses on the state‐of‐the‐art CRISPR delivery systems and their applications, categorized by three types of cargo formats, that is, Cas: single‐guide RNA ribonucleoprotein, Cas mRNA and single‐guide RNA, and Cas plasmid expressing CRISPR/Cas systems.

Eye-safety analysis is very important in the civil application of infrared laser imaging. In order to meet the requirements of human eye-safety protection, a model of eye-safety analysis is established based on ANSI Z136.1 Standard. When the value of maximum permissible exposure is given, one can estimate laser power and beam divergence angle under desired eye-safety distances from the model. We have simulated the model by MATLAB and given the laser power curve at different distances. Based on the curve, the eye-safety parameters of laser imaging systems can be easily designed. Therefore, the proposed model of eye-safety analysis can help to standardize infrared laser imaging products.

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.

Previous studies have shown increases in the prevalence of obesity and hypertension, but nationally representative data on recent changes in prevalence adjusted for population structure changes are lacking. Two nationwide surveys were conducted in 2007 and 2017 to assess the prevalence changes of these conditions in China.

Peptide vaccines exhibit great potential in cancer therapy via eliciting antigen-specific host immune response and long-term immune memory to defend cancer cells. However, the low induced immune response of many developing vaccines implies the imperatives for understanding the favorable structural features of efficient cancer vaccines. Herein, we report on the two groups of self-adjuvanting peptide vaccines with distinct morphology and investigate the relationship between the morphology of peptide vaccines and the induced immune response. Two nanofibril peptide vaccines were created via co-assembly of a pentapeptide with a central 4-aminoproline residue, with its derivative functionalized with antigen epitopes derived from human papillomavirus E7 proteins, whereas utilization of a pentapeptide with a natural proline residue led to the formation of two nanoparticle peptide vaccines. The immunological results of dendritic cell (DCs) maturation and antigen presentation induced by the peptide assemblies implied the self-adjuvanting property of the resulting peptide vaccines. In particular, cellular uptake studies revealed the enhanced internalization and elongated retention of the nanofibril peptide vaccines in DCs, leading to their advanced performance in DC maturation, accumulation at lymph nodes, infiltration of cytotoxic T lymphocytes into tumor tissues, and eventually lysis of in vivo tumor cells, compared to the nanoparticle counterparts. The antitumor immune response caused by the nanofibril peptide vaccines was further augmented when simultaneously administrated with anti-PD-1 checkpoint blockades, suggesting the opportunity of the combinatorial immunotherapy by utilizing the nanofibril peptide vaccines. Our findings strongly demonstrate a robust relationship between the immune response of peptide vaccines and their morphology, thereby elucidating the critical role of morphological control in the design of efficient peptide vaccines and providing the guidance for the design of efficient peptide vaccines in the future.

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